Handbook of Medical Psychiatry (Medical Psychiatry, 20)

Handbook of Medical Psychiatry edited by Jair C. Soares University of Texas Health Science Center at San Antonio San A...

Author: Jair C. Soares | Samuel Gershon

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Handbook of Medical Psychiatry edited by

Jair C. Soares University of Texas Health Science Center at San Antonio San Antonio, Texas, U.S.A.

Samuel Gershon Western Psychiatric Institute and Clinic University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, U.S.A.

MARCEL DEKKER, INC.

NEW YORK • BASEL

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0835-0 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/ Professional Marketing at the headquarters address above. Copyright Cg2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

Medical Psychiatry Series Editor

William A. Frosch, M.D. Weill Medical College of Cornell University Afevi York New York

1 Handbook of Depression and Anxiety A Biological Approach, edited by Johan A den Boer and J M Ad Sitsen 2 Anticonvulsants in Mood Disorders, edited by Russell T Joffe and Joseph R Calabrese 3 Serotonm in Antipsychotic Treatment Mechanisms and Clinical Practice, edited by John M Kane, H -J Moller, and Frans Awouters 4 Handbook of Functional Gastrointestinal Disorders, edited by Kevin W Olden 5 Clinical Management of Anxiety, edited by Johan A den Boer 6 Obsessive-Compulsive Disorders Diagnosis • Etiology • Treatment, edited by Eric Hollander and Dan J Stem 7 Bipolar Disorder Biological Models and Their Clinical Application, edited by L Trevor Young and Russell T Joffe 8 Dual Diagnosis and Treatment Substance Abuse and Comorbid Medical and Psychiatric Disorders, edited by Henry R Kranzler and Bruce J Rounsaville 9 Geriatric Psychopharmacology, edited by J Craig Nelson 10 Panic Disorder and Its Treatment, edited by Jerrold F Rosenbaum and Mark H Pollack 11 Comorbidity in Affective Disorders, edited by Mauncio Tohen 12 Practical Management of the Side Effects of Psychotropic Drugs, edited by Richard Baton 13 Psychiatric Treatment of the Medically III, edited by Robert G Robinson and William R Yates 14 Medical Management of the Violent Patient Clinical Assessment and Therapy, edited by Kenneth Tardiff 15 Bipolar Disorders Basic Mechanisms and Therapeutic Implications, edited by Jair C Scares and Samuel Gershon 16 Schizophrenia A New Guide for Clinicians, edited by John G Csernansky 17 Polypharmacy in Psychiatry, edited by S Nassir Ghaemi 18 Pharmacotherapy for Child and Adolescent Psychiatric Disorders Second Edition, Revised and Expanded, David R Rosenberg, Pablo A Davanzo, and Samuel Gershon 19 Brain Imaging In Affective Disorders, edited by Jair C Scares 20 Handbook of Medical Psychiatry, edited by Jair C Scares and Samuel Gershon

ADDITIONAL VOLUMES IN PREPARATION

Aggression Psychiatric Assessment and Treatment, edited by Emil F Coccaro

Series Introduction

In the late 1950s and early 1960s many of the senior professors of psychiatry, including those who were psychoanalysts, also had extensive training in neurology. Some departments, including the one in which I trained, were departments of psychiatry and neurology. To be certified as a psychiatrist, one of the three patients you examined and were questioned about was a patient with primary neurological disease. We were expected to know how to recognize seizure spindles in an EEG, and to be able to point out the anatomy and pathology visible in brain slices. The neurology candidates were similarly examined and questioned in psychiatry. Many practitioners did a bit of both: for example, the senior neurologist in the department in which I trained made his own diagnoses of depression, and administered ECT to the patient in his office. Outside the ‘‘black box’’ of the skull, our ties to the rest of medicine were not as strong. This was true despite the attempts to promote both concepts of ‘‘psychosomatic’’ medicine and humane care. Unfortunately, neither the concepts nor the data

were strong enough to carry the day. More recently, however, the development of new technologies, such as imaging and explication of the genetic code, has resulted in an explosion of knowledge about human biology and pathology. Newer findings have begun to break down the barriers between psychiatry and neurology, and between our understanding of behavioral disorders and the rest of medicine. While I do not believe that we will ever be able to do without a psychology in psychiatry, it is also increasingly clear that psychiatry cannot function without understanding the biology of the brain. Drs. Soares and Gershon have done an excellent job in bringing together a group of outstanding contributors who bring this new understanding to our field. They have presented the complex material clearly and comprehensively, making it easier to master—a necessary task if we are to continue to help our patients. William A. Frosch

iii

Foreword

With the publication of the Handbook of Medical Psychiatry, Drs. Soares and Gershon have recaptured the traditions of psychiatry over the past century, added the impressive technical capacities of the field in the last decade, and created an important educational resource for this new century. The deceptively simple title of the book belies the scope and depth of the volume. The chapters are organized, in part, by major diagnostic categories (e.g., mood disorders, schizophrenia, and related disorders, etc.), but also by significant crosscutting issues such as research methods and psychopharmacology. Within this rich composite of important theoretical and practical information the editors have integrated critical themes of modern psychiatry such as:

Mechanisms. Ultimately, a disease-based classification will require the elucidation of the basic mechanisms underlying mental disorders. The book presents, in a provocative manner, current leads in neurochemistry, neurocircuitry, molecular biology, and genetics, among other fields. Tools. Realizing that a more comprehensive understanding of basic mechanisms will evolve over decades, the authors have provided the reader with an understanding of the remarkable tools now available in imaging, molecular biology, and genetics. These new technologies enable researchers to open the ‘‘black boxes’’ of the brain, the cell, and the gene. Understanding how these tools are applied and getting a taste of current findings will enhance the reader’s ability to become educated consumers of the barrage of information that is, and will be, emanating from the tremendous growth of research activity in psychiatry.

Classification/nosology. DSM-III and -IV and ICD-10 are clearly interim steps in the development of disease-based classification systems for psychiatry. However, movement from phenomenology to etiolopathogenesis will have many steps along the way. This book examines fundamental issues in diagnosis across the range of psychiatric disorders and will help prepare psychiatrists to better understand strategies to move along that path.

Evidence. Over the past decades, the values of psychiatry have become more and more closely aligned with the values of science. As such, the ability to interpret and evaluate scientific evidence and augment it with clinical insights is a critical skill. It is a skill that must be not only learned during medical school and v

vi

residency but also continuously exercised over the course of every psychiatrist’s career. The authors have effectively captured the essence of that task in this volume. Readers who engage this important and challenging material will be revitalizing those skills and also preparing themselves for the future. Impressively, Drs. Soares and Gershon have enlisted the talents of many of the world’s leading clinicians and scientists in this ambitious work. Even more importantly, they have tapped some of the most promising younger psy-

Foreword

chiatrists who will be major contributors in expanding our understanding of psychiatric disorders in the future. Harold Alan Pincus, M.D. Professor and Executive Vice Chairman Department of Psychiatry Western Psychiatric Institute and Clinic University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Preface

Over the past few decades, increasing emphasis has been given to the study of brain mechanisms that may be dysfunctional in neuropsychiatric illnesses. In recent years, new methodologies from various disciplines in the clinical neurosciences have made available substantially improved and more sophisticated tools for studies of causation of these severe illnesses. For instance, we have seen tremendous progress in knowledge from disciplines such as molecular genetics, neuropsychopharmacology, and brain imaging, which has provided unprecedented tools for studies of the human brain and neuropsychiatric illnesses. These efforts have begun to produce important findings and are beginning to contribute to a better understanding of the basic mechanisms involved in these disorders and the mechanisms of actions of treatments for these condi-

tions, and lead to the development of new therapeutic possibilities. The Handbook of Medical Psychiatry summarizes the main advances in the understanding of the basic mechanisms and therapeutics of the major psychiatric illnesses that have taken place in recent years. The format provides easy access to new information in these areas, making the book of significant interest to academicians, researchers, practitioners, students, residents, and trainees in psychiatry, clinical neuroscience, and the mental health professions. We believe this book will be a helpful, comprehensive, and important resource for individuals in psychiatry and related fields. Jair C. Soares Samuel Gershon

vii

Contents

Series Introduction William A. Frosch Foreword Harold Alan Pincus Preface Contributors

iii v vii xv

Methodological Issues in Psychiatric Research 1.

Animal Models of Neuropsychiatric Disorders: Challenges for the Future William T. McKinney

2.

Methodological Advances in Psychiatric Genetics Yoav Kohn and Bernard Lerer

13

3.

New Developments in the Regulation of Monoaminergic Neurotransmission Alan Frazer, David A. Morilak, and Lynette C. Daws

25

4.

Developments in Psychiatric Neuroimaging Roberto B. Sassi and Jair C. Soares

43

5.

Classification of Childhood and Adolescent Psychiatric Disorders Norah C. Feeny and Robert L. Findling

55

6.

Classification of Schizophrenia and Related Psychotic Disorders Tonmoy Sharma and Priya Bajaj

69

7.

Classification of Mood Disorders: Implications for Psychiatric Research Acioly L. T. Lacerda, Roberto B. Sassi, and Jair C. Soares

79

ix

1

x

Contents

8.

Classification of Anxiety Disorders: Implications for Psychiatric Research Kerrie L. Posey, Susan G. Ball, and Anantha Shekhar

89

9.

Classification of Dementias and Cognitive Disorders Fre´de´ric Assal and Jeffrey L. Cummings

99

10.

Classification of Personality Disorders: Implications for Treatment and Research Dragan M. Svrakic, Robert Cloninger, Stana Stanic, and Secondo Fassino

117

Psychiatric Manifestations in Childhood and Adolescence 11.

Mood Disorders in Childhood and Adolescence: Basic Mechanisms and Therapeutic Interventions Melissa P. DelBello and Robert A. Kowatch

149

12.

Anxiety Disorders in Childhood and Adolescence: Basic Mechanisms and Therapeutic Interventions Tiffany Farchione, Shauna N. MacMillan, and David R. Rosenberg

175

13.

Psychotic Disorders in Childhood and Adolescence: Basic Mechanisms and Therapeutic Interventions Andrew R. Gilbert and Matcheri S. Keshavan

197

Neurobiology of Autism and Other Pervasive Developmental Disorders: Basic Mechanisms and Therapeutic Interventions Antonio Y. Hardan

205

14.

Schizophrenia and Related Psychotic Disorders 15.

Cognitive Deficits in Schizophrenia Cameron S. Carter and Stefan Ursu

223

16.

Neuroimaging Findings in Schizophrenia: From Mental to Neuronal Fragmentation Lawrence S. Kegeles and Marc Laruelle

237

17.

The Dopamine Hypothesis of Schizophrenia Philip Seeman and Mary V. Seeman

259

18.

Serotonergic Dysfunctions in Schizophrenia: Possible Therapeutic Implications Johannes Tauscher and Nicolaas Paul Leonard Gerrit Verhoeff

267

19.

The GABA Cell in Relation to Schizophrenia and Bipolar Disorder Francine M. Benes and Sabina Berretta

277

20.

Genetic Findings in Psychotic Disorders Michael O’Donovan and Michael Owen

295

21.

Membrane Abnormalities in Psychotic Disorders Wagner Farid Gattaz and Orestes V. Forlenza

307

22.

Animal Models of Psychosis J. David Jentsch, Peter Olausson, and Holly Moore

317

Contents

xi

Mood Disorders 23.

Affective Disorders: Imaging Studies Warren D. Taylor and Ranga R. Krishnan

24.

Role of Acetylcholine and Its Interactions with Other Neurotransmitters and Neuromodulators in Affective Disorders David S. Janowsky and David H. Overstreet

335

347

25.

GABA and Mood Disorders: A Selective Review and Discussion of Future Research Frederick Petty, Prasad Padala, and Surender Punia

363

26.

Signal Transduction Abnormalities in Bipolar Disorder Yarema B. Bezchlibnyk and L. Trevor Young

371

27.

Molecular Genetics and Mood Disorders Daniel Souery and Julian Mendlewicz

395

28.

Biological Distinction Between Unipolar and Bipolar Disorder Xiaohong Wang and Charles B. Nemeroff

407

Anxiety Disorders 29.

Neurobiology of Obsessive-Compulsive Disorder Bavanisha Vythilingum and Dan J. Stein

423

30.

Neurobiology of Panic Disorder Sanjay J. Mathew, Jack M. Gorman, and Jeremy D. Coplan

433

31.

Neurobiology of Posttraumatic Stress Disorder Across the Life Cycle Michael D. De Bellis

449

32.

Genetics of Panic Disorder, Social Phobia, and Agoraphobia Joel Gelernter and Murray B. Stein

467

Dementia and Cognitive Disorders 33.

Imaging Brain Structure and Function in Aging and Alzheimer’s Disease Vicente Ibań˜ez and Stanley I. Rapoport

477

34.

Brain Imaging in Dementia Francesca Mapua Filbey, Robert Cohen, and Trey Sunderland

497

35.

Genetics of Alzheimer’s Disease M. Ilyas Kamboh

521

36.

Neurobiology of Alzheimer’s Disease Oscar L. Lopez and Steven T. DeKosky

537

xii

Contents

Substance Abuse and Dependence 37.

Psychiatric Comorbidity: Implications for Treatment and Clinical Research Jack R. Cornelius, Ihsan M. Salloum, Oscar G. Bukstein, and Duncan B. Clark

553

38.

Neurobiology of Alcoholism Charles A. Dackis and Charles P. O’Brien

563

39.

Biological Basis of Drug Addiction Tony P. George

581

40.

Neuroimaging Abnormalities in Drug Addiction and Alcoholism Wynne K. Schiffer, Douglas A. Marsteller, and Stephen L. Dewey

595

41.

Genetics of Addictive Disorders Tatiana Foroud and John I. Nurnberger, Jr.

615

Other Psychiatric Conditions 42.

Biological Basis of Eating Disorders Walter H. Kaye and Nicole C. Barbarich

633

43.

Biological Basis of Personality Disorders Cuneyt Iscan, Charlotte L. Allport, and Kenneth R. Silk

643

44.

Iatrogenic Sexual Dysfunction Marlene P. Freeman and Alan J. Gelenberg

657

45.

Neurobiology of Violence and Aggression Michael S. McCloskey, Royce J. Lee, and Emil F. Coccaro

671

46.

Pathological Gambling: Clinical Aspects and Neurobiology Marc N. Potenza

683

47.

Neurobiology of Suicide Leo Sher and J. John Mann

701

48.

Sleep Disorders Eric A. Nofzinger

713

Developments in Pharmacotherapy 49.

Perspectives in the Pharmacological Treatment of Schizophrenia Larry Ereshefsky

731

50.

Multiple Mechanisms of Lithium Action Alona Shaldubina, Robert H. Belmaker, and Galila Agam

757

51.

Mechanisms of Action of Anticonvulsants and New Mood Stabilizers Robert M. Post, Elzbieta Chalecka-Franaszek, and Christopher J. Hough

767

Contents

xiii

52.

Mechanisms of Action of New Mood-Stabilizing Drugs Joseph Levine, Yuly Bersudsky, Carmit Nadri, Yuri Yaroslavsky, Abed Azab, Alex Mishori, Galila Agam, and Robert H. Belmaker

793

53.

Advances in Treatment and Perspectives for New Interventions in Mood and Anxiety Disorders Sandeep Patil, Saeeduddin Ahmed, and William Zeigler Potter

807

54.

Perspectives for Pharmacological Interventions in Eating Disorders Guido K. Frank

827

55.

Perspectives for New Pharmacological Treatments of Alcoholism and Substance Dependence Ihsan M. Salloum, Antoine Douaihy, and Subhajit Chakravorty

843

56.

Perspectives on the Pharmacological Treatment of Dementia Bruno P. Imbimbo and Nunzio Pomara

865

57.

Pharmacological Interventions in Psychiatric Disorders Due to Medical Conditions E. Sherwood Brown and Dana C. Perantie

899

58.

Perspectives on Treatment Interventions in Paraphilias Florence Thibaut

909

59.

Potential of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric Conditions Thomas E. Schlaepfer and Markus Kosel

60.

Pharmacokinetic Principles and Drug Interactions Ahsan Y. Kahn and Sheldon H. Preskorn

Index

919

933

945

Contributors

Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Galila Agam, Ph.D.

Saeeduddin Ahmed, M.D. U.S.A.

Department of U.S. Medical Affairs, Eli Lilly and Company, Indianapolis, Indiana,

Charlotte L. Allport, R.N., B.S.N. Michigan, U.S.A. Fre´de´ric Assal, M.D. California, U.S.A. Abed Azab, M.Sc.

Department of Psychiatry, University of Michigan Health System, Ann Arbor,

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles,

Department of Clinical Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Priya Bajaj, D.P.M., D.N.B. England Susan G. Ball, Ph.D. U.S.A.

Clinical Neuroscience Research Centre, Stonehouse Hospital, Dartford, Kent,

Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana,

Nicole C. Barbarich, B.S. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Robert H. Belmaker, M.D.

Department of Psychiatry, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Francine M. Benes, M.D., Ph.D. Department of Psychiatry, McLean Hospital, Belmont, and Harvard Medical School, Boston, Massachusetts, U.S.A. Sabina Berretta, M.D. Department of Psychiatry, McLean Hospital, Belmont, and Harvard Medical School, Boston, Massachusetts, U.S.A. xv

xvi

Contributors

Yuly Bersudsky, M.D., Ph.D.


Yarema B. Bezchlibnyk, B.Sc. Hamilton, Ontario, Canada

Department of Psychiatry and Behavioral Neurosciences, McMaster University,

E. Sherwood Brown, M.D., Ph.D. Dallas, Texas, U.S.A.

Department of Psychiatry, University of Texas Southwestern Medical Center,

Oscar G. Bukstein, M.D., M.P.H. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Cameron S. Carter, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Subhajit Chakravorty, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Elzbieta Chalecka-Franaszek, Ph.D. Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland, U.S.A. Duncan B. Clark, M.D., Ph.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Robert Cloninger, M.D. Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri, U.S.A. Emil F. Coccaro, M.D.

Department of Psychiatry, University of Chicago, Chicago, Illinois, U.S.A.

Robert Cohen, M.D., Ph.D.

National Institute of Mental Health, Bethesda, Maryland, U.S.A.

Jeremy D. Coplan, M.D. Department of Psychiatry, SUNY Health Science Center at Brooklyn, and New York State Psychiatric Institute, New York, New York, U.S.A. Jack R. Cornelius, M.D., M.P.H. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Jeffrey L. Cummings, M.D. California, U.S.A.

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles,

Charles A. Dackis, M.D. U.S.A.

Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania,

Lynette C. Daws, Ph.D. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A. Michael D. De Bellis, M.D., M.P.H. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, U.S.A. Steven T. DeKosky, M.D. Pennsylvania, U.S.A.

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh,

Contributors

xvii

Melissa P. DelBello, M.D. Department of Psychiatry, University of Cincinnati College of Medicine, and Children’s Hospital Medical Center, Cincinnati, Ohio, U.S.A. Stephen L. Dewey, Ph.D.

Chemistry Department, Brookhaven National Laboratory, Upton, New York, U.S.A.

Antoine Douaihy, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Larry Ereshefsky, Pharm.D., F.C.C.P. Department of Pharmacotherapy, College of Pharmacy, University of Texas at Austin, Austin, Texas, U.S.A. Tiffany Farchione, M.D. Secondo Fassino, M.D.

Department of Psychiatry, Wayne State University, Detroit, Michigan, U.S.A. University of Turin, Turin, Italy

Norah C. Feeny, Ph.D. Department of Psychiatry, University Hospitals of Cleveland, and Case Western Reserve University, Cleveland, Ohio, U.S.A. Francesca Mapua Filbey, Ph.D.


Robert L. Findling, M.D. Department of Psychiatry, University Hospitals of Cleveland, and Case Western Reserve University, Cleveland, Ohio, U.S.A. Orestes V. Forlenza, M.D., Ph.D. Paulo, Brazil

Department of Psychiatry, Faculty of Medicine, University of Saõ Paulo, Saõ

Tatiana Foroud, Ph.D. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. Guido K. Frank, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Alan Frazer, Ph.D. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, and South Texas Veterans Health Care System, San Antonio, Texas, U.S.A. Marlene P. Freeman, M.D. Arizona, U.S.A.

Department of Psychiatry, University of Arizona College of Medicine, Tucson,

Wagner Farid Gattaz, M.D., Ph.D. Paulo, Brazil Alan J. Gelenberg, M.D. U.S.A.

Department of Psychiatry, Faculty of Medicine, University of Saõ Paulo, Saõ

Department of Psychiatry, University of Arizona College of Medicine, Tucson, Arizona,

Joel Gelernter, M.D. Department of Psychiatry, Yale University School of Medicine, New Haven, and Veterans Administration Medical Center, West Haven, Connecticut, U.S.A. Tony P. George, M.D. U.S.A.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut,

Andrew R. Gilbert, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

xviii

Contributors

Jack M. Gorman, M.D. Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, New York, U.S.A. Antonio Y. Hardan, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Christopher J. Hough, Ph.D. Bethesda, Maryland, U.S.A.

Department of Psychiatry, Uniformed Services University of the Health Sciences,

Vicente Ibań˜ez, M.D. Division of Neuropsychiatry, University of Geneva, Geneva, Switzerland Bruno P. Imbimbo, Ph.D. Cuneyt Iscan, M.D.

Research and Development, Chiesi Farmaceutici, Parma, Italy

University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.

David S. Janowsky, M.D. North Carolina, U.S.A. J. David Jentsch, Ph.D. California, U.S.A.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill,

Department of Psychology, David Geffen School of Medicine at UCLA, Los Angeles,

M. Ilyas Kamboh, Ph.D. Department of Human Genetics, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Walter H. Kaye, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Lawrence S. Kegeles, M.D., Ph.D. New York, U.S.A.

Departments of Psychiatry and Radiology, Columbia University, New York,

Matcheri S. Keshavan, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Ahsan Y. Khan, M.D. U.S.A.

Department of Psychiatry, University of Kansas School of Medicine, Wichita, Kansas,

Yoav Kohn, M.D. Department of Psychiatry, Hadassah University Hospital and Hebrew University School of Medicine, Jerusalem, Israel Markus Kosel, M.D.

Department of Psychiatry, University of Bern, Bern, Switzerland

Robert A. Kowatch, M.D. Department of Psychiatry, University of Cincinnati College of Medicine, and Children’s Hospital Medical Center, Cincinnati, Ohio, U.S.A. Ranga R. Krishnan, M.D. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, U.S.A. Acioly L. T. Lacerda, M.D., Ph.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Marc Laruelle, M.D. U.S.A.

Departments of Psychiatry and Radiology, Columbia University, New York, New York,

Contributors

Royce J. Lee, M.D.

xix


Bernard Lerer, M.D. Department of Psychiatry, Hadassah University Hospital and Hebrew University School of Medicine, Jerusalem, Israel Joseph Levine, M.D.


Oscar L. Lopez, M.D. Department of Neurology, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Shauna N. MacMillan, B.S. Detroit, Michigan, U.S.A.

Department of Psychiatry and Behavioral Neuroscience, Wayne State University,

J. John Mann, M.D. Department of Psychiatry, Columbia University, New York, New York, U.S.A. Douglas A. Marsteller, B.A. U.S.A.

Chemistry Department, Brookhaven National Laboratory, Upton, New York,

Sanjay J. Mathew, M.D. Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, New York, U.S.A. Michael S. McCloskey, Ph.D.


William T. McKinney, M.D. The Asher Center for the Study and Treatment of Depressive Disorders, Northwestern University Medical School, Chicago, Illinois, U.S.A. Julian Mendlewicz, M.D., Ph.D.

Department of Psychiatry, Erasme Hospital, Brussels, Belgium

Alex Mishori, M.D.


Holly Moore, Ph.D.

Department of Psychiatry, Columbia University, New York, New York, U.S.A.

David A. Morilak, Ph.D. Texas, U.S.A.

Department of Pharmacology, University of Texas Health Science Center, San Antonio,

Carmit Nadri, B.Med.Lab.Sc.

Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Charles B. Nemeroff, M.D., Ph.D. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, U.S.A. Eric A. Nofzinger, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. John I. Nurnberger, Jr., M.D., Ph.D. Indianapolis, Indiana, U.S.A. Charles P. O’Brien, M.D., Ph.D. Pennsylvania, U.S.A.

Department of Psychiatry, Indiana University School of Medicine,

Department of Psychiatry, University of Pennsylvania, Philadelphia,

Michael O’Donovan, Ph.D., F.R.C.Psych. Medicine, Cardiff, Wales

Department of Psychological Medicine, University of Wales College of

xx

Peter Olausson, Ph.D. U.S.A.

Contributors

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut,

David H. Overstreet, Ph.D. North Carolina, U.S.A.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill,

Michael Owen, Ph.D., F.R.C.Psych., F.Med.Sci. College of Medicine, Cardiff, Wales

Department of Psychological Medicine, University of Wales

Prasad Padala, M.D. Department of Psychiatry, Creighton University, and Omaha Veterans Administration Medical Center, Omaha, Nebraska, U.S.A. Sandeep Patil, M.D., Ph.D. Dana C. Perantie, B.S. Texas, U.S.A.

Department of Neuroscience, Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas,

Frederick Petty, M.D., Ph.D. Department of Psychiatry, Creighton University, and Omaha Veterans Administration Medical Center, Omaha, Nebraska, U.S.A. Nunzio Pomara, M.D. Department of Psychiatry, New York University School of Medicine, New York, and Geriatric Psychiatry Program, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, U.S.A. Kerrie L. Posey, M.D. U.S.A.

Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana,

Robert M. Post, M.D. U.S.A.

Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland,

Marc N. Potenza, M.D., Ph.D. Connecticut, U.S.A.

Department of Psychiatry, Yale University School of Medicine, New Haven,

William Zeigler Potter, M.D., Ph.D. Indiana, U.S.A. Sheldon H. Preskorn, M.D. Kansas, U.S.A.

Neuroscience Therapeutic Area, Eli Lilly and Company, Indianapolis,

Department of Psychiatry, University of Kansas School of Medicine, Wichita,

Surender Punia, M.D. Department of Psychiatry, Creighton University, and Omaha Veterans Administration Medical Center, Omaha, Nebraska, U.S.A. Stanley I. Rapoport, M.D. U.S.A.

National Institute on Aging, National Institutes of Health, Bethesda, Maryland,

David R. Rosenberg, M.D. Detroit, Michigan, U.S.A.

Department of Psychiatry and Behavioral Neuroscience, Wayne State University,

Ihsan M. Salloum, M.D., M.P.H. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Roberto B. Sassi, M.D. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

Contributors

xxi

Wynne K. Schiffer, Ph.D.

Chemistry Department, Brookhaven National Laboratory, Upton, New York, U.S.A.

Thomas E. Schlaepfer, M.D. Department of Psychiatry, University of Bern, Bern, Switzerland, and Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Mary V. Seeman, M.D., D.S.C., F.R.C.P.C. Canada Philip Seeman, M.D., Ph.D., D.Sc. Canada Alona Shaldubina, M.Sc. Beer-Sheva, Israel

Department of Pharmacology, University of Toronto, Toronto, Ontario,

Departments of Psychiatry and Pharmacology, Ben-Gurion University of the Negev,

Tonmoy Sharma, M.B.B.S., M.R.C.Psych. Dartford, Kent, England Anantha Shekhar, M.D., Ph.D. Indiana, U.S.A. Leo Sher, M.D.

Department of Psychiatry, University of Toronto, Toronto, Ontario,

Clinical Neuroscience Research Centre, Stonehouse Hospital,

Department of Psychiatry, Indiana University School of Medicine, Indianapolis,

Department of Psychiatry, Columbia University, New York, New York, U.S.A.

Kenneth R. Silk, M.D. U.S.A.

Department of Psychiatry, University of Michigan Health System, Ann Arbor, Michigan,

Jair C. Soares, M.D. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A. Daniel Souery, M.D., Ph.D. Stana Stanic, M.D.

Department of Psychiatry, Erasme Hospital, Brussels, Belgium

University of Trieste, Trieste, Italy

Dan J. Stein, M.D., Ph.D. University of Stellenbosch, Cape Town, South Africa, and University of Gainesville, Gainesville, Florida, U.S.A. Murray B. Stein, M.D. Department of Psychiatry, University of California, San Diego, La Jolla, and Veterans Affairs San Diego Healthcare System, San Diego, California, U.S.A. Trey Sunderland, M.D.


Dragan M. Svrakic, M.D., Ph.D. Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri, U.S.A. Johannes Tauscher, M.D.

Department of General Psychiatry, University of Vienna, Vienna, Austria

Warren D. Taylor, M.D. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, U.S.A. Florence Thibaut, M.D., Ph.D.

Department of Psychiatry, Rouen University Hospital, Rouen, France

Stefan Ursu, M.D. Departments of Neuroscience and Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

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Contributors

Nicolaas Paul Leonard Gerrit Verhoeff, M.D., Ph.D., F.R.C.P.(C) Department of Psychiatry, University of Toronto, and Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada Bavanisha Vythilingum, M.B., Ch.B. South Africa

MRC Unit on Anxiety Disorders, University of Stellenbosch, Cape Town,

Xiaohong Wang, M.D., Ph.D. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, U.S.A. Yuri Yaroslavsky, M.D.


L. Trevor Young, M.D., Ph.D., F.R.C.P.(C) University, Hamilton, Ontario, Canada

Department of Psychiatry and Behavioral Neurosciences, McMaster

1 Animal Models of Neuropsychiatric Disorders Challenges for the Future WILLIAM T. McKINNEY Northwestern University Medical School, Chicago, Illinois, U.S.A.

I.

INTRODUCTION

rights movement), the stage is set for continuing major problems. This in summary represents the major future challenges for the field of animal modeling research. The above situation is ironical given the role that research utilizing animal models has played in advancing the understanding of psychiatric disorders. As will be discussed in the historical section, the first databased integrative theories of psychopathology grew largely out of animal research and/or improving treatment approaches. Since psychiatric disorders need to be understood by using a multivariate approach, animal studies, where variables can be controlled, have the potential for permitting the study of both the main effects of single variables and especially their interaction. Such approaches are highly relevant to what has recently been termed the ‘‘biopsychosocial’’ view of human psychopathology [5]. Research with animals has also been critical in broadening our understanding of human development and in providing empirical support for the importance of early experiences for behavioral and neurobiological development. Work with multiple species has documented the central importance of early social attachment systems and has clarified the behavioral and neurobiological variables mediating the development of these attachment systems [6–10]. Such concepts are

The major challenges for future animal modeling research primarily involve conceptual and philosophical issues. Despite the fact that there are a variety of animal models available for many psychiatric disorders [1–3] there are still widespread perceptions that (1) one cannot reasonably study human psychiatric disorders in animals, because psychiatric illnesses are inherently human, and (2) there are no animal models of the various psychiatric disorders available. In medicine in general, animal models are generally accepted as important for research directed at understanding the mechanisms underlying human disease as well as the development of new treatments. In contrast, modeling of mental disorders in experimental animals has often been regarded as ‘‘a highly controversial or outright heretical idea’’ [4]. There is widespread skepticism regarding animal models in psychiatry, with virtually no organized federal programs/initiatives for encouraging and supporting research in this field. When the active opposition of components of the animal rights movement to research with animals is coupled with the above-mentioned lack of understanding of the role of animal models by leaders in the field (who sometimes have backed off encouraging further developments in this field in the face of the animal 1

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by now woven into the fabric of development theory in adult and child psychiatry, and it was experimental animal research that provided the fundamental basis for this knowledge. Furthermore, research with experimental animal systems has documented the devastating and long-term behavioral and neurobiological effects, including effects on brain cytoarchitecture, of never letting such attachment systems develop or of their intermittent disruption at certain developmental stages [11–14]. Studies utilizing animal models have also focused on the interaction between social functioning and neurobiological status and have documented the interactive and reciprocal nature of these relationships in paradigms that would be impossible to implement in human studies [15,16]. In addition, the impact of different types of stress has been extensively explored in animal models and in some instances genetic strains have also been identified or developed which exhibit similarities to clinical syndromes [17,18]. Though there is no perfect animal model with regard to predicting clinical efficacy of pharmacological agents, their use has been critical in the discovery and development of drug treatments [19–22]. There are always false positives and false negatives, but there are experimental paradigms with a high degree of empirical validity. Given a new era of drug discovery and development, there will likely continue to be many challenging issues in this context. Despite these and many other contributions, acrimonious debates about the validity and/or usefulness of animal models for psychiatric disorders persist. The evaluation of animal models for psychiatric disorders is complex. Unfortunately, there is not yet any single laboratory finding or set of findings for any clinical psychiatric syndrome that one could insist upon as part of the validating criteria. Thus, one largely relies on a combination of behavioral measures and response to known clinically effective agents. Part of the challenge for the future may be to reconsider the validity measures of animal models and to reconceptualize expectations. There is no ‘‘perfect,’’ complete, or comprehensive single animal model for any specific psychiatric disorder. Indeed, there will likely never be an animal model in any field of medicine that is a perfect fit with the human condition; rather the emphasis in the development and study of disease models in animals needs to increasingly focus on specific components of the human illness.

McKinney

Animal models of diseases in medicine, including psychiatry, need to be understood in a historical and evolutionary perspective and their advantages as well as limitations recognized. Neither overextended crossspecies comparisons nor unjustified negativism about animal models seems defensible. An especially critical challenge in the continuing development and utilization of biobehavioral animal models in psychiatry is their relationship to the molecular neurosciences, including genetics. Given recent advances in the molecular neurosciences relevant to mental disorders, the role of animal models in this context needs to be reconsidered. Failure to do so could lead to an excessively narrow view of animal models or a dismissal of the entire area. Danger signals already exist in this regard. Some contend that, given the new molecular techniques, animal models no longer have a place in psychiatric research. Others have taken the position that since psychiatric illnesses are so difficult to model in animals, we will need to do most of the research on mental disorders in clinical populations [23]. There is also tension between those who think that while one can, with high validity and reliability, measure, for example, receptor functioning in certain brain regions, the measure of behavior in animals lacks comparable scientific precision [24]. Unfortunately, the latter reflects a serious lack of communication between fields because the quantitative assessment of animal behavior is a well-developed science. With the increasing advances in molecular biology and genetics, functional neuroimaging, and other methods for studying mental disorders, conceptualization of and research on behaviorally based animal models needs to be able to keep pace to maximally enrich psychiatric research. Despite several recent publications about the animal modeling field [25–28], there are many indications that the area remains poorly understood. This paper is an attempt to provide an overview of the past contributions of animal models and to propose some new perspectives that might be helpful in reevaluating the role of animal models in better understanding the major psychiatric illnesses. In an attempt to focus on some fundamental issues and challenges regarding animal models as they relate to neuropsychiatric disorders, a review of available models for each disorder becomes impossible. To attempt such a review would certainly shortchange many important areas, so, rather than attempt this, appropriate references will be provided to articles where such models are discussed.

Animal Models of Neuropsychiatric Disorders

II.

HISTORICAL CONTEXT

Pavlov, often said to have been the originator of research relevant to animal modeling of human psychopathology in general, used clinical terms and experimental techniques that now seem foreign to most clinicians. However, the fact that his work represented one of the first moves away from a strictly correlational method of behavioral analysis to the experimental study of psychopathology is of central importance [29]. Considering Pavlov and other early scientists [30–33], it is difficult to know what conclusions to draw about the early history of the field of experimental psychopathology research. From one standpoint it was not a particularly noteworthy beginning. However, the early pioneers may have been more successful than it appears in developing certain principles that seem to be being rediscovered today, including: 1. Demonstration that psychopathology could be experimentally studied in animals as well as in the strictly correlational studies done previously in humans. 2. Demonstration of the importance of both careful behavioral observations and serendipity. Although most of the early workers did not use the more sophisticated and quantifiable behavioral scoring techniques now available, they were keen observers and literate in their descriptions. 3. The repeated proposal of an interactive model of psychopathology. The role of the temperament of the animals, along with a variety of social and neurobiological variables, was repeatedly stressed in the early literature. The concept of individual variability was part of the early work, and investigation of the sources of such variability continues to be an important area of research. 4. Recognition that there could be a persistent internal response, even after the inducing stimulus was no longer present, a discovery that remains a major contribution to the understanding of a number of forms of psychopathology. 5. Recognition of the importance of unpredictability and uncontrollability of which systematic investigations continue today [5]. III.

ETHOLOGICAL CONTEXT

This section touches on some principles of ethology important in evaluating and understanding experimental animal research and a few selected research

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approaches. Avoidance of misleading clinical labeling based on superficial comparisons across species is critical. However, behavioral profiling in a given species can be done with a degree of precision comparable to other methods in neurobiology. Evolutionary biology principles then need to be understood and applied when it comes to interpretation of these phenomena. Ethology focuses on describing and understanding ‘‘animal behavior in the natural habitat and assumes operation of evolutionarily conserved basic plans encoded in the genome. Such basic plans determine behavioral patternings including flexible variants involving learning. Human ethology has emerged as a subdiscipline, including observations of psychiatric patients. The research involved has produced an enormous and varied literature’’ [34]. Gardner describes this interface as follows: Sensitive observers have noted that relationshipless psychiatry seems the objective of much current psychiatric practice augmented by the cost-conscious managed care industry. Such a peculiar objective can stand almost unopposed in part because psychiatry has no basic science other than that limited to drug actions on the one hand and venerable, used but unproven and unphysiological theories of psychotherapy on the other hand. Adopting a perspective that shows human relatedness to other animals (near identity of genome) yet human uniqueness (with a massively larger brain) would underline the importance of people for other people that would augment the psychiatric enterprise. Human bonding and human competition shares much in common with other species, yet has its own flavor likely stemming from the human capacity to use stories in many ways. An important step towards psychiatry as a relationshipfocused enterprise might come about if there was an explicit label for it. Sociophysiology could furnish that label to emphasize the importance of weighing the following as equally important while interactive: complex behaviors especially communicative ones, ancient reaction patterns, brain functions, cellular actions and genomic mechanisms [35]. Gardner described modeling as depending upon brain-body factors that the animal and humans possess in common. While behavior patterns may be species specific, ‘‘core components shared by related animals are typically embroidered through natural selection to produce modified methods of survival and reproduc-

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McKinney

tion’’ [34]. He cites the example of human brains which contrast in size to those of other animals, weighing three times more than brains of surviving large primates or those of human ancestors 3 million years ago. The contrast with other primates especially stems from a massively enlarged neocortex, especially the frontal lobes, with these increases likely stemming from advantages of social functions. Despite differences, the human brain and behavior also show comparability to those of other species through widely shared, conserved features. Gardner contends that this comparability makes continued use of animals important for the study of the pathogenesis, mechanisms, and treatment of mental disease. ‘‘Lack of a sufficient database as yet limits other modeling efforts such as computer simulations, mathematical models, and experimentally induced states in hums, and research on animals remains indispensable’’ [34]. Homology and convergence are important ethological concepts which can serve as frameworks for helping to understand comparative cross species behavior. Homology means that a common ancestor once possessed a trait now shared by two species. At points in the past, humans shared common ancestors with monkeys, mice, chickens, fish, insects, and single celled organisms, each such forebear more remote in biological history. In contrast, convergent traits are similar features that stem from environmental shaping through natural selection, although basic plan starting points vary. Wings of insects, bats and birds illustrate this. Ancestors of each animal group had not flown so airborne ability evolved separately and the three kinds of wings illustrate convergent evolution on the level of aerial locomotion. As vertebrate upper extremities, however, wings of bats and birds are homologous to each other but not to the wings of insects. If the starting point of the basic plan generalizes to contractile tissue, however, locomotory body extensions of all three achieve homology [34]. There is great excitement with genome projects of species at different phylogenetic levels and importance. The genome seems to contain at least a partial record of the organism’s ancestry, and therefore genomic analysis may help determine evolutionary history (homology) which in turn may foster knowledge of proximal neuronal determinants of behavior. However, this is a very complicated area, and simplistic and overly optimistic expectations will likely fail. As Gardner says, at the behavioral level, redundant, multiply determined

brain-behavior adaptations complicate inference, and at the DNA level, genetic transformations such as chromosomal crossovers will reduce certainty about genomic hypotheses [34]. IV.

DEFINITIONAL/CONCEPTUAL ISSUES

Animal models are experimental paradigms developed in one species for the purpose of studying specific phenomena occurring in another species. By definition they are not the ‘‘real thing.’’ There will always be differences and similarities between models and what is being modeled; otherwise it is not a model. Furthermore, there is no single comprehensive animal model for any mental disorder and probably not for any general medical illness. Thus, animal models should be judged primarily by their relevance to specific questions that they are being used to address rather than their scope. They permit the evaluation of selected aspects of human psychopathology in a systematic and controlled manner and represent simplified and abstracted versions of behavior and physiology, which can be used to develop hypotheses applicable to humans and/or to test hypotheses originating from clinical work [34]. V.

TYPES OF ANIMAL MODELS

The following overlapping categories of animal models [29,36–39] have been proposed. A.

Behavioral Similarity Models

These types of models are designed to simulate specific symptoms of a human disorder in animals. The primary intent is to produce a particular set of behaviors that are similar to those shown by humans with a certain illness, rather than to evaluate any specific etiological theory or to study underlying mechanisms or even treatment responsiveness. The validity of these models is judged by how closely the model approximates the human disorder from a phenomenological standpoint [29]. Inducing conditions became secondary. B.

Theory-Driven Models

In these approaches a theory drives the development of specific experimental paradigms. One does not assume the validity of the theory in order to proceed with the research. Rather, the goal is to operationalize the theory one wants to evaluate and study prospectively


the efforts of specific manipulations designed to represent putative causative factors. C.

Mechanistic Models

In these kinds of models, animals are used to study mechanisms. With the increasing array of methods for studying pathophysiology, there has been a preoccupation with the molecular and submolecular basis of altered behavior seen in many animal models. Some would consider that the only useful animal models are those which permit these types of studies. While mechanistic studies can include evaluation of both neurobiological mechanisms as well as social, behavioral, and developmental mechanisms, one cannot necessarily transpose techniques of mechanism studies cross species, i.e., from humans to rodents to primates or vice versa from rodents to monkeys. The study of mechanisms needs to be specific for a particular species. A serious challenge for animal modeling research is the development and utilization of techniques for mechanism studies in socially behaving animals. Some compromises between invasiveness of neurobiological studies and assessment of social behavior may be necessary [29]. Insistence on cross-species mechanistic similarities is premature given that at present we have no mental disorders in humans uniquely linked with a specific mechanism. D.

Empirical Validity Models

Perhaps the best-known and widest use of animal models involves the use of animal preparations to develop and test potential clinically active drugs. In this context, an ideal animal model is one in which there are no false positives and no false negatives; that is, when a drug works in animals it is predictive of its clinical effects in humans, and when it is inactive in animal models it will not have clinical efficacy in humans. Although there are a number of models with high empirical validity, there is never 100% correspondence between the effects of a drug in an animal model and in a clinical condition. The establishment of an animal model as valid on empirical grounds (or on any other grounds) does not necessarily establish its validity on other parameters. E.

Genetic Models

Genetic models involve studying strains that exhibit spontaneous behaviors that mimic a given illness.

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Through selective breeding, some investigators have developed animal strains that are especially sensitive on certain tests. This topic is discussed more extensively elsewhere in this chapter.

VI.

VALIDATION CRITERIA FOR ANIMAL MODELS

In 1969 McKinney and Bunney [36] made explicit the concept of using animal models for studying human depression and proposed for the first time criteria to consider in developing and evaluating animal models in general. Subsequently, modified or expanded sets of criteria were presented [5]. Willner [39] has described three different concepts of validity: 1. Predictive validity primarily concerns the correspondence between drug actions in the animal model and in clinical situations. Manipulations which have certain effects in humans should have similar effects in the animal model for that model to be valid from this standpoint. Using this criterion, there will always be false positives and false negatives. Not all agents that work in an animal model will also work in humans, and not all drugs that work in humans will necessarily work in animal models. There is no animal model that has perfect concordance in this regard. In terms of evaluating animal models according to this criteria it is the pharmacological profiling that is critical rather than the response to just one drug. 2. Face validity means that there are phenomenological similarities between the model and the illness being studied. In any one model it is never possible to model all the composite patterns of behaviors shown rather than the presence or absence of any one behavior or symptom. 3. Construct validity refers to the theoretical rationale for the model, which in turn relates to the theoretical understanding of the clinical condition and its causation. Unfortunately, too many proposed animal models utilize single proposed etiologies rather than a concept involving multiple risk factors. One of the exciting challenges for future animal models is the evaluation of the relative contributions of various risk factors thought to be important in the human syndrome in question. Geyer [1] makes the point that, before criteria can be considered, it is important to be explicit about the intended purpose of the model which will determine in part the criteria that should be utilized in evaluating its

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McKinney

validity. He contends that for a model to be of value in it must satisfy only two criteria: reliability and predictive validity. He does not think that construct validity is essential. VII.

SIGNIFICANCE OF ANIMAL MODELS

As Willner has stated [37,39,40], animal models form an important interface between clinical psychiatry and basic research in behavioral neuroscience. In this context they represent major modalities by which developments at the basic level can be brought into a clinical perspective and clinical theories can be evaluated in a controlled manner. This viewpoint contrasts sharply with the position that animal models have no more use since, for example, we can now discover and design drugs that are very specific and can go directly to testing in humans. The significance of animal models is also their role in the specification and study of focused components of a clinical syndrome. Experimental paradigms in animals permit evaluation of selected aspects of human psychopathology in a systematic and controlled manner. Their obvious advantage is in the ability to precisely control and alter inducing conditions and to permit the collection of prospective data on both a short- and a long-term basis and permit a broader range of mechanistic studies. For example, in relation to depression, prospective studies examining the effects of developmental events on behavior and on neurobiology can be done much more easily in animals. The timing and exact nature of certain alterations in development can be specified, and the short- and long-term consequences studied. That aspect of modeling research is relevant to the question of developmental vulnerability based on early experiences and the mediating mechanisms of vulnerability. Animal models make possible the dissection of mechanisms in a more direct way than is possible in human clinical research, and they complement ongoing efforts in human protocols, although such procedures need to be suited to both the species and the overall purpose of the experimental paradigm. The research questions have to be clear and specific. It is easier in animal studies to isolate and evaluate single variables in terms of their main effects and their interaction with each other. For example, the nature of the interactions among genetic, developmental, social, and biological variables can be studied in various combinations in different species. In human clinical

research, multiple variables interact simultaneously, and it has been virtually impossible to sort them out in any quantifiable way. Of course, animal models are most widely utilized in the preclinical evaluation of drugs. A related aspect is their contribution to a better understanding of the mechanism of the action of drugs in altering specific behavior patterns that goes beyond a mere prediction of whether drugs work or not [29]. Studies utilizing animal models can also help to understand the mechanisms of established treatment techniques, i.e., why do some treatment work in certain paradigms whereas others do not? A type of significance which is often not recognized is that animal modeling research has led to the development of improved behavioral, ethologically based rating methods that are now widely used in clinical research settings. The following quote is focused on affective disorders but, when considering the significance of animal models for psychopathology in general, contains principles applicable to any psychiatric disorder: The traditional difficulties in accepting animal models for psychopathology stem from the argument that there is no evidence for what occurs in the brain of the animal that is equivalent to what occurs in the brain of a human. However, if one models any or some core aspects of affective disorder, this model can become an invaluable tool in the analysis of the multitude of causes, genetic, environmental or pharmacological, that can bring about symptoms homologous to those of patients with affective disorders. Animal models can also allow the study of the mechanisms of specific behaviors, their pathophysiology, and can aid to develop and predict therapeutic response to pharmacological agents. The use of animal models in the research of affective disorders is multifold. Firstly, these models offer experimental systems that may provide insights into the multitude of causes, genetic, environmental or pharmacological, that can bring about symptoms homologous to those of patients with affective disorders. Models also allow study of the development of specific behaviors and their underlying neuroanatomical substrates and neurochemical mechanisms. Finally, animal models can be utilized to develop and predict therapeutic response to pharmacological agents and investigate their putative mechanisms of action [41].


VIII.

A.

CHANGING ROLE OF ANIMAL MODELS Neurosciences

Rapid developments in the basic and clinical neurosciences have presented and will continue to present opportunities yet also serious challenges for animal modeling research. On the positive side has been the general recognition of the importance of having experimental animal models if one is going to better understand the pathophysiology of psychiatric illness and move beyond correlative research. Indeed, some contend that the only useful animal models are those that permit molecular mechanistic studies to be done. However, as important as these types of models are, they are not the only useful types of animal models. There is also a role for more integrative models that will facilitate the study of vulnerability factors in a broader context. Conceptualizing animal models narrowly in a deterministic basic neuroscience context has had some unfortunate consequences in terms of the field’s development in that attention to the development and study of new biobehavioral models has been diminished along with critical research on already existing models. ‘‘Mechanisms’’ should not be viewed as synonymous with ‘‘molecular.’’ There is far more involved in understanding mechanism of behavior than molecular genetics and molecular biology. Some animal models will lend themselves to molecular biological studies of mechanisms; others will allow other kinds of contributions. Many major discoveries that have significantly impacted clinical psychiatry have come from either behaviorally oriented studies in animals, e.g., the significant enhancement of our understanding of developmental theories and attachment systems, and/ or have been based on empirical observations of animal behaviors in relation to drug treatment, e.g., the initial observations by Cade of lithium’s calming effects in guinea pigs [42]. A major challenge/opportunity for the development of animal models in the future relates to alterations of circadian rhythms which remain among the most pervasive and consistent findings in several types of mental disorders, especially the mood disorders. A considerable amount of research needs to be done to understand the mechanisms that underlie this connection. One context to begin to understand these mechanisms is at the interface between development/ early experience, social stress, and circadian rhythms. This approach could serve as the nexus of a new

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approach to animal models which incorporates genetic, developmental, and social stress issues. With the identification and characterization of the first mammalian circadian clock gene [43], some exciting cross-species approaches with high relevance to human disorders are going to become possible. B.

Stress Vulnerability

Early theories of the origins of human psychopathology focused on the importance of a variety of early life relationships and events. With the advent of a new era of neurosciences, interest in such developmental events has waned in many quarters. However, research utilizing animal models over the past 25 years has continued to steadily emphasize that these development stressors are important and can have long-term effects on brain and neurobiological development [44–47]. Obviously such events do not operate in a vacuum. The role of genetic vulnerability and how this interacts with developmental events and their consequences is an extremely important and newly emerging area of research in which experimental animal models can play an increasingly important role. Major theories have been proposed that provide an integrated developmental neurobiological perspective of depressive disorders [48–51] and of schizophrenia [52]. In terms of this approach, animal models have already contributed and have great potential for the future [13,53–59]. C.

Clinical Disorders

At present, diagnostic criteria for most human clinical disorders involve both a time dimension and signs and symptoms. Since the defining criteria for animal models of psychiatric disorders rely heavily on observed behaviors, a research challenge is to operationalize in animals what in humans are reported as subjective symptoms. Of course, an animal cannot tell one whether it has a certain symptom or not; however, it is possible to measure in animals such things as motor activity, food and water intake, weight, sleep, a range of social activities, changes in self-rewarding activities, and cognitive behaviors. A collection of changes in such behaviors might be postulated to resemble the symptoms or behavioral changes shown by humans diagnosed as having a certain illness, and by working within proper ethological frameworks cross-species research can aid in the understanding of human illness. Rather than trying to model an aggregate of symptoms, another approach is to focus on the experimental production of a more limited set of behaviors and to

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McKinney

use animal preparations to study these behaviors, e.g., anhedonia, uncontrollability, or changes in social and self-directed behaviors. What induction techniques to use? There are two broad approaches in utilizing induction procedures. One approach is to use those for which there are data to suggest that they might be important in the etiology of human clinical disorders. An alternative approach is to not worry too much about the crossspecies compatibility of inducing conditions, but to use procedures that will produce a set of behaviors in animals that bear some phenomenological similarity to a human illness.

IX.

GENETICS

Statements are beginning to appear that the best, or even only, approach to animal models is ‘‘genetic,’’ though it is not totally clear what this means. However, with the established importance of genetic vulnerability, experimental paradigms to systematically study genetic variables in animal models are needed as part of an overall approach to the creation and development of animal models. Many techniques are possible. For example, two lines of work, both from the animal models of depression literature, can be summarized as illustrative of this approach. One involves selective breeding and the other study of a specified strain [5]. A.

Selective Breeding: Flinders–Sensitive Line (FSL) of Rats

The Flinders line rats [17,60,61] were developed by selective breeding for differences in effects of the anticholinesterase, di-isopropylfluorophosphate (DFP) on temperature, drinking, and body weight. The FSL line rats are more sensitive to DFP as well as cholinergic agonists and have more brain muscarinic receptors in comparison with the Flinders-resistant line (FRL). They were originally proposed as an animal model of depression because of reports that human depressives are also more sensitive to cholinergic agonists. The FSL rats also resemble depressed humans in some other ways: elevated REM sleep, appetite and weight changes, reduced activity and increased anhedonia after exposure to chronic mild stress, and exaggerated immobility in the forced swim test. Imipramine, desipramine, and sertraline have all been shown to reduce immobility in the forced swim test in the Flinders line rats. Lithium, bright lights, and DFP do not. Likewise,

amphetamine and scopolamine have no effect in the forced swim paradigm. The calcium channel blockers verapamil and nicardipine were effective in reducing immobility in the forced swim test. Overstreet [62] has also presented data that the FSL rats exhibit altered sensitivity to the locomotor suppressant effects of diazepam; however, anxiolytic effects of diazepam are similar in the FSL. They do not voluntarily drink much alcohol, unlike some depressed individuals. They also do not exhibit any model schizophrenic behavior. They found that swim test immobility cosegregates with serotonergic but not cholinergic sensitivity in cross breeds of Flinders line rats. In conclusion, they present the FSL rat as fulfilling the criteria of face, construct, and predictive validity for an animal model of depression. B.

Specified Strain: Wistar Kyoto (WKY) Rats

Okamoto and Aoki [63] isolated a strain of Wistar rats with spontaneously developed hypertension, the SHR rat. Its normotensive inbred progenitor strain, the WKY rat not only differs from the SHR in respect to resting blood pressure, but also displays smaller stress-induced increases in plasma catecholamines [64], heart rate, and blood pressure [65–67]. In contrast, WKYs show larger endocrine and behavioral responses to stress than SHRs and a heightened susceptibility to stress ulcer. WKY rats [18,68,69] have been proposed as another animal model of depression based on the fact that they (1) exhibit hypoactivity in open field and defensive burying tests (2) readily acquire a learned helplessness task as well as a passive avoidance task; and (3) exhibit more depressive behavior in the Porsolt forced swim test of ‘‘behavioral despair’’ and desipramine reduces the immobility seen in this test. WKY rats also have a heightened susceptibility to stress ulcer and show evidence of heightened emotionality and an exaggerated stress response. C.

Other Genetic Strategies

Another genetic approach would be to utilize targeted mutagenic strategies that rely on transgenic and recombinant DNA-based knockout technologies to create animal models in available biobehavioral tests, thus permitting, within the limitation of these strategies, better understanding of the role of various genes in the control of specific behaviors. A critical research challenge for the future is the question of what specific


strategies should be used to develop such models based on current knowledge of the pathophysiology of various mental disorders. Other genetic approaches could involve genetic manipulation of candidate genes leading to knockout or transgenic mice, chance findings of altered behavioral phenotypes in other, not a priori designed, mouse mutants, or systematic behavioral screening of mutagenized mice to gain novel animal models [41]. A theoretical advantage of the transgenic or knockout approaches is that a specified behavioral alteration can be assigned to a single gene mutation. However, compensatory mechanisms and genetic background are always at work and sometimes obscure the role of a specific gene in a behavior. A method that will gain influence over the next years is genome-wide or directed mutagenesis followed by screens for relevant phenotypes. The forced swim test has already been used as a pilot behavioral assay in a random mutagenesis screen [70], but the identification of a series of well-defined and well characterized tests with high predictive validity would dramatically increase the efficacy of such an enterprise. X.

NEW THERAPIES

A.

New Methods of Discovering and Developing Pharmacological Therapies

Drug discovery is a multidisciplinary effort requiring chemical, structural, and biological approaches. This last includes animal models. Historically, one of the major uses of animal models has been for the preclinical screening of proposed pharmacological treatment agents. In this context, a variety of experimental animal models have been developed which have reasonable empirical validity. Unfortunately, the presence of false negatives and false positives has led some to sharply criticize animal models and even refuse to use them in drug discovery and development. A related position is that animal models, in the context of drug discovery and development, are irrelevant given newer molecular techniques for discovering and developing drugs. Newer therapies can be discovered based on hypothesized molecular mechanisms of illness and then moved directly to clinical trials. However, one of the major problems with this approach is that not enough is yet known about the specific pathophysiology of psychiatric illnesses to let that alone drive

9

the therapeutic discovery and development process. Some in vivo testing in animals remains critical to complement drug discovery based on novel mechanisms. Also, since psychiatric disorders are still largely defined by behaviors, it does not intuitively make sense to bypass behavior in the drug discovery and development process [5]. XI.

ANIMAL RIGHTS ISSUES

This is one of the foremost challenges with regard to animal modeling research [71,72]. The use of animals for biomedical research in general, and especially for neuropsychiatric disorders, continues under serious threat [73–80]. Detailed discussion of the various groups and strategies is beyond the scope of this chapter; however, the issue is not animal welfare organizations who, in so many invaluable ways, help look after the welfare of needy animals and deserve our enthusiastic support. Likewise, the problem is not the thoughtful groups that share our genuine concern about the welfare of all animals and work to establish reasonable regulations. The problem is with those organizations that are dedicated to stopping animal research at all costs, including violence to researchers and to physical property, and who advocate senseless bureaucracy to discourage researchers from pursuing animal research. We all support the humane treatment of all animals in research and careful and diligent review of all research by independent groups—as is done with human clinical research. However, with the escalating tempo of violence and intimidation in this area that has occurred over the last 10–20 years, some government agencies have hesitated to move ahead with programmatic initiatives in the animal modeling research area, and some universities have been, at best, ambivalent in backing faculty doing animal research. The field has lost productive people as a result, and new, junior people have sometimes hesitated to enter the field. This is a major challenge for the field in the future. XII.

SUMMARY

There are a variety of animal models available for many psychiatric disorders. Just as in any other field of medicine, none are perfect. Indeed, if they were, they would be replicas rather than models. Continuing efforts need to be made to further understand and utilize the models that are available as well as to develop new ones. However, major challenges for the

10

future will also include dealing with the conceptual and philosophical issues that surround animal modeling research in psychiatry. Many of these have been summarized in this chapter.

REFERENCES 1. MA Geyer, A Markou. Animal models of psychiatric disorders. In: FE Bloom, DJ Kupfer, eds. Psychopharmacology: the Fourth Generation of Progress. New York: Raven Press, 1995, pp 787–798. 2. WT McKinney. Models of Mental Disorders: A New Comparative Psychiatry. New York: Plenum, 1988. 3. GF Koob, CL Ehlers, DJ Kupfer, eds. Animal Models of Depression. Boston: Birkaeuser, 1989. 4. BK Lipska, DR Weinberger. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23(3):223–239, 2000. 5. WT McKinney. Overview of the past contributions of animal models and their changing place in psychiatry. Semin Clin Neuropsychiatry 6(1):68–78, 2001. 6. J Bowlby. Attachment and Loss: Attachment, Vol. 1. New York: Basic Books, 1969. 7. CL Coe, SP Mendoza, WP Smotherman, S Levine. Mother-infant attachement in the squirrel monkey: adrenal responses to separation. Behav Biol 22:256–263, 1978. 8. GD Jensen and CW Tolman. Mother-infant relationship in the monkey, Macaca nemestrina: the effect of brief separation and mother-infant specificity. J Comp Physiol Psychol 55:131–136, 1962. 9. IC Kaufman, LA Rosenblum. The reaction to separation in infant monkeys: anaclitic depression and conservation-withdrawal. Psychosom Med 29:649–675, 1967. 10. WT McKinney Jr, SJ Suomi, HF Harlow. Repetitive peer separations of juvenile-age rhesus monkeys. Arch Gen Psychiatry 27(2):200–203, 1972. 11. RA Hinde, LM Davies. Changes in mother-infant relationship after separation in rhesus monkeys. Nature 239:41–41, 1972. 12. GW Kraemer, MH Ebert, DE Schmidt, WT McKinney. A longitudinal study of the effect of different social rearing conditions on cerebrospinal fluid norepinephrine and biogenic amine metabolites in rhesus monkeys. Neuropsychopharmacology 2(3):175–189, 1989. 13. SJ Siegel, SD Ginsberg, PR Hof, SL Foote, WG Young, GW Kraemer, WT McKinney, JH Morrison. Effects of social deprivation in prepubescent rhesus monkeys: immunohistochemical analysis of the neurofilament protein triplet in the hippocampal formation. Brain Res 619(1–2):299–305, 1993.

McKinney 14. SJ Suomi, HF Harlow, CJ Domek. Effect of repetitive infant-infant separation of young monkeys. J Abnorm Psychol 76:161–172, 1970. 15. GD Mitchell, DL Clark. Long term effects of social isolation in non-socially adapted rhesus monkeys. J Genetic Psychol 13:117–128, 1968. 16. JM Weiss, HI Glazer, LA Pohorecky, WH Bailey, LH Schneider. Coping behavior and stress-induced behavioral depression: studies of the role of brain catecholamines. In: RA Depue, ed. Psychobiology of Depressive Disorders. New York: Academic Press, 1979, pp 125–160. 17. DH Overstreet. The Flinders sensitive line rats: a genetic animal model of depression. Neurosci Biobehav Rev 17(1):51–68, 1993. 18. WP Pare, E Redei. Depressive behavior and stress ulcer in Wistar Kyoto rats. J Physiol Paris 87(4):229–238, 1993. 19. F Petty, AD Sherman. A pharmacologically pertinent animal model of mania. J Affect Disord 3:381–387, 1981. 20. RD Porsolt. Pharmacological models of depression. In: Dahlem Conference on the Origins of Depression: Current Concepts and Approaches. Berlin: Dahlem University Press, 1982. 21. KA Roth, RJ Katz. Further studies on a novel animal model of depression: therapeutic effects of a tricyclic antidepressant. Neurosci Biobehav Rev 5:253–259, 1981. 22. SJ Suomi, SF Seaman, JK Lewis, RD DeLizio, WT McKinney Jr. Effects of imipramine treatment of separation-induced social disorders in rhesus monkeys. Arch Gen Psychiatry 35(3):321–325, 1978. 23. NIMH. Genetics and Mental Disorders: Report of the National Institute of Mental Health’s Genetics Workgroup, 1998. 24. TM Burton. Drug maker’s goal: Prozac without the lag. Wall Street Journal, 1998: B1:3. 25. LD Dorn, GP Chrousos. The neurobiology of stress: understanding regulation of affect during female biological transitions. Semin Reprod Endocrinol 15:19–35, 1997. 26. J Flint, R Corley. Do animals models have a place in the genetic analysis of quantitative human behavioral traits? J Mol Med 74(9):515–521, 1996. 27. KP Lesch. Gene transfer to the brain: emerging therapeutic strategy in psychiatry? Biol Psychiatry 45:247– 253, 1999. 28. E Sibille, Z Sarnyai, D Benjamin, J Gal, H Baker, M Toth. Antisense inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice. Mol Pharmacol 52:1056–1063, 1997. 29. WT McKinney. Animal research and its relevance to psychiatry. In: BJ Sadock, VA Sadock, Kaplan and Sadock’s Comprehensive Textbook of Psychiatry/VII. eds. Philadelphia: Lippincott Williams and Wilkins, 2000, pp 545–562.

Animal Models of Neuropsychiatric Disorders 30. DO Hebb. Spontaneous neurosis in chimpanzees: theoretical relations with clinical and experimental phenomena. Psychosom Med 9:3–6, 1947. 31. IP Pavlov. Lectures on Conditioned Reflexes, Vol 1. New York: International Publishers, 1928. 32. IP Pavlov. Lectures on Conditioned Reflexes, Vol 2. New York: International Publishers, 1941. 33. EL Thorndike. Experimental study of rewards. New York: Columbia University Press, 1933. 34. RJ Gardner, WT McKinney. Ethologie und die ansendung von tiermodellen (Ethology and the use of animal models). In: F Henn, ed. Psychiatry der Gegenwart, Heidelberg: Springer-Verlag, 1999, pp. 507–524. 35. RJ Gardner. Evolutionary perspectives on stress and affective disorder. Semin Clin Neuropsychiatry 6(1):32–42, 2001. 36. WT McKinney Jr, WE Bunney Jr. Animal model of depression. I. Review of evidence: implications for research. Arch Gen Psychiatry 21(2):240–248, 1969. 37. P Willner. The validity of animal models of depression. Psychopharmacology 83(1):1–16, 1984. 38. P Willner. Animal models of depression: validity and applications. In: GL Gessa et al., eds. Depression and Mania: From Neurobiology to Treatment. Advances in Biochemical Psychopharmacology. New York: Raven Press, 1995, pp 19–41. 39. P Willner. Animal models of depression: validity and application. Adv Biochem Psychopharmacol 49:19–41, 1995. 40. P Willner. Animal models of depression. In: JA den Boer, A Sitsen, eds. Handbook of Depression and Anxiety: a Biological Approach. New York: Marcel Dekker, 1994, pp 291–316. 41. EE Redei, N Ahmadiyeh, A Baum, D Sasso, J Slone, LC Solberg, C Will, A Volenec. Novel animal models of affective disorders. Semin Clini Neuropsychiatry 6(1):43–67, 2001. 42. JFJ Cade. Lithium salts in treatment of psychotic excitement. Med J Aust 2:349–352, 1949. 43. MH Vitaterna, DP King, AM Chang, JM Kornhauser, PL Lowrey, JD McDonald, WF Dove, LH Pinto, FW Turek, JS Takahashi. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264(5159):719–725, 1994. 44. L Arborelius, MJ Owens, PM Plotsky, CB Nemeroff. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160(1):1–12, 1999. 45. AS Clarke, GW Kraemer, DJ Kupfer. Effects of rearing condition on HPA axis response to fluoxetine and desipramine treatment over repeated social separations in young rhesus monkeys. Psychiatry Res 79:91–104, 1998. 46. JD Coplan, LA Rosenblum, JM Gorman. Primate models of anxiety: longitudinal perspectives. Psychiatr Clin North Am 18:727–743, 1995.

11 47. MA Hofer. On the nature and consequences of early loss. Psychosom Med 58:570–581, 1996. 48. HS Akiskal, WT McKinney Jr. Depressive disorders: toward a unified hypothesis. Science 182(107):20–29, 1973. 49. HS Akiskal, WT McKinney Jr. Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame. Arch Gen Psychiatry 32(3):285–305, 1975. 50. RM Post. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149(8):999–1010, 1992. 51. PC Whybrow, HS Akiskal, WT McKinney. Mood Disorders: Towards a New Psychobiology. New York: Plenum, 1984, p 228. 52. DR Weinberger. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669, 1987. 53. GK Bryan, AH Riesen. Deprived somatosensorymotor experience in stumptailed monkey neocortex: dendritic spine density and dendritic branching of layer IIIB pyramidal cells. J Comp Neurol 286(2):208–217, 1989. 54. MK Floeter, WT Greenough. Cerebellar plasticity: modification of Purkinje cell structure by differential rearing in rhesus monkeys. Science 206:227–228, 1979. 55. SD Ginsberg, PR Hof, WT McKinney, JH Morrison. The noradrenergic innervation density of the monkey paraventricular nucleus is not altered by early social deprivation. Neurosci Lett 158(2):130–134, 1993. 56. SD Ginsberg, PR Hof, WT McKinney, JH Morrison. Quantitative analysis of tuberoinfundibular tyrosine hydroxylase- and corticotropin-releasing factor-immunoreactive neurons in monkeys raised with differential rearing conditions. Exp Neurol 120:95–105, 1993. 57. WT Greenough, JE Black, and CS Wallace. Experience and brain development. Child Dev 58:539–559, 1987. 58. LJ Martin, DM Spicer, MH Lewis, JP Gluck, LC Cork. Social deprivation of infant rhesus monkeys alters the chemoarchitecture of the brain: I. Subcortical regions. J Neurosci 11:3344–3358, 1991. 59. RG Struble, AH Riesen. Changes in cortical dendritic branching subsequent to partial social isolation in stumptail monkeys. Dev Psychobiol 11:479–486, 1978. 60. DH Overstreet. Selective breeding for increased cholinergic function: development of a new animal model of depression. Biol Psychiatry 21(1):49–58, 1986. 61. DH Overstreet, O Pucilowski, V Djuric. Genetic/environment interactions in chronic mild stress. Psychopharmacology 134(4):359–360, 1997. 62. DH Overstreet, O Pucilowski, AH Rezvani, DS Janowsky. Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders sensitive line rats as an animal model of depression. Psychopharmacology 121(1):27–37, 1995.

12 63. K Okamoto, K Aoki. Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293, 1963. 64. R McCarty, CC Chiueh, IJ Kopin. Spontaneously hypertensive rats: adrenergic hyperresponsivity to anticipation of electric shock. Behav Biol 23:180–188, 1987. 65. S Knardahl, ED Hendley. Association between cardiovascular reactivity to stress and hypertension or behavior. Am J Physiol 259:H248–257, 1990. 66. JE LeDoux, A Sakaguchi, DJ Reis. Behaviorally selective cardiovascular hyperreactivity in spontaneously hypertensive rats. Hypertension 4:853–863, 1982. 67. R Rettig, MA Geyer, MP Printz. Cardiovascular concomitants of tactile and acoustic startle responses in spontaneously hypertensive and normotensive rats. Physiol Behav 36:1123–1128, 1986. 68. DH Overstreet, DS Janowsky, O Pucilowski, AH Rezvani. Swim test immobility co-segregates with serotonergic but not cholinergic sensitivity in cross-breeds of Flinders line rats. Psychiatric Genet 4(2):101–107, 1994. 69. WP Pare. Open field, learned helplessness, conditioned defensive burying, and forced-swim tests in WKY rats. Physiol Behav 55(3):433–439, 1994.

McKinney 70. PM Nolan, D Kapfhamer, M Bucan. Random mutagenesis screen for dominant behavioral mutations in mice. Methods 13(4):379–395, 1997. 71. Editorial. In defence of animal research. Nature 407(6805):659, 2000. 72. FK Goodwin, AR Morrison. Science and self-doubt. Reason 32(5):22, 2000. 73. J Kaiser. Animal rights. Activists ransack Minnesota labs [news]. Science 284(5413):410–411, 1999. 74. J Kaiser. Animal rights. Booby-trapped letters sent to 87 researchers. Science 286(5442):1059, 1999. 75. S Nadis. Threats to US primate researchers [news]. Nature 402(6757):7–8, 1999. 76. P Aldhous. Protests force primate farm to close. Nature 404(6775):215, 2000. 77. Editorial. Legal challenges to animal experimentation. Nature Neurosci 3(6):523, 2000. 78. D Malakoff. Animal research. Activists win big on rodent, bird rules [news]. Science 289(5478):377, 2000. 79. N Loder. Britain may boost protection of researchers from intimidation [news]. Nature 407(6800):3, 2000. 80. Q Schiermeier. As German activists wage propaganda war [news]. Nature 407(6800):3, 2000.

2 Methodological Advances in Psychiatric Genetics YOAV KOHN and BERNARD LERER Hadassah University Hospital and Hebrew University School of Medicine, Jerusalem, Israel

I.

RATIONALE FOR GENETIC RESEARCH IN PSYCHIATRY

different from research on metabolic disorders, where a biochemical imbalance is obvious and allows rapid characterization of the enzymatic defect and its etiology. In the case of schizophrenia numerous changes probably occur, from the hypothesized maldevelopment of the embryonic central nervous system during the first trimester of pregnancy until the onset of disease at the age of 15–20 years. That psychotic symptoms improve after the administration of dopamine D2 receptor antagonists tells us very little about the beginning of the process two decades before, nor can it help us define the contribution of inherited and environmental factors to the development of the illness. This complexity of mental phenomena makes genetic research crucial to their understanding. Genes have been implicated in the etiology of almost every psychiatric disorder. The etiological role of environmental and psychosocial factors is also well recognized and, as noted above, may be substantially mediated through genes. Unlike environment, which is constantly changing and always difficult to characterize, genes remain unchanged for the most part from conception until death. Although the level of activation of genes does change throughout life, the DNA sequence remains practically constant. Thus we can find in the adult person with schizophrenia the same inherited predisposing genes that started the process of the disorder in fetal life. Identifying these genes would allow

Genes play a major role in determining and controlling every phenomenon in life. The inherited potential of the new embryo is encoded in the genes transmitted to him by both his parents. The activation or deactivation of certain genes at certain times governs the differentiation of embryonic stem cells into different tissues and systems. This influence goes on after birth and throughought the life span when the production of enzymes and structural proteins is under genetic control. In this way genes control the activity of cells, tissues, and body systems, produce disorders, and determine programmed cell death. Genes also mediate the influence of the environment. Nutrition, toxins, infectious agents, and psychosocial stresses can all affect the organism by activating or deactivating certain genes. Also, genes may affect the environment that a subject is exposed to. For example, it was found that monkeys with an inborn tendency to have low levels of serotonin metabolite in the CSF were more likely to be subject to violent death in a younger age [1]. When we try to better understand the etiology and pathogenesis of complex phenomena such as behavior, personality traits, and psychiatric disorders, it seems almost impossible to disentangle the numerous factors involved in their development. The situation is very 13

14

Kohn and Lerer

us to understand the unfolding of this process and characterize the relative contribution of environmental factors. Ultimately, this would lead to improvement not only of diagnosis and treatment, but also of prevention. The strategy of starting research on the etiology of disorders by first finding the contributing genes, and then revealing the pathogenesis, is opposite in direction from classical research in medicine and therefore is called ‘‘reverse genetics.’’ This methodology will be described in the following sections and is summarized in Table 1.

II.

clusters of specific symptoms (such as negative or positive ones), neuropsychological tests or imaging studies (e.g., enlarged or nonenlarged ventricles). On the other hand, too much narrowing could lead us to false-negative results and to missing a gene that is expressed differently in different individuals. For example, the genetic liability to develop schizophrenia can also lead to a spectrum of related disorders such as schizotypal and schizoid personality disorders [3].

III.

ESTABLISHMENT OF GENETIC ETIOLOGY IN PSYCHIATRIC DISORDERS

A.

Family Studies

DEFINITION OF PHENOTYPES

Before a search for a disease-causing gene begins, one should correctly define the phenotype—who has the disease and who does not. It is widely aknowledged that psychiatric diagnosis is limited to subjective measures. The identification of genes that cause psychiatric disorders should improve our diagnostic capabilities imensely. The circular problem is that in order to find these genes we should make the correct diagnosis. Broadening the diagnosis to include as many individuals as possible with similar symptoms is doomed to hamper our effort to find the gene. It was shown, for example, that the transmission of schizophrenia is independent of the transmission of bipolar disorder [2]. But even categories such as DSM-IV-defined schizophrenia might be too broad. It is concievable that what we define today as one disorder comprised dozens of different diseases with different etiologies and clinical pictures. Narrowing down the diagnosis is an important step in ensuring that a homogeneous sample with the same genetic etiology is studied. This process should be based not only on theoretical hypotheses but on empirical data. Thus, patients can be subdivided according to

Table 1

The first step in genetic research on any disease is to establish its heritability. The most obvious way of doing so is by studying the recurrence rate of the disorder in relatives of affected individuals. This rate should not be measured simply against the rate in the general population. Rather, the comparison should come from the study of relatives of healthy controls, who should be diagnosed using the same instruments. Raters should be blind to the proband’s diagnosis. Family studies have revealed increased risk in relatives of probands with schizophrenia [2,4], bipolar disorder [2], major depressive disorder [5], obsessive-compulsive disorder [6], autism [7], attention deficit hyperactivity disorder [8], and anorexia nervosa [9], among others. Increased risk for relatives would suggest that the disorder is familial. This is not equivalent to its being genetic since family members share more than genes. Environmental factors such as nutrition, infections, and psychosocial stressors are also common to family members.

Methods of Identifying Genes for Medical Disorders

Establishment of Heritability Family studies Adoption studies Twin studies Segregation analysis

Localization of Genes Parametric Linkage Analysis Nonparametric methods Association studies: case control and family based Haplotype relative risk (HRR) Transmission disequilibrium test (TDT) Allele sharing methods (sibpairs and pedigrees) Linkage disequilibrium in genetic isolates Quantitative trait loci (QTL)

Methodological Advances in Psychiatric Genetics

B.

Adoption Studies

Adoption studies are designed to try to disentangle inherited from environmental etiological factors. The rate of the studied disorder is compared between biological and adoptive parents of individuals with a certain disorder. Alternatively, the risk of the disorder can be compared between offspring of affected individuals who were given for adoption and offspring of healthy individuals who were also given for adoption. A third and obviously rare paradigm would be the comparison of offspring of healthy parents who were either adopted by affected individuals or by healthy ones. The last variation is the study of offspring of affected parents who were either reared by them or adopted or reared outside their families (as in foster homes). These methods have mainly been used for the study of schizophrenia [3,10], bipolar disorder, and major depressive disorder [11,12], and have shown the major role of genetics in their etiology. C.

Twin Studies

Twin studies are the gold standard of research on the genetic etiology of disease. The recurrence risk or concordance of a disorder is compared between monozygotic (MZ) and dizygotic (DZ) twins. MZ twins share 100% of their genes while DZ twins share on average 50% of their genes, as do any other pair of siblings. Researchers assume that MZ and DZ twins are similar in the degree to which they share environmental influences. While it is probably true that twins are exposed to the same kind of environment more than nontwin siblings, it is obvious that MZ twins experience a more unique and shared environment than DZ twins. The only way to overcome this limitation is by comparing concordance rates of MZ twins who were reared together or apart. As this is a rare phenomenon, it is quite impractical for genetic research. Nevertheless, twin studies are considered the best estimate of the heritability of the disorder, which is calculated from the difference in concordance between MZ and DZ twins. Thus, autism is considered to be highly heritable with an MZ concordance rate of 92% compared to 10% for DZ twins [13]. Bipolar disorder has also a high heritabilty rate with MZ concordance of 67% against 20% for DZ twins [14]. In schizophrenia the rates are also suggestive of a strong genetic component in etiology: 48% concordance in MZ twins and 4% in DZ twins [15]. Concordance rates also teach us about the importance of environment in the etiology of disorders. The 48% concordance rate for schizophre-

15

nia between MZ twins is a striking example. While a strong genetic influence is suggested, it also means that a person with the genetic predisposition to develop the disorder has >50% chance of avoiding it, perhaps by avoiding a noxious environment or by experiencing some as yet unknown, protective factors. The study of discordant sibs or preferably discordant MZ twins can thus teach us on the role of environment. For example, it was shown that MZ twins with Tourette syndrome (TS), a neuropsychiatric disorder characterized by motor and vocal tics, varied in the severity of symptoms. The twins with a more severe clinical course had a lower birth weight [16]. D.

Segregation Analysis

After establishing the role of genetic factors in the etiology of a disorder, the next step is to try to define its mode of inheritance. This is done by studying large pedigrees with multiple affected individuals. The observed inheritance is compared with expected inheritance under various genetic models. The goodness of fit is calculated and certain solutions are rejected. Those that are not rejected are considered consistent with the data, which supports this solution as a possible mode of inheritance (although it does not prove it to be the right one). Using this method, most psychiatric disorders show a complex mode of inheritance. None of them is consistent with simple Mendelian inheritance (i.e., autosomal dominant or recessive, X-linked). Even models of oligogenic or polygenic inheritance (few or many genes with small contribution of each of them) must take into account the role of environment to fit the data. Thus, the model consistent with the inheritance of psychiatric disorders is usually termed multifactorial [17]. The impact of this on the choice of methods for genetic analysis is discussed below.

IV.

LOCALIZATION OF GENES THAT PREDISPOSE TO PSYCHIATRIC DISORDERS

A.

Parametric Methods

Until a decade ago the most widely used method employed to detect genes for inherited disorders was parametric linkage analysis. In this method large pedigrees with multiple affected members are studied. In each pedigree the inheritance of the studied disorder is compared with the inheritance of DNA markers with a known location on the human genome. The marker

16

can be chosen because of an a priori idea regarding the genetic location of the disease gene. This idea might stem from the study of affected individuals with chromosomal aberrations. This was the case in Douchene muscular dystrophy (DMD). The gene for this Xlinked disorder was localized after the study of two females who had the disorder were found to have a deletion and a translocation in a certain region on chromosome X [18]. More frequently there is no idea about the putative location of the disease gene. In this case DNA markers spanning the whole genome are used in what is called a genome scan. These markers are usually DNA sequences with no genetic function known to us, but with slight variations from person to person. These variations, or polymorphisms, serve to mark a specific location on the human genome. Depending on the number of markers (usually in the order of hundreds), some gaps are left unchecked. Nevertheless, as nearby genes and markers are usually transmitted together from parent to offspring, we can compare the inheritance of the marker and of the disease in a certain pedigree. If the studied disease is inherited together with a specific marker, we have a clue about the location of the disease gene. Take for example the hypothetical pedigree in Figure 1. From looking at the pedigree it seems that the inheritance of the disorder is indeed linked to the inheritance of the studied marker. The affected grandfather (#400) has transmitted the disease coupled with allele 1 of the marker to some of his offspring. The

Figure 1 A hypothetical pedigree for linkage analysis. Affected individuals are marked by a dark symbol. Individuals are given identifying numbers from 400 to 606. Genotypes for a certain marker are shown for each individual by the two alleles found in this individual.

Kohn and Lerer

possibility that true linkage exists between the two phenomena is compared with the possibility of observing this by chance. The ratio between these two probabilities is calculated. A ratio of 1000 in favor of linkage is traditionally considered significant. For practical reasons the ratio logarithm is used and called the LOD (logarithm of the odds) score. The LOD scores of different pedigrees can be summed together. Tight linkage (LOD score of >3) implies that the disease gene is located close to the studied marker. LOD score of 2 excludes the region as the possible location for the disease gene. When a genome scan is carried out, multiple testing for hundreds of markers is being done and thus a higher level of significance is needed. A LOD score of 3.3 was shown to correlate to a P value of .05 in this situation and is thus considered significant evidence for linkage in a genome scan [19]. LOD scores of 1.9, the magnitude of most positive findings in psychiatry, are considered only suggestive of linkage. Recombination, the exchange of DNA between a pair of chromosomes during meiosis, can decrease the evidence for linkage by separating the disease gene from the linked allele. Thus, in our hypothetical pedigree the disease gene can be transmitted by individual #400 to one of his offspring with allele 2 instead of allele 1. This might decrease the evidence for linkage in the pedigree. To overcome the problem, the recombination rate is allowed for in the calculation of the LOD score in relation to the estimated distance between the disease gene and the marker. The recombination rate (or fraction) can vary from 0% if they are in exactly the same location to 50% (or 0.5) if they are on different chromosomes. As stated above, parametric linkage analysis was the main method of genetic analysis employed until recently. It led to the discovery of genes causing disorders with simple Mendelian inheritance such cystic fibrosis [20] and Huntington’s disease [21]. In disorders with a more complex inheritance, such as diabetes, hypertension, and psychiatric disorders, it has not proved to be as useful. The main limitation of this method is that in order to correctly calculate the probability of linkage, certain parameters regarding the inheritance of the disease have to be taken into account. First of all, the mode of inheritance has to be specified. As noted before, in psychiatric disorders, mode of inheritance is probably polygenic with a considerable environmental contribution. For many years the genes for psychiatric disorders were sought under the incorrect assumption of simple Mendelian inheritance, which yielded mainly negative results or some unreplicable positive results. For exam-


ple, researchers who studied Tourette syndrome, were very optimistic at first regarding the chances of finding the gene causing the disorder. It seemed that the inheritance of the disorder was autosomal dominant. It took many years and a great deal of effort with no significant results of parametric linkage analysis to realize that even in TS the inheritance is probably more complex [22,23]. As the exact number of genes that act together to cause psychiatric disorders and the relative role of environment are not known, it is very hard to define the right model for linkage calculations. Unfortunately, the only way to overcome this problem is by finding these genes and isolating their etiological influence from that of environment. Mode of inheritance is only one of the parameters that linkage analysis is dependent upon. Other parameters are also not known for psychiatric disorders and have to be guessed. Gene frequency, for example, is estimated from disease frequency and the number of implicated genes. The rate of genetic heterogeneity is also estimated. This is the proportion of pedigrees in the studied sample where the disease is caused by different genes. Penetrance has to be taken into account as well. This is the probability that a certain person who carries the disease gene will actually express the disorder. Correct definition of the phenotype is a serious problem that limits the use of parametric linkage in psychiatric genetics, and has been already discussed. But even if we had an accurate diagnostic measure, we would probably still encounter people who carry the gene but for some reason, such as protective factors, do not express the disorder. This might be the case of the person in Figure 1 (#500) who transmitted the disease gene with the linked allele to his affected son from his affected father. Thus, with no correction for penetrance, true linkage can be missed. Another related parameter that has to be specified in linkage analysis is the rate of phenocopies. These are affected members in the pedigree who acquired their disease because of another, nongenetic factor. This might be the explanation for the occurrence of the disease in individual #606 in the hypothetical pedigree in Figure 1. She has the disease but not the 1 allele. Another possible explanation is that this woman inherited the disease gene or another gene causing the disorder from her mother who is unrelated genetically to the affected grandfather. This phenomenon of disease genes coming from different founders of the pedigree is called bilineality. It is common in pedigrees with psychiatric disorders where assortative mating (between two affected individuals, or between relatives of affected individuals) is common. Bilineality is another

17

parameter that has to be considered to calculate linkage. Usually, researchers attempt to exclude bilineal families from their samples, but absence of bilineality is very difficult to establish with certainty. Thus, most of the parameters needed for the calculation of linkage are not known for psychiatric disorders and will be known only after the genes for the disorders have been found. When running parametric linkage analyses, many estimates and guesses are made. For each analysis, a specific model composed of the estimated parameters is being used. The many parameters and the numerous different options for each of them make endless numbers of combinations. Examining all of them is impractical and carries the risk of obtaining false-positive results because of multiple testing. Examining only a limited number of models, as is usually done in linkage analysis, is unlikely to include the correct one. This is probably the reason why parametric linkage analysis has been unable as yet to identify a gene for any of the major psychiatric disorders. Notwithstanding the limitations of parametric linkage analysis in the study of psychiatric disorders, there might be rare instances where its application can be fruitful. Some rare neuropsychiatric disorders such as Rett’s disorder, a severe autisticlike X-linked disease, have a more simple Mendelian inheritance. The gene for Rett’s disorder was cloned after linkage analysis had been localized to a certain location on chromosome X [24]. The identification of such disease genes, even if rare, could shed light on the pathogenesis of other more common disorders. B.

Nonparametric Methods

Unlike parametric linkage analysis, nonparametric methods are not dependent upon the specification of parameters regarding inheritance. Thus, their use is more suitable for the study of disorders with complex inheritance. Nonparametric methods have been used extensively in the past decade and have shed light on the genetics of disorders such as diabetes, hypertension, Alzheimer’s disease, and psychiatric disorders. 1.

Association Studies

Case control association studies overcome the problems encountered in genetic analyses of complex disorders by studying a sample of unrelated affected individuals. In this group the frequency of alleles of certain genes is determined and compared to the frequency of the same alleles in a control group of un-

18

affected individuals. Because the affected individuals are not related, increased frequency of a certain allele in them does not usually imply linkage with the disease gene. Rather, it points to a direct role of the studied allele in the etiology of the disorder. Because of that, different alleles or DNA polymorphisms of genes must be studied instead of merely studying DNA markers. This means that the DNA variations that can be used in association studies must occur in the regions of the genome that code for proteins. The variations can occur in an exon, which is the coding region of the gene, meaning that sequence encodes the sequence of amino acids in the product protein. In other cases the polymorphism occurs in a noncoding region of the gene, or intron. As noted above, if a polymorphism occurs in a noncoding region between genes, it is not useful for association studies, as linkage to a nearby gene cannot be studied in a group of unrelated subjects. Polymorphism can also occur in a regulatory region of the gene, which is a sequence of DNA where certain molecules bind and affect the rate of transcription. A functional DNA polymorphism occurs in a coding region of a gene and affects the function of the product protein. Functional polymorphisms, or those occurring in the regulatory region of the gene, are usually preferred in association studies, as genes with a suspected role in etiology of disorders are investigated in this paradigm. It was thought until recently that association studies were not suitable for a genome scan because they cannot detect linkage. Now, with the completion of the Human Genome Project, almost the entire DNA sequence of the human genome is known. Thus, theoretically, association can be studied in polymorphism in each and every gene. Practical, technical, and computation limitations make this option not feasible yet. Many association studies of psychiatric disorders have been performed using candidate genes. These are genes for proteins with a hypothetical function in the pathogenesis of the disorder. In psychiatric genetics these candidate genes are usually genes involved in the production, metabolism, and signal transduction of neurotransmitters. For example, a repeat polymorphism in the gene for the dopamine receptor D4 was found to be associated with ADHD [25] and with the novelty-seeking personality trait [26], and a certain allele of the serotonin transporter gene was associated with anxious personality [27]. These associations were significant but of small magnitude. They explained only a small part of the variance of the studied traits. This means that these genes might have a small con-

Kohn and Lerer

tribution to the etiology of the studied phenomena. Combinations of alleles for two different genes were studied and shown to be associated with tardive dyskinesia, for example [28]. Looking at larger numbers of genes simultaneously would yield a greater number of combinations that might be too numerous to study without enormous samples. The relatively small role of each gene found to be associated with disorders is only one limitation of this study design. As the Human Genome Project has revealed, there are 30,000 genes (many fewer than once thought, but still an enormous number). A third of these genes are estimated to be expressed in the brain. Most of them are still not known. Moreover, our understanding of the pathogenesis of psychiatric disorders is limited to current processes in the brain of the affected individual. These may be very different from the genetic vulnerability that started the disease many years before. A genomewide association scan might overcome these obstacles but, as stated above, is not feasible yet. Notwithstanding the above-mentioned difficulties of association studies, their main limitation is the need to find a perfectly matched control group. Controls should resemble affected individuals in every measure that might be related to the studied genes, apart from disease status. The most problematic confounding factor in this regard is ethnicity. Variations of allelic distribution are highly dependent on ethnicity. Significant variations of allelic distribution are found even among ethnic subgroups of a relatively homogeneous population such as Jews [29]. The choice of an ethnically unmatched control group might be the reason for the failure to replicate some of the positive associations reported between psychiatric disorders and certain alleles. Indeed, some of these nonreplications were in studies in which the patient and control group came from a homogeneous population [30]. It is hard to say whether the positive results or the nonreplications were spurious. To overcome this problem researchers are turning more and more to methods that employ unaffected family members as controls. Two widely used family based methods are haplotype relative risk (HRR) and the transmission disequilibrium test (TDT). 2.

Haplotype Relative Risk (HRR)

In HRR allele frequencies are studied in a group of affected individuals. The comparison group is made up of hypothetical sibs of these individuals. These made up sibs are presumably healthy and have inher-


ited from their parents the alleles that were not transmitted to the affected sib (Fig. 2). To be able to make up the control group, both parents of the affected individual must be studied for the same alleles. Thus, HRR requires the ascertainment of ‘‘trios’’ of affected individual and both parents, alive and willing to participate in the study. This makes the research design more complicated. On the other hand, the hypothetical control group in this design is perfectly matched for ethnicity to the patient group. 3.

Transmission Disequilibrium Test (TDT)

In TDT, as in HRR, trios are needed for the analysis. In this research design, affected individuals with a parent heterozygous for the allele of interest are studied. In each such case it is determined whether the studied allele was transmitted to the affected offspring or not (Fig. 2). A transmission rate that is significantly higher than the random rate of 50% is considered as evidence for a role of the allele in the etiology of the disorder. The inheritance of multiple genes or haplotypes can be investigated as TDT is studied in families. Although addressing the issue of ethnicity, both HRR and TDT are limited, as association studies in populations, to the study of candidate genes. Nevertheless, both methods are useful for the attempts to further establish findings from population-based association studies. For example, HRR was used to both replicate and (in other populations) not replicate the association of DRD4 with ADHD [31,32].

Figure 2 Family based association studies using two different methods. The first method is haplotype relative risk (HRR). Two parents and one offspring (a trio) are studied. The nontransmitted alleles (2 and 4 in this pedigree) comprise the control group of hypothetical healthy sibs made up from many trios. Allele frequencies are compared between groups. The second method is transmission disequilibrium test (TDT). Trios are studied in which one of the parents is heterozygous for a certain allele of the studied marker (1, for example). Transmission of the allele is counted for each trio. The rate of transmission is compared with random rate of transmission, which is 50%.

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C.

Allele Sharing Methods

1.

General Principles

In allele sharing methods of genetic analysis, the degree of sharing of alleles of certain genes or markers is examined in related individuals with the investigated disorder. This can be done either in affected sibs, which is called sibpair analysis, or in affected individuals with a more distant relationship (grandfather and grandson, cousins, etc.). Sharing of alleles can be incidental or can be secondary to inheritance of the same allele from a common ancestor (parent, grandparent, etc.). When the reason for the sharing is not known, it is called ‘‘identity by state.’’ When it can be shown that both individuals inherited the same allele from a common source, we use the term ‘‘identity by descent.’’ Identity by descent allele sharing is a more powerful tool in genetic analysis. If related individuals with the disorder share the same alleles, identical by descent, more often than expected by chance, an association between the allele and the disease is implied. Alternatively, as the individuals are related, increased sharing can stem from linkage of the marker to the disease gene. Thus a genome scan can be performed with these methods, as well as the study of candidate genes. When allele sharing is studied, no assumption has to be made about mode of inheritance, genetic heterogeneity, gene frequency, penetrance, rate of phenocopies, and so on. This nonparametric method is model free. This is its great advantage over parametric linkage analysis. On the other hand, parametric linkage under the correct model is much more powerful in the detection of linkage. In order to compare their power to that of parametric linkage, allele sharing methods need to use very large samples of the order of hundreds of sibpairs or dozens of multiplex pedigrees. These are hard to ascertain in one population. Researchers usually combine samples from different populations, which increases the risk of genetic heterogeneity and decreases the chance of finding significant linkage. For this reason allele sharing methods are used in combination with parametric linkage analysis, which means that in the same pedigrees both parametric and nonparametric methods are used. For example, the addition of sibpair analysis to parametric linkage analysis was helpful in supporting suggestive linkage to a locus on chromosome 22q in schizophrenia [33]. Significant linkage between two forms of dyslexia and markers on chromosome 6p and 15p were found using parametric linkage for one form and allele sharing methods for the other [34].

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2. Sibpair Analysis Take for example the sibpair in Figure 3. Affected sibs can either inherit the same two alleles from their parents, one shared allele and one nonshared allele, or two different alleles. If there is no relation between affection status and the studied allele, we expect the probabilities for each of the three cases to be 0.25, 0.5, 0.25, respectively. The actual allele sharing is studied in many sibpairs, and the observed frequency of sharing of one, two, or zero alleles is compared with the theoretical random frequencies. Any deviance from random distribution is considered evidence for increased allele sharing. 3. Allele Sharing in Pedigrees In this paradigm allele sharing is compared between affected pedigree members with any degree of relationship apart from parent and offspring (as the allele sharing will always be 0.50 in this case). Observed sharing is compared with expected sharing under no association or linkage. As for parametric linkage analysis, large pedigrees with many affected members are ascertained. But unlike traditional linkage analysis, only allele sharing between affected individuals is studied. Take Figure 1 for example. In allele sharing analysis, only the affected individuals (#400, #502, #600, #603, and #606) will be studied, and allele sharing will be examined in every possible combination of two out of these individuals (apart from parent and child). The other unaffected pedigree members do not contribute to the calculation, apart from verifying that iden-

Figure 3 Sibpair analysis: two affected sibs and their parents are studied. In this example one daughter received alleles 1 and 3 from her parents. Her sister can either receive the same two alleles, only one of them (1/4 or 2/3), or the two that were not transmitted to her sister (2/4). The probabilties for each case are equal, and thus for sharing the same two alleles are 0.25, only one allele 0.5, and no sharing 0.25. Actual sharing in many sibpairs is compared to these random probabilities. Significant deviance implies association or linkage.

tity between individuals is indeed by descent and not by chance. Thus it is clear that this paradigm is model free, as it is not dependent on the parameters required by parametric linkage. The most widely used software that employs this paradigm is called Genehunter [35], which can also calculate parametric linkage in the same pedigree. D.

Linkage Disequilibrium in Isolated Populations

One of the main limitations of both parametric and nonparametric methods of genetic analysis is the problem of genetic heterogeneity. Researchers use large samples to increase power, and thus run the risk of mixing subpopulations with different genetic etiologies. Studying small populations that are genetically isolated can overcome this obstacle. In such a population, affected individuals are more likely to represent a homogeneous sample, in terms of etiology. It is plausible that most of the affected individuals in a genetic isolate, who have a certain disorder, carry the same disease-causing mutation, which they inherited from a common ancestor. If the mutation process is relatively new, or more possibly if the genetic isolate is relatively young (and the mutation was introduced to it relatively late), we expect that affected individuals share more than the mutation itself. Large regions of DNA on both sides of the mutation should be identical in these individuals, as the short time that elapsed since the isolate was founded did not allow recombination to change them considerably. Thus, these individuals share not merely alleles but large haplotypes identically by descent. The aggregation of certain alleles into haplotypes that are more frequent than what is expected by chance is called ‘‘linkage disequilibrium,’’ and is evidence for the presence of a shared mutation in this region. The main advantage of this paradigm is that only a few affected individuals (as few three or four) need to be examined. These people do not have to be related (apart from being part of the same isolate), and their relatives are not needed for the study. The disadvantages are that these genetic isolates are not easy to find, and are even more difficult to study. Also, genes responsible for psychiatric disorders in these unique populations might be very well specific to them only. Nevertheless, finding one gene for one psychiatric disorder in one population has not yet been achieved by any other method. Linkage disequilibrium in genetic isolates has been used to locate genes for rare medical disorders with simple Mendelian inheritance [36], and


also for a common disorder with a more complex inheritance such as Hirschprung’s disease [37]. Lately, it is being applied to the study of psychiatric disorders as well. E.

Quantitative Trait Loci (QTL)

As implied by its name, QTL is suited for the study of quantitative traits, such as height and weight. It allows the study of many genes, each with a small contribution, to the expression of one continuous variable. QTL is easily applied in laboratory animals, where pure strains can be inbred and the change in the studied trait can be measured under different genetic conditions. Obviously this cannot be done with human beings. Rather, sibs or unrelated subjects with extremely different values of the studied trait are studied and their genotypes compared. It is also debatable whether most psychiatric disorders can be perceived as quantitative traits. Medical psychiatry assumes in most cases a more categorical approach to psychiatric disorders. On the other hand QTL might prove beneficial to the study of personality traits and intelligence [38].

V.

ADVANCES IN THE LABORATORY

The significant expansion of DNA marker maps enables the performance of better genome scans. More and more polymorphisms of the human DNA are known. These include single nucleotide polymorphisms (SNP) and certain sequences (from two or three to several dozen nucletodies) that vary in the number in which they are repeated in different individuals. This improved map increases the chances of finding association or linkage with a studied disorder. Data are shared through the Internet and are freely available to any researcher. Technology is improving from day to day. Methods that identify different DNA sequences are much easier to perform and are less timeconsuming. The recent completion of the Human Genome Project opens new and endless horizons for the study of psychiatric genetics. One aspect is the further improvement of marker maps. Moreover, in a short while we should be able (with sufficient computation power) to study association of disorders with each and every of the human genes. Thus we will be able to desert the study of candidate genes that were chosen merely because of our limited knowledge. In this way association studies (both case control and family-based

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paradigms) will be used for the purpose of hunting genes in genome scans. When the location of a gene for a psychiatric disorder is eventually found, the new map of the human genome will enable its rapid identification and cloning. The mutations that cause the disorders will be characterized shortly thereafter, and shorten the way to the study of pathogenesis and the application to diagnosis, prevention, and treatment.

VI.

SUMMARY AND FUTURE DIRECTIONS

Finding a significant linkage between a psychiatric disorder and a DNA marker, which is replicated consistently, is an objective that has not yet been accomplished. The further objectives of mapping actual disease genes, cloning them, and determining their protein structure and function, are more distant. The inherent obstacles have been described in this chapter, as well as newer methods of genetic analysis that aim to overcome them. Advances in molecular technology constantly improve our technical tools. Eventually one gene for one psychiatric disorder in (at least) one population will be found. And then? The journey just begins. The gene for Huntington’s disease (HD) was discovered a decade ago [21]. No dramatic change has occurred in the treatment and prognosis of HD patients since then, even though diagnosis is now possible before the onset of the disorder. This has raised painful ethical questions. Is it justified to test young healthy individuals for a dreadful, incurable disease? When we finally find genes for schizophrenia won’t we be in the same position? We will have to deal with difficult ethical questions regarding prenatal diagnosis of susceptibility to a disorder with a variable clinical course that has its onset 15–20 years later. We will also be at the very beginning of the long road which will need to be traversed in order to understand how genes start the process that eventually culminates in psychiatric disorder. Apart from the complexities inherent to the field of psychiatric genetics, there are additional ones. These are related to the fact that interposed between the gene and the protein for which it codes are variations in transcription, translation, and posttranslational modifications that prevent us from being able to assume a simple relationship between gene and disease. Also, epigenetic factors modify expression of genes in ways that can be time specific and tissue specific. Thus, even when a gene for a psychiatric disease is eventually found, a

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long route will have to be traversed before we undertand how it affects the disease process. 13.

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3 New Developments in the Regulation of Monoaminergic Neurotransmission* ALAN FRAZER University of Texas Health Science Center at San Antonio, and South Texas Veterans Health Care System, San Antonio, Texas, U.S.A.

DAVID A. MORILAK and LYNETTE C. DAWS University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A.

I.

INTRODUCTION

mediated by specific transporters located in the plasma membrane, plays the key role in regulating the concentration of these amines in the extracellular fluid (ECF). Furthermore, these protein transporters are not merely constitutive membrane components but undergo a variety of regulatory processes. Finally, in the past decade it has become more accepted, even if still not completely understood, that effects of released amines can be influenced by other peptide transmitters colocalized in the same neurons. Our emerging concepts of the functioning of transporters and the processes of cotransmission and VT have not been well integrated into current views of psychoactive drug action. Yet it is likely that they influence profoundly the effects produced by such drugs. Because of this, it is appropriate to view such processes from the perspective of their potential neuropsychopharmacologic impact.

The process of synaptic transmission is the key target for all psychoactive drugs. Transmission may be influenced by drugs affecting the synthesis, storage, release, inactivation, and postsynaptic effects of transmitter substances. Further, drugs effective in major psychiatric illnesses such as depression and schizophrenia have prominent effects on transmission mediated by biogenic amines such as dopamine (DA), norepinephrine (NE), and 5-hydroxytryptamine (5HT; serotonin). The past decade has seen marked advances in our understanding of key features of the transmission process mediated by these amines. Of particular importance is the emerging concept that transmission mediated by these substances appears, at least in part, to occur through diffusion-mediated signaling, termed extrasynaptic or volume transmission (VT). Also, it is now recognized that the inactivation process of reuptake,

II. Some of the material in this chapter was presented in a review article by Frazer A, Gerhardt GA, and Daws LC: New views of biogenic amine transporter function: implications for neuropsychopharmacology. Int J Neuropsychopharmacol 2:305–320, 1999.

HARD-WIRED VS. PARACRINE OR VOLUME TRANSMISSION

The most widely accepted model for synaptic transmission, including that which occurs in brain, was devel25

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oped from studies involving cholinergic transmission through nicotinic receptors, particularly at the neuromuscular junction. This model was derived in part from the morphological characteristics of such synapses, involving a presynaptic knob with specialized features, a cleft of 40–60 nm, and the postsynaptic membrane containing both receptors and invaginations. Such specialized features within the synapse pose barriers to transmitter diffusion and help to ensure that the transmitter acts only within the strict confines of such conventional synapses. Further contributing to acetylcholine (ACh) having only synaptic effects is the presence of its degradative enzyme acetylcholinesterase within the synapse. This type of transmitter process has been termed ‘‘hardwired.’’ However, in the mid-1970s, anatomic studies on brain tissue generated data that were interpreted as favoring a different model of synaptic transmission. This model has been referred to as extrasynaptic communication or paracrine transmission (which, historically, relates to a hormone affecting the function of cells at a distance from its site of release) or volume transmission (VT). The essence of such transmission is the passage of chemical messages along multiple, largely unpredictable channels such that transmitters may pervade the extracellular space to act at distant receptors outside the strict confines of conventional synapses. Although there are attractive features of this concept, it has been elusive and difficult to prove. It is outside the scope of this chapter to review this subject in detail. The interested reader is referred to comprehensive reviews of this topic in a recent volume [1]. Since the mid-1970s, anatomic, physiologic, and pharmacologic data have been generated that are consistent with VT, although not proving it. If such transmission does occur in the brain, it could have profound neuropsychopharmacologic implications. The original observation that there may be nontraditional types of transmission in brain was that of Descarries et al. [2]. These investigators, using 3H-5HT autoradiography in the neocortex of rats, claimed that serotonergic terminals were rarely engaged in morphologically differentiated synapses and speculated about ‘‘nonsynaptic’’ release of 5HT in this brain area. Subsequently, Beaudet and Descarries [3] suggested that 5HT acted on a large number of cortical cells rather than just a restricted number of postsynaptic targets. Their notion was of a predominantly nonjunctional serotonergic innervation of the cortex having paracrine-like properties. Although this work has

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been criticized [4] and others have found much higher percentages of typical synaptic specializations for 5HT [5,6], there does seem to be a body of data showing a reasonable percentage of nonsynaptic varicosities for biogenic amines in brain [7–9]. The presence of nontraditional synapses may be specific to certain brain regions [10], indicating that these biogenic amines may function both at conventional synapses and nontraditional ones. Further, in different brain regions the extent to which VT is involved in, for example, dopaminergic transmission may vary [11]. Consistent with the view of diffusion of transmitter to act at distant, nonsynaptic receptors is the realization that channels between cells are of sufficient width to allow the passage by diffusion of neuroactive compounds [12]. Although fraught with a variety of assumptions, it has been estimated that DA can diffuse at least 10 mm and 5HT 20 mm from its release site in brain tissue within one half-life [13,14], distances that would permit action at extrasynaptic receptors. Also, in a series of elegant investigations, Wightman and his colleagues [13–15] showed the concentration of either DA or 5HT in ECF to be directly proportional to the number of electrical pulses in an electrical train, a result not consistent with the buffered diffusion that occurs with hard-wired transmission. Further, peak extracellular concentration of either transmitter after a single stimulus was not altered by uptake inhibitors, suggesting that the uptake process is not altering the efflux of these transmitters into the extrasynaptic space. As is discussed in the section on transporters, one explanation for such data is that the uptake sites are extrasynaptic. If DA or 5HT can ‘‘escape’’ from the synapse and diffuse in ECF some distance from the synapse, is there any evidence that they will encounter appropriate receptors outside the synapse? There appears to be. Although certainly not conclusive, much has been made of, and considerable controversy has been generated by, the many observations showing a ‘‘mismatch’’ in brain between areas receiving very little innervation by a specific type of neuron yet having a high density of receptors for the particular transmitter [16]. For example, in rat cerebral cortex, only the 5HT2 receptor has a distribution that appears to match the regional and laminar density of serotonergic innervation [17]. More convincing, though, are studies carried out with electron microscopy which reveal receptor immunoreactivity outside of synapses. This has been found for both D1 and D2 dopamine receptors [18,19], 5HT1A [20] and 5HT2A [21] receptors.

Regulation of Monoaminergic Neurotransmission

The foregoing lends credence to the view that DA, 5HT, and perhaps NE can spill out from synapses to diffuse to distal sites in concentrations that may be sufficient to activate extrasynaptic receptors [13,14]. This issue and its neuropsychopharmacologic implications are highlighted in the sections dealing with the localization of transporters and their regulation.

III.

BIOGENIC AMINE REUPTAKE AND TRANSPORTERS

It has been 40 years since the initial observation that tritiated NE could be taken up from blood into organs containing sympathetic nerves [22], due to an active transport process contained in these nerves. Further research revealed that the primary means of terminating synaptic activity of NE, DA, or 5HT was by these active transport processes. Key neuropsychopharmacological discoveries were that many antidepressants inhibited the uptake of NE and 5HT [23,24], whereas psychostimulants, such as cocaine and methylenedioxymethamphetamine (MDMA; ‘‘Ectasy’’), blocked the uptake of DA as well as that of 5HT, and, for some of the drugs in this class, uptake of NE was also inhibited [25–27]. The inhibition of uptake was thought to be responsible for the efficacy of antidepressants, whereas the inhibition of DA uptake was linked to the euphoric and reinforcing properties of psychostimulants. Although the uptake processes for these three amines had similar characteristics, the uptake of each amine is mediated by a specific protein termed a transporter. Furthermore, the transporter proteins were presumed to have a synaptic localization to account for the enhancement of synaptic transmission thought to occur when pharmacological agents inhibited the uptake process. In other words, reuptake (and diffusion) altered the magnitude, duration, and spatial domain of transmitter-induced receptor activation and, in so doing, modified neurotransmission. More recent work [28] has substantiated the idea that these transporters are the key cellular elements regulating the concentrations of biogenic amines in ECF. The cloning of biogenic amine transporters in the early 1990s [29–32] and the development of selective radioligands for them at about the same time permitted a range of studies not possible previously. These studies have begun to provide important information about transporter function and regulation that in some cases expands and amplifies our previously held concepts, but in other ways, fundamentally changes them.

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A.

Structure of Monoamine Transporters

The dopamine transporter (DAT), norepinephrine transporter (NET), and 5-hydroxytryptamine transporter (5HTT) are part of a family of neuronal plasma membrane transporters that include the monoamines and certain amino acids such as gamma-aminobutyric acid (GABA), glycine, and proline [33]. These three transporters share considerable structural homology. They are all Naþ and Cl dependent, have 12 membrane-spanning domains, N- and C-termini located intracellularly and a large extracellular loop with glycosylation sites which may alter trafficking and/or function of the transporters. The extracellular and intracellular portions of the proteins have phosphorylation sites that likely contribute to the functional properties of the transporters. The DAT, NET and 5HTT are each believed to represent a single gene product [33]. Since they represent single gene products, this means that posttranslational or other intracellular regulatory mechanisms must play a role in regulation of the function of these transporters. Data, reviewed below, are starting to appear that support the theory that phosphorylation of transporters through a variety of protein kinases and phosphatases causes changes in their function and plays a role in the trafficking and incorporation of transporters into the plasma membrane. B.

Models of Transporter Function

Current ideas about the function of monoamine transporters have led to proposals that transporters may operate in at least two modes: (1) as an alternating access carrier [34], or (2) in a channel mode [35]. In the more standard alternating access carrier mode (Fig. 1) [36], the protein is first in a conformation such that the cotransported ions, Naþ and Cl , and the substrate (e.g., DA, NE, or 5HT) bind to a cleft in the transporter that is open to the extracellular space. The transporter then converts to a form that is accessible to the intracellular space, allowing the cotransported ions and the substrate access to the cytoplasm. This internal-facing form releases the transported substances into the cytoplasm and then interconverts so as to expose the now empty binding sites to the extracellular environment. This is the transport cycle. In the case of the 5HTT [34], Kþ ion binds to the transporter protein when it is open to the cytoplasm and may facilitate the interconversion of the protein to the form that exposes binding sites to the extracellular space to reinitiate the transport process. According to this model, the rate of

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influx of extracellular solute determines the rate of efflux of intracellular solute; i.e., influx and efflux rates are modulated equivalently. Data have been obtained recently with the 5HTT and the DAT showing independent modulation of inward and outward transport [38–40]. Thus, some features of transport seem inconsistent with the classical alternating access carrier model. By contrast, in the channel mode, which is thought to be a low probability event, the transporter protein functions as an ion channel (Fig. 1). Evidence in support of the channel mode of conductance is that the 5HTT and NET have transmitter-activated currents that are not linked stoichiometrically to substrate movement [35, 36, 41–45]. For example, if charge movement were merely linked to coupled transport for the NET, then one would predict one charge/NE molecule. What has been found for the human NET expressed in cultured cells is 200 charges/NE molecule. Such data have been interpreted to mean that these charges are carried by the positively charged NE molecules and cotransported ions [41]. Moreover, when the transporter is in the channel mode, a single transport event carries many more NE molecules than would be predicted by the classic alternating access model [46]. One way this could occur would be if the transporter

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acted as a channel permitting bulk flow of substrate through the open pore. This behavior of the transporter may be explained by the existence of two gates, one directed intracellularly and one extracellularly. In the case of the alternating access model, the two gates open sequentially during the transport cycle to allow the exchange of ions and substrate between ECF and cytosol by alternating access to the cleft of the transporter [36]. On occasion, the ‘‘gates’’ on both the extracellular and cytoplasmic sides of the transporter open simultaneously, permitting bulk flow of substrate and associated ions through an ‘‘ion’’ channel. It seems possible that transporters are really combined carriers and channels. One implication of transporters acting as ion channels is that it should be possible to develop drugs that change the probability of the transporter acting in the channel mode, akin to the effect of benzodiazepines at the GABAA receptor. Such drugs should markedly influence the effect of synaptically released transmitter. If, for example, some psychotic states are linked to excessive dopaminergic transmission, drugs that change the probability of the DAT acting in the channel mode might be effective in these states. Another interesting aspect of the realization of transport-associated currents is that it permits analysis of the effects

Figure 1 Schematic for biogenic amine transport in the alternating access and channel mode. In the alternating access model, the carrier has an aqueous lumen or cleft that exposes alternatively to the extracellular or intracellular environments. This transition state (A) , (B) results in transport of the substrate (S) and co-transported ions (empty circles) that is coupled stoichiometrically. The channel mode (C) is a low probability event, in which the ions and substrate move through the channel pore down their electrochemical gradients. The constrictions indicated on the cytoplasmic (A) or extracellular (B) domains of the transporter may be viewed as ‘‘gates’’, both of which are open simultaneously to form a pore (C). (Diagram courtesy of Dr. Aurelio Galli, Department of Pharmacology, University of Texas Health Science Center, San Antonio TX.).


of psychoactive drugs on such currents. These analyses may provide some explanation for differences in the pharmacological properties of ‘‘similar’’ drugs. For example, amphetaminelike compounds (including the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) acted like DA and caused transport-associated currents at DATs whereas cocainelike drugs (including methylphenidate) blocked such currents [47]. C.

Electrogenic Processes

The DA, NE, and 5HT transport cycles involve cotransport of ions and therefore the processes are potentially electrogenic. One or two Na+ ions and one Cl ion are cotransported, resulting in a net inward flux of positive charge [45,48]. In general, the electrogenic processes involved in transport may contribute substantially to the resting membrane potential of a given nerve terminal and affect not only the relative activity of the transporters but also other processes such as transmitter release. Flux of charges associated with substrate uptake has been demonstrated for all of the monoamine transporters [41,44,46,49]. Consistent with this is the finding that depolarization decreased whereas hyperpolarization enhanced DA uptake in xenopus oocytes [47]. It seems that the DAT is regulated similarly in a voltage-dependent fashion in the mammalian CNS [48,50–53]. The implication of this is that when DA neurons are depolarized, DAT will decrease its transporter activity, allowing for greater diffusion of DA to its receptors [54,55], perhaps distant from a synapse or varicosity (see above). By contrast, hyperpolarization of DA neurons would enhance uptake of DA so as to decrease its receptor-mediated effects. This scheme makes sense physiologically since, for example, situations that would call for depolarization-induced release of DA would ‘‘turn off’’ its inactivation mechanism (i.e., the DAT) in order to facilitate dopaminergic transmission. This regulatory process now appears likely for DAcontaining neurons, and may also occur for the NET and 5HTT as well [41,46,56]. D.

Anatomical Localization of Transporters

Although transporters were presumed to have a localization within the synapse, results of studies visualizing either the DAT or 5HTT by electron microscopy have revealed the presence of these transporters outside the synapse. For example, Zhou et al. [57] found the majority of 5HTTs to exist in small unmyelinated axons, suggesting 5HT uptake to be mainly extrasynaptic;

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they found also that 5HTTs on axons outside synapses were engaged in high-affinity uptake of 5HT. They speculated that 5HT can spill out from the synaptic cleft and that the 5HTT located just outside the synapse can take up 5HT near the synapse whereas axonal 5HTT takes up 5HT that has diffused to more distal sites. Evidence for extrasynaptic localization of 5HTTs has also been found in both the shell and core of the nucleus accumbens [21]. Similarly, Nirenberg et al. [58,59] visualized the DAT under electron microscopy in the substantia nigra, the dorsolateral striatum, and the nucleus accumbens, and found evidence in all areas for the DAT being outside of synapses. The extrasynaptic localization of transporters, coupled with the idea of VT, means, for example, that DA may come into contact with NETs. This is of importance as it has been shown that the NET transports DA even better than NE [60]. By contrast, the DAT does not transport NE, but it has been demonstrated that 5HT can be taken up by the DAT in the striatum [61]. Much earlier work of Shaskan and Snyder [62] showed, using rat brain slices, that noradrenergic nerves could take up 5HT, albeit much less potently than they transported NE; however, their capacity to take up 5HT was much greater than that for NE. Thus, transporter ‘‘promiscuity’’ coupled with VT could result, for example, in DA reaching NETs in sufficient concentrations so as to be taken up into noradrenergic nerves, or 5HT reaching DATs or NETs so as to be removed by these transporters. There is evidence in support of this concept. For example, in the ventral mesencephalon 3H-DA can be taken up by serotonergic neurons and this effect is partially blocked by fluoxetine [63]. Results with in vivo microdialysis have shown that systemic administration of selective inhibitors of the NET raise DA in the prefrontal cortex [64], and local application into the nucleus accumbens of selective inhibitors of the NET raised extracellular levels of 5HT and DA in addition to NE [65]. Using in vivo voltametry, we also obtained evidence for the uptake of 5HT into noradrenergic nerves [66]. In the dentate gyrus of the hippocampus, where the density of NETs outnumbers 5HTTs by roughly 2:1 (unpublished observations), exogenously administered 5HT was taken up by both serotonergic and noradrenergic nerves. By contrast, in the CA3 region, where 5HTTs outnumber NETs about fourfold (unpublished observations) no evidence of 5HT uptake into noradrenergic nerves was obtained. Relevant to this issue is an interesting result of Bel and Artigas [67]. These investigators measured the con-

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centration of 5HT in the ECF of the frontal cortex, obtained by microdialysis. Systemic administration of desipramine alone did not raise the concentration of 5HT whereas administration of fluoxetine did. However, when the concentration of 5HT was elevated by a dose of fluoxetine that produced a maximal effect, administration of desipramine was able to raise further the concentration of 5HT. One explanation for this result is that blockade of the 5HTT permitted 5HT to reach noradrenergic nerves where it was taken up by NETs located on them. All the results cited above have certain limitations which make their extrapolation to the clinical situation problematic. Nevertheless, such results are consistent with data showing that depressed patients treated with selective inhibitors of the 5HTT show decreases not only in the concentration of 5-hydroxyindoleacetic acid (5HIAA) in spinal fluid but in the norepinephrine metabolite 3,4,dehydroxyphenylglycol (MHPG) as well; similarly, treatment of patients with selective noradrenergic uptake inhibitors results in decreases in both MHPG and 5HIAA in spinal fluid [68]. One implication, then, of VT and extrasynaptic localization of transporters is that administration of selective uptake inhibitors could facilitate the uptake of a specific transmitter into other types of nerves producing as yet unknown effects. Another implication is that administration of dual uptake inhibitors (e.g., imipramine, which inhibits the uptake of both NE and 5HT) could result in even greater diffusion of NE or 5HT from their release sites so as to reach receptors on targets that they would not if only one transporter was inhibited. The consequences of this are not clear, but this could be an important area for future research. Thus, even though uptake inhibitors were developed for clinical use because of the idea that they would prolong ‘‘synaptic’’ transmission (and they may do so by inhibiting perisynaptic transporters), they may produce many other effects as well, both on the membrane potential and intracellular processes of the nerves containing the transporter that they inhibit and on other nerves at a distance from the site of transmitter release. E.

Regulation of Transporter Function

Because transporters for the biogenic amines both are critical in regulating the extracellular concentrations of these amines, and are key targets for a number of psychotherapeutic drugs, understanding how their function is regulated has come under intense scrutiny in recent years. Once the mechanisms for regulation of the biogenic amine transporters are understood, there

is great potential for developing new classes of drugs for the treatment of disorders such as depression, mania, anxiety, schizophrenia, and drug abuse. It is becoming clear that transport of biogenic amines is not simply a constitutive property of synaptic membranes but a dynamically regulated component of aminergic signaling. 1.

Acute Regulation of Transporter Function

Acute changes in transporter function can occur rapidly (within minutes). Consequently, it is unlikely that such changes are mediated via alterations in gene expression given that at least several hours are required for increases in transporter mRNA to translate into increased transporter expression in the plasma membrane [69]. Commensurate with the finding that transporters for the biogenic amines contain sites for protein phosphorylation by a number of kinases [33], several groups reported rapid changes in transport capacity following activation of cellular kinases. The most common observation was that activation of protein kinase C (PKC) led to a reduction in amine transport capacity [70–72]. There are also considerable data implicating a role for calcium, calmodulin, and other kinase-dependent as well as kinase-independent pathways in the acute regulation of transporter function [73–78]. The decrease in transport capacity ensuing PKC activation is due to a reduction in Vmax with Km remaining largely unaltered. The reduction in Vmax is associated with a decline in the number of transport proteins in the cell membrane [75,79]. This seems to result from sequestration of the transporter for recycling rather than degradation [77,79–81]. New techniques have enabled researchers to track changes in the distribution of transporters within cells. The most extensive studies to date have been carried out in cell lines transfected with the DAT and have consistently demonstrated PKC activation to evoke internalization of this transporter [82–85]. The fate of internalized DATs remains under debate, with evidence for both recycling [85] and degradation [82]. Nevertheless, it is apparent that cell surface redistribution of biogenic amine transporters is a mechanism that contributes to regulation of extracellular levels of transmitter. Such cell surface redistribution has pharmacological significance. For example, Saunders et al. [86] showed that amphetamine, a substrate for the DAT, caused trafficking of the human DAT (hDAT) from the plasma membrane to the cytosol of cultured cells. Callaghan and coworkers [87] subsequently showed that cocaine exerted the opposite


effect, that is, mobilization of the hDAT from the cytosol to plasma membrane of cultured cells. Determining the pathways through which such psychotropic drugs are able to alter the distribution of transporters on the plasma membrane will have important ramifications for the development of new drug therapies for the treatment of numerous psychiatric disease states and drug abuse. 2.

Mechanisms for Trafficking of Biogenic Amine Transporters

One way in which protein kinases can be activated is via presynaptic receptors. Apparsundaram and coworkers [79,81] demonstrated that activation of muscarinic acetylcholine receptors linked to PKC rapidly and selectively decreased the transport capacity (Vmax) of the NET. In another study, Miller and Hoffman [88] reported that activation of A3 adenosine receptors in cells increased 5HT uptake. This increase could be blocked by inhibitors of nitric oxide synthase and cGMP-dependent kinases, providing evidence for a nitric oxide–cGMP pathway in the acute regulation of the 5HTT. In vivo studies have also provided evidence for receptor-mediated pathways in acute transporter regulation. For example, using high-speed chronoamperometry, Daws et al. [89,90] reported that antagonism of the 5HT1B autoreceptor prolonged clearance of 5HT in rat hippocampus. Importantly, antagonism of the 5HT1B autoreceptor in 5HTT knockout mice failed to alter clearance of 5HT, indicating that the presence of both proteins is required for this effect [91]. These observations are consistent with the idea that activation of 5HT1B autoreceptors enhances 5HTT function. Similarly, blockade of the dopamine D2 receptor has been shown to inhibit clearance of DA from extracellular fluid [50,51], an effect that was absent in mice lacking the D2 receptor [52]. Whether autoreceptor regulation of transporter activity leads to transporter trafficking is unknown, as are the signal transduction pathways linking receptor to transporter. Many signaling proteins, including receptors and ion channels, are modulated via direct protein phosphorylation, and there is evidence that this is also true for biogenic amine transporters [for a recent review, 72]. Blakely and colleagues [92] demonstrated that 5HT reduced phosphorylation of the 5HTT both under basal conditions and following PKC activation. These effects could be blocked by paroxetine, a selective serotonin reuptake inhibitor (SSRI), suggesting that the effects of 5HT were mediated by an action

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on the transporter and not on 5HT receptors. Ramamoorthy and Blakely [77] later showed that PKC-induced transporter internalization was reduced in the presence of 5HT [77]. The inhibitory effect of 5HT on phosphorylation of the 5HTT is due to its binding to the 5HTT and/or its translocation by it. This indicates that phosphorylation of the 5HTT occurs when it is in the plasma membrane, and further suggests that such phosphorylation serves as a signal for its trafficking and internalization. The ability of 5HT to suppress phosphorylation may be a mechanism to maintain high transporter function when extracellular levels of 5HT are elevated [71]. In contrast to the 5HTT, direct phosphorylation of the DAT does not appear to be involved in PKC-mediated regulation of DAT function [93]. Further, it now appears that phosphatases are also involved in regulating the state of phosphorylation of amine transporters [72,94], providing yet another approach to regulating the function of transporters in vivo. 3.

Long-Term Regulation of Transporter Function

Several lines of evidence, including changes in transporter activity and/or expression in response to environmental perturbations (e.g., altered photoperiods) [73], fluctuations in hormone levels (e.g. corticosteroids, estrogen) [95–97], and as a consequence of aging [98,99], suggest that biogenic amine transporters also undergo long-term regulation. Most relevant to the present review are the changes in transporter activity/expression observed in certain disease states and as a consequence of therapeutic intervention. For example, reductions in both 5HTT and NET binding have been reported in patients with depression [100–102], and significant reductions of 5HTT binding and DAT immunoreactivity have been observed in patients with Parkinson’s disease [reviewed in 103]. Depressive disorders are commonly treated with selective inhibitors of 5HT and/or NE uptake. Pharmacologic inhibition of transporters occurs rapidly. However, maximal therapeutic benefit takes weeks to occur, so adaptive changes induced by such drugs on biogenic amine systems have been investigated extensively. Although much of this work focused on receptors and receptor-mediated responses [104], data on transporter function have also been obtained. Numerous studies have assessed the effect of chronic antidepressant treatment on the density of binding sites for the 5HTT and NET. The results have not been consistent [reviewed in 73,105]. Similarly, although

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several studies have shown no effect of chronic treatment with antidepressants on mRNAs for the 5HTT and NET, others have reported increases and still others, no change [101,105,106]. Obviously, differences in the duration of chronic drug dosage and route of drug delivery, which inevitably exist in such in vivo studies, make firm conclusions regarding alterations in gene expression by chronic drug treatment difficult. Using high-speed chronoamperometry, we [107] measured the ability of an SSRI, fluvoxamine, applied locally to the hippocampus, to inhibit uptake of exogenously applied 5HT in rats treated for 21 days by osmotic minipump with the SSRI paroxetine. The more constant level of drug in plasma obtained by administration via minipump may better model clinical administration of uptake inhibitors. Acute local administration of fluvoxamine did not inhibit uptake of 5HT in chronically treated rats (as it did in nontreated rats). This lack of an inhibitory effect of fluvoxamine may be due to a robust decrease in 5HTTbinding sites in paroxetine-treated rats [107]. Pineyro et al. [108] also found chronic administration of paroxetine by minipump to cause a decrease in 5HTT function and density. More recently, we [109] showed that the time course for decreased 5HTT function following chronic treatment of rats with an SSRI was gradual. This functional decrease was paralleled by a decrease in 5HTT density but not by mRNA levels for the 5HTT. These data suggest that posttranscriptional events mediate changes in 5HTT function caused by long-term administration of SSRIs. One implication of these data for the clinical setting is that antidepressantinduced decreases in 5HTT density may need to reach a ‘‘critical’’ level before therapeutic benefits are seen. In keeping with this, Alvarez et al. [102] reported that platelet 5HTTs were decreased in patients treated with fluoxetine. Thus, if transporter density can be reduced more rapidly, perhaps clinical improvement can be accomplished in a shorter time frame. F.

Genetic Knockout and Polymorphisms of Biogenic Amine Transporters

Perhaps the most striking demonstration of the importance of transporters in regulating extracellular fluid concentrations of biogenic amines comes from studies using transporter deficient mice. In vivo studies using voltametric recording techniques show that homozygous 5HTT knockout (KO) [91], DAT KO [110], and NET KO [111] mice have a profoundly reduced ability to clear 5HT, DA and NE, respectively, from ECF. However, in most cases, clearance remains more

rapid than simple diffusion would predict. This implies that other mechanisms must compensate, at least to some extent, for the loss of transporter. One possibility is that transporters other than the specific transport protein for a given biogenic amine are able to compensate. As has been discussed, transporters for the biogenic amines exhibit some ‘‘promiscuity’’ for transmitters. In addition, the presence of nonneuronal monoamine transporters, such as the extraneuronal monoamine transporter and organic cation transporter 2 (OCT2), in brain [112] may also account for clearance of biogenic amines from ECF in 5HTT-, DATand NET-deficient mice. Indeed, OCT2 is reportedly increased in the brains of 5HTT KO mice [113] and may represent an adaptive response to the loss of 5HTT. The advent of transporter-deficient mice and their altered responses to drugs as well as inherent differences in amine levels, receptors, and behavior [28,111,114], prompted researchers to look for genetic variants in transporter proteins that may predispose to psychiatric disorders. Variants have now been uncovered in the promoter region of the gene encoding the 5HTT that alter mRNA and protein expression both in vitro and in vivo. An association between these variants and a number of disorders, including anxiety, affective disorder, autism, and alcoholism, have been reported. Such associations include a predisposition for the disorder and altered sensitivity to drugs used to treat the disorder [115–118]. Clearly, this is an area for active research which should lend important insights into the underlying etiology of such disorders and improved treatments for them. G.

Implications for Neuropsychopharmacology

Our changing views on modes of neurotransmission (hard-wired vs. VT) and on transporter function (carrier vs. channel mode), together with the marked advances in our understanding of transporter regulation, have paved the way for the development of new drugs. For example, drugs that cause immediate activation of certain protein kinases (or inhibition of certain phosphatases) may speed or enhance the therapeutic efficacy of current antidepressant treatments by either (1) causing a rapid reduction in the number of active transporters at the plasma membrane (e.g., through sequestration) and/or (2) bringing about more rapid changes in transporter gene expression. Likewise, the development of drugs that alter the probability of transporters acting in channel mode, or of drugs that


allow greater diffusion of transmitter from their release sites, is also an area for active research because of their therapeutic potential. In addition, understanding the regulation of transporters and the consequences of VT may result in determination of the mechanisms that underlie the reinforcing properties of cocaine, amphetamine, and other drugs of abuse. Although our understanding of the role of transporters and of diffusion in regulating monoaminergic neurotransmission has increased tremendously in recent years, these remain more ‘‘classical’’ concepts. More recently the idea of peptidergic regulation of monoaminergic neurotransmission has emerged. In particular, there is new evidence that neuropeptide receptors may be novel targets for antidepressant and anxiolytic drugs. Therapeutic efficacy induced by antagonists of certain neuropeptide receptors is thought to be due to changes in noradrenergic and serotonergic activity. Because of this it is timely to review our current understanding of neuropeptide regulation of monoaminergic neurotransmission.

IV.

NEUROPEPTIDE MODULATION OF MONOAMINERGIC NEUROTRANSMISSION

In the late 1970s and early 1980s, much fanfare hailed the emergence of a ‘‘new’’ class of brain neurotransmitter, the neuropeptides. Every year, more peptides were isolated, identified, quantified, and mapped anatomically in the brain. There was much excitement and anticipation that this era would generate a new understanding of neurotransmission and regulation of brain function. A noteworthy feature of neuropeptides that emerged from this period of research is that they seem invariably to be colocalized in the same nerve terminals with other neurotransmitters, including the monoamines [119], essentially forcing an obligatory inteaction between the two transmitter classes. Nonetheless, the nature of this interaction and the contexts in which it occurs must be determined by the complement of receptor subtypes expressed by the postsynaptic target neuron, and also by the differential release characteristics of the colocalized peptidergic and monoaminergic neurotransmitters. A.

Neuropeptides Are ‘‘Slow’’ Modulatory Transmitters

The general characteristics of peptide neurotransmission differ in many important respects from those of

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monoamines [see 120]. Unlike monoamine transmitters, which are derived from a single amino acid by enzymatic synthesis, neuropeptides are small proteins comprising a chain of several amino acids. As such, they are synthesized in the cell body by ribosomal translation of messenger RNA. Like other proteins, they are usually synthesized first in the form of a precursor protein, which is then further cleaved and modified before the peptide is shipped via axonal transport to the nerve terminal. There it is incorporated into large dense-core synaptic vesicles [121]. Thus, unlike the relatively rapid changes that can be induced in the rate of enzymatic synthesis of monoamines directly in the nerve terminal, regulatory induction of neuropeptide synthesis is a slow process, requiring hours or even days for the activation of gene expression, de novo protein synthesis, and axonal transport before any change in releasable peptide becomes available to the nerve terminal. The localization of peptide transmitters in large, dense-core synaptic vesicles, as opposed to the small, clear vesicles in which monoamines are found, also confers unique release characteristics on peptides. These large vesicles are situated father from the socalled active zones [122], than are the small clear vesicles. Thus, they are farther from vesicle docking and release sites, and farther from calcium entry sites, rendering them less sensitive to low levels of electrical activity in the nerve terminal. The practical implication of this is that monoamines show a fairly graded relationship between firing rate in the presynaptic fiber and the amount of neurotransmitter released into the synapse, whereas neuropeptides are preferentially released under conditions of intense activation or burst firing [123]. Thus, whatever regulatory interactions the peptides may have with monoamines, they are likely to occur preferentially under conditions of intense activation of the neuron in which the two transmitters are colocalized. Unlike the monoamines, for which reuptake by specific transporters is so important to the regulation of synaptic effects, no such reuptake transporters have been identified for neuropeptides in the brain. Rather, termination of the synaptic action of peptides appears to depend upon bulk diffusion and extracellular enzymatic degradation by general peptidases, which can be located at some distance from the synapse [124]. Thus, not only is the synthesis and release of neuropeptides slower than that of monoamines, but the termination of action is slower as well. Moreover, the lack of transporter-mediated reuptake means that peptides are likely to engage in VT, as defined earlier in this

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chapter. This is supported, perhaps even more strongly than with monoamines, by frequent ‘‘mismatches’’ between the distribution of peptide-containing nerve terminals and appropriate postsynaptic receptors in the brain [reviewed in 125]. These characteristics have all led to the general view that neuropeptides function primarily as neuromodulators, altering effects exerted by other neurotransmitters on the activity of target brain circuits. The monoamines have themselves been described as serving neuromodulatory functions in the brain [126]. Thus, the corelease of neuropeptides and monoamines during stress, arousal, reward, etc., confers a much higher level of complexity on this modulatory process. With increasing neuronal activity, proportionately more monoaminergic transmitter is released, and its modulatory effect is presumably increased accordingly. However, at some threshold level of activity, the release of a neuropeptide cotransmitter may be progressively recruited. The peptide may itself have modulatory effects on the same target, or it may modify the presynaptic release or the postsynaptic effects of the monoamine with which it has been coreleased. B.

Potential Modes of Interaction Between Neuropeptides and Monoamines in the Brain

There are several ways that neuropeptides and monoamines may interact in the brain. They can be colocalized and coreleased onto common targets, whereby they may exert their respective postsynaptic modulatory effects independently, cooperatively, synergistically, or in opposition, depending on the physiological context and the complement of receptors expressed by the post-synaptic target neuron (see reviews [120,127] for general discussions of colocalized transmitter interactions). Alternatively, they may originate in different afferents that converge onto a common target. In this case, the possibilities for postsynaptic interaction are the same, though independent activation of the different afferent pathways allows for more context specificity in the modulatory interaction. Finally, peptidergic neurons may innervate monoaminergic neurons or terminals, thereby affecting the firing rate or release of the monoamine transmitter in its target region. The recent development of new tools and techniques, together with the novel application of established approaches, is just now providing both the means and the mindset for making substantive progress in understanding the functional interaction between brain neu-

ropeptides and monoamine transmitters [128]. As this understanding progresses, we are forging a richer understanding of the potential contribution of neuropeptides, and their interaction with monoamine transmitters, in the development or treatment of affective disorders, including depression and anxiety [see reviews 129–133]. C.

Substance P Antagonists as Novel Antidepressant/Anxiolytic Drugs

Substance P (SP) and its receptors are present in high concentrations in many forebrain limbic areas that have been implicated in affect and anxiety, including the hypothalamus, septal region, amygdala, and bed nucleus of the stria terminalis, as well as the periaqueductal gray, locus coeruleus, and raphe nuclei [134]. As for its relationship with NE and 5HT, the monoamines most implicated in the etiology and treatment of affective disorders, the substrates exist for many potential modes of interaction between these transmitters. Substance P terminals and receptors overlap those of both NE and 5HT. Likewise, SP fibers innervate serotonergic neurons of the dorsal raphe and noradrenergic neurons of the locus coeruleus. Finally, SP is colocalized with 5HT in ascending projections innervating the limbic forebrain in humans, other primates, and certain other species such as guinea pigs, though apparently not in rats or mice [135]. Surprisingly, whereas SP itself exerts primarily excitatory effects, blockade of SP receptors enhances both noradrenergic and serotonergic activity, most likely through a process of multisynaptic disinhibition [136]. Thus, SP antagonists may have an effect on monoaminergic transmission that is similar, at least acutely, to the effect of classical antidepressants that block monoamine reuptake. In preclinical behavioral assays, systemic or intraventricular administration of a SP antagonist attenuated anxietylike behaviors [137]. In animal models of anxiety- or depressive-like behavior, SP antagonist administration had effects similar to those of established antidepressant and antianxiety compounds [138]. These experiments on the affective response to SP antagonist administration culminated in a clinical study of the antidepressant and antianxiety efficacy of a centrally active SP antagonist in depressed patients [137]. The results of this study showed that the SP antagonist exerted both antidepressant and antianxiety effects, comparable to those of the SSRI paroxetine. This study showed great promise for the establishment of a novel antidepressant agent. Caution is necessary, though, until these clinical results


can be replicated. Nonetheless, should SP antagonists ultimately prove useful and efficacious against depression, their targeting a specific neuropeptide that interacts in a novel way with monoamines opens a new possibility for more widely effective, more efficient, or faster treatment of affective disorders.

D.

Interaction of Neuropeptide Y and Galanin with Norepinephrine in Modulating Behavioral Reactivity to Stress

Two neuropeptides are prominently colocalized with NE in the locus coeruleus (LC)—neuropeptide Y (NPY) and galanin (GAL). Galanin is expressed in nearly all noradrenergic neurons in the locus coeruleus [139]; thus it likely serves as a cotransmitter in the many limbic forebrain sites innervated by the LC. By contrast, NPY is found in a much smaller proportion of noradrenergic neurons in the LC, but is extensively colocalized with NE in medullary noradrenergic neurons [140]. The central nucleus of the amygdala and the bed nucleus of the stria terminalis, two closely related components of the extended amygdala, are targets of dense noradrenergic innervation, and both have been implicated in fear and anxiety [141]. In a recent series of experiments, we demonstrated that the stress-induced release of NE in these regions facilitates the expression of anxietylike behavioral responses to acute stress [142,143]. This is consistent with the role proposed for NE in modulating affective components of the stress response, including vigilance, arousal, and anxiety [144–146]. By contrast, administration of NPY into the central nucleus exerts distinct anxiolytic effects [147–148], while local administration of NPY antagonist drugs into LC target regions can be anxiogenic [149]. Much like the autoinhibitory effects of NE acting on presynaptic alpha-2 adrenergic autoreceptors, it has been shown that NPY also acts on presynaptic NPY autoreceptors, reducing the release of both NE and NPY [150,151]. In addition, NPY receptors located on noradrenergic cell bodies inhibit the activity of these cells [152,153]. Thus, corelease of NPY with NE invoked when high levels of activity have been stimulated in noradrenergic neurons, may attenuate the anxiogenic effects of NE released in the limbic forebrain, exerting direct anxiolytic effects postsynaptically while at the same time acting presynaptically to inhibit the further release of NE.

35

Even more than NPY, galanin is extensively coexpressed with NE in the LC [139]. Like NPY, NE neuronal activity is also inhibited by galanin [154,155], and galanin receptors located on NE terminals, which may function either as postsynaptic heteroreceptors or as inhibitory autoreceptors that limit the release of galanin from those terminals, also inhibit the release of NE [151]. In a recent series of studies, we have shown that galanin exerts an anxiety-buffering effect in the central amygdala, attenuating the anxiogenic effects of acute stress that we showed were attributable to NE [156]. In this case, however, the galaninmediated anxiolytic effect was elicited specifically when stress-induced activation of the noradrenergic system had been accentuated by prior administration of the autoreceptor antagonist yohimbine [158,159]. Along with this context specificity in the CeA related to the level of activation of the noradrenergic system, additional studies revealed that the functional interaction between NE and galanin in other regions of the limbic forebrain during stress were more complicated. In the bed nucleus, acute stress also induced NE release to facilitate anxietylike behavioral responses, but in this region, galanin facilitated these same behavioral responses [156,157], thus acting in the same direction as NE. Moreover, this facilitatory effect of galanin in the BST did not require prior treatment with yohimbine, as did the anxiolytic NE-buffering effects of galanin in the CeA. This is perhaps due to the fact that the major source of noradrenergic innervation in the bed nucleus arises from caudal medullary noradrenergic cell groups rather than the LC. Unlike the LC, these other noradrenergic cell groups do not show a high degree of galanin colocalization [139]. Thus, anxiolytic effects in the CeA may have originated from the corelease of galanin and NE from noradrenergic terminals, while anxiogenic effects in the bed nucleus may have originated from the activation of galanin-synthesizing neurons within the nucleus itself. These neurons may themselves be targets of noradrenergic innervation [160], which would explain why their activity was elicited specifically in response to stress. Thus, depending on the level of activation of the noradrenergic system, the specific physiological context in which that activation occurred, and the specific brain region involved, galanin could either act in concert with or oppose the stress-induced behavioral effects of NE. Likewise, any drug that mimicked or blocked the effects of galanin in the brain could have anxiogenic, anxiolytic, or mixed effects depending on the context and the circumstance by which the behavioral response had been elicited.

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Such complex interactions between transmitters of different classes may be subject to modification by a number of factors, including prior exposure to stress, chronic drug treatment, or genetic predisposition. Given the nature of this interaction, it is clear that drugs that affect monoaminergic neurotransmission could induce regulatory changes in both neuropeptide and monoaminergic functions, disrupting or resetting the delicate balance between these modulatory transmitters, either contributing to or interfering with their clinical effects. In summary, then, the past decade has witnessed tremendous increases in our understanding of the complexity of the process of monoaminergic transmission and its regulation. This increased understanding has not yet been translated into substantial therapeutic advances but clearly has the potential to do so.

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4 Developments in Psychiatric Neuroimaging ROBERTO B. SASSI Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

JAIR C. SOARES University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A.

I.

INTRODUCTION

cytoarchitectonics of different cortical areas, and the electrophysiological experiments on animal and later human cortex have set up the theory of cortical localization of mental functions as the mainstream scientific framework for brain investigation. Event-related potentials and single-neuron recording, 50 years ago, provided further experimental support for cortical localization. But it was only in the early 1970s, with the advent of X-ray computed axial tomography (CT), that it was possible to visualize the brain parenchyma in vivo [2]. Since then, the field of neuroimaging has undergone astonishing developments, and these new methods have rapidly become the most powerful tools to contribute to the understanding of neural organization and mechanisms underlying the mental phenomenon. The present chapter does not intend to be an exhaustive review of the various neuroimaging techniques currently in use. The specific findings of neuroimaging studies in various psychiatric disorders will be presented in other sections of this book. In this chapter, we have focused on the imaging methods of highest relevance for investigations of the neural basis of behavior, providing an overview of the physiological rationale underlying each method. Each available method

The scientific inquiry into the human mind seeks to decode how brain structure and activity result in the vast range of cognitive and emotional processes each of us experiences. It also attempts to identify the anatomical and functional correlates of abnormal mental activity, as represented in the neurological and psychiatric disorders. In this perspective, neuroimaging has effected a radical change on the study of the connection between brain and mind. Early investigations of brain function had to depend on indirect approaches. Lesion experiments on animals and postmortem clinicopathological correlations were the usual methods to investigate cerebral function, with obvious limitations. It was only at the end of the 18th century that the idea that different structures of the nervous system could perform distinct functions began to predominate. During the 19th century, the notion of functionally distinct cortical areas became well established, initially with the controversial works of Gall and the Phrenology school, and later with the discovery of the association of frontal cortex lesion and aphasia by Paul Broca [1]. Afterward, the conceptualization of the neuron, the discovery of specific 43

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assesses a specific feature of the intricate cerebral machinery, with its typical resolution on the spatial and temporal domains, and characteristic methodological limitations. For didactical reasons, we grouped the various techniques into three groups: structural neuroimaging, including the methods designed to explore brain anatomy and structure; chemical neuroimaging, for the methods dedicated to evaluate cell metabolites, neurotransmitters, and receptors in the brain; and functional neuroimaging, encompassing the techniques that evaluate cerebral perfusion, metabolism, and neuronal activation.

II.

STRUCTURAL NEUROIMAGING

Before the first CT studies, only highly invasive radiological approaches could be utilized to evaluate brain structural abnormalities in human subjects. Pneumoencephalography, which consisted of an Xray after air injection into the encephalon through a lumbar puncture, was utilized during the first half of the 20th century to examine the ventricular system. This technique has provided the first in vivo indications of enlarged ventricles and cortical atrophy on schizophrenic patients [3]. The advent of CT yielded a booming interest on structural neuroimaging of psychiatric disorders. Measurements of ventricular dilatation and cortical and cerebellar atrophy could then be performed in several psychiatric disorders [4]. But the evaluation of specific brain structures was still challenging, due to the limited contrast between gray and white matter observed in the CT images. Also, artifacts on the posterior fossa were relatively common owing to dense bone structures surrounding this region, which made brainstem and cerebellum more difficult to evaluate with CT scans. Most of the shortcomings in the earlier structural brain imaging studies were overcome with the advent of magnetic resonance imaging (MRI). The first commercially available MRI scans appeared in the early 1980s, but the phenomenon of nuclear magnetic resonance has been under study since the 1930s, through the landmark works of the American physicist Isaac Rabi [5], who received the Nobel Prize in physics in 1944. Structural MRI is one of the several brain-imaging technologies that explore the magnetic properties of the atomic nucleus. The MR method is based on the property of some atoms, whose nuclei present an odd number of either protons or neurons, to posses ‘‘spin’’—i.e., a net magnetic charge, like a small bar magnet. Only the atoms

that have this property will be ‘‘visible’’ through nuclear magnetic resonance (NMR). Some biologically relevant examples include 1H, 31P, and 23Na. Also, 7Li and 19F can be detected using NMR. Although present in negligible concentrations in the human brain, these atoms have important pharmacological relevance. On the other hand, atoms such as 12C and 16O are invisible to NMR. The atoms visible to NMR present a random distribution of the orientation of their nuclear magnetic moment when no external magnetic field is applied. However, when under an external magnetic field (B0), the nuclei of these atoms tend to align with this field, in the same (lower energy) or the opposite direction (higher energy) (see Fig. 1). This is the first step in the acquisition of MR images: to immerse the brain in a strong magnetic field, usually 0:5–3 Tesla. For comparison, 1 Tesla is 20,000 times the Earth’s magnetic field. Under the action of the magnetic field, the nuclei will spin and generate a movement of precession (see Fig. 2), whose frequency is characteristic for each

Figure 1 The nuclei of the individual atoms have a random distribution of their magnetic moment (A), with no net direction. When an external magnetic field B0 is applied (B), all spins align either against or on the same direction of the field.

Developments in Psychiatric Neuroimaging

Figure 2

Spinning and precession.

atomic nucleus, and is proportional to B0 strength. The next step is to expose these nuclei to a short-duration electromagnetic field (B1, orthogonal to B0), usually in the radio frequency range. This pulse excites the nuclei, disturbing the previous equilibrium state and inducing a transient phase coherence among the nuclei. This resonance can then be detected as a radio signal through a receiver coil. After turning off B1, all nuclei return to equilibrium, i.e., from high-energy (excited) to low-energy (equilibrium) state. This process is associated with exponential loss of energy to surrounding nuclei; the time required for the magnetization to return to 63% of its original value is called T1. Since the process is exponential, the spins are usually completely relaxed after 3–5 T1 times. When returning to equilibrium, spins with high and low energy can also exchange energy without loosing it to surrounding nuclei. This phenomenon is termed spin-spin relaxation, and it is related to exponential loss in the transverse magnetization. Similarly, the time required for 63% of transverse magnetization to subside is called T2. For pure water, T1 and T2 are practically the same, around 2–3 secs. However, for most biological materials T2 is far shorter than T1. By varying parameters such as the repetition time or echo time of the radio-frequency signal, it is possible to acquire T1- or T2-weighted images, and consequently obtain distinct information from the biological tissues under analysis. Of course, this is a very simplified explanation of the mechanisms underlying the NMR phenomenon. Nonetheless, it is important to keep in mind that NMR can provide a varied range of information in a noninvasive fashion, from hemodynamics to cell chemistry. In the case of MRI, the resonance of large amounts of 1H in the brain provides high-quality structural image, with spatial resolution of 6000 children identified 1.5% as having some sort of intellectual deficiency; of these, 32% were also identified as having a comorbid psychiatric disturbance [36]. The rates of comorbidity were significantly higher among those with intellectual deficiencies than among those who were not intellectually disabled [32% vs. 13.5%). Similarly, in an investigation of all children identified with MR in a Norwegian county, 37% were diagnosed with a comorbid psychiatric disorder, most commonly a pervasive developmental disorder [37]. Rates obtained were higher for those with severe MR than with those with mild MR: 42% and 33%, respectively. This pattern is consistent with the adult literature where those with more severe MR have significantly higher rates of comorbidity as well [e.g., 38]. The course of MR varies somewhat depending on the severity of the disorder, associated medical conditions, and environmental opportunities. As mentioned above, a diagnosis of MR necessitates that the disorder

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be present prior to 18 years of age. More severe retardation tends to be diagnosed at younger ages, especially when associated with a characteristic, syndromal presentation (e.g., trisomy 21) [4]. MR is only diagnosed when clear deficits in adaptive behavior, judged within a developmental context, are present (assessed using standardized tools such as the Vineland Adaptive Behavior Scales). Such deficits can include impaired self-help skills, communication, academics, safety, and work performance. Less severe cases are often not diagnosed until children are old enough to have noticeable difficulties in school. Academic deficits are among the most easily documented and measured, perhaps accounting for the relatively high prevalence of MR during the school years [39]. Indeed, in adulthood, many individuals previously diagnosed with MR may be able to function adaptively enough outside of the academic arena that they are no longer classifiable as MR. That is to say, MR is not necessarily a lifelong disorder; for those adults who can develop good adaptive life skills in various domains (e.g., self-care and work), their level of functioning precludes an MR diagnosis [4]. C.

Learning, Communication, and Motor Disorders

This group of disorders is characterized by academic, motor, or communication skills that are below developmental and intellectual expectations. Learning disorders are a fairly heterogeneous group of difficulties distinguished by academic achievement that is substantially below that expected for one’s age, intellect, and/ or schooling [4]. As a group they include: reading disorder, mathematics disorder, disorder of written expression, and learning disorder not otherwise specified. In the DSM-IV [4], it is specified that achievement deficits be measured by a standardized, individualized test and that they significantly interfere with academic performance or daily life. Developmental coordination disorder, the only motor skills disorder, is characterized by a significant impairment in motor coordination that causes functional impairment; the specific manifestations of this disorder vary with age and development. The communication disorders include expressive language disorder, mixed expressive-receptive language disorder, phonological disorder, stuttering, and communication disorder not otherwise specified (NOS). Those diagnosed with expressive language disorder have deficient expressive language skills, including small vocabul-

aries, few multiple-word combinations, and idiosyncratic word ordering. Mixed expressive-receptive disorder is characterized by delays in both expressive language and receptive language (i.e., comprehension). Phonological disorder is defined as the failure to develop typical speech sounds (e.g., ch, bu) at the expected age, and stuttering is characterized by speech dysfluency, syllable and sound repetition, and disrupted speech timing. The prevalence of these disorders is thought to be relatively high, but estimates vary according to sample characteristics and measures used. According to most estimates, 5–15% of school-age children have learning disabilities [40], and these are diagnosed more commonly in boys than in girls [41]. Approximately 6% of young children have developmental coordination disorder [42], and 5–10% of children are estimated to have communication disorders [4,43]. Among the communications disorders, expressive language delays have been found to be the most common. Stuttering, in particular, is much more common in boys than in girls [3:1]. Many children with learning disorders also have associated comorbidities. Conversely, 10–15% of those with conduct disorder, oppositional defiant disorder, ADHD, and depressive disorder also have learning disorders [4]. Although developmental coordination disorder has not been well researched yet, associated difficulties are thought to include other developmental delays, in particular language delays [4]. More research has focused on communication disorders, and at this point, it is fairly well established that young children with communication difficulties are at increased risk for continued language problems, learning disorders, and psychiatric difficulties [e.g., 44–46]. Learning disorders as a group are thought to have a similar course over time. They are most commonly diagnosed in the elementary school years when academic challenges begin to go unmet. The school dropout rate for children with learning disabilities is 40%, significantly higher than the rate for those without such disorders [4]. Higher IQ is associated with better outcome for those with learning disorders. Depending on severity, learning disabilities may persist until adulthood and cause impaired occupational functioning [47]. Among the communication disorders, the course is more variable. Age of identification is predictive of language disorder severity, with later-identified children typically having more severe and persistent

Classification of Psychiatric Disorders in Youths

delays. Phonological difficulties that are not severe are the most likely to resolve. Among those with expressive language difficulties, 50% will ‘‘recover’’ and the rest will continue to manifest significant language difficulties [e.g., 48–50]. We know very little about the course of developmental coordination disorder; future research should examine the longitudinal course of significant motor skills deficits. D.

Pervasive Developmental Disorders

The pervasive developmental disorders (PDDs) are characterized by severe impairment in several crucial areas of development: communication, social interaction skills, and/or the presence of stereotyped behavior, play, or interests. These disorders are often diagnosed in the first years of life and are typified by behaviors and skills that are grossly developmentally delayed and/or inappropriate. PDDs as defined by the DSM-IV include autistic disorder (autism), Rett’s disorder, childhood disintegrative disorder, Asperger’s disorder, and pervasive developmental disorder not otherwise specified (PDD NOS) [4]. Autism’s essential features include abnormal or impaired social interaction and communication and a severely restricted inventory of interests and activities. Delays or abnormalities must be present before the age of 3 in at least one of the following areas: social interaction, language in social communications, or symbolic/imaginative play. Most children with autism are also mentally retarded [4]. Rett’s disorder, which has only been seen in girls, is distinguished by a period of typical functioning followed by the development of multiple specific deficits. For these children, head growth decelerates between 5 and 48 months, previously acquired hands skills are lost between 5 and 30 months, and subsequently, stereotyped hand movements similar to hand-wringing or hand-washing appear. In addition, interest in social interaction diminishes, expressive and receptive language are impaired, psychomotor retardation develops, and poorly coordinated gait or trunk movements appear. Childhood disintegrative disorder (CDD) is similar to Rett’s disorder in that severe regression occurs after a period of typical development, but normal development must have lasted at least 2 years. A diagnosis of CDD requires that after the age of 2 (but before 10) there is a clinically significant loss of previously acquired skills in at least two of the following areas: expressive and receptive language, social skills or adaptive behavior, bowel or bladder control, and/or play or

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motor skills. Children with CDD exhibit social and communication deficits that are similar to those observed in children with autism. Asperger’s disorder like autism, is characterized by persistent and severe impairments in social interaction and restricted, repetitive behavior, interests, and activities. However, with Asperger’s disorder there are no characteristic language delays or deficits, nor are there cognitive impairments or deficits in age-appropriate adaptive behavior. PDD NOS is a diagnosis for those children who exhibit many, but not all, of the specific features required for a diagnosis of a specific PDD. In terms of prevalence, PDDs are quite rare. Epidemiological studies suggest a rates of autism to be two to five cases per 10,000 individuals [4]. Data specific to prevalence for the other PDDs are very limited. Rett’s disorder has only been discussed in limited case studies and only seen in females. Childhood disintegrative disorder (CDD) is thought to be very rare (much less common than autism) and more common in males than females. Asperger’s disorder is also thought to be very rare, and also appears to be more common in males than in females. PDDs are typically lifelong disorders with characteristic developmental shifts in symptom patterns. However, with early, intensive behavioral treatment some children with autism, Asperger’s, or PDD NOS may benefit significantly enough that they lose their PDD diagnosis [51]. Unfortunately, this is not the case for most children; this sort of treatment is not widely available, and is variable in its success depending on factors such as severity of initial symptoms, comorbid mental retardation, and other individual differences that we do not yet well understand. Children with autism typically develop better functioning with age and often show some improvements in language and social interaction. For children with Rett’s disorder there are characteristic developmental changes: between 1 and 3 years symptoms are very similar to those of autism, between 2 and 10 years of age, social interest increases somewhat, and after age 10, there are worsening motor problems [52]. For children with CDD, the long-term outcome is typically not very good, with little improvement in specific skills over time. Across the PDDs the prognosis is typically best for those with Asperger’s, as they have communicative and cognitive skills that enable them to function well despite substantial social skill deficits. In adulthood, Asperger’s (or mild autism) might be confused with schizoid or schizotypal personality disorders because of the overlapping social deficits [4].

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III.

PSYCHIATRIC DISORDERS USUALLY DIAGNOSED IN ADULTHOOD

A.

Mood Disorders

1.

Major Depressive Disorder (MDD) and Dysthymia

Although depression was not officially recognized as a disorder of childhood until 1980, at this point it is relatively well established that the clinical presentation of depressive disorders in children is similar to that seen in adults [4,53]. The DSM-IV uses adult criteria to diagnose depressive disorders in children, but places a greater emphasis on the developmental course of the disorder than DSM-III or DSM-III-R. Documented developmental differences in the presentation of MDD include increased suicide attempts and impairment in functioning with age, and decreased somatic complaints, phobias, and behavioral problems, which occur more in childhood than adulthood [e.g., 54]. In the DSM-IV [4], a diagnosis of MDD is made in individuals who demonstrate at least one major depressive episode (MDE) without previous experience of a manic, mixed, or hypomanic episode. Two weeks of a depressed mood or the loss of interest or pleasure in nearly all activities characterizes an MDE. In children, irritability rather than sadness can be the predominant emotion. In addition to a mood disturbance, at least four other symptoms from the following list must be present: changes in sleep, appetite/weight, or psychomotor activity; reduced energy; feelings of worthlessness or guilt; difficulty thinking concentrating or making decisions; and thoughts of death or suicidal ideation, intent, or plan. To be considered symptoms of MDD, these difficulties must represent a clear change from previous functioning. Dysthymia is a more chronic depressive disorder characterized by similar symptoms of a lessor severity and longer duration (at least 2 years). In the following sections, we will focus primarily on MDD, as the majority of research data pertains to this diagnosis rather than dysthymia. Depressive disorders in youths are not rare: population studies estimate that between 0.04% and 2.5% of children and 0.04% and 8.3% of adolescents have MDD [54] and 3% have dysthymia. In a largescale study of adolescent psychopathology, MDD had the highest lifetime prevalence rate (20%) of all disorders surveyed, and a point prevalence rate of 2.92 [55]. These findings are consistent with other studies of adolescent depression, and with lifetime rates of MDD

found among adults [e.g., 56,57]. In childhood, rates of depression are similar for girls and boys; in adolescence, however, the female-to-male ratio jumps to 2:1, which is comparable with ratios found in adult depression [e.g., 3,58). MDD in youths is often comorbid with other psychiatric disorders. Rates of comorbidity in youths are comparable with, or slightly higher than, rates seen among adults with depression [59]. Epidemiological studies have shown that 40–70% of depressed children and adolescents have a comorbid psychiatric disorder, and that approximately 20–50% have more than one comorbid condition [e.g., 60–62). Dysthymia cooccurs with depression in 30% of youths and adults [59]. Diagnoses that are most commonly comorbid with depression in youths include anxiety disorders (30– 80%), disruptive behavior disorders (10–80%), and substance abuse (20–30%) [63]. Indeed, anxiety disorders so commonly co-occur with depression that some have argued that they are manifestation of the same, not distinct disorders [64]. Others have cogently argued that although anxiety and depression do share some overlapping symptoms, the absence of positive affect is characteristic of depression, not anxiety [see 65]. Depression in youths is disabling and chronic, though perhaps somewhat less so than among adults. In a large, randomly selected sample of high school students, those who were identified as depressed were likely to have moderate to severe depression (88.6%) and to be judged in need of treatment (93.2%) [55]. The average length of a depressive episode is 9 months in youths [66], while on average 12 months for adults. Relapse rates are disturbingly high for children and adolescents with depression; 70% will relapse with in 5 years [55,59). Moreover, follow-up studies of depressed youths indicate that 20–40% will go on to develop bipolar disorder within 5 years of the onset of their depression [e.g., 67,68). 2.

Bipolar Disorders

Though not without controversy, in recent years it has become more recognized that children can manifest symptomatology that is consistent with a diagnosis of mania, or bipolar disorder (BPD). Indeed, several exhaustive reviews of the literature have supported the validity of this diagnosis in youths [69–71]. According to DSM-IV, the occurrence of one or more manic or mixed episodes determines BPD. A manic episode is characterized by a distinct period of an abnormally elevated, irritable, or expansive mood that lasts at least a week. In addition to this mood


disturbance, three symptoms from the following list must be present: inflated self-esteem or grandiosity, decreased need for sleep, pressured speech, increased activity or psychomotor agitation, distractibility, flight of ideas or racing thoughts, or involvement in pleasurable activities with a high potential for negative consequences (e.g., buying sprees or indiscriminant sexual encounters). A mixed episode is defined as a period of at least 1 week during which criteria for both a manic and depressed episode are met. Often there is also a history of depressive episodes in these individuals. As classified in DSM-IV, bipolar disorders include: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified. These disorders are differentiated based on the duration of symptoms and presence or absence of a full-blown manic or mixed episode. Empirical work suggests that while bipolar disorder is difficult to diagnose in children, in part because it differs from adult mania in presentation, prevalence rates are higher than previously thought in youths, particularly among inpatients. However, few welldone studies of the prevalence of BPD exist. In one recent study of > 250 consecutively referred preadolescent children, Wozniak and colleagues [72] found that a surprising 16% met diagnostic criteria (DSM-III-R) for mania. In light of such high rates of mania documented by some researchers in specialty mood clinics and low rates seen in epidemiological studies (lifetime prevalence rate of 0.58) [73], the ‘‘real’’ prevalence of BPD in youths and how to best diagnose the disorder is still a hotly debated topic [see, 74–76]. To resolve this debate, more well-designed research needs to be conducted in the area of diagnosis and prevalence of pediatric bipolarity. Comorbidity with childhood mania is the rule rather than the exception. However, the exact nature of the relationship between childhood mania and other disorders, in particular, attention deficit hyperactivity disorder (ADHD), is still being debated [77]. Indeed, symptom overlap with ADHD (e.g., impulsivity, concentration problems) is one of the most challenging aspects of accurately assessing and diagnosing bipolar disorder in children. Studies have shown rates of ADHD ranging from 60% to up to 90% among children with mania [72,78,79]. Studies involving children with bipolar disorder have also documented a high degree of overlap with conduct disorder [72,80,81]. For example, Kovacs and Pollack [81] reported that among children with BPD, an astonishing 69% also had conduct disorder. A recent epidemiological study also documented high rates of cooccurrence between

61

these disorders [73]. Such complicating comorbidities, as is typical with other disorders, predict a worse course for these youths [e.g., 81]. Age of onset for a first manic episode is typically during late adolescence, but, as alluded to above, some cases start in early adolescence or childhood [4]. The course and presentation of pediatric mania is often atypical when compared to adult mania. Adult and adolescent mania is typically episodic with an acute onset, and is characterized by the presence of euphoric mood. With children, on the other hand, some have asserted that mania during childhood is characterized by a chronic, mixed mood state [72,76] and that the mood disturbance often manifests as irritability rather than euphoria [82,83]. In a recent review of the empirical literature related to pediatric bipolar disorder, it was concluded that, ‘‘pre-pubertal BPD is a nonepisodic, chronic, rapid cycling, mixed manic state.’’ [70]. This suggests that BPD in youths is indeed atypical when compared to adult BPD, but that it is predictably atypical. B.

Anxiety Disorders

Excessive fear, distress, and/or avoidance of particular situations or objects, thoughts/memories, or physical sensations characterize anxiety disorders. In the DSMIII-R, three anxiety disorders were listed in the child section: overanxious disorder (OAD), separation anxiety disorder, and avoidant anxiety disorder. In DSMIV, questions regarding the validity of these diagnostic categories led to a reorganization so that only separation anxiety disorder currently remains in the childhood disorders section (in the category ‘‘other disorders of childhood’’). In addition, the criteria for social phobia and generalized anxiety disorder were modified so that they incorporated the symptoms of children who would have been previously diagnosed with avoidant or overanxious disorder. As such, according to DSM-IV, the general anxiety disorders include: panic disorder with and without agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder (ASD), generalized anxiety disorder (GAD), anxiety disorder due to a general medical condition, substance-induced anxiety disorder, and anxiety disorder NOS. After describing each disorder, we will focus on those that are most relevant to children and adolescents and for which the most research exists: social phobia (previously avoidant disorder in children), generalized anxiety disorder (formerly overanxious disorder in children), and

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separation anxiety disorder. Although, as previously mentioned, separation anxiety disorder is not formally classified with the anxiety disorders, we will discuss it in this section because of the considerable theoretical and clinical overlap it shares with the anxiety disorders as listed in DSM-IV. In terms of the features that are specific to each disorder, panic disorder with and without agoraphobia is characterized by panic attacks (sudden onset of intense fear and physical symptoms such as racing heart, shortness of breath, feeling dizzy or faint) about which there is persistent concern. Avoidance of or anxiety about places from which escape would be difficult or embarrassing in the event of panic characterizes agoraphobia. Specific phobias are defined by significant anxiety related to a specific object (e.g., insects or needles) or situation (e.g., elevators or flying) which often leads to avoidance. Social phobia is characterized by anxiety and resultant avoidance related to social or performance situations. OCD is defined by the presence of intrusive, upsetting thoughts (obsessions) and compulsions (repetitive or ritualized behaviors or mental acts) designed to reduce anxiety. PTSD is characterized by reexperiencing (e.g., in nightmares or intrusive thoughts) a traumatic event accompanied by avoidance of trauma-related stimuli and increased arousal (e.g., sleep and concentration difficulties). Acute stress disorder is defined by symptoms that are similar to those of PTSD (with an emphasis on dissociative symptoms) that occur very soon after the traumatic event. GAD is typified by persistent worry and anxiety that is difficult to control that lasts at least 6 months. Separation anxiety disorder is characterized by developmentally inappropriate anxiety (lasting at least 4 weeks) regarding separation from the home or people to whom the child is attached. Anxiety disorders are among the most commonly diagnosed psychiatric disorders in both children and adults [84]. Epidemiological studies show rates of anxiety disorders ranging from 5.7% to 17.7% in children and adolescents [e.g., 57,61,85,86]. Additionally, these studies show a trend for rates of anxiety disorders to increase with age. Looking at specific disorders, epidemiological studies show prevalence rates as follows: social phobia, 0.06%–7.9%; GAD/OAD, 2.9–10.8%; and separation anxiety disorder, 2.0–4.7%. Though there is a good deal of variability in these estimates, GAD appears to be most common in youths, followed by social phobia, which is also very common. Anxiety disorders in children (specifically social phobia, GAD, and separation anxiety disorder) are often comorbid with other psychiatric disorders.

Feeny and Findling

Indeed, for most children with significant anxiety, comorbidity is the rule rather than the exception. As mentioned previously, depression and anxiety in particular very commonly cooccur; anxiety disorders are three to four times as likely to occur in youths with depressive disorders as in youths without such disorders [e.g., 85,86]. Anxiety disorders are also often comorbid with disruptive behavior disorders. Several studies have found them to be two to three times more common among children with ODD and CD [e.g., 85–87]. Data regarding the course of anxiety disorders in youths are scarce. In a recent study, children diagnosed with an anxiety disorder were followed up 3–4 years later [88]. Eighty percent of the children had recovered from the originally diagnosed disorder, and only a small percentage (8%) experienced a relapse of their disorder. However, these children were likely to develop new disorders. These results are consistent with findings from a 5-year follow-up study of children and adolescents initially diagnosed with anxiety disorders; at follow-up, most of the children had either recovered from the initial diagnosis or had developed a different disorder—most typically, a different anxiety disorder [28]. To date, two studies have found that continuity of anxiety disorders is more common among girls than among boys [85,89]. C.

Psychotic Disorders

Psychotic disorders are characterized by the presence of hallucinations or delusions, and grossly disorganized behavior or speech. As with affective disorders, the assumption in DSM-IV is that adult criteria for psychotic disorders should be extended downward to apply to children. However, it has been suggested that the lack of specific attention to developmental issues and the focus in DSM-IV on disorganized speech may lead to errors of overdiagnosis in children [90,91]. In DSM-IV, the psychotic disorders include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a medical condition, substance-induced psychotic disorder, and psychotic disorder NOS. The psychotic syndromes are differentiated based on duration and pattern of presenting symptoms. Schizophrenia is characterized by the presence of at least two of the following symptoms present for at least 1 month: hallucinations, delusions, disorganized speech or behavior, and negative symptoms (e.g., anhedonia, avolition). The disturbance must last at least 6


months overall and cause significant clinical impairment. In terms of symptoms, schizophreniform disorder is the same as schizophrenia, but does not last as long (1–6 months) and need not cause functional impairment. Schizoaffective disorder is typified by a mood disturbance that occurs simultaneously with the positive symptoms of schizophrenia, and is preceded by at least 2 weeks of delusions or hallucinations without concomitant mood disturbance. Delusional disorder is characterized by at least 1 month of delusions that are not bizarre in content. Shared psychotic disorder is a disturbance that develops in one person owing to the influence of another person with a similar delusion. Psychotic disorders in children are considered rare, but few studies have been conducted in this area, and most focus exclusively on schizophrenia. The prevalence of schizophrenia in very young children (12 years old and younger) has been estimated at rates of 1.6–1.9 per 100,000 [92,93]. Among adolescents, rates of schizophrenia are estimated at 0.23% in the general population, 1% among outpatients [94], and 5% among inpatients [95]. Among adults, estimates of schizophrenia prevalence rates range from 0.2% to 2% [4]. Schizophrenia with onset at a very young age is about twice as likely in males as in females [96]. In youths with psychotic disorders it is thought that comorbidity is fairly common, particularly with disorders of behavior, attention, and motor skills. However, little empirical work exists in this area. Histories that are suggestive of premorbid pervasive developmental disorders are common [97,98], as are comorbid behavior and attention problems [99]. Results of one study indicated that among youths diagnosed with schizophrenia, 13% had a history suggesting preexisting attention or motor skills deficits [100]. Psychotic disorders are typically first diagnosed in the late teens through early 30s, with onset before the teen years being uncommon [4]. Age of onset has been found to be prognostic: children with very early onset schizophrenia tend to have a very poor prognosis [91,101]. In general, studies of adult schizophrenia show a variable course of the disorder, with some individuals remaining chronically ill, and others experiencing periods of remission and exacerbation [4]. There are some common developmental variations in symptoms: in children, visual hallucinations may be more common than in adults, and hallucinations/delusions may be less elaborate. Delusions are only seen in 50% of cases of childhood schizophrenia [102,103]. Additionally, disorganized speech is common to several disorders typically seen in children (e.g., pervasive

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developmental disorders, communication disorders), so this symptom is less indicative of a psychotic disorder in this group then when seen in adults. Acute onset of the disorder is more likely the older the age of the child [96].

IV.

CONCLUSIONS

This chapter has reviewed many of the major diagnostic classifications as listed in DSM-IV and highlighted diagnostic issues that pertain to children and adolescents. Overall, psychiatric disorders are common in youths and typically increase in prevalence with age. Comorbidity is also quite common in children and adolescents, and is associated with poor outcome. The course of the various psychiatric disorders is variable, but on average, early age of identification predicts a more chronic course, and as such, may serve as a proxy for severity. In terms of developmental sensitivity, in the DSM-IV, there are very few diagnostic criteria differences across the life cycle, but the presentation of symptoms is modified and mediated by developmental influences. As such, we have attempted to outline characteristic developmental symptom patterns for each disorder. As we noted at the start of this chapter, the classification and diagnosis of psychiatric disorders in children and adolescents have undergone substantial change and progress in the past 20 or so years. We, as a field, have begun to accumulate empirical work that to varying degrees support or make us question our diagnostic categories as they now stand. More research that examines the presentation, course, and outcome of various psychiatric disorders in youth is needed, particularly in the area of bipolar disorders, pervasive developmental disorders, and psychotic disorders.

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lation-based study of 46 cases followed through puberty. J Autism Dev Disord 17:273–287, 1987. Evans J, Acton WP. A psychiatric service for the disturbed adolescent. Br J Psychiatry 120:429–432, 1972. Steinberg D, Galhenage DP, Robinson SC. Two years’ referrals to a regional adolescent unit: some implications for psychiatric services. Soc Sci Med Part E Med Psychol 15:113–122, 1981. Werry JS. Child and adolescent (early onset) schizophrenia: a review in light of DSM-III-R. J Autism Dev Disord 22:601–624, 1992. Asarnow JR, Ben-Meir S. Chidren with schizophrenia spectrum and depressive disorders: a comparative study of premorbid adjustment, onset pattern and severity of impairment. J Child Psychol Psychiatry Allied Disciplines 29:477–488, 1988. Watkins JM, Asarnow RF, Tanguay PE. Symptom development in childhood onset schizophrenia. J Child Psychol Psychiatry 29:865–878, 1988.

67 99. Asarnow JR. Annotation: childhood-onset schizophrenia. J Child Psychol Psychiatry 35:1345–1371, 1994. 100. Hellgren L, Gillberg IC, Bagenholm A, Gillberg C. Children with deficits in attention, motor control and perception (DAMP) almost grown up: psychiatric and personality disorders at age 16 years. J Child Psychol Psychiatry 35:1255–1271, 1994. 101. Asarnow RF, Asarnow JR, Strandburg R. Schizophrenia: a developmental perspective. In: D Cicchetti, ed. Rochester Symposium on Developmental Psychology. New York: Cambridge University Press, 1989: 189–220. 102. Green WH, Campbell M, Hardesty AS, Grega DM, Padron-Gaylor M, Shell J, Erlenmeyer-Kimling L. A comparison of schizophrenic and autistic children. J Am Acad Child Adolesc Psychiatry 4:399–409, 1984. 103. Russell AT, Bott L, Sammons C. The phenomenology of schizophrenia occurring in childhood. J Am Acad Child Adolesc Psychiatry 28:399–407, 1989.

6 Classification of Schizophrenia and Related Psychotic Disorders TONMOY SHARMA and PRIYA BAJAJ Clinical Neuroscience Research Centre, Stonehouse Hospital, Dartford, Kent, England

I.

INTRODUCTION

However, a clear definition and accurate classification of a disorder are the first steps in any systematic attempt to understand the pathophysiology and etiology of the disorder. The revolution in biological psychiatry can, in part, be attributed to advances in nosology [3].

The need for a classification of mental disorders has been clear throughout the history of medicine, but there has been little agreement on which disorders should be included and the optimal method for their organization. The many nomenclatures that have been developed during the past two millennia have differed in their relative emphasis on phenomenology, etiology, and course as defining features. Some systems have included only a handful of diagnostic categories whereas others have included thousands. Moreover, the various systems for categorizing mental disorders have differed with respect to whether their principal objective was for use in clinical, research, or statistical settings [1]. Attitudes to psychiatric classification have also undergone a revolution in the last generation. In the 1950s and 1960s, psychiatric diagnoses did not occupy center stage in clinical practice. Their reliability was known to be low; it was known that key diagnostic terms like schizophrenia had different meanings in different parts of the world. On the other extreme, there were some who argued that diagnostic categories should be abandoned and they believed that all patients require the same treatment—the ‘‘moral regime’’ of the asylum for Neumann and Prichard in the 19th century, and psychotherapy of Rogers and Menninger in the 20th century [2].

II.

EVOLUTION OF CLASSIFICATION SYSTEMS

Ethnographic studies have demonstrated that schizophrenia is present in all existing cultures, from the preliterate to the most advanced. Psychotic symptomatology and schizophrenialike syndromes were clearly present in ancient civilizations. However, more accurate and systematized classifications of psychological disturbances began to evolve only in the 1st and 2nd centuries AD. The physician Aretaeus of Cappadocia defined a state of melancholy, which included depression as well as schizophrenialike withdrawal. In the 1700s there was an increasing emphasis on detailed and accurate descriptions of abnormal mental processes and states. Philippe Pinel, a French physician, considered to be one of the founders of modern psychiatry, argued for an objective medicophilosophical approach to psychological disorders. Jean Etienne Esquirol, a student of Pinel, defined hallucinations 69

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and identified ‘‘monomania’’, a clinical syndrome similar to modern descriptions of paranoid schizophrenia. Attempts were also being made to divide the clinical landscape into syndromes sharing both clinical features and course. Benedict Augustin Morel was the first to use the term dementia praecox (dementia precoce). Other symptom complexes identified included delusional states (France) and paranoid states, as described by the German physician Vogel in 1764. Johann Christian Augusts Heinroth outlined 48 distinct disease entities and thereby epitomized the general inability to develop straightforward, reliable criteria. These theoretical controversies and confusion led Heinrich Neumann to reject all systems of classifications and suggest that it was necessary to ‘‘throw overboard the whole business of classifications’’ to bring order to the field. He suggested that ‘‘there is but one type of mental disturbance, and we call it insanity.’’ Nevertheless, despite the intermittent sense of frustration and confusion, classificatory efforts continued unabated [4].

III.

20TH CENTURY CLASSIFICATORY SCHEMAS OF KRAEPLIN AND BLEULER

It was in the latter part of the 19th century that Emil Kraeplin was able to integrate the diverse clinical phenomena into a coherent and far-reaching classificatory system. His synthetic formulation included the identification of ‘‘dementia praecox’’ to refer to the clinical entity we now call schizophrenia. ‘‘Dementia’’ referred to the progressive deteriorating course of both emotional and cognitive processes; ‘‘praecox’’ indicated the early age of onset in previously healthy individuals. Thus, fundamental to the diagnosis were both cross-sectional and longitudinal components. Importantly, he differentiated the generally deteriorating course of dementia praecox from the more episodic and customarily better outcome seen in manic-depressive disorder. He furthermore divided it into four subtypes: paranoid, hebephrenic, catatonic, and simple. Eugen Bleuler used Kraeplin’s systematic classification of psychoses and a theoretical model of etiological processes to reformulate dementia praecox as ‘‘schizophrenia,’’ derived from the Greek words for ‘‘split’’ and ‘‘mind’’ [5]. He asserted that there were four cardinal features almost invariably present in schizophrenia patients, the ‘‘four A’s’’: blunted affect, loosening of association, ambivalence, and autism.

He viewed schizophrenia as being composed of several different entities rather than a single disease state as Kraeplin conceptualized. Other symptoms of schizophrenia include delusions, catatonia, negativism, and stupor. These were thought to be ‘‘secondary’’ symptoms and to present in reaction to the individual’s intentions, drives, psychotic state, and environmental conditions. Bleuler noted that these secondary symptoms were present in schizophrenia as well as in other disorders. He also asserted that despite the secondary nature of these symptoms, they formed the basis of Kraeplin’s classificatory system. It is noteworthy that two psychotic features emphasised by today’s Diagnostic and Statistical Manual (DSM)—hallucinations and delusions—were not crucial for Bleuler’s diagnosis of schizophrenia. His emphasis on theory as a means for determining the diagnostic relevance of signs and symptoms contrasted sharply with Kraeplin’s reliance on empirical observations. Bleuler’s approach was also notable for three other reasons. First, his reformulation of dementia praecox as ‘‘the group of schizophrenia’’ foreshadowed the contemporary view that schizophrenia is a heterogeneous group of disorders with similar clinical presentations. Second, he included defects in affect as a core feature of the disorder. Third, his view of schizophrenia allowed for the possibility of recovery. Other clinicians also advocated a hierarchical system of symptom classification like Bleuler. In 1959, Kurt Schneider termed the core features ‘‘first-rank symptoms’’. These symptoms included: hearing one’s thoughts spoken aloud; auditory hallucinations commenting on one’s behavior; thought withdrawal, insertion, and broadcasting; and somatic hallucinations, or the experience of one’s thoughts as being controlled or influenced from the outside. Manifestations of first-rank symptoms in the absence of organic disease, persistent affective disorder, or drug intoxication, were sufficient for a diagnosis of schizophrenia. Second-rank symptoms included other forms of hallucinations, depressive or euphoric mood changes, emotional blunting, perplexity, and sudden delusional ideas. When first-rank symptoms were absent, schizophrenia might still be diagnosed if a sufficient number of second-rank symptoms were present. Although the schneiderian criteria have been criticized as being nonspecific, they have been incorporated into clinical diagnostic tools such as the Research Diagnostic Criteria (RDC) and Diagnostic and Statistical Manual of Mental Disorders (DSM) classificatory systems [4].

Classification of Schizophrenia

IV.

CLASSIFICATION ON THE BASIS OF SYMPTOMS

It is widely believed that classification of diseases should, wherever possible, be based on etiology. Unfortunately, the same principle does not apply to psychiatric disorders, since the etiology of most is still unknown or all that is known for certain is that both genetic and environmental factors are involved. For this reason, most contemporary classifications of psychiatric disorders are largely based on clinical symptoms. This state of affairs has a number of important consequences. Decisions about the presence or absence of symptoms are relatively unreliable; and because few psychiatric conditions have pathognomonic symptoms, most conditions have to be defined by the presence of some or most of a group of symptoms rather than the presence of one key symptom. In the jargon of nosology, they are polythetic rather than monothetic. This invites ambiguity and lowers reliability still further, unless operational definitions are adopted. Another important consequence is that most psychiatric diagnoses can never be confirmed or refuted, for there is no external criterion to appeal to. For these and other reasons it has often been suggested that symptoms should be ignored and a new classification developed on an entirely different basis. Psychoanalysts have frequently advocated a classification based on psychodynamic defense mechanisms and stages of libidinal development. In the 1950s, clinical psychologists extolled the advantages of a classification based on scores on batteries of cognitive and projective tests. More recently, learning theorists have argued that we should classify patients on the basis of a comprehensive analysis of their total behavioral repertoire. In principle, all of these approaches are perfectly legitimate. In practice, however, none of them has ever progressed beyond the stage of advocacy. Two other alternatives proposed are (1) classification on the basis of treatment response, and (2) classification on the basis of the course or outcome of the illness. Unfortunately, neither is feasible since there are few if any specific treatments available in psychiatry, and most disorders can have a wide range of outcomes. It is sometimes assumed that Kraeplin’s classification or at least his distinction between dementia praecox and manic-depressive insanity, was based on long term outcome, but this is a misunderstanding. Kraeplin certainly emphasized the difference in the lifetime course of his two great rubrics, and perhaps subdivided the functional psychosis in the way he did to maximize the difference in outcome between them. But he used out-

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come as a validating criterion (i.e., as evidence that his two rubrics were fundamentally different disorders), not as a defining characteristic. Thus, when patients with dementia praecox recovered completely, he would automatically have changed their diagnosis [2]. As things stand, we have no choice but to use a classification, which is largely based on symptoms, despite its shortcomings and imperfections, because no practical alternative has yet been developed. Kraeplin’s and Bleuler’s observations evolved into today’s psychiatric classification: the International Classification of Diseases (ICD) and the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM) [5].

V.

DIAGNOSTIC CRITERIA: DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS (DSM)

In this chapter we shall discuss the evolution of the different classification systems over time using the diagnosis of schizophrenia as an example. We will first address the reliability and validity of DSM and then address how ICD later synchronized with the DSM system.

A.

DSM-I

In 1949, the American Psychiatric Association in collaboration with the New York Academy of Medicine began an initiative to standardize the diagnostic system throughout the United States. The result was the Diagnostic and Statistical Manual of Mental Disorders-1 (DSM-I), published in 1952. It was influenced by the theories of Adolf Meyer, and psychiatric disorders were viewed as reactions of the personality to psychological, social, and biological factors [4]. In addition to its use of Kraeplin’s and Bleuler’s views on the signs and symptoms of schizophrenia, the first DSM defined schizophrenia in a way that at least implied environmental causes. For example, all schizophrenic (and other psychiatric) diagnoses included the term ‘‘reaction’’ (as in ‘‘schizophrenic reaction, simple type’’). Moreover, definitions were vague and did not discuss differential diagnosis. Such imprecise definitions allowed clinicians much discretion in making a diagnosis. As a result, in the United States, schizophrenia became the diagnosis of choice for psychotic conditions that lacked a clear ‘‘organic aetiology’’ [5].

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B.

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DSM-II

The manual had gone through several major revisions. The DSM-II was published in 1968, but did not differ significantly from its predecessors [4]. It dropped the term ‘‘reaction’’ from its diagnoses and added some discussion of differential diagnoses, but continued the DSM-I tradition of brief, vague descriptions of schizophrenia disorders, without specific operational criteria. Interestingly, both of these early systems viewed psychosis as the key feature of the disorder. DSM-II did not contain a category (‘‘schizophrenia latent type’’) to describe people with ‘‘clear symptoms of schizophrenia but no history of a psychotic schizophrenia episode.’’ This category was intended to encompass individuals with a variety of conditions (e.g., ‘‘incipient,’’ ‘‘prepsychotic,’’ and ‘‘borderline schizophrenia,’’ as well as ‘‘schizophrenic reaction, chronic undifferentiated type,’’ from DSM-I). This did not reflect an important attempt to clarify the role of psychosis in schizophrenia illness [5]. Thus, the diagnosis, with schizophrenia as an example, lacked validity and was too vague in its description. C.

DSM-III

DSM-III was radically different from any previous classification. Published in 1980, it brought about a sea change in psychiatric classification, spearheaded by the ‘‘neo-Kraeplinian’’ movement in the 1960s and 1970s and by investigators in psychiatry and clinical psychology who emphasized the importance of empirical, psychometric validation of psychiatric syndromes. Its innovations were a response to the evidence that had accumulated over the previous 20 years that psychiatric diagnoses were generally unreliable, that there were systematic differences in the usage of key terms like ‘‘schizophrenia’’ between the United States and other parts of the world [2]. It contained several innovations, including field tests of diagnostic reliability, specific inclusion and exclusion criteria for diagnoses, multiaxial diagnosis, and a focus on the description of syndromes and course of disorders rather than inferences about their etiology. This last point made psychiatric diagnosis more explicitly consistent with the diagnosis of other medical disorders of unknown etiology. The traditional distinction between neuroses and psychoses was abandoned to allow all affective disorders to be brought together. Also, in the absence of data to support diagnostic hierarchies, the system encourages comorbidity. DSM-III’s use of clearly

defined criteria limited the clinician’s discretion and narrowed the construct of schizophrenia. This development improved the clinical homogeneity of the disorder, better delimited it from other serious mental illnesses, and raised diagnostic reliability to respectable levels. Nevertheless, DSM-III retained the view that psychosis was fundamental to the definition of schizophrenia. Fewer patients now had the diagnosis of schizophrenia, and more were diagnosed as having unipolar or bipolar affective disorder. However, many senior American psychiatrists criticized this classification and its principal architect Robert Spitzer for introducing what they regarded as a crude ‘‘Chinese menu’’ approach to diagnoses, with a theoretical bias and phenomenology being favored over mental processes. D.

DSM-III-R

DSM-III was replaced by an extensive revision DSMIII-R (revised) in 1987. In this classification schizoaffective disorders were given an operational definition for the first time; the definition of paranoid disorders was enlarged to include patients with grandiose, somatic, and erotomanic delusions as well as with delusions of persecution and jealousy, and the inappropriate stipulation that schizophrenia must start before the age of 45 years was dropped. Being introduced only 7 years after DSM-III, this classification was criticized for disrupting research and practice because of the evolution of new definitions [2]. E.

DSM-IV and DSM-IV-TR

The primacy of psychosis defining schizophrenia also survived DSM-III’s revision and its evolution into DSM-IV (published in 1994) and DSM-TR (text revision published in 2000) [6]. DSM-IV was published in 1987 with the following goals [3]: 1. To develop criteria that are more constant with ICD-10, with regard to schizophrenia. Primarily, this had to do with changing the required duration of the psychotic symptoms from 1 week (as in DSM-III-R) to 1 month (as in ICD-9 and ICD-10) 2. To provide a simplified criterion of symptoms by reducing redundancy in the items of criterion A. 3. To include symptoms with proven reliability. 4. To include symptoms only with acceptable prevalence. 5. To provide maximum coverage (sensitivity) for existing cases, thus reducing the reclassification rate.


These goals were met by adopting a ‘‘thorough process’’ by the Psychotic Disorders Work Group, which consisted of comprehensive reviews of literature, reanalyses of previously collected data, input from the field, and issue-focused field trials that included testing of alternative sets of diagnostic criteria. Changes proposed ranged from minor modifications in the DSM-III-R criteria to more weightage for negative symptoms, expansion of the minimum duration of symptoms to 2 weeks or 4 weeks, to the introduction of a concept of ‘‘schizophrenia spectrum disorders.’’ Psychosis was deemphasized in DSM-IV, in that a patient could receive a diagnosis of schizophrenia according to DSM-IV criteria without having delusions or hallucinations. In that case, however, gross disorganization of speech and/or behavior, which are also psychotic symptoms, would still be required because criterion A (i.e., characteristic symptoms) requires at least two of the five symptoms in the category. Thus, four of the five symptoms are still related to psychosis (negative symptoms are the fifth symptom in the category). Moreover, delusions alone can satisfy the criterion if they are bizarre, and hallucinations alone can satisfy the criterion if they involve one or more voices engaging in running commentary or ongoing conversation. Diagnostic changes in DSMIV thus expanded the nature of the required psychotic symptoms more than they deemphasized psychosis itself [5]. In the DSM-IV ‘‘Schizophrenia and other related disorders’’ include schizophrenia, delusional disorder, and schizoaffective disorder. Schizophrenia is divided into five subtypes including paranoid, disorganized, catatonic, undifferentiated, and residual [4]. The criteria for schizoaffective disorder has been changed to focus on an uninterrupted period of illness rather than on the lifetime pattern of symptoms. In Brief Psychotic Disorder, eliminating the requirement for a sever stressor has broadened the DSM-III-R construct of Brief Reactive Psychosis, and the minimum duration of the psychotic symptoms has been increased from a few hours to 1 day. The importance of psychotic symptoms in diagnosis extends to other diagnostic systems. Schneider’s firstrank symptoms, which form the basis of ‘‘nuclear schizophrenia,’’ are types of hallucinations and delusions that have come (more than other, ‘‘second-rank’’ symptoms) to characterize the nature of psychosis in the disorder. More important, they have helped to define the disorder itself, although Schneider himself reviewed them more as diagnostic tools than as theoretical constructs about the etiology of the disorder. First-rank symptoms heavily influenced the develop-

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ment of Research Diagnostic Criteria for schizophrenia, which in turn formed the basis of DSM-III criteria for schizophrenia. These criteria, particularly, continue to influence ICD-10 in the first three symptom groups ‘‘that have special importance for the diagnosis’’ for schizophrenia [5].

VI.

DIAGNOSTIC CRITERIA: INTERNATIONAL CLASSIFICATION OF DISEASES (ICD)

The Mental Disorders section of ICD-6 was primarily a classification of ‘‘psychoses and mental deficiency.’’ The eighth revision of the International Classification of Diseases, Injuries and Causes of Death (ICD-8) came into use in 1969, owing to strenuous efforts by the World Health Organization. It was replaced by ICD-9 a decade later, in 1979. However, the definitions provided in ICD-8 and ICD-9 were not operational definitions [2]. A.

Preparation of ICD-10

The process of drafting ICD-10 started in 1983 but it came into use in United Kingdom and most other countries in 1993. It had a new title, the International Statistical Classification of Diseases and Related Health Problems, and a new alphanumeric format. The main purpose of the latter is to provide more categories and so leave space for future expansion without the whole classification having to be changed. It incorporates many of the radical innovations introduced in DSM-III. Most categories are provided with both diagnostic guidelines for everyday clinical use and separate ‘‘diagnostic criteria for research,’’ providing unambiguous rules of application. There is also provision for multiple axes, as in DSM-III and its predecessors. Field trials of the 1986 draft text were held in 194 different centers in 55 different countries, and the final text benefited greatly from the comments of users in these varied settings and the evidence they provided of the acceptability, coverage, and interrater reliability of the provisional categories and definitions of the draft [2]. B.

Differences between ICD-9 and ICD-10

F20–F29, which included schizophrenia, schizotypal states, and delusional disorders have been expanded by the introduction of new categories such as undiffer-

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entiated schizophrenia, postschizophrenic depression, and schizotypal disorder. The classification of acute short-lived psychoses, which are commonly seen in most developing countries, is considerably expanded compared with that in the ICD-9 [7].

VII.

A.

OTHER PSYCHOTIC DISORDERS: DSM AND ICD DEFINITIONS Schizoaffective Disorder

The study of Schizoaffective Disorder, since it has generally been ill defined, has always presented unique problems due to the lack of producing comparable populations. Several conceptual models of schizoaffective disorder exist, e.g., the episode-based versus the course-based co-occurrence of mood and psychotic symptoms. Both the ICD and the DSM use a common definition of episode-based coexistence of symptoms and are very similar in the other criteria. A rare, small subgroup of patients may, however, be diagnosed as Schizophrenia by the DSM-IV, and Schizoaffective Disorder by the ICD-10. This occurs because the ICD requires that at least 2 weeks of psychosis precede any concurrent psychotic and mood symptoms of schizophrenia, whereas the DSM does not. A patient presenting with concurrent psychotic and mood symptoms from the onset of the episode could be diagnosed Schizophrenia by DSM-IV if satisfying all the other criteria, but might be diagnosed Schizoaffective by ICD-10.

B.

Delusional Disorder

For delusional disorder it is likely that some difference in subject selection will persist between the two major symptoms because of differing requirement in duration, i.e., 1 month in DSM versus 3 months in ICD.

C.

Acute/Brief Psychotic Disorder

Although termed differently, acute psychotic disorders provide substantially the same coverage in the two systems. In DSM, the terms brief psychotic disorder and schizophreniform disorder are used, while the ICD uses the terms acute and transient disorder with and without schizophrenialike symptoms [3].

VIII.

A.

INTERNATIONAL DIFFERENCES IN DIAGNOSTIC CRITERIA Diagnostic Hierarchies

In ICD-10, schizophrenia and affective disorders are at the same level. A diagnosis of schizophrenia cannot be made if the full depressive/manic syndrome is also present ‘‘unless it is clear’’ that schizophrenic symptoms antedated the affective disturbance. However, in the DSM classification, schizophrenia traditionally follows the ‘‘organic psychosis,’’ and the third place in the hierarchy is occupied by the affective disorders. A very similar sequence is involved in the decision pathway of computer programs like Catego [2]. B.

Threshold for Diagnosis

Comparative studies carried out by the US/UK diagnostic project in 1960s established that, in comparable series of patients, psychiatrists in New York diagnosed schizophrenia twice as frequently as their counterparts in London. The International Pilot Study of Schizophrenia confirmed that American psychiatrists had an unusually broad concept of schizophrenia, and also showed that the same was true of Russian psychiatrists. The very broad American concept of schizophrenia was psychoanalytic in origin, and the decline of psychoanalytic influence in the 1970s, together with a renewed interest in descriptive psychopathology and classification, led to rapid change. The widespread adoption of the operational definitions of DSM-III and DSM-III-R by research workers in many different parts of the world has also played an important role in reducing the international differences in usage [2].

IX.

RELIABILITY AND VALIDITY: THE PREREQUISITES OF A CLINICAL DIAGNOSES

The introduction of structured interviews and operational definitions has improved the reliability and validity of psychiatric diagnosis over the years. But the existing evidence for the validity of most psychiatric diagnoses is rather meager. It is considerably better for the major syndromes like schizophrenia in comparison to sub-categories of major syndromes such as catatonic schizophrenia [2].


A.

Reliability and Field Trials

Modern classification schemes such as ICD-10 and DSM-IV have made it possible to assign psychiatric patients reliably to different diagnostic categories [8]. A classificatory system, which has little reliability, has little practical utility [9]. Field trials have been conducted at seven USA sites (each of which contributed 50 subjects) to assess the concordance and symptom reliability within different systems, namely, DSM-III, DSM-III-R, and ICD-10 [1]. Some of the major highlights of the results were: 1. Concordance between diagnostic systems. 2. Symptom reliability. 3. Reliability of diagnostic criteria. 4. Agreement between ICD and DSM-III-R was high (87.6%) for schizophrenia, but 13% of DSM-IIIR schizophrenia was classified by ICD as schizoaffective, acute and transient psychotic disorder, schizotypal, or none of the above. 5. Reliability of schneiderian symptoms was similar to that of other symptoms. Likewise, bizarre delusions were as reliably rated as nonbizarre, and even negative symptoms had good reliability in the trial. 6. The length of symptoms is a principal difference in criteria between ICD and DSM. The field trial demonstrated that 5% of DSM-III-R schizophrenia and >30% of schizophreniform disorder would have to be reclassified to psychosis not otherwise specified (NOS) when the required duration of symptoms is changed to 1 month.

B.

Validity of Classification Systems

As yet no clinical or pathological gold standard exists for the diagnosis of schizophrenia. The uncertain validity of the diagnostic categories assigned to the patients is a matter of serious concern because the usefulness of a particular diagnostic construct is greatly reduced if it carries no therapeutic implications. The validity of diagnostic classification rests to some extent on its ability to predict outcome. In a study by Mason et al. [10], it was found that DSMIII-R and ICD-10 diagnosis of schizophrenia had high predictive validity and were superior to ICD-9. ICD10, however, had superior sensitivity to DSM-III-R. This study thus suggests that ICD-10 should be preferred for studies needing high sensitivity as well as specificity for the diagnosis of schizophrenia in the acute phase, such as studies of incidence. It also sug-

75

gests that dropping the 6-month duration criterion should be considered for a future DSM-V [10]. In another study, by Van Os et al. [8], the introduction of a ‘‘treatment-relevant’’ classification of psychiatric disorders such as the functional psychoses was explored. In a sample of 706 patients aged 16–65 years with chronic psychosis, psychopathology was measured using the Comprehensive Psychopathological Rating Scale (CPRS). The principal component factor analysis of the 65 CPRS items on cross-sectional psychopathology yielded four dimensions of positive, negative, depressive, and manic symptoms. The authors concluded that although it was possible to reliably label combinations of psychopathological phenomena, the resulting diagnostic entities reveal very little about the patients. In patients with chronic psychosis, the dimensional approach constitutes a treatment-relevant alternative or complementary strategy. Its use in clinical practice, research, and service evaluation was in need of further investigation [8]. C.

International Pilot Study of Schizophrenia: Symptom Frequencies in Cross-Cultural Groups

Computerized statistics have often been used to select diagnostic criteria. Such an approach will seek to select a set of symptoms that are relevant and distinct. The symptoms selected would be required to satisfy the following conditions: They should be common in a representative sample of the population under investigation. Thus, catatonia is not useful, although it’s quite a striking symptom, because it is relatively infrequent; they require a high interrater reliability, and this eliminates symptoms that are difficult to identify consistently to serve well as diagnostic criteria the symptoms should be nonredundant; that is, they should be fairly independent of each other but necessary for the diagnosis (this means that they should not have high mutual intercorrelation to avoid tautology); and symptoms to be preferred should have discriminant value for the purpose of differential diagnoses, occurring quite often in concordant cases and rarely, if at all, in discordant cases with an alternative diagnosis. All these conditions define the following statistical criteria for the evaluation of symptoms characteristic of the illness: an adequate rate of occurrence, good interrater reliability, low intercorrelation of symptoms, and a high frequency ratio for concordant versus discordant groups. Symptom frequencies in concordant and discordant groups from large-scale cross-cultural investigations

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were published in the International Pilot Study of Schizophrenia (IPSS). Those data can be used to explore the potential for establishing the new diagnostic rules or criteria for schizophrenia. The IPSS teams found that >40% of patients in concordant and 60% of familial AD with mutations in PS and APP genes [110], and more recently in 48–60% of sporadic AD [111,112]. Unlike PD and DLB, alphaS-positive inclusions in multiple system atrophy (MSA) are found in cytoplasm and nuclei of both nerve cells and glial cells, mainly oligodendrocytes. From the clinical point of view, MSA includes striatonigral degeneration, ShyDrager syndrome, and olivopontocerebellar atrophy, depending on the predominant symptom (respectively axial parkinsonism and gait disturbances, postural hypotension, cerebellar syndrome) [113]. Dementia is usually absent [113], but patients frequently exhibit executive deficits with no impairment in language or

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visuospatial skills [114]. These symptoms reflect frontal and cerebellar involvement of alphaS-positive inclusions [115]. C.

Amyloid-Beta Protein Pathologies

Both the biochemistry and the genetics of the amyloidbeta protein (A-beta) are described above. Main disorders of A-beta are listed in Table 4. Cerebral amyloid angiopathy (CAA) may cause lobar cerebral hemorrhages and, less frequently, ischemic brain lesions, especially in nonhypertensive elderly [116]. It thus shares features with VaD. Nevertheless, the pathology (fibrillar amyloid gradually replacing the arteriolar media) and its increasing prevalence with age are characteristics shared with degenerative disorders [117]. Sporadic CAA is common in AD, and several mutations of the APP gene have been described in familial CAA [118–120]. Therefore, it has been suggested that CAA was the microvascular link between parenchymal (AD) and VaD [121].

V.

CLINICAL CLASSIFICATION

This classification is based on using clinical phenomena to classify diseases. It derives from more than a century of classic brain lesion studies in humans, and more recently from structural and functional neuroimaging. These data allow clinical neuroscientists to distinguish between two patterns of CNS involvement: cortical and subcortical. Together with the neurological examination, these two major syndromes aid clinicians in making a clinical diagnosis of dementia or other cognitive disorders.

Table 5

A.

Subcortical Dementias

The term subcortical dementia has been replaced by frontosubcortical dementia (FSCD) because of the advances of our understanding in the basic circuitry of basal ganglia and frontal lobes. The striatum, globus pallidus, anterior and medial thalamus, and substantia nigra are interconnected with the prefrontal cortex in multiple parallel circuits with unique functional properties [122–124]. The broad dichotomy between cortical dementia and frontosubcortical dementia has been challenged [125–128], but is a very useful tool for the clinician in terms of diagnosis and understanding some of the basic processing of cognitive functions. A third category has emerged since the original descriptions of subcortical dementia. FTD, DLB, and CBD have both cortical and frontosubcortical features. Compared to patients with the classic cortical dementia of AD, patients with FSCD show prominent executive deficits, explicit memory impairment with retrieval deficit and no significant aphasia, apraxia, agnosia or encoding memory impairment [29,30,129]. These deficits are presented in Table 5, where differential characterisitics of FSCD and AD are summarized. As an example, one disease is presented here. Other FSCDs are summarized in Table 6. Progressive supranuclear palsy (PSP) is characterized by supranuclear ophthalmoplegia, axial dystonia, pseudobulbar palsy, bradykinesia, postural instability, and dysarthria [99]. Historically and clinically, PSP is the quintessential example of FSCD [130], but early severe dementia is rare [131]. Recently, a clinicopathologic analysis of nine patients with PSP showed greater frontal lobe atrophy compared to controls, which correlated with increasing NFT densities, and a correlation with clinical dementia [132]. These findings concur

Main Symptoms of Frontosubcortical Dementias Compared to Alzheimer’s Disease

Feature

FSCD

AD

Attention Speed of cognitive processing Language Speech Visuospatial skills Executive functions: Set planning and shifting Verbal fluency Memory impairment

Normal (slow) Slow Most often preserved Dysarthric Impaired (poor planning, perseveration errors)

Normal Normal Impaired Normal More impaired

Severely impaired Severely impaired (especially letter fluency) Retrieval deficit

Impaired late Impaired (especially category fluency) Encoding deficit

Dementias and Cognitive Disorders Table 6 Profile

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Classification of Dementias and Related Cognitive Disorders According to Their Clinical

Frontosubcortical dementia Degenerative PSP Multiple system atrophy Spinocerebellar ataxias Idiopathic basal ganglia calcification Wilson’s disease Huntington’s disease Neuroacanthocytosis Vascular Binswanger Lacunar state Strategic infarcts (pallidum and caudate) Infectious AIDS Dementia Complex Whipple Neurosyphilis Creutzfeldt-Jakob disease Demyelinating Multiple sclerosis

Cortical dementia

Both

Alzheimer’s disease

Frontotemporal dementia Dementia with Lewy Bodies Corticobasal degeneration Leukodystrophies

Multi-infarct dementia

Multi-infarct dementia

Strategic infarct (angular gyrus syndrome)

with neuroimaging data showing a reduced frontal perfusion or metabolism in PSP and impaired executive functions [133,134].

B.

Cortical Dementias

Cortical dementias, mostly AD, have been discussed above. FTD can present with features of FSCD or with cortical dementia syndrome. Primary progressive aphasia syndrome (PPA) was described relatively recently by Mesulam [135,136] and is a cortical form of FTD. The main core of PPA is a fluent or nonfluent aphasia, starting as an anomia with phonemic paraphasias, unlike AD [137]. There are no significant apathy, disinhibition, memory, visuospatial or visual recognition impairments within the initial 2 years of the disease. Mild acalculia and ideomotor apraxia may be present in the first 2 years. The neuropathology lacks AD-type changes. Neuronal loss, gliosis, mild spongioform changes within superficial layers in the left perisylvian cortex with ubiquitin-positive, taunegative inclusion bodies or rarely tau-positive neuronal and glial inclusions, and sometimes Pick bodies have been described.

Others Normal pressure Hydrocephalus Toxic-metabolic Post-traumatic Vasculitis

VI.

CONCLUSION

These different classifications by etiology, genetics, pathophysiology, and clinical features have had their importance in the history of dementia and behavioral neuroscience, and all of them are still relevant in the 21st century. Increasingly they are converging to provide a molecular pathogenesis relevant to clinical presentations. The clinical classification is crucial in terms of which cognitive systems are involved and gives clues to the anatomical basis of the disease. Together with the associated neurological signs, it allows the clinician to make a diagnosis. The most recent classifications (genetics and pathophysiology) offer new insights in the dementias and cognitive disorders. Although familial AD comprises only a small proportion of all dementias, it has provided considerable information about the biochemical pathways involved in sporadic forms and how to develop new drugs, such as the antiamyloid vaccine [138], and other mechanism-based strategies. Selective vulnerability of brain regions and subpopulations of neurons and glial cells is one of major issue of most of dementias and cognitive disorders. The pattern of vulnerability determines the clinical presen-

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tation. The pathophysiology of this selective cellular risk has not yet been explained, and will be the critical next step in linking pathophysiology to clinical syndrome. The issue of phenotypic differences not only between families with different mutations but also within families having the same mutation, remains unsettled. This may suggest that other genetic and/or environmental factors play a role in the pathogenesis of these diseases. Similarities at the clinical, pathological, and molecular levels among different diseases imply the existence of common pathways in all neurodegenerative disorders. Cell death pathways, for example, appear to involve similar apoptotive cascade across disease entities, and oxidative stress appears to be a common contributive factor to many disorders. Protein aggregation increasingly links many disorders. More basic and translational research is needed to understand both relationships and differences of major cognitive disorders and dementias. The resolution of issues in basic neuroscience will enhance with our understanding of molecular genetics and our ability to provide effective treatments of affected patients.

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ACKNOWLEDGMENTS This project was supported by an NIA Alzheimer’s Disease grant (AG16570), an Alzheimer’s Disease Research Center of California grant, the SidellKagen Foundation (J.L.C), and a scholarship from the University Hospital, Geneva, Switzerland (F.A.).

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10 Classification of Personality Disorders Implications for Treatment and Research DRAGAN M. SVRAKIC and ROBERT CLONINGER Washington University School of Medicine in St. Louis, St. Louis, Missouri, U.S.A.

STANA STANIC University of Trieste, Trieste, Italy

SECONDO FASSINO University of Turin, Turin, Italy

I.

INTRODUCTION

etiology and treatment of personality disorder. Clinically, the temperament and character traits are used to classify and diagnose personality disorder and to differentiate its clinical subtypes. In this paper, we first review the basic aspects of the seven-factor psychobiological model of personality and then outline treatment implications, based on this model, for extreme personality variants classified as personality disorder.

Modern psychobiological theory conceptualizes personality as a self-organizing, complex adaptive system involving a bidirectional interaction between heritable neurobiological dispositions to behavior (temperament) and developing concepts about self and external objects (character). As introduced by the seven-factor psychobiological model of personality in 1993 [1,2], the concepts of temperament and character synthesize advances from a wide variety of scientific disciplines—evolutionary biology, genetics, neuroscience, theory of learning, sociology, philosophy—each contributing from its specific angle to the present eclectic understanding of personality development and structure. ‘‘Biological’’ temperament traits and ‘‘conceptual’’ character traits, two distinct but interacting components of personality, are distinguished based on the corresponding neurobiological and psychological mechanisms underlying behavior. These mechanisms provide guidelines for testable hypotheses about

II.

TEMPERAMENT AND CHARACTER (NATURE AND NURTURE)

Structurally, the seven-factor model describes four temperament traits (Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence) and three character traits (Self-Directedness, Cooperativeness, and Self-Transcendence) (Tables 1 and 2). The temperament traits are largely heritable (up to 60%), relatively stable over lifetime, and universal across cultures and ethnic groups. These traits are 117

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Table 1 Descriptors of Individuals Who Score High and Low on the Four Temperament Dimensions Descriptors of extreme variants Temperament dimension

High

Low

Harm Avoidance

pessimistic fearful shy fatigable

optimistic daring outgoing energetic

Novelty Seeking

exploratory impulsive extravagant irritable

reserved deliberate thrifty stoical

Reward Dependence

sentimental open warm affectionate

detached aloof cold independent

industrious determined enthusiastic perfectionist

lazy spoiled underachiever pragmatist

Persistence

etiologically associated with basic (or primary) emotions of fear (Harm Avoidance), anger (Novelty Seeking), attachment (Reward Dependence), and perseverance (Persistence). In contrast, character

Table 2 Descriptors of Individuals Who Score High and Low on the Three Character Dimensions Descriptors of extreme variants Character dimension

High

Low

Self-Directedness

responsible purposeful resourceful self-accepting disciplined

blaming goal-less passive wishful undisciplined

Cooperative

tender-hearted empathic helpful compassionate principled

intolerant insensitive selfish revengeful opportunistic

Self-Transcendent

imaginative intuitive acquiescent spiritual idealistic

conventional logical doubtful materialistic relativistic

traits are weakly heritable, tend to change with age and maturation, and are associated with social (or secondary) emotions, such as honor, integrity, morality, altruism, respect. Roughly, temperament is what we are born with, character is what we make out of ourselves. The Temperament and Character Inventory (TCI) has been developed to measure the above temperament and character traits (Table 3). As described in the TCI Manual [3], the psychobiological model has been translated into many languages, its psychometric validity confirmed in clinical and nonclinical samples, its

Table 3 Temperament and Character Inventory (TCI) Harm Avoidance (HA) HA1: worry and pessimism vs. uninhibited optimism HA2: fear of uncertainty HA3: shyness with strangers HA4: fatigability and asthenia Novelty Seeking (NS) NS1: exploratory excitability vs. stoic rigidity NS2: impulsiveness vs. reflection NS3: extravagance vs. reserve NS4: disorderliness vs. orderliness Reward Dependence (RD) RD1: sentimentality RD2: sociability vs. aloofness RD3: attachment vs. detachment RD4: dependence vs. independence Persistence (PS) PS1: eagerness of effort vs. laziness PS2: work hardened vs. spoiled PS3: ambitiousness vs. underachieving PS4: perfectionism vs. pragmatism Self-Directedness (SD) SD1: responsibility vs. blaming SD2: purposefulness vs. lack of goal direction SD3: resourcefulness vs. helplessness SD4: self-acceptance vs. self-striving SD5: congruent second nature Cooperativeness (CO) C1: social acceptance vs. social intolerance C2: empathy vs. social disinterest C3: helpfulness vs. unhelpfulness C4: compassion vs. revengefulness C5: pure hearted vs. self-serving Self-Transcendence (ST) ST1: self-forgetful vs. self-conscious ST2: transpersonal identification vs. Self-differentiation ST3: spiritual acceptance vs. rational materialism ST4: enlightened vs. objective ST5: idealistic vs. practical

Classification of Personality Disorders

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cross-cultural applicability established in many different ethnic groups, countries, and continents.

III.

TEMPERAMENT AND CHARACTER: TWO DISTINCT MEMORY AND LEARNING SYSTEMS

Temperament (or the ‘‘emotional core’’ of personality) involves heritable dispositions to early emotions (such as fear, anger, and attachment), and related automatic behavior reactions (such as inhibition, activation, and maintenance of behavior) in response to specific environmental stimuli (danger, novelty, and reward, respectively). Temperament traits are based on presemantic perceptual processing of visuospatial information and affective valence regulated by the corticostriatolimbic system, primarily the sensory cortical areas, amygdala, and the caudate and putamen (the so-called procedural memory). In other words, temperament traits are heritable biases in procedural learning that underlie asso-

ciative conditioning of automatic behavior responses to danger, novelty, and reward. Temperament traits are genetically homogeneous, independently inherited, relatively stable over lifetime, and cross-culturally universal [4]. Character (or the ‘‘conceptual core’’ of personality) involves higher cognitive functions, such as abstraction and symbolic interpretation, analytical and inductive logic, symbolism, etc., regulated by the hippocampus and neocortex. These functions (also called propositional memory) are critical for cognitive processing of sensory percepts and affects regulated by temperament, leading to the development of abstract conceptual and volitional processes. Character traits reflect one’s developing concepts about oneself and the external world [2]. Basic differences between character and temperament are presented in Table 4.

Table 4 Key Differences Between Temperament (associative or procedural learning) and Character (conceptual or propositional learning) Variable properties

Temperament

Character

Awareness level

automatic

intentional

Memory form

percepts procedures

concepts propositions

Learning principles

associative conditioning

conceptual insight

Role of subject in mental activity

passive reproductive

active constructive

Key brain system

Limbic system Striatum

Temporal cortex Hippocampus

Form of mental representation

stimulus-response sequences varying additively in strength

interactive networks (conceptual schema) varying qualitatively in configuration

40–60% 0% 40–60%

10–15% 30–35% 40–60%

Etiological components Genetic heritability Family environment Random environment

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IV.

Svrakic et al.

INTEGRATED VIEW OF PERSONALITY: TEMPERAMENT AND CHARACTER INTERACT TO PRODUCE PERSONALITY

Personality is conceptualized as a self-organizing, complex adaptive system characterized by multiple internal and external, constraining and facilitating factors, interacting nonlinearly to finally funnel into only one (out of several possible) developmental outcome [4]. Personality development is graphically presented as a fitness landscape, where hills and valleys represent high and low adaptive levels, respectively. Periods of stability (i.e., local adaptive optima represented by hills) alternate with relatively rapid transitions (through the valleys) to new adaptive levels [4]. Heritable biological dispositions develop into actual temperament traits, amenable to observation and measurement (i.e., avoidant, exploratory, persistent, or sociable behaviors) as a nonlinear function of the relative strength of the underlying disposition and the characteristics of the interacting environment (e.g., suppression or facilitation of certain behaviors). With growing perceptual and cognitive capacities, early percepts and affects based on temperament are transformed into more complex concepts about self and the external world. This internalization of new concepts and their associated social emotions (honor, pride, altruism) further neutralizes raw temperament traits, most importantly fear and anger, and provides the stage for personality to crystallize around positive, gratifying experiences associated with attachment. In other words, through this bidirectional interaction of temperament and character,

developing concepts about self and the external world modify the significance and the salience of sensory percepts and affects regulated by temperament, and vice versa. Temperament regulates what we notice, and, in turn, character modifies its meaning, so that the salience and significance of all experience depend on both temperament and character.

V.

DIFFERENTIATING NORMAL FROM DEVIANT PERSONALITY: WHEN TO TREAT AND WHO NEEDS TREATMENT

The distinction between temperament and character, i.e., between biological and psychological mechanisms underlying behavior, provides guidelines for testable hypotheses about etiology, diagnosis, and treatment of personality disorder. This is not possible for models that confound temperament and character. The TCI has repeatedly proven useful to predict categorical diagnoses of personality disorder in numerous clinical and nonclinical samples, cross-culturally, in patients with and without personality disorder and varying mood and anxiety states [3]. The concepts of temperament and character are essential to decompose the symptoms of personality disorder into common features shared by all subtypes (used for diagnosis) and distinguishing features unique for each subtype (used for differential diagnosis) [4]. The following major findings are noteworthy: Low scores on Self-Directedness and Cooperativeness correlate highly with the number of symptoms for personality disorder (Tables 5 and 6) The TCI character traits predict the presence or absence of

Table 5 Correlations Between TCI Scales and Total No. of Symptoms for PDs, Cluster A, Cluster B, and Cluster C Inpatients ðN ¼ 136Þ Total No. of symptoms

Cluster A symptoms

Cluster B symptoms

Cluster C symptoms

Novelty Seeking Harm Avoidance Reward Dependence Persistence

.22c .31b .14 .00

.02 .23b .37a .07

.44a .08 .08 .04

.06 .43a .04 .01

Self-Directedness Cooperativeness Self-Transcendence

.56a .44a .02

.35a .44a .08

.43a .40a .03

.50a .28b .04

a

20% in globus pallidus [7]. This may be a medication effect, since studies of patients receiving atypical antipsychotic medications show smaller increases than patients taking typical neuroleptics, and patients taking minimal or no antipsychotic medications have no change or even a decrease in basal ganglia volumes [16,17]. Thalami were found to be reduced in relative volume by 3–4% on meta-analysis, consistent with a review that found abnormalities in four of six studies of this region. B.

Summary and Significance

In conclusion, the major findings to date are [1] very minor deficits of whole brain or intracranial volume; [2] consistently replicated enlargement of the lateral and third ventricles; [3] parenchymal deficits in the temporal lobes, including medial temporal lobe structures such as hippocampus and superior temporal gyrus, frequently reported to be more pronounced on the left compared to the right side. While frontal lobes have been implicated functionally in schizophrenia, volumetric deficits have been less reliably found, possibly because any such deficits are near threshold of detectability with MRI methods. Subcortical structures including thalamus and basal ganglia have been reported to show volume changes, with increases in basal ganglia generally thought to be medication related. These volume deficits have been found to be associated with clinical manifestations of the illness, including positive symptoms, memory impairment, thought disorder, and negative symptoms. Frontal lobe [18] and temporal lobe [19] volume deficits have been found to progress in longitudinal studies, although

Neuroimaging Findings in Schizophrenia

an earlier study reported absence of cortical or ventricular volume progression [20]. Because of its absence of ionizing radiation, MRI is a modality particularly suited to longitudinal studies, including the prodrome, and this is an area of active research. Such studies will help address the issue of timing of anatomic disturbances relative to symptom onset, and the relative roles of neurodevelopment and neurodegeneration in the illness.

III.

FUNCTIONAL IMAGING

Over the last 40 years, measurement of neuronal activity underwent major technical advances, each bringing new insights about alterations in brain regional function in schizophrenia. The main imaging modalities included SPECT studies with the xenon inhalation technique, PET studies measuring rate of glucose utilization with [18F]fluorodeoxyglucose ([18F]FDG) or measuring regional blood flow with H215O, and more recently fMRI, using blood-oxygen-level-dependent (BOLD) contrast. Each of these techniques provided improvements in terms of spatial and temporal resolution, as discussed in Chapter 7. A.

Resting-State Studies

In 1974, Ingvar and Franzen [21] published a landmark report describing lower flow in anterior compared to posterior regions of the brain, a finding termed hypofrontality. A large number of studies have attempted to replicate this finding [for review see 22,23–29]. Hypofrontality has not been consistently replicated, and the opposite observation (hyperfrontality) has been reported, especially in acutely ill patients. The lack of consistent pattern emerging from these studies has been interpreted as reflecting the heterogeneity of the illness and of the ‘‘baseline’’ or ‘‘resting’’ conditions. Regarding the heterogeneity of the condition, an influential study was the report of Liddle et al. [30], who described several patterns of flow alterations in psychomotor poverty (hypofrontality), disorganization (anterior cingulate overactivity), and reality distortion (underactivity of left temporal lobe). Many of these findings have been replicated; for example, several studies suggested that low prefrontal flow or metabolism at baseline might be associated with severity of negative symptoms. Abnormalities in temporal region have frequently been reported and have been linked with positive symptoms and noted more frequently on the left side. Temporal activation has also be

239

recorded during the experience of hallucinations by several investigators, although the details of anatomical activation patterns differed. Regarding the impact of antipsychotic medications, an increase in basal ganglia activity has been the most reliable finding. B.

Task-Related Activation Studies

Hypofrontality has been more consistently observed during performance of executive and working memory tasks engaging the frontal cortex. For example, lower activation of the frontal cortex has been reported during the Wisconsin card sort task [31], the Tower of London task [32], word generation task [33,34], or nback task [35]. A general problem with these observations is that the level of performance in the patient group is generally found to be diminished compared to controls, raising questions regarding the interpretation of these data as reflecting a primary abnormality of prefrontal cortex and its connectivity, a lower engagement of the patients during the tasks, or some combination of both factors [see discussion in 36]. Another very interesting approach is to examine patterns of covariance between regions during task performance [37]. The introduction of fMRI, allowing multiple determinations of dorsolateral prefrontal cortex (DLPFC) activation at various WM loads has provided new insights into the relationship between working memory tasks and DLPFC activation in schizophrenia. Increasing working memory load while keeping other aspects of the task constant is easily achieved with parametric tasks such as the n-back test, and, in healthy subjects, a significant relationship is observed between working memory load and DLPFC activation [38,39]. Using this new approach, a more subtle pattern of alterations in DLPFC activation (decreased efficiency and lower disengagement threshold) is emerging from studies in patients with schizophrenia. The concept of efficiency refers to the magnitude of DLPFC activation required to perform a task at a given level. Manoach et al. [40,41] demonstrated that, on a working memory task designed specifically to engage schizophrenic patients, patients showed greater DLPFC activation for a given level of performance than controls. Callicott et al. [42] examined the effect of parametric increases in the n-back test and found that patients with schizophrenia had greater DLPFC activation than controls on the 1-back and 2-back condition (low to moderate working memory load). These data suggest that schizophrenia might be associated with reduced DLPFC efficiency, i.e., with larger metabolic

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activation to reach a given level of performance in a relatively easy task. Several studies [40–42] also documented that, at high working memory load, patients with schizophrenia show decreased performance and decreased activation compared to controls. This observation also suggests that most earlier brain imaging studies were performed in a range where the complexity or load of the task reached the disengagement threshold for patients, resulting in apparent hypofrontality. In conclusion, functional imaging studies during resting state as well as during task-related activation documented that schizophrenia is associated with a disrupted pattern of activation in cortico-limbic networks, and that the prefrontal cortex is a critical deficient node in this network. IV.

NEUROCHEMICAL AND NEUROPHARMACOLOGICAL IMAGING

A.

PET and SPECT Neurochemical Imaging

The principles of PET and SPECT neurochemical imaging are reviewed elsewhere in this volume. Numerous PET and SPECT radiotracers are currently available to study key proteins in the living brain, such as receptors, transporters, and enzymes. Regarding schizophrenia, the majority of clinical investigations studied various aspects of dopaminergic transmission. Dopamine (DA) D2 receptors were the first neuroreceptors visualized in the living human brain [43]. Since then, several DA related radiotracers have been developed, allowing the study of many aspects of dopaminergic transmission (DA synthesis, DA release, D1 and D2 receptors, DA transporters). Given the availability of these tools and the important role that DA transmission is believed to play in schizophrenia, it is not surprising that most of the research effort focused on this system. Despite marked limitations, these studies provide a relatively consistent picture suggesting that schizophrenia, at least during periods of clinical exacerbation, is associated with dysregulation of DA transmission. 1.

Imaging DA Transmission

The classical DA hypothesis of schizophrenia, formulated over 30 years ago, proposed that a hyperactivity of the dopaminergic transmission is associated with this illness [44,45]. This hypothesis was essentially based on the observation that all antipsychotic drugs provided at least some degree of D2 receptor blockade, a proposition that is still true today [46,47]. As D2

receptor blockade is most effective against positive symptoms, the DA hyperactivity model appeared to be most relevant to the pathophysiology of positive symptoms. That sustained exposure to DA agonists such as amphetamine can induce a psychotic state characterized by some salient features of positive symptoms of schizophrenia (emergence of paranoid delusions and hallucinations in the context of a clear sensorium) also contributed to the idea that positive symptoms might be due to sustained excess dopaminergic activity [48,49]. These pharmacological effects indeed suggest, but do not establish, a dysregulation of DA systems in schizophrenia. On the other hand, negative and cognitive symptoms are generally resistant to treatment by antipsychotic drugs. Functional brain imaging studies suggested that these symptoms are associated with prefrontal cortex (PFC) dysfunction [36]. Studies in nonhuman primates demonstrated that deficits in DA transmission in PFC induce cognitive impairments reminiscent of those observed in patients with schizophrenia [50], suggesting that a deficit in DA transmission in the PFC might be implicated in the cognitive impairments presented by these patients [51,52]. In addition, a recent postmortem study described abnormalities of DA terminals in the PFC associated with schizophrenia [53]. Thus, a current view on DA and schizophrenia is that subcortical mesolimbic DA projections might be hyperactive (resulting in positive symptoms) and that the mesocortical DA projections to the PFC are hypoactive (resulting in negative symptoms and cognitive impairment). Furthermore, these two abnormalities might be related, as the cortical DA system generally exerts an inhibitory action on subcortical DA systems [54,55]. The advent in the early 1980s of techniques based on PET and SPECT for measuring indices of DA activity in the living human brain held considerable promise for investigating these questions. Striatal DA Transmission D2 RECEPTORS. Striatal D2 receptor density in schizophrenia has been extensively studied with PET and SPECT imaging (Table 1). In a recent meta-analysis [56], we identified 17 imaging studies comparing D2 receptor parameters in patients with schizophrenia (total of 245 patients, 112 neuroleptic naive, and 133 neuroleptic free), and controls (n ¼ 231), matched for age and sex [57–73]. These studies are summarized in Table 1. Radiotracers included butyrophenones ([11C]N-methyl-spiperone, [11C]NMSP,

[57] [58] [59] [60] [61] (62) (63) [64] [65] [66] (67) [68] [69] [70] (71) [72] [73]

[11C]NMSP [76Br]SPI [76Br]SPI [76Br]SPI [11C]NMSP [11C]NMSP [11C]NMSP [11C]Raclopride [11C]Raclopride [123I]IBZM [123I]IBZM [123I]IBZM [11C]Raclopride [123I]IBZM [123I]IBZM [76Br]Lisuride [76Br]Lisuride

Butyrophenones

c

b

a

11 8 8 12 17 7 18 20 10 20 15 16 12 15 18 14 10

n Controls 15 (10/5) 16 (12/4) 8 (0/8) 12 (0/12) 10 (8/2) 7 (7/0) 17(10/7) 18 (18/0) 13 (0/13) 20 (17/3) 15 (1/14) 21 (1/20) 11 (6/5) 15 (2/13) 18 (8/10) 19 (10/9) 10 (2/8)

DN = drug naive; DF = drug free Mean normalized to mean of control subjects Effect size calculated as (mean patients mean controls)/SD controls

Ergot Alk

Benzamides

Study

Radiotracer

n Patients (DN/DF)a Kinetic Ratio Ratio Ratio Kinetic Kinetic Kinetic Equilib Equilib Ratio Equilib Equilib Equilib Equilib Equilib Ratio Ratio

Method Bmax S/C S/C S/C Bmax Bmax k3 Bmax Bmax S/FC BP BP BP BP BP S/C S/C

Outcome 253 111 104 101 173 133 104 107 112 99 115 97 100 102 104 104 100

105 12 14 15 143 63 16 18 43 7 33 38 30 49 14 12 13

50 14 14 11 80 25 21 29 22 8 26 29 18 20 13 10 10

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

Patients (mean SD)b

Controls (mean SD)b

Imaging Studies of Striatal D2 Receptor Parameters in Drug Naive and Drug-Free Patients with Schizophrenia

Class radiotracer

Table 1

3000 patients, acamprosate has been found to enhance abstinence [63] and normalize glutamate overactivity during alcohol withdrawal [64]. Alcohol also affects nongated voltage-sensitive Ca2þ channels. These channels become increasingly permeable to Ca2þ as the neuron begins to depolarize, speeding up the process that generates an action potential. Calcium channel blockers, such as dihydropyridine (DHP), are widely prescribed in the treatment of hypertension and cardiac illness and produce their therapeutic effects by antagonizing voltage-sensitive Ca2þ channels. Interestingly, chronic alcohol administration has been shown to increase the number of DHP-binding sites by 50%, contributing further to neuronal excitability during alcohol withdrawal [65]. In fact, mice bred specifically to experience severe alcohol withdrawal show a greater increase in DHPbinding sites. The role of voltage-sensitive Ca2þ channels in alcohol withdrawal has led to the consideration of calcium channel blockers as a treatment for this condition. A final consideration regarding glutamate systems and alcoholism is that of glutamate toxicity, a cause of neuronal death secondary to the toxic effects of excessive Ca2þ influx. Excessive levels of intraneuronal Ca2þ can result from the upregulation of NMDA receptors and voltage-sensitive Ca2þ channels, both known consequences of chronic alcohol exposure. It has been suggested that glutamate toxicity is more likely to occur with a binge pattern of drinking because episodic high levels of alcohol alternate with abstinence [66]. Alcohol-induced activation of the HPA [67] may also contribute to glutamate toxicity since glucocorticoids augment Ca2þ conductance through NMDA-gated ion channels [68]. Glutamate toxicity is thought to be the cause of alcohol-related brain toxicity, such as that seen with delirium tremens, Wernicke-Korsakoff syndrome [69], dementia, and fetal alcohol syndrome [70].

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The full implications of glutamate toxicity in alcoholism are potentially far-reaching. Aside from its proposed involvement in severe forms of neurotoxicity, glutamate toxicity could contribute to more subtle impairment of cortical function, which is evident on imaging studies. A number of these studies report reduced frontal-lobe metabolism in chronic alcoholics, affecting the prefrontal cortex, orbitofrontal cortex, and the anterior cingulate regions. Hypofrontality in alcoholics could result from glutamate toxicity and contribute to phenomena indicative of poor executive function such as denial, difficulty suppressing destructive impulses, and maladaptive decision-making capabilities. Hypofrontality in alcoholics could also explain, to some extent, the notorious ineffectiveness of logical treatment recommendations in the clinical setting.

VII.

SEROTONIN

Serotonin pathways, known to influence emotion, motivation, and attention, have also been implicated in the neurobiology of alcoholism [18]. Serotonin cell bodies located in the raphe nuclei and hypothalamus modulate brain reward through projections to the VTA, amygdala, NAc, and other crucial reward regions. Animal studies generally show that manipulations of serotonin neurotransmission have an inverse effect on alcohol intake [71]. For instance, serotonin depletion increases alcohol self-administration while serotonin enhancement reduces alcohol intake [72]. In animal studies, the acute administration of alcohol

Table 2

releases brain serotonin and specifically elevates serotonin levels in the NAc [73]. Similarly, human subjects show increased levels of serotonin metabolites in the blood and urine after alcohol administration [71]. The ability of alcohol to release serotonin is diminished with repeated administration [74] and may represent a significant neuroadaptation in the development of alcohol dependence. Serotonin receptors are linked to G-proteins that activate second messenger cascades and alter ion channels, causing multiple effects on neuronal function and gene expression. These receptors are dense in limbic regions, and 5HT3 receptors are found on the terminals of mesocorticolimbic DA neurons. Alcohol enhances 5HT3 neurotransmission through an allosteric receptor action [75], an effect that would be expected to release DA from NAc terminals. Furthermore, with repeated administration of alcohol, the 5HT3 receptor is upregulated [74], perhaps to compensate for reductions in alcohol-induced serotonin release noted above. Some studies suggest that EOP release with alcohol administration, thought to underlie alcohol reward, may be a consequence of 5HT3 activation. Serotonin agonists increase levels of bendorphin [76], and a recent study demonstrated that serotonin, applied directly into the NAc, produced a 190% increase in b-endorphin [77]. This may explain findings that alcohol-induced positive mood effects can be blocked by administration of ondansetron, a 5HT3 antagonist [78]. These data suggest that serotonin release may contribute to alcohol reward by activating the endogenous opioid systems through the 5HT3 receptor.

Summary of Acute and Chronic Effects of Alcohol in Animals and Humans Acute

Chronic

Animals

Increased GABAA neurotransmission Decreased NMDA neurotransmission DA release and burst firing Acute reversal of DA depletion b-Endorphin and enkephalin release Serotonin release (NAc) Increased 5HT3 neurotransmission Brain reward by alcohol (lever pressing)

Decreased GABAA neurotransmission Increased NMDA neurotransmission DA depletion and reduced firing Chronic worsening of DA depletion Decreased b-endorphin levels Reduced serotonin release after alcohol 5HT3 upregulation Reduction in brain reward (ICSS Increased CRF levels

Humans

Increased b-endorphin release Metabolic suppression (GABAA effect) Serotonin release

Decreased b-endorphin levels Low levels of GABAA receptor (imaging) Serotonin deficiency

Neurobiology of Alcoholism

Genetic studies further link alcoholism with serotonin mechanisms. Alcohol-preferring rats have a number of serotonin abnormalities, including lower brain content of serotonin, fewer receptor sites, and a reduced number of immunostained serotonin fibers [73]. In addition, alcohol-preferring rats have fewer serotonin cell bodies and reduced serotonin levels in the NAc [71]. Conversely, mice bred to overexpress 5HT3 receptors are very sensitive to the intoxicating effects of alcohol, and show reduced consumption [79]. There is evidence that a subgroup of alcoholics have constitutionally low levels of serotonin as well as early onset, a positive family history of alcoholism, and antisocial behaviors [1,71,80]. These alcoholics have reduced CSF concentrations of 5-hydroxyindoleascetic acid (5HIAA), consistent with reduced brain levels of serotonin [71]. Serotonin deficiency states could result from polymorphism affecting the synthetic enzyme of serotonin, tryptophan hydroxylase, which has been associated with alcoholism, suicidality, and impulsivity [81]. Since alcohol releases serotonin, individuals with inherited reductions of serotonin function may be predisposed to using alcohol as a means of achieving balance [82]. Serotonin pathways may also influence alcohol reward through DA mechanisms. The application of a 5HT3 selective agonist into the NAc produces a 1000% rise in DA levels [83], thought to be mediated by 5HT3 receptors located on the terminals of mesolimbic DA neurons [84]. Also, pretreatment with a 5HT3 antagonist prevents the ability of alcohol to release DA into the NAc [73], similar to the ability of opioid antagonists to block alcohol-induced DA release [16]. Serotonin has also been reported to enhance DA release by alcohol through 5HT2 receptor activation [85]. Although serotonin systems are clearly involved in the neurobiology of alcoholism, and their pharmacological manipulation can alter alcohol intake by laboratory animals, clinical trials with serotonin agents have yielded inconsistent results in alcoholics. There is some evidence that a subgroup of alcoholics with serotonin deficiency may benefit from serotonin agonists, such as selective serotonin reuptake inhibitor (SSRI) agents [63]. Ondansetron, a 5HT3 antagonist, may be effective in a subgroup of alcoholics, but requires further study [78]. It appears that serotonin affects alcohol reward indirectly, by facilitating either the release of endogenous opioids or the release of DA after alcohol administration. This indirect effect may explain the modest action of serotonergic agents in the clinical setting.

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VIII.

DOPAMINE

Mesocorticolimbic DA neurons are intrinsically involved in natural reward states, and are directly and indirectly activated by alcohol. Alcohol increases the release, synthesis, and turnover of DA, and numerous animal studies have implicated this system in the neurobiology of alcoholism [48]. Rats bred to prefer alcohol show enhanced DA release after alcohol, while D2 knockout rats (rats genetically lacking D2 receptors) show aversion to alcohol (Table 3). Biological impairment of D2 receptors in the NAc of rats with antisense oligodeoxynucleotide sharply reduces alcohol intake [86], again suggesting a role for the D2 receptor in alcohol reward. Disassociated DA neurons from the VTA show robust firing when bathed in alcohol [87]. Since this effect is independent of neuronal interconnections, it demonstrates the ability of alcohol to directly stimulate DA neurons. In addition, the systemic administration of alcohol releases DA into the NAc and other regions of the extended amygdala [88]. Therefore, it is tempting to conclude that DA activation contributes significantly to alcohol reward. However, a number of animal studies link the rewarding properties of alcohol more to EOP receptor activation, as will be discussed. DA neurotransmission has not been established to be essential to the rewarding action of alcohol. DA antagonists administered systemically or applied directly into reward centers do not consistently alter lever pressing for alcohol [48], and show no effect in some studies [72]. Furthermore, the destruction of mesolimbic DA neurons projecting to the NAc fails to alter the acquisition or maintenance of alcohol self-administration [72], strongly suggesting a DAindependent mechanism in the rewarding action of alcohol. Another study reported that the chemical ablation of DA projections to all regions of the extended amygdala failed to alter alcohol self-administration [89], again suggesting that while DA release occurs during alcohol ingestion, it is not a critical mechanism for alcohol reward. In fact, the ability of alcohol to release DA into the NAc can be completely blocked by naltrindole, a d opioid antagonist [16], strongly implicating the involvement of EOP neurotransmission in the mechanism of alcohol reward. As seen with other addictive substances, chronic exposure to alcohol produces functional inhibition of DA pathways. Repeated alcohol administration results in decreased DA release [88] and an inhibition of DA neuronal firing [90]. The latter effect was found to be associated with dramatic reductions in DA outflow

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that persisted well past the period of alcohol withdrawal. It has been suggested that DA depletion is a clinically significant phenomenon in alcoholism, contributing to craving and hedonic inhibition in alcoholics [91]. An animal model of hedonic function has been developed that utilizes intracranial self-stimulation (ICSS), in which electrical current is delivered into DA-containing regions of the reward centers. Chronic exposure to alcohol increases the threshold of electrical current that is required for ICSS [92], indicating a reduction of hedonic tone that is thought to result from DA depletion. Given the important role of mesocorticolimbic neurons in orchestrating natural reward states, and the action of alcohol on reward thresholds, it is a reasonable hypothesis that DA depletion by alcohol might have an adverse effect on human hedonic function. This could explain the high prevalence of depression and suicide in alcoholics, and the dysphoria commonly experienced with abstinence. Therefore, the link between DA depletion and craving, first proposed with cocaine [93], may also hold with alcohol. Interestingly, DA depletion is acutely reversed by the administration of alcohol [90], and drinking may relieve craving through a DA mechanism. In effect, alcohol may be consumed to temporarily correct the very imbalance it produces. DA depletion by alcohol, measured through microdialysis in the NAc, can also be reversed by the administration of an NMDA

antagonist [94]. NMDA antagonism may release DA by suppressing GABA/EOP reciprocals to the VTA. D2 receptor agonists, such as bromocriptine, have not been found to be particularly effective in alcoholics. However, the dysregulation of mesocorticolimbic neurons by alcohol may be too profound to be reversed by mere DA receptor stimulation.

IX.

OPIOIDS

Endogenous opioids in the brain are classified as endorphins, enkephalins, and dynorphins, with each class derived from a distinct precursor molecule. These molecules are cleaved by peptidases and then modified through the addition of various chemical groups, creating many representatives of each of the three classes in the brain. Enkephalin-containing neurons tend to have short axons while those that synthesize b-endorphin and dynorphin have longer axons and project to more distant brain regions. Several brain areas that form part of the reward circuitry, such as the extended amygdala and the hypothalamus, are populated by opioid-containing cell bodies. The pituitary and adrenal glands also synthesize endogenous opioids that are released in response to stress and a number of physiological conditions. Three opioid receptor families (m, d, and k) have been identified,

Table 3 Summary of Effects of Alcohol in Alcohol-Craving Animals, Animals Bred with Specific Traits, and Nonalcoholic Humans with a Positive Family History of Alcoholism Genetic predisposition

Alcohol effect

Alcohol-craving animals

Increased b-endorphin release after alcohol Increased m opioid receptor density Decreased k opioid receptor density Decreased serotonin function Enhanced DA release after alcohol Decreased GABA response to alcohol Reduced alcohol self-administration Genes encode GABAA receptor complex are affected Greater number of Ca2þ -binding sites Reduced alcohol consumption Increased dynorphin levels in the NAc

D2 knockout rats Rats bred for enhanced withdrawal Excessive 5HT3 sites Alcohol noncraving Nonalcoholic humans (family history of alcoholism)

Enhanced b-endorphin release by alcohol Low baseline b-endorphin levels Serotonin deficiency (reduced CSF 5HIAA) Increased rewarding effects of benzodiazepines Reduced intoxicating effects from alcohol Reduced GABAA function


sequenced, and cloned. Their activation produces hyperpolarization, primarily by increasing Kþ conductance, thereby reducing the firing rate and neurotransmitter release of the signal-receiving neuron. As with DA receptors, EOP receptors are coupled to Gproteins that produce sustained changes in target cells, including altered gene expression through second-messenger cascades. The involvement of EOP systems in alcohol reward is based on several lines of research. Animals bred to prefer alcohol have alterations in EOP function, including increased b-endorphin release in the hypothalamus after alcohol administration [95]. Alcohol preferring rats have been reported to show high levels of EOPrelated mRNA in the hypothalamus, prefrontal cortex, and mediodorsal nucleus of the thalamus [96]. This study also reported increased m opioid receptor density in the NAc and PFC, and decreased k opioid receptor density in these animals. Alcohol-non-preferring animals have increased NAc dynorphin levels [97]. It is also possible that alcohol increases the expression of d receptors and affects binding properties of other EOP receptors in the brain [27]. In a number of animal studies, alcohol administration increases levels of b-endorphin and enkephalin in the brain while alcohol withdrawal is associated with decreased EOP brain levels [22]. b-Endorphin elevations after alcohol are specifically seen in discrete reward regions of the hypothalamus [98], VTA, and NAc [99]. It is important to note that b-endorphin-deficient rats continue to selfadminister alcohol, suggesting that this substance does not exclusively produce alcohol reward [100]. The importance of m opioid receptor activation as a mechanism for alcohol reward is underscored by the fact that alcohol consumption in alcohol-preferring rats is persistently reduced after inactivating m opioid receptors in the NAc [86]. Human studies also implicate EOP systems in the neurobiology of alcoholism. Direct measurements of b-endorphin in the cerebrospinal fluid of alcoholics show increased levels after alcohol intake and decreased levels during alcohol withdrawal [48,101]. Reduced levels of plasma b-endorphin are found in chronic alcoholics tested several hours after their last drink [102]. Low baseline b-endorphin levels may be inherited. Subjects with a family history of alcoholism have low baseline b-endorphin levels and display a 170% rise after alcohol, as compared to an absence of b-endorphin release in subjects without a family history [9]. This study indicates the ability of alcohol to normalize low b-endorphin levels in subjects with genetic loading for alcoholism. Also consistent with an inher-

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ited EOP-related vulnerability is the finding that polymorphism of the m-opiate receptor may contribute to alcoholism [103]. In addition, the ACTH response to naltrexone is consistent with b-endorphin deficiency in alcoholics and in nonalcoholics with genetic loading for the disorder [103]. That b-endorphin may be deficient in these individuals is interesting, especially in light of the fact that alcohol acutely releases b-endorphin. Reversal of an EOP deficit, either due to genetic or alcoholinduced mechanisms, could be a significant factor in the neurobiology of alcoholism. Additionally, the surge of b-endorphin seen in alcoholics and individuals with genetic predisposition may reflect enhanced euphoria, comparable to the action of an exogenous opiate. After receiving doses of alcohol in a laboratory setting, nonalcoholic volunteers with a family history of alcoholism experience more euphoria than do those without a family history of the disorder [104]. Furthermore, the euphoria experienced by subjects in this study was blocked by naltrexone, strongly suggesting an opioid mechanism. It stands to reason that individuals experiencing enhanced reward from alcohol would be more vulnerable to alcoholism. Additional evidence of EOP involvement in alcohol reward is provided by numerous animal studies showing that opioid antagonists reduce alcohol consumption in animals [10,103]. Nonspecific opioid antagonists such as naltrexone, and those specific for m and d receptors, clearly reduce alcohol intake in a number of paradigms. Conversely, low doses of opioid agonists increase alcohol consumption [105] owing to a priming effect, although high doses of opiates replace alcohol consumption [27]. Opioid antagonists also reduce alcohol intake when administered directly into the central nucleus of the amygdala [10], specifically implicating this component of the extended amygdala in alcohol reward [48]. Given the evidence for EOP involvement in alcohol reward and the ability of opioid antagonists to reduce alcohol intake by animals, naltrexone was investigated in alcoholics [106,107]. Nearly all controlled clinical trials conclude that naltrexone reduces alcohol intake and prevents full relapse in subjects who resume drinking [106,108,109]. Naltrexone may also ameliorate craving [110] and diminish the pleasurable effects of alcohol [111], presumably by interfering with opioid mediated mechanisms. Studies with naltrexone were so conclusive that it was approved by the Food and Drug Administration in 1994 as a treatment for alcoholism. It is possible that naltrexone may be particularly effective for patients with a family history of alcoholism, or individuals who show enhanced release

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of b-endorphin after alcohol administration. Unfortunately, the clinical use of naltrexone has not been widely adopted by practitioners, and poor adherence remains an impediment to its effectiveness. The role that EOP systems play in the acquisition and perpetuation of alcohol dependence requires further clarification and additional research. While genetic factors may influence EOP function and predispose some individuals to alcoholism, the repeated administration of alcohol may also produce significant EOP neuroadaptations. For instance, rats undergoing alcohol withdrawal have increased NAc levels of prodynorphin mRNA in conjunction with robust dynorphin release [23]. This finding is interesting in light of the fact that enkephalin and dynorphin have opposite regulatory actions on mesolimbic DA neurons. While alcohol reward is associated with the stimulation of m and d opioid receptors by enkephalin and b-endorphin, alcohol withdrawal (and perhaps craving) is associated with the stimulation of k opioid receptors with dynorphin. Dynorphin-containing neurons in the striatum may represent a separate population of GABA/EOP cells that specifically express D1 receptors and mediate compensatory actions in response to excessive DA stimulation [10]. Dynorphin inhibits DA activity and produces aversion, perhaps as a result of this action. Since naltrexone antagonizes k opioid receptors, in addition to m and d opioid receptors, its efficacy against craving and relapse may result, in part, from the reversal of dynorphin overactivity. More research is required to determine how chronic alcohol exposure affects EOP and DA neuromodulator systems, and how their dysregulation affects rewarding and aversive states associated with alcohol intake.

X.

CONCLUSIONS

This chapter has reviewed the neurobiology of alcoholism with a focus on neurotransmitter systems that are involved in the rewarding and aversive effects of alcohol. Rewarding and aversive states represent positive and negative reinforcers that drive alcohol addiction, particularly in genetically vulnerable individuals. Research into brain reward centers has provided significant insight into the mechanisms of alcohol reward and chronic neuroadaptations that lead to tolerance, withdrawal, and altered hedonic function. Tolerance and withdrawal involve compensatory changes in the balance of excitatory and inhibitory neurotransmission and become unopposed by alcohol after its abrupt discontinuation. Although alcohol withdrawal can be ser-

ious and even life-threatening, it responds very well to an appropriate and timely detoxification regimen. Less treatable are the persistent craving and dysphoria that are often reported by alcoholics who are attempting to achieve sobriety. This chapter has presented evidence that altered hedonic function by chronic alcohol exposure involves the dysregulation DA and EOP neuromodulator systems. These reward-related neuromodulators are intensely regulated by GABA, glutamate, and serotonin circuits which are extensively interconnected and integrated. Improving our understanding of the actions of alcohol on these complicated neuronal systems should identify pharmacological strategies to ameliorate aversive states associated with alcohol abstinence and thereby enhance recovery from this prevalent disorder. The neurobiology of alcoholism supports many clinical strategies currently employed in the treatment of this disorder. The notion that alcoholics should strive for total sobriety is supported by the fact that repeated alcohol administration produces opposite effects on neurotransmitter systems. These compensatory actions produce brain imbalances that are temporarily normalized by alcohol, but then exacerbated. Examples of this vicious cycle include the actions of alcohol on the GABAA and NMDA receptor complexes, and on EOP and DA function. Also, common actions by all substances of abuse, such as the release of DA into the NAc, provide a scientific basis for the established clinical principle that alcoholics attempting sobriety should avoid using all addictive agents, including benzodiazepines and barbiturates, which actually have similar allosteric actions on GABAA receptors. Denial, often attributed merely to the alcoholic’s strong wish to continue drinking, could have a basis in hypofrontality, which would explain its tenacity in the clinical setting. Finally, the prudence of avoiding ‘‘people, places, and things’’ associated with alcohol use is illustrated by studies showing limbic activation during cue-induced craving for alcohol. Given its biological basis, alcoholism should be viewed as a brain disease rather than a character weakness, and alcoholics should have the same access to treatment that has become the right of patients suffering from any medical illness.

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39 Biological Basis of Drug Addiction TONY P. GEORGE Yale University School of Medicine, New Haven, Connecticut, U.S.A.

I.

INTRODUCTION

for all addictive disorders, including those that do not currently have effective pharmacotherapies such as cocaine and methamphetamine addiction [2]. The purpose of this chapter is to delineate the biological underpinnings of drug addiction, and to describe current and future biological treatment approaches for these disorders based on such knowledge.

Drug abuse and dependence constitute a major public health problem in the United States. The consequences of licit (e.g., alcohol and nicotine) and illicit (e.g., cocaine, heroin, marijuana, phencyclidine) drug use leads to significant medical morbidity, mortality, and health care expenditure, and contributes to significant personal, family, and social misfortune. It is estimated that drug addiction costs U.S. society $67 billion each year in terms of crime, lost job productivity, and other social problems [1]. However, drug addiction continues to be both underrecognized and undertreated by primary care physicians and psychiatrists. This is particularly unfortunate since there are several very effective treatments for alcohol, opioid, and nicotine dependence disorders, especially when combined with appropriate psychosocial interventions (e.g., Alcoholics Anonymous, drug counseling, smoking cessation counseling). The belief among health care providers that drug addiction is a ‘‘moral failing’’ or ‘‘bad habit’’ is, unfortunately, still a common one, and it is well appreciated that many physicians (including psychiatrists) take a stance of ‘‘therapeutic nihilism’’ with respect to treatment of individuals with drug addiction. However, there is increasing evidence that addictive disorders have a strong biological basis, and this knowledge will most likely lead to effective treatments

II.

DEFINITIONS: DRUG ABUSE, DEPENDENCE AND ADDICTION:

It is important to clearly define common terms that are used to describe drug-seeking behaviors, and the functional consequences of drug misuse syndromes, since these terms have specific connotations, and should not be used interchangeably. Drug abuse, according to the DSM-IV [3], refers use of a psychoactive substance that leads to impairment of social and/or occupational functioning as evidenced by one of: (1) use of the drug under hazardous circumstances (e.g., driving a car); (2) drug use leads to neglect of external obligations (e.g., intoxicated and then forgets to pick up their child from daycare); (3) legal problems arising from drug use (e.g., driving under the influence [DUI] conviction); (4) interpersonal problems related to persistent drug use (e.g., loss of job, divorce). The above-referred pneumonic (‘‘h-e-l-p’’) is useful for remembering the four com581

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ponents that contribute to the diagnosis of drug abuse disorders. In contrast, drug dependence describes a constellation physiological adaptations (e.g., tolerance and withdrawal) and functional consequences of such physiological adaptation (drug taken in larger amounts, and for longer than intended, social and occupation activities impaired by drug use). It is important to note that the terms abuse and dependence are not mutually exclusive when describing drug use disorders, and it is possibly to be diagnosed with one, both, or neither diagnosis when classifying drug use. Finally, drug addiction refers to compulsive drugseeking, loss of control, and the adverse social and occupational consequences related to use of drugs of abuse.

III.

NEURAL SUBSTRATES OF DRUG ADDICTION

A.

Summary of Receptor Site(s) of Action of Drugs of Abuse

Table 1 describes the major classes of drugs of abuse, their purported site(s) of action at the molecular level, and the endogenous neurotransmitters that appear to mediate their actions. One common mechanism of all addictive drugs is their ability to increase dopamine (DA) release and turnover in the mesolimbic (‘‘reward’’) pathway (Fig. 1). In fact, there is increasing evidence for afferent regulation of mesolimbic DA neurons by most other major central neurotransmitter systems including serotonin, GABA, glutamate, endogenous opioid peptide, and nicotinic cholinergic systems [2]. B.

Mesolimbic DA System

A number of studies over the past 25 years have suggested that mesolimbic DA neurons, which project from the ventral tegmental area (VTA) in the midbrain to the anterior forebrain nucleus accumbens (NAS) mediate the reinforcing effects of drugs of abuse (Fig. 1). This is suggested by experiments involving lesions to the VTA by mechanical (e.g., electrolytic), chemical (6-hydroxydopamine, kainic acid) methods that have implicated the involvement of this pathway in drug reward [4]. However, the normal function of the mesolimbic DA system seems to relate to forming relevant associations between salient and arousing chemical and behavioral stimuli (e.g., food, sex, stress) and internal rewarding or aversive states.

Thus, this system helps the organism acquire behaviors reinforced by both natural rewards and drug stimuli. It is thought that the activity of mesolimbic DA neurons normally habituates with repeated exposure [5,6]. However, drugs of abuse abort this habituation leading to a change in the set point of the mesolimbic DA system [7], which may underlie addictive behaviors.

C.

Endogenous Opioid Peptide Reward Pathways

There is increasing evidence for afferent regulation of mesolimbic DA pathways by EOP systems. In addition, it appears that m- and k-opioid systems have opposing actions on mesolimbic DA neurons, with stimulation of m-receptors (in the VTA) increasing DA release, and stimulation of k-receptors (in the NAS) inhibiting DA release [8]. There is good neuroanatomic and function evidence for this interaction of opioid and DA systems at the level of the VTA [9]. In addition, recent studies suggest that EOP regulation of central DA pathways extends to tuberoinfundibular [10] and mesocortical DA pathways [11]. Besides mediating the reinforcing effects of opioid drugs, there is evidence from preclinical and clinical studies for EOP involvement in the reinforcing actions of other drugs of abuse, including alcohol [12–14], cocaine [15,16], methamphetamine [17], and nicotine [11,12]. These effects may ultimately be mediated through the DA reward system, given the afferent regulation of these DA neurons by opioidergic systems.

D.

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Evidence from animal and human studies indicates that environmental stress appears to be an important factor in drug relapse, and successful drug addiction treatment involves helping patients cope and address life stressors that inexorably lead to relapse. Numerous preclinical studies have documented that physical (e.g., footshock, restraint stress) and psychological (e.g., cue-induced) stressors can cause drug use reinstatement [16], and that stressors can lead to drug craving behaviors in human addicts [18]. In fact, increased cortisol (or corticosterone in rats) levels are known to potentiate the mesolimbic DA system, and may be a basis for stress-induced drug craving [16].

a

Serotonin

Glutamate Dopamine

Dopamine Serotonin Norepinephrine

Anandamide Dopamine Endogenous opioids

Endogenous opioids Dopamine Glutamate

Dopamine Norephinephrine Serotonin GABA Glutamate Endogenous opioids

No proven pharmacotherapy



Nicotine Replacement (patch, gum, inhaler, spray) Sustained-Release Bupropion


Methadone Clonidine Naltrexone Buprenorphine

No proven pharmacotherapy Desipramine (and other TCAs) Dopamine Agonists, Disulfiram

Disulfiram Naltrexone Acamprosate SSRIs

Pharmacologic treatments

Examples of pharmacological agents which have been devised for use in the treatment of these drug abuse disorders are also given.

Serotonin transporter (SERT) Serotonin synthesis

MDMA (Ectasy)

? Monoamine oxidase (A/B isoforms)

NMDA receptors Dopamine transporter (DAT)

Nicotinic acetylcholine receptors

Nicotine (tobacco)

Phencyclidine

Cannabinoid (CB1, CB2) receptors

Marijuana

Vesicular monoamine transporter (VMAT) Monoamine transporter (DA, 5HT, NE)

Dopamine Serotonin Norephinephrine GABA Glutamate Endogenous opioids

m-Opioid receptors (e.g., morphine, heroin)

Opioids

Amphetamine

Acetylcholine

Dopamine transporter (DAT) Norephinephrine transporter (NET) Serotonin transporter (SERT)

Cocaine

Glutamate GABA Dopamine Serotonin Endogenous opioids

Nonspecific membrane effects NMDA receptors (noncompetitive site) GABAa receptors (chloride channels) Voltage-dependent calcium channels

Alcohol/sedatives

Endogenous neurotransmitter systems

Site of action

Site(s) of Action of Various Drugs of Abuse and Neurotransmitters Implicated in Their Actionsa

Drug

Table 1

Biological Basis of Drug Addiction 583

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which correlate with a profoundly enhanced cocaine ‘‘high’’ compared to oral and intranasal routes. Interestingly, in controlled animal studies, the correlations between plasma levels of cocaine and reinforcing effects are not exact, and this may relate to differential tolerance with intravenous versus oral administration and differences in metabolite profiles produced by these two routes of cocaine administration [20].

IV.

Figure 1 Mesolimbic dopamine (‘‘reward’’) pathways. The dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAS) and prefrontal cortex (PFC) are diagrammed.

E.

Pharmacokinetics of Addictive Drugs: Implications for Drug Reward

There is substantial evidence that the rewarding effects of drugs of abuse correlate with how much drug gets into the brain and how quickly the drug reaches the brain. That is, in pharmacokinetic studies, both the drug level obtained and the rate of rise (e.g., ascending portion of curve) are important factors in predicting drug ‘‘liking’’ and ‘‘rewarding’’ effects. An example of cocaine pharmacokinetics with administration of cocaine by various routes, as assessed by plasma cocaine levels (in arbitrary units) over time after cocaine administration [19], is presented in Figure 2. Oral cocaine (A) administration (e.g., chewing coca leaves) leads to very slow absorption of cocaine hydrochloride, which is a charged molecule that does not easily cross the mucous membranes. Consequently, the reported drug ‘‘high’’ is modest. Intranasal (i.e., snorted) cocaine (B) has a slightly faster rate of absorption and therefore produces more drug ‘‘high’’ than orally ingested cocaine. Finally, intravenous and freebase (crack) uses of cocaine (C) have much faster rates of absorption (in the first case due to an intravenous bolus of cocaine which gets to the brain in large amounts; in the second case because freebase cocaine is more membrane permeable and is rapidly absorbed through the pulmonary circulation and into the brain),

BIOLOGICAL THEORIES TO EXPLAIN COMPULSIVE DRUG USE

There are several current and seemingly contradictory theories regarding the development of compulsive drug-seeking behavior and ultimately drug addiction [4,7,21–23]. Several aspects of these theories are compatible with the clinical course of addictive disorders, and the disagreements between the theories relate to the complexities of drug addiction and the biochemical, neuroendocrine behavioral models in preclinical studies on which these theories are based. A.

Allostatic Dysregulation Model

This theory of drug addiction has been proposed by Koob and LeMoal [7,21]. Allostasis refers to the counteradaptive changes in brain function induced by

Figure 2 Pharmacokinetics of cocaine administration by three routes. The plasma concentrations of cocaine (in arbitrary units) produced by three routes of cocaine administration (oral, intranasal, and intravenous/inhalation) are depicted. The rewarding effects of cocaine and other drugs of abuse relate to how rapidly the drug enters the brain, which directly correlates with plasma drug levels.

Biological Basis of Drug Addiction

chronic drug administration, such that there is a chronic deviation of the brain reward ‘‘set point,’’ which relates to reward circuit dysregulation. The brain circuits involved are presumably in the corticostriatothalamic loop [24]. They describe a cycle of ‘‘spiraling distress’’ whereby alternating binge intoxication (with resultant drug tolerance) and negative affect associated with acute drug withdrawal leads to adaptive changes in brain reward mechanisms (e.g., the mesolimbic dopamine pathway, endogenous opioid systems) that consequently produce compensatory compulsive drug-seeking behavior, leading to the classical impairments in social and occupational functioning that constitutes drug addiction. Environmental stressors are seen as an important cofactor in both initiation and perpetuation of this cycle, presumably through alterations in HPA axis function [16]. As such, this view focuses on the positive (drug-liking) and negative (drug withdrawal) aspects of drug addiction, which are both processes that occur in the short term and lead to a dysregulation of ‘‘hedonic homeostasis.’’ B.

Incentive-Sensitization Model

This theory, proposed by Berridge and Robinson [22], purports that like the allostatic model, chronic drug use leads to changes in reward system function, such that an addict becomes sensitized to drug use, but that these brain systems do not mediate euphoric effects of drug use (e.g., drug liking) but mediate a specific component of drug reward (‘‘drug wanting’’), which they refer to as ‘‘incentive salience.’’ This view of drug addiction, in contrast, is not based on short-term drug reward and withdrawal syndromes to explain the process of addictive behaviors, and may in fact be compatible with the observations that many drug users who achieve initial abstinence often relapse to drug use in the context of exposure to environmental cues that potentiate drug ‘‘wanting,’’ which is dissociable from drug ‘‘liking’’ [22]. Experimental support for the ‘‘incentive sensitization’’ model comes from recent functional neuroimaging studies in cocaine addicts [25] which demonstrated that the nucleus accumbens showed increases in blood flow (activation) during craving for cocaine, and not during acute intravenous administration. C.

Phasic/Tonic DA Release Model

This model of drug addiction, posited by Grace [23], was first formulated in the context of understanding

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how dysregulated dopamine dynamics may mediate the symptoms of schizophrenia [26]. It suggests that the mesolimbocortical dopamine system is dysregulated by chronic drug administration and that this dysregulation leads to drug addiction. Functionally, mesolimbic DA neurons have two types of activity: (1) tonic DA release, which is mediated by cortical glutamatergic afferents that ensures an appropriate basal level of mesolimbic DA activity; and (2) phasic DA release, which refers to evoked DA release, and is typically the type of DA activity stimulated by drugs of abuse like cocaine, amphetamine, and nicotine that leads to a large increase in synaptic DA levels. Of note, mesolimbic DA neurons have release-inhibiting preterminal DA autoreceptors (D2 ) that normally function to shut down mesolimbic DA neuron function when synaptic DA levels are excessive. With chronic drug exposure, tonic DA levels would be expected to rise, causing enhanced presynaptic DA autoreceptor stimulation, thus inhibiting mesolimbic DA neuron activity. Accordingly, the experience drug user will take drugs to offset this dysregulation in tonic DA release in an attempt to augment the diminished phasic DA release that is counteracted by increased tonic DA levels. This model assumes that the mesolimbic DA system is the unitary biological substrate of drug addiction, and is similar in concept to the allostatic state proposed by Koob and LeMoal [7,21]. D.

Cognitive Deficits Model

The prefrontal cortex is important in regulation of judgment, planning, and other executive functions, and it sends inhibitory projections to subcortical areas, which include the mesolimbic DA reward pathway. This model posits that: (1) individuals who develop addictive disorders have preexisting cognitive (e.g., prefrontal cortical) deficits that predispose them to impulsivity and compulsive drug-seeking behavior [27,28]; and (2) continued drug use further worsens the severity of these deficits through chronic and repeated insults to the prefrontal cortex [24]. For example, it is known that cocaine addicts have cerebral cortical perfusion deficits [28]. Such abnormalities in the ‘‘frontostriatal loop’’ are believed to contribute to impulsivity, compulsive drug-seeking behavior, and loss of behavioral control, which are associated with frontal cortical cognitive deficits and may explain the increasing severity of drug addiction with chronic and persistent drug use, especially in individuals with known deficits in PFC function (e.g., schizophrenia, antisocial personality disorder).

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V.

MECHANISMS OF ADDICTIVE DRUG ACTION

A.

Cocaine and Psychostimulants

The monoamine transporter proteins, which act as a reuptake mechanism for terminating synaptic monoaminergic neurotransmission, are the primary site(s) of cocaine’s action in the brain. Cocaine inhibits the reuptake of monoamine transmitters, in the order: dopamine ðDAÞ > norepinephrine ðNEÞ > serotonin (5-hydroxytryptamine; 5HT). Accordingly, cocaine administration leads to a massive elevation of synaptic monoamine levels [29]. DA is thought to be the most important neurotransmitter relevant to the reinforcing effects of cocaine, and DA agonists and antagonists have been tested as potential pharmacotherapies based on this putative mechanism. With repeated cocaine administration, a constellation of changes in brain function are induced, including in levels of postsynaptic receptors (e.g., downregulation of DA-D2 receptors) and in second-messenger systems (e.g., cyclic-AMP response element binding protein [CREB], neurotrophins, [30]), which may explain some of the long-term clinical effects of chronic cocaine administration such as tolerance, withdrawal, and sensitization [31]. Psychostimulants (including methamphetamine, methyphenidate, and congeners) work primarily by releasing monoamines (DA, NE, 5HT) from presynaptic nerve terminals by two mechanisms: (1) blocking the vesicular monoamine transporter (VMAT), which sequesters monoamines in presynaptic vesicles, leading to increased levels of presynaptic free monoamines; and (2) reversing transport through monoamine transporter proteins (probably a consequence of #1). This leads to massive elevation of synaptic monoamine levels, the most important being DA. While the molecular mechanisms of psychostimulant drugs other than cocaine have received less study, there appear to be similar chronic adaptations in neural systems involved [22,32]. B.

Alcohol and Sedative Hypnotic Drugs

A discussion of the mechanisms of action of alcohol is given in Chapter 38 (‘‘Biological Basis of Alcoholism’’). Sedative-hypnotic agents like barbiturates (e.g., phenobarbital, secobarbital) appear to work through mechanisms in common with alcohol, including facilitation of GABAA -linked chloride ion transients (leading to target membrane hyperpolariza-

tion and reduced firing rates). The role of GABA-ergic and glutamatergic systems in mediating the effects of sedative-hypnotic drugs is becoming clearer [7], especially in light of the observation that benzodiazepines and related agents inhibit mesolimbic DA release (through stimulation of GABA-ergic afferent inputs onto these DA neurons). C.

Nicotine and Tobacco

Nicotine is the primary constituent of tobacco products that appears to be responsible for the reinforcing effects of tobacco use [33]. The most common method of nicotine delivery is through smoking cigarettes. The primary site of action of nicotine is the nicotinic acetylcholine receptor (nAChR). The nAChR is a heteromeric ion channel complex that is composed of combinations of two a (a2-9) and three b (b2-4) subunits, with the a4b2 nAChR being the predominant subunit complex in human brain [34]. The main ions that permeate this channel are sodium (Naþ ) and calcium (Ca2þ ), leading to neuronal membrane depolarization. Autoradiographic and immunocytochemical studies have demonstrated that nAChRs are located presynaptically on numerous neurotransmitter secreting neurons [34,35], including those for DA, NE, 5HT, GABA, glutamate, and EOPs, and stimulation of these receptors by nicotine leads to release of these transmitters. In contrast to other agonist drugs, after nicotine stimulates the nAChR, the receptor desensitizes almost immediately, and this progresses to nAChR inactivation. With repeated nicotine administration (as is the case with habitual smoking), this leads to a compensatory upregulation of nAChRs, known as the ‘‘paradoxical upregulation’’ of nAChRs by nicotine. This phenomenon may explain why dependent smokers find that the most satisfying cigarette of the day is the first one, and why nicotine cravings and withdrawals are so intense in the majority of dependent smokers. Animal models of nicotine dependence suggest that it takes 2–3 weeks for upregulated nAChR levels to return to normal after cessation of nicotine administration. Such a change in nAChR number and function is consistent with an allostatic alteration in these systems induced by repeated nicotine administration [7,21]. There is recent evidence from in vitro and positron emission tomography (PET) studies to suggest that an unidentified component of tobacco smoke (not nicotine) inhibits monoamine oxidase A (5HT) and B (DA, NE) isoforms, which are responsible for the degrada-


tion of monoamines. This additional action of tobacco may contribute to its psychopharmacologic properties [36,37]. D.

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noid administration increases, and cannabinoid abstinence decreases, mesolimbic DA release [41], suggesting that mesolimbic DA systems subserve the reinforcing effects of cannabinoids.

Opioids

All opioid drugs work through agonism at the mopioid receptor, at which the enkephalin subclass of endogenous opioid peptides (EOPs) are the endogenous neurotransmitters for these receptor systems. Full m-receptor agonist drugs include morphine, heroin (a morphine pro-drug), oxycodone, and methadone, and binding of opioid drugs to the m-receptor leads to activation of cAMP systems and inhibition of an outwardly rectifying Kþ current, leading the membrane hyperpolarization [31,32]. Most addictive opioids are short acting (e.g., morphine, heroin, oxycodone), and long-acting preparations (e.g., methadone) have been used to treat opioid addiction using long-term maintenance (e.g., methadone maintenance). Most recently, partial m-receptor agonists (mixed agonistantagonists) such as buprenorphine (which also has k-antagonist properties, which presumably augments mesolimbic DA function) have shown effectiveness for the treatment of opioid dependence and addiction. In addition, there is good evidence that long-acting mopioid antagonists (e.g., naltrexone) can be useful as a relapse prevention pharmacotherapy for opioid dependence.

F.

Also known as angeldust, PCP is an arylcyclohexylamine which has well-described psychotomimetic properties. In healthy human subjects, its produces a constellation of cognitive and clinical symptoms which resemble a schizophrenic psychosis [42], and produces cognitive deficits similar to those present in schizophrenic patients when repeatedly administered to nonhuman primates and rats [24,43]. PCP binds to the NMDA receptor complex at its noncompetitive (ion channel) site. It closely resembles the actions of ketamine, a dissociative anesthetic and veterinary tranquilizer, which produces similar effects in human subjects. At higher concentration, PCP is known to inhibit the DAT, which could contribute to its propensity to lead to positive symptoms of psychosis such as delusions, hallucinations and thought disorder. It is chemically similar to ketamine (‘‘Special K’’), a frequently abused psychotogenic and recreational drug.

G. E.

Cannabinoids

Cannabinoids are plant alkaloids (from Cannabis sativa) with well-described euphoric, sedating, analgesic, antiemetic, and appetite-stimulating properties. In 1990, several groups cloned brain cannabinoid receptors which bound with high affinity to delta9 tetrahydrocannabinol (THC), the principal psychoactive component of marijuana and related preparations. It was later shown that a condensation product of two constituents of lipid membranes, arachidonic acid and ethanolamine, known as anandamide (arachidonylethanolamine), was the endogenous ligand for the cannabinoid receptor [38]. There is evidence for two distinct subtypes of cannabinoid receptor, designated CB1 and CB2 [39]. CB receptors are G-protein-coupled receptors. The exact physiological functions of CB receptors are not known, though a recent study with CB1 transgenic mice (with ‘‘knockout’’ of the CB1 receptor) demonstrated an attenuated morphine withdrawal behavioral syndrome [40]. There is strong evidence that cannabi-

Phencyclidine (PCP):

Methylenedioxymethamphetamine (MDMA; Ecstasy)

MDMA is a psychedelic drug which is a derivative of methamphetamine that has become frequently abused by young adults, particularly at ‘‘rave’’ parties [44]. Typical single doses of MDMA are 100–200 mg, and it produces a ‘‘rush’’ similar to methamphetamine lasting 3–4 hours and feelings of ‘‘connectedness,’’ tranquility, apathy, and alterations in time perception. While not well studied, there may be a withdrawal syndrome associated with MDMA cessation in chronic users which resembles psychostimulant abstinence. Its mechanism involves indirect 5HT agonist activity by potentiation of 5HT release and through 5HT reuptake blockade. Further, there is evidence that it inhibits the synthesis of 5HT and that it may be toxic to serotonergic neurons. It has been associated with a posthallucinogen perception disorder reminiscent of that observed with LSD, and with serotonin syndrome, because of excessive central serotonergic activity. At present, no specific pharmacologic treatment exists for MDMA abuse.

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CLINICAL ASSESSMENT OF THE DRUG-ADDICTED INDIVIDUAL: IMPLICATIONS FOR PHARMACOTHERAPY OF ADDICTIVE DISORDERS

The emerging biological knowledge about drug addictions has had profound implications for our treatment approaches to addictive disorders. In this section, I will briefly discuss available pharmacotherapies for addictive disorders, including opioid, nicotine, and cocaine (stimulant) addiction. Subsequently, I will describe a general approach to the assessment and treatment of individuals with addictive disorders in three specific populations: the monodrug user; the polydrug user; and the drug user with a comorbid psychiatric disorder(s).

A.

1.

Specific Pharmacotherapies for Addictive Disorders Pharmacotherapy of Opioid Dependence Methadone (Including LAAM).

This full m-opioid receptor agonist has become the mainstay of opioid maintenance treatment in the United States [45]. The pioneering studies of Dole and Nyswander established its efficacy as a treatment for opioid addiction in the 1960s [16]. The drug is classified as a schedule II controlled substance by the Drug Enforcement Agency (DEA), and can only be administered in federally sponsored methadone programs which require careful monitoring of patients and weekly drug counseling [46]. The half-life of the drug is 24–36 hr in patients without hepatic disease, and methadone is primarily metabolized by the CYP 3A4 system. Patients beginning treatment are generally started on a daily dose of 20–30 mg/day, with weekly dose increases of 5–10 mg/day until a dose of 60– 100 mg/day is achieved, that produces full suppression of opioid craving symptoms and resultant opioid-free urine toxicology [46]. Patients generally stay on methadone for 6 months to 3 years, although it is still common for some patients to receive lifelong methadone maintenance. A longer-acting derivative of methadone (L-alpha-acetomethadol; LAAM) is also FDA approved, and because of its long half-life (48–72 hr) can be given three times per week.

Naltrexone (Trexan) Naltrexone is a long-acting (half-life 24 hr) congener of naloxone, the short-acting (half-life 0:5 hr) m-opioid receptor antagonist. It is generally given to opioid-dependent individuals who have been successfully detoxified from opioids; in opioid-dependent patients, administration will produce the rapid onset of the opioid withdrawal syndrome. It is typically started at 12.5–25 mg/day once daily with food, and titrated to a dose of 50–100 mg/day. Nausea and gastric irritation are common side effects. Liver function tests should be obtained at baseline prior to initiation of treatment since naltrexone is associated with elevation of transaminases and, rarely hepatotoxicity, necessitating periodic monitoring of liver function [47]. In addition, naltrexone (ReVia) was approved in 1992 for the treatment of alcohol dependence [13,14]. Buprenorphine (Subutex) Buprenorphine is a partial m-opioid receptor agonist and k-antagonist which is expected to be approved for the treatment of opioid dependence in 2001. Several recent clinical trials have established its safety and efficacy (comparable to methadone) in opioid-dependent patients [48,49]. Because of its partial agonist properties, it appears to be safer in drug overdoses, and since it has a half-life of 36 hr, it can be given three times per week. Because of its safety and convenience of dosing, it may be useful for the treatment of opioid addiction in primary care settings, which is especially helpful since most opioid addicts have significant medical problems (e.g., hepatitis B/C, HIV). Buprenorphine will be available in 4- and 8-mg tablets, and as a combination tablet with naloxone (Suboxone; to reduce illegal diversion of the medication) it is also likely to be approved by the FDA by the end of 2001. The daily maintenance dose of buprenorphine is 24–36 mg/day. 2.

Pharmacotherapy of Nicotine Dependence Nicotine Replacement Therapies (NRTs)

The best studied of the pharmacological treatments for tobacco addiction are the nicotine replacement therapies (NRTs), which include the nicotine gum, nicotine patch, nicotine nasal spray, and nicotine inhaler [33,50,51]. The more slowly absorbed formu-


lations (gum and patch) appear to be helpful to alleviate nicotine withdrawal symptoms, and the fasterabsorbed preparations (nasal spray and inhaler) appear to better substitute for the rewarding effects of cigarettes. The smoking cessation rates at the end of treatment are typically 50–70%, and 30–40% of subjects remained abstinent at 6- and 12-month follow-up assessments [52]. The gum and patch are available over the counter (OTC), but the nasal spray and inhaler are prescription drugs. Unfortunately, the cost of these preparations ($25–35/week) are prohibitive for many smokers who want to quit, and the prescription preparations are often not covered by health insurance [52]. Sustained-Release Bupropion Bupropion is a heterocyclic antidepressant agent which was approved by the FDA for the treatment of depression (Wellbutrin) in the late 1980s. Several clinical studies in the early 1990s documented than it could reduce smoking [53–55], and the drug was approved as a treatment for nicotine dependence by the FDA in 1997 as Zyban. The initial dose is 150 mg PO QD, and the dose is increased to 150 mg PO BID (300 mg/day) by the second week of treatment; patients are encouraged to try to quit smoking when they reach the 300 mg/day dose. Treatment with Zyban is recommended for 6–12 weeks. Smoking cessation rates with Zyban are typically higher than for the nicotine patch, but are reduced after the medication is discontinued [54], and there appears to be a modest (but nonsignificant) improvement in quit rates when Zyban is combined with the nicotine patch [56]. A history of seizures is a contraindication for the use of this drug. Other Promising Agents for the Treatment of Nicotine Addiction Other, nonapproved agents which may be useful for the treatment of nicotine addiction include clonidine [57,58]; an a2 agonist which may reduce withdrawal symptoms]; buspirone [59], a 5HT1a agonist and anxiolytic agent; nortriptyline [60], a tricyclic antidepressant; moclobemide [61], a monoamine oxidase A inhibitor; and the combination of nicotine patch and mecamylamine, a high-affinity nicotinic receptor antagonist [62,63].

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3.

Pharmacotherapy of Cocaine (Stimulant) Dependence Desipramine and Other Tricyclic Antidepressants (TCAs)

Desipramine hydrochloride (DMI) is the beststudied TCA, and several early studies (particularly those which used open-label designs [64]), and three placebo-controlled studies at Yale [65,66], found that DMI was efficacious for reducing cocaine use in cocaine-dependent subjects. However, the results of subsequent placebo-controlled studies, including those at other sites, have been equivocal, and based on a meta-analysis of the initial six placebo-controlled trials, the efficacy of DMI for cocaine addiction treatment has been questioned [67]. Similar equivocal findings have been reported with imipramine [68] for both cocaine and methamphetamine addiction. However, DMI and other TCAs may have some benefit in cocaine-addicted individuals with a history of depression [69]. Selective Serotonin Reuptake Inhibitors (SSRIs) There is little evidence that SSRI drugs are effective treatments for cocaine dependence [70], except perhaps in individuals with comorbid major depressive symptoms. Dopaminergic Agonists and Antagonists Amantadine and bromocriptine have shown limited success [71,72], but dopamine D2 antagonists (chlorpromazine, haloperidol) have not [73]. D1 agonists have looked promising in animal self-administration studies [32] and in human cuereactivity studies [74], but preliminary clinical trials have not been encouraging. Bupropion, a catecholamine reuptake inhibitor, and mazindol, a selective dopamine reuptake inhibitor, have also not shown efficacy in cocaine pharmacotherapy trials [75,76]. Disulfiram Disulfiram, best known as an aldehyde dehydrogenase inhibitor used in the treatment of alcohol dependence, has been shown in three studies at Yale University to have efficacy for the treatment of cocaine addiction [65,66,77]. Its mechanism of action appears to be independent of effects in reducing comorbid alco-

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hol use [66], and it may act through increasing plasma cocaine levels by inhibiting plasma esterases which metabolize [78], and inhibition of the dopamine-bhydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, thus presumably increasing synaptic DA levels, which are thought to be depleted in chronic cocaine users. The drug is associated with some toxicity (e.g., transaminase elevations, psychotic reaction) and with severe reactions when combined with alcohol, so widespread use for the treatment of cocaine addiction may be limited. B.

Approach to the Addicted Individual

1.

The Monodrug User

The approach to the monodrug using patients entails selecting an effective agent for the treatment of the single addictive disorder. Such effective treatments are available for opioid dependence (e.g., methadone, buprenorphine), alcohol dependence (e.g., disulfiram and naltrexone), and tobacco (nicotine replacement therapies, sustained-release bupropion), but not as yet for cocaine or other psychostimulants. The effectiveness of these pharmacotherapies has been reviewed elsewhere, and is greatly enhanced by the patient’s motivation to quit using drugs at the beginning of treatment [79,80], though effective addiction pharmacotherapies can often be helpful in those individuals without substantial motivation to quit (e.g., the individual who just wants to take a pill, rather than do behavioral treatment). With respect to pharmacotherapies, one must strive to use the safest agent available (minimal side effects) balanced with one that will have treatment effectiveness. Accordingly, in an opioiddependent patient who is noncompliant with treatment and at risk for drug overdose, treatment with buprenorphine (which can be given three times daily and has minimal overdose potential) might be preferable to methadone (daily administration, high risk of overdose) treatment. Use of structured assessment scales like the Addiction Severity Index (ASI [81]) provides multimodal assessment of preexisting functional impairment prior to drug treatment, and can provide individualized information that can be used to tailor treatments (e.g., treatment matching). 2.

The Polydrug User

Similarly, any effective pharmacotherapy(ies) for the individual drug abused may be helpful, but targeting only one drug of abuse in a polysubstance abuser is often likely to fail since the use of one drug of abuse

can condition use of another (e.g., a cocaine user who also injects heroin and drinks alcohol during cocaine binges may promote cocaine craving after initial abstinence if he uses heroin or alcohol). Furthermore, the severity of addiction is likely to be higher in the polydrug abuser and these patients are more likely to have concurrent (chronic) mental and medical illness [82] and therefore to have poor treatment outcomes. In general, if one of the drugs of abuse has a defined pharmacotherapy (e.g., heroin), then a specific treatment can be initiated (e.g., methadone, naltrexone) and this addiction stabilized, prior to addressing abuse of a substance that does not have a well-established pharmacotherapy (e.g., concurrent cocaine dependence in a methadone-maintained individual). 3.

The Drug User with Psychiatric Comorbidity

The psychiatric drug abuser poses considerable diagnostic and therapeutic challenges for clinicians, and the therapeutic approach taken with these ‘‘dually diagnosed’’ individuals is often colored by the treatment philosophy of the treating clinician (e.g., mental health versus addictions treatment provider). Accordingly, mental health clinicians tend to underemphasize (or ignore) substance abuse treatment in their psychiatric patients, and primary substance abuse providers tend to overlook psychiatric issues in their patients [83]. Given the typical fragmentation of mental health and addictions treatment in most health care systems, these individuals often ‘‘fall between the cracks,’’ and in many cases this is related to their low motivation to receive treatment [84], which is frequently related to a lack of insight into the severity of their combined mental health and addiction problems. Nonetheless, in cases where individuals may be self-medicating psychiatric symptoms with substances of abuse (e.g., the depressed cocaine user), pharmacotherapies directed at the underlying psychiatric disorder may be useful. For example, it has been shown that the tricyclic antidepressant desipramine, which may have some efficacy in the pharmacotherapy of cocaine dependence, may be especially effective in depressed cocaine addicts [69]. Furthermore, individuals with schizophrenia may use nicotine to alleviate clinical (e.g., negative symptoms, extrapyramidal side effects) and cognitive (e.g., working memory, attentional) deficits associated with this illness [53,85]. There is evidence that the atypical antipsychotic drug clozapine [86–88] can reduce smoking and that clozapine and other atypical antipsychotic drugs such as risperidone and olanzapine can increase smoking cessation rates in combination with the nico-


tine transdermal patch, compared to typical antipsychotic agents (e.g., haloperidol, chlorpromazine) [89]. Methods that increase compliance with pharmacotherapies, like using medications with minimal side effects (e.g., SSRIs vs. TCAs in substance-abusing depressed patients; atypical antipsychotic drugs in drug-abusing schizophrenics), medications that can be given once daily, or by injection on a monthly or bimonthly basis (e.g., haloperidol and fluphenazine decanoate, respectively), and those with low overdose potential (e.g., anticonvulsant mood stabilizer [e.g., sodium valproate or gabapentin] vs. lithium in a substance abuser with bipolar disorder) are all strategies to deliver more effective and tolerable treatment in dually diagnosed individuals. More research is needed on the efficacy of substance abuse pharmacotherapies in psychiatric populations, but conducting such research is difficult owing to the poor compliance of dually diagnosed subjects with the study interventions, and the high subject attrition rates in these trials. Nonetheless, conducting research in dually diagnosed subjects will yield important new information which can guide clinicians as to what pharmacological and behavioral interventions are useful and practical in this challenging patient population.

VII.

TREATMENT OPTIMIZATION: COMBINATION OF BIOLOGICAL AND PSYCHOSOCIAL (BEHAVIORAL) TREATMENT OF ADDICTIVE DISORDERS

Use of substance abuse pharmacotherapies is most effective when combined with standardized psychosocial (behavioral) treatments for these disorders [90]. For individuals who are attempting abstinence initiation (e.g., trying to stop using drugs), the motivational enhancement therapies, which encourage individuals to make the choice to become abstinent for their own reasons, are the psychosocial therapy of choice. Individuals who have stopped using drugs and who want to maintain their sobriety from drug use are best treated with the relapse prevention therapies, a derivative of cognitive-behavioral therapies, which emphasize strategies for avoiding cues that promote drug relapse (people, places, and things associated previously with their drug use). Several studies have reported an interaction between pharmacotherapeutic and psychotherapeutic interventions [60,90]. In fact, in federally funded methadone maintenance programs,

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drug counseling is a mandatory part of treatment with methadone [46]. VIII.

CONCLUSIONS

There is increasing preclinical and clinical evidence for a biological basis to addictive disorders, which should lead to a new era of innovative and effective pharmacotherapies for addictive disorders. Addictive disorders should be considered as chronic medical disorders like hypertension, schizophrenia, and diabetes [1], given the long-term nature of these disorders, frequent symptom relapse, need for extended treatment, and absence of any ‘‘cure’’ for these disorders. The common biological system that appears to be involved in the pathophysiology of all addictive disorders is the mesolimbic dopamine (DA) system, but other neural pathways including the endogenous opioid peptide systems and the HPA axis are probably of relevance to several addictive drugs, including opioids, alcohol, cocaine, and nicotine. Treatments for these addictive disorders are increasing with the emerging knowledge of the biological basis of addiction, but one glaring deficit is the absence of an effective pharmacotherapy for cocaine dependence and other illicit psychostimulant addictions. The effective use of any such pharmacotherapy for addictive disorders will necessitate combination with effective psychosocial treatments for addiction, especially given the complex biological, psychological, and social aspects of addictive illnesses. ACKNOWLEDGMENTS Supported in part by grants P50-DA-12762 (PI: T.R. Kosten), P50-DA-13334 (PI: S.S. O’Malley) and R01DA-14039 (to T.P.G.) from the National Institute on Drug Abuse (NIDA), the VISN 1 Mental Illness Research, Education and Clinical Center (MIRECC) of the Department of Veterans Affairs and a Wodecroft Foundation Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) to T.P.G. The helpful comments of Thomas R. Kosten, M.D. and Richard S. Schottenfeld, M.D. on the manuscript are gratefully acknowledged. REFERENCES 1.

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40 Neuroimaging Abnormalities in Drug Addiction and Alcoholism WYNNE K. SCHIFFER, DOUGLAS A. MARSTELLER, and STEPHEN L. DEWEY Brookhaven National Laboratory, Upton, New York, U.S.A.

I.

INTRODUCTION

application of treatment and prevention. One is to determine the actions of these drugs on the brain, with the hopes of clarifying those actions that contribute to the rewarding or reinforcing processes of drug dependence. This is critical both to the development of treatment options and to potential hereditary effects produced by prolonged drug exposure. The second objective, then, is to elucidate the physiological nature of drug vulnerability, such that an increased susceptibility to drug dependence might be expressed by different physiological markers or functional responses to rewarding drugs. For example, chronic drug abusers might express an increased number of receptors compared to healthy controls, which might subsequently alter the neurochemical and behavioral response of these patients to drug therapies targeting other symptoms (like anxiety). Finally, given the subtle plasticity of the brain and the vulnerability of neural systems to chronic drug exposure, it is likely that prolonged drug abuse produces physiological and functional changes that may possess hereditary significance. Given that PET can measure both neurophysiology and neurochemical function, the third objective is to use our understanding of drug mechanisms and drug effects to locate and protect vulnerable populations. PET can be used to label proteins of physiological relevance, such as receptors, transporters, and enzymes in the human brain, as well as to provide an indirect

Although the theoretical premise of positron emission tomography (PET) research has remained largely the same over the past two decades, advances in chemistry and PET instrumentation coupled with a detailed examination of the biochemistry of new radiotracers have allowed PET to be applied to new areas of biology and medicine. The basis for the PET method is the use of tracer kinetics in the study of human biochemistry and physiology in vivo. Thus, any PET study involves a multiplicity of processes which together result in the PET image and the pharmacokinetics that define that image. PET studies allow us to observe, noninvasively, the morphology associated with addiction both in terms of physiology and function. In this, PET is not used to define a biochemical pathway in a single cell, and it does not compete with the elegant basic work or the structure and function of single cells or small groups of cells. By the same token, and this is one of the great powers of PET, the ability to assay the dynamic activity of a large aggregate of cells in vivo, especially the human brain, involving systems with numerous complex interactions in quantitative terms, is unique to PET. As a whole, neurochemical imaging studies of addiction and the addictive process have three main goals, which are integrated into the overall clinical 595

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index of synaptic neurotransmitter activity in the living system. These studies also allow an evaluation of the relationship between the kinetics of an abused drug in the brain and the temporal relationship to its behavioral effects (Fig. 1). PET radiotracers are chemically similar to the endogenous compounds whose actions they probe and possess similar pharmacological profiles to many drugs under investigation. To date, methamphetamine [Nakamura et al. 1996, 1997), nicotine [Nyback et al. 1994], opiates [Hartvig et al. 1984], cocaine [Fowler et al. 1989], and methylphenidate [Ding et al. 1994] have been successfully labeled. Thus, some radiotracers probe biochemical and physiological changes directly, while others provide an indirect mechanism of what we believe a drug action is in the brain. Studies exploring the pharmacologic activity of marijuana use a labeled compound that mimics the activity of what we believe to be an endogenous ligand for the cannabinoid receptor [Gatley et al. 1998]. PET is uniquely suited to simultaneously manipulate and measure synaptic neurotransmitter responsiveness in the living brain. This approach can be used to assess the functional integrity of neurotransmitter systems and the multiple mechanisms of drug action. In this, the development of radiotracers for studying various systems remains one of the major thrusts of PET research. At this point, a broad spectrum of radiotracers has been developed and applied to

Figure 1 Time activity curves for ½11 Ccocaine in the striatum plotted alongside the temporal course for the self reported ‘‘high’’ induced by intravenous cocaine administration. Measures are shown as percentage change from peak response. (From Volkow et al. 1995.)

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the study of the brain with a special focus on drug mechanisms and the physiological changes associated with drug addiction. This chapter will begin with a brief overview of current philosophies regarding the nature of drug reward and drug abuse as they relate to possible physiological adaptations in the addicted patient. In the next section, we provide a summary of findings in our laboratory and others using carbon-11-labeled cocaine to examine both drug mechanism and physiological changes specific to psychostimulant abuse. Since the development of ½11 Ccocaine provided the impetus for quantitative methods that are widely applied today, we will briefly discuss issues related to the application of these methods. This will be followed by sections describing the status of other labeled drugs of abuse, and what they have contributed to our understanding of the addicted brain. A discussion of the use of PET to develop various treatments for addiction will be included following that, and the chapter will conclude with a section on the challenges facing the development of appropriate pharmacotherapies for addiction given the altered physiological states associated with chronic drug abuse or vulnerability to drug abuse.

II.

UNDERSTANDING DRUG DEPENDENCE

All drugs of abuse initially interact with specific receptor or reuptake proteins, which, depending on the pharmacokinetic and pharmacodynamic properties of the drug, produce a chain of events that activates a central reward system in the brain. Given that drugs with different mechanisms can produce similar rewarding behaviors, it follows that the mechanism of the drug per se might not be responsible for drug dependence and that subsequent physiological adaptations might extend beyond the site of action of the drug in question. Neural circuits within the mesolimbic/mesocortical system have been identified that mediate the acute reinforcing effects of most abused drugs [Koob 1992]. In particular, dopaminergic neurotransmitter systems in the striatum (including the nucleus accumbens; NAc, which is the ventral striatum), ventral tegmental area (VTA) and prefrontal cortex appear sensitive to addictive compounds, since lesions to any one of these areas reduces drug self-administration or drug-seeking behaviors [Roberts and Koob 1982]. Further, the addictive liability of many abused drugs appears to be a function of the magnitude to which they increase dopamine activity in these regions [Di Chiara and Imperato 1988; Di Chiara et al. 1999].

Neuroimaging Abnormalities

Since the dopamine system appears fundamental to addiction, many PET studies have focused on physiological and functional alterations within this system. It is important to clarify the different ways in which PET is used to study these adaptations. First, PET studies exploring physiological alterations in the brain typically employ radiotracers with a high affinity for a given dopamine receptor (either presynaptic dopamine transporters, DAT, or postsynaptic D2 receptors). This ensures that the binding of the radiotracer will not be influenced by changes in synaptic dopamine, since presumably they are both competing for the same receptor site [Seeman et al. 1989]. Second, PET studies exploring dynamic fluctuations in radiotracer concentrations use radiotracers with a moderate receptor affinity, comparable to or lower than that of dopamine itself. The theory behind this approach is that radiotracers which compete equally with dopamine for a given receptor site are sensitive to changes in synaptic dopamine concentrations [Dewey et al. 1993]. For example, increases in synaptic dopamine have repeatedly demonstrated the ability to reduce the binding of the moderate-affinity D2 radiotracer, ½11 Craclopride [Dewey et al. 1993, 1999; Endres et al. 1997; Smith et al. 1998; Volkow et al. 1999]. The reverse holds true for decreases in synaptic dopamine, such that drugs which inhibit dopaminergic systems increase the binding of [11C]raclopride [Dewey et al. 1992, 1995; Ginovart et al. 1997; Hietala et al. 1997]. This allows quantification of changes in the releasable pool of dopamine resulting from chronic drug abuse, such that chronic exposure to a psychostimulant might diminish the dopaminergic response to a drug challenge, without affecting receptor number. In humans, both the effects of drug intake on emotional variables and the motivation for drug seeking usually, initially, depend on psychological variables (i.e., stress) and individual differences in sensitivity and response. For example, PET studies with the high-affinity dopamine D2 receptor ligand [18F]Nmethylspiroperidol and indices of glucose metabolic activity with [18F]DG suggest that a disruption of mesocortical dopamine systems from chronic cocaine use leads to abnormal glucose metabolic activity in terminal, primarily cortical, areas [Fowler and Volkow 1994]. Dysregulation of these frontal regions in cocaine addicts might favor the emergence of behaviors associated with addiction, such as the loss of control leading to compulsive drug-taking behavior. Thus, the central reward system of the brain appears to integrate individual variables and to adjust drug seeking and drug taking accordingly.

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Under healthy conditions, the dopaminergic reward system is regulated by several physiological mechanisms that remain sensitive to pharmacologic, environmental, and behavioral interventions [Deutch et al. 1990; Dewey et al. 1991; Innis et al. 1992]. Although the initial effects of rewarding drugs on the brain are related to alterations within the dopaminergic system, it is likely that the development of drug dependence is also a function of the ability of dopamine to modulate or be modulated by other neurotransmitter systems. Serotonin, GABA, glutamate, and dopamine neurotransmitter systems are continually interacting to maintain a level of functional homeostasis, such that changes in one system may be compensated for by endogenous alterations in a related system. In turn, each of these neurotransmitter systems plays a specific role in mediating behaviors associated with drug dependence like craving, stress, or withdrawal. Thus, although addiction has been classically attributed to isolated changes in the dopamine system, each of these systems is most likely modified during the development of dependence, and they appear to remain sensitive to future perturbations. For example, cocaine produces a large influx in synaptic dopamine concentrations by blocking dopamine reuptake in the striatal region of the brain. The expression of dopamine-mediated behaviors requires the activation of GABA pathways [Scheel-Kruger 1986], which are therefore a particularly susceptible target for cocaine’s effects. Further, repeated overstimulation of dopaminergic systems by chronic cocaine use might alter the responsivity of the GABA system to a perturbation of the dopaminergic system. Consistent with this hypothesis, studies in our laboratory have demonstrated that cocaine-dependent subjects have an enhanced metabolic response to a drug targeting the GABA system [Volkow et al. 1998]. In addition, there appear to be significant reductions in striatal dopamine D2 receptors in cocaine dependent subjects that persist long after detoxification [Volkow et al. 1990, 1993]. Taken together, these findings suggest an involvement of GABA in the dopamine abnormalities characteristic of chronic cocaine abuse.

III.

PET STUDIES OF DRUG MECHANISM AND THE ADDICTED BRAIN

PET is uniquely suited to simultaneously manipulate and measure changes in synaptic neurotransmitter responsiveness or physiology in the living brain. This approach can be used to assess the functional integrity

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of neurotransmitter systems and the multiple mechanisms of drug action. In this, the development of radiotracers for studying various systems remains one of the major thrusts of PET research. At this point, a broad spectrum of radiotracers has been developed and applied to the study of the brain with a special focus on drug mechanisms and the physiological changes associated with drug addiction. A.

PET Studies of Cocaine Addiction

Cocaine possesses a reward value such that laboratory animals, given free access, will self-administer until death [Koob and Bloom 1988]. This phenomenon distinguishes cocaine from other drugs of abuse, since most are not self-administered at the expense of selfpreservation. In humans, cocaine is one of the most widely abused drugs [Gawin and Ellinwood 1988], and it is also associated with major medical problems like myocardial infarction, seizures, and psychosis [Johanson and Fischman 1989]. Acute cocaine administration increases subcortical dopamine levels by blocking the dopamine transporter (DAT), preventing reuptake and subsequent catabolism [Reith 1988]. Studies in primates revealed that the binding of [11C]cocaine in the striatum is reduced by prior treatment with nomifensine, a drug that binds to DAT sites, supporting in vitro evidence that cocaine binding occurs to a site associated with the DAT [Fowler et al. 1989]. When animals were pretreated with other drugs that inhibit norepinephrine and serotonin transporters, ½11 Ccocaine binding was not altered [Volkow et al. 1995b]. These studies are consistent with the notion that while the mechanisms for cocaine’s reinforcing properties are complex, they primarily involve the brain dopamine system [Ritz et al. 1987]. Given that PET measures the regional distribution and kinetics of radioisotopes in tissues of living subjects [Mullani and Volkow 1992], it has been used to address these measurements with respect to cocaine’s behavioral and toxic effects. The ability of PET to measure sequential changes in the distribution of positron labeled compounds makes it an ideal technique to investigate the binding characteristics of psychoactive drugs in vivo. From studies using ½11 Ccocaine, several observations have revealed significant biological characteristics that relate to its abuse liability. First, pharmacokinetic PET investigations of ½11 Ccocaine in the brain indicate maximal uptake in the striatum. Figure 2 presents the radioactivity distribution in the human brain (Fig. 2a), the nonhuman primate brain (b), and the rodent brain

Figure 2 Radioactivity distribution of ½11 Ccocaine in the human brain (a), the primate brain (female Papio anubis baboon (b), and the rodent brain (c). The color scale has been normalized to the injected dose of ½11 Ccocaine.

(c) measured with PET. Figure 3a presents these temporal dynamics in the primate striatum and cerebellum, where the intensity and duration of ½11 Ccocaine binding are clearly greater in the striatum. This information has been used to demonstrate that the dose of cocaine typically used by cocaine addicts ( 25–50 mg/ kg IV) [Verebey and Gold 1988] occupies roughly 63% of DAT high-affinity sites [Volkow et al. 1996a], although given considerations of pharmacokinetics, these occupancies might be underestimated. Second, these studies demonstrate that the uptake kinetics of cocaine are very rapid, with a peak concentration at 4– 8 min after injection. Previous studies suggest that the rate of change at which total DAT occupancy is achieved will affect the intensity of cocaine’s effects [Pettit and Justice 1991; Volkow et al. 1995a]. When compared with the DAT inhibitor, methylphenidate (Ritalin), which is much less addictive and clears from the brain at a much slower rate than cocaine, it appears that pharmacokinetics play a critical role in the addictive liability of abused substances [Volkow et al. 1995a]. Thus, while the relationship of DAT blockade to euphoria can be estimated, it is likely that higher doses will achieve total blockade faster, and will also maintain this blockade for a longer period of time [Volkow et al. 1995a]. In this, analysis of the pharmacokinetic behavior of cocaine in the human brain reveals that it is not only an affinity for the DAT that makes cocaine uniquely addictive, but also its fast uptake. These studies are critically dependent on the modeling parameters used to estimate change in radiotracer distribution over time. Studies with ½11 Ccocaine initiated the development of a graphical method for the calculation of binding potential from time-activity curves and radiotracer plasma concentrations [Logan et al. 1990]. In going from the labeled compound to the

Figure 3 Strategy for graphical analysis from the time activity curves corrected for plasma concentrations of ½11 Ccocaine (a), followed by conversion to striatum over cerebellum ratio of ½11 Ccocaine (b), converted to a Logan plot for graphical analysis. Data are given as baseline scan (scan 1, circles) and challenge scan (scan 2, triangles). For the challenge scan, phencyclidine (PCP) was co-injected with ½11 Ccocaine, and the decrease in ½11 Ccocaine binding most likely represents direct competition from PCP for dopamine transporter (DAT) sites (c).

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biochemical basis of the PET image, we enter an area which is the heart of the PET method and one which is far beyond the scope of this chapter. Mechanistic information must be derived from in vivo PET studies where kinetic radiotracer effects and pharmacokinetics must be estimated from mathematical models. One method, described below, is generally suited to tracers characterized by rapid pharmacokinetic profiles and is also widely applied to PET studies assessing either regional or drug-induced changes in brain pharmacodynamics. For this reason, it is critical to the interpretation of PET studies to understand the parameters used to quantitate the data, especially where measures of change over time are fundamental to the outcome of a given experiment. 3.

Graphical Analysis of PET Data

A Logan plot, describing functions of time relative to tissue and plasma concentrations of the radiotracer gives a reliable index of the binding potential (affinity for and density of DAT sites). This is critical to the interpretation of any studies using radiotracers with fast kinetic profiles. Figure 3 demonstrates the analytical procedure through which regionally specific temporal dynamics are used to calculate the binding potential of ½11 Ccocaine. For comparison, data from animals given phencyclidine (PCP) which has an affinity for the DAT similar to cocaine, are also presented. In these studies, animals were given a baseline ½11 Ccocaine scan followed by administration of saline or PCP, immediately prior to a second ½11 Ccocaine scan. These data indicate that that there is a linear relationship between radiotracer tissue concentration and plasma volume. Linearity is expressed as the slope, which corresponds to the steady state space of the radiotracer (distribution volume; DV). The ratio of distribution volumes in a receptor/transporter-rich region to that in a receptor/transporter-poor region (Fig. 3b, c) is called the distribution volume ratio (DVR) and is related to the apparent binding potential. Usually, at least with ligands for D2 receptors and DAT sites, the receptor rich region comprises the striatum while the receptor poor region consists of cerebellar areas. Binding potential is fundamental to the interpretation of PET studies, and is defined as Bmax =Kd , where Bmax is the number of binding sites and Kd1 represents the binding affinity [Mintun et al. 1984]. This graphical method has been applied to the given PET study in Figure 3c, which represents a typical Logan plot. The graphical analysis allows a mea-

sure of change over time that incorporates both the intensity and duration of radiotracer binding, such that subsequent comparisons can be made with related variables. The DAT, located on the presynaptic terminal of the dopamine neuron, is an important subject of research not only because it is linked to the addictive properties of cocaine but also because it is a marker for the integrity of the dopamine neuron. DAT sites appear to be related to neuronal mass and thus these tracers have been of particular value in monitoring the progress of neurodegenerative processes secondary to chronic drug abuse. For example, a logical prediction would be that through prolonged targeting of the DAT protein, chronic cocaine abuse induces compensatory alterations in the physiology and function of these sites. ½11 CCocaine was used to evaluate the DAT in 12 detoxified cocaine abusers with 20 agematched controls who had never used cocaine [Volkow et al. 1996d]. Cocaine abusers had significantly lower global radiotracer uptake in the striatum compared to control subjects; however, they also had less uptake in the cerebellum. As a result, their DVR was not significantly different. However, since neither current nor detoxified cocaine abusers demonstrated the typical age-related decline in DAT characteristic of healthy populations [Wang et al. 1997a], it might be that excessive blockade of the DAT induces some neuroprotection, although this merits further investigation. B.

PET Studies of Simultaneous Cocaine/ Alcohol Abuse

A significant medical issue in cocaine abuse is the documented increased risk in toxicity when cocaine and alcohol are used in combination. In fact, the concurrent use of cocaine and alcohol confers an 18-fold increase in the risk of sudden death relative to the use of cocaine alone [Rose et al. 1990]. It has been proposed that cocaethylene, an enzyme formed by the reaction of cocaine with alcohol in the presence of liver esterases found in the blood and other organs of postmortem polydrug abusers [Hearn et al. 1991a, b), might be toxic. However, PET studies with ½11 Ccocaethylene demonstrated this is unlikely [Fowler et al. 1992b]. Alternatively, since the combined use of cocaine and alcohol is one of the most frequent patterns of polydrug use, it is possible that alcohol changes the pharmacokinetics of cocaine in the brain and in the heart. Since later studies used concurrent ½11 Ccocaine and alcohol administration to demon-


strate that the pharmacokinetics of cocaine were not changed by alcohol administration [Fowler et al. 1992a], this is also unlikely. These PET studies are consistent with the notion that the direct effects of cocaine and alcohol contribute to the fatality of the combination, rather than their metabolic interaction. Cocaine abusers express a blunted response to alcohol in limbic regions and in cortical regions connected to limbic areas, which might be a result of tolerance from prolonged cocaine exposure [Volkow et al. 2000]. Similarly, PET studies of alcoholics indicate significant reductions in D2 receptors (postsynaptic marker) but not in DAT availability (presynaptic marker) when compared with nonalcoholics [Hietala et al. 1994; Volkow et al. 1996c)]. C.

PET Studies of Methamphetamine Abuse

Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it is neurotoxic to dopamine terminals in animal studies [Villemagne et al. 1998]. While the mechanisms of methamphetamine are unclear, it appears to increase the synthesis of dopamine [Schmidt et al. 1985]. PET studies using radiotracers with a high affinity for the DAT have demonstrated significant reductions in DAT density in methamphetamine abusers [McCann et al. 1998; Villemagne et al. 1998; Volkow et al. 2001]. These studies suggest loss of DAT or loss of dopamine terminals, and raise the possibility that as this population ages, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions associated with diminished activity of dopamine neurons [McCann et al. 1998]. Moreover, reduced DAT density in the caudate/putamen and nucleus accumbens has been associated with the duration of methamphetamine use, and closely related to the severity of persistent psychiatric symptoms [Sekine et al. 2001]. These studies also suggest that even if methamphetamine use ceases, DAT reduction may be prolonged [Melega et al. 1997; Sekine et al. 2001]. Although a neuroprotective phenomenon provides a salient explanation for findings in cocaine abusers, more studies are needed to rule out sampling effects as well as confounding variables like cigarette smoking. D.

PET Studies of Nicotine Abuse

In spite of the fact that there are 45 million cigarette smokers in the United States and there are 400,000

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deaths per year associated with smoking, surprisingly little is known about the neurochemical actions of tobacco smoke on the human brain. Imaging studies have been summarized in a recent book [Domino 1995]. Nicotine stimulates nicotinic acetylcholine receptors, which in turn are thought to stimulate dopaminergic transmission [Clarke et al. 1988]. The pharmacokinetics of inhaled nicotine have been measured using ½11 Cnicotine [Bergstrom et al. 1995], and acute administration of intravenous nicotine has been reported to reduce brain metabolism [Stapleton et al. 1993]. Recently, monoamine oxidase A and B (MAO A and B) have been examined in the human brain (Fowler et al. 1996a, b]. MAO breaks down neurotransmitter amines like dopamine, serotonin, and norepinephrine, as well as amines from exogenous sources. It occurs in two subtypes, MAO A and MAO B, which can be imaged in vivo using ½11 Cclorgyline and ½11 CL-deprenyl, respectively. It has been proposed that MAO is one of the molecular targets proposed to link smoking and depression [Berlin et al. 1995; Yu et al. 1988], due to the antidepressant properties of MAO inhibitors. Since the antidepressant effects of the nonselective MAO inhibitors are generally attributed to the inhibition of MAO A [Caldecott-Hazard and Schneider 1992], it is possible that depressed smokers are self-medicating an overactive MAO A system. ½11 CL-Deprenyl is a labeled version of the MAO B inhibitor drug L-deprenyl. Both clorgyline and Ldeprenyl act through irreversible mechanisms, so when they are labeled with 11 C, they provide the opportunity to visualize enzymatic activity in vivo and to study the pharmacodynamics of MAO. PET studies indicate that smokers have a 28% reduction in MAO A [Fowler et al. 1996b] and a 40% reduction in MAO B, relative to age-matched nonsmokers [Fowler et al. 1996a]. Since MAO inhibition is associated with enhanced activity of dopaminergic systems, this reduction may account for the reduced rate of Parkinson’s disease in smokers [Newhouse and Hughes 1991]. Further, these findings indicate that smoking-induced changes in MAO activity may also contribute to some of the features of smoking epidemiology, including high rates of smoking in people with psychiatric disorders like depression and schizophrenia, or polydrug abuse. There is evidence that smokers are self-medicating in the case of certain psychiatric disorders and that they use smoking to reduce anxiety and to increase alertness and cognition [Levin et al. 1996; Newhouse and Hughes 1991].

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PET Studies of Opiate Abuse

Morphine and related drugs activate G-proteincoupled receptors whose physiological ligands are peptides. Three classes of opioid receptors, each comprising two or more subtypes, are generally recognized, termed mu (m), delta (d) and kappa (k) receptors. mOpioid receptors appear to be the major targets involved in drug dependence. ½11 Ccarfentanil [Saji et al. 1992], a tracer which binds selectively to the m-opiate system, has been shown to concentrate in regions of the brain such as the basal ganglia and the thalamus, which contain high levels of m-opiate receptors [Frost et al. 1985]. Its uptake can be reduced by pretreatment with nalaxone, an opiate antagonist [Lee et al. 1988]. In addition, the opioid antagonist ½11 Cdiprenorphine has also been labeled for PET studies. However, ½11 Cdiprenorphine labels other opiate receptor subtypes in addition to the m-opioid sites selectively labeled by ½11 Ccarfentanil, thus limiting its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases [Frost et al. 1990]. Stabilized heroin addicts treated with effective doses of methadone have markedly reduced drug craving; reduction or elimination of heroin use; normalized stress-responsive hypothalamic-pituitaryadrenal, reproductive, and gastrointestinal function; and marked improvement in immune function and normal responses to pain, all of which are physiological indices modulated in part by endogenous and exogenous opioids directed at the m-opiate receptors and, in some cases, the k-opioid systems. In a PET study using the m- and k-opioid receptor antagonist [18 F]cyclofoxy, recovering heroin addicts on maintenance methadone therapy demonstrated altered receptor binding in the thalamus, amygdala, caudate, anterior cingulate cortex, and putamen when compared with healthy controls [Kling et al. 2000]. This finding agrees with prior studies of glucose metabolism in healthy controls given an acute dose of fentanyl [Firestone et al. 1996] or morphine [London et al. 1990]. Although the differences in radiotracer binding may be related to receptor occupancy with methadone, this study suggests that significant numbers of opioid receptors may be available to function normally, despite chronic blockade of the opiate system [Kling et al. 2000]. Inasmuch as dopamine plays a role in opiate withdrawal and dependence, chronic opiate exposure might alter the dopaminergic system in a manner to that demonstrated by cocaine and methamphetamine. ½11 Craclopride has been used to measure D2 receptor

availability in opiate-dependent subjects at baseline, and then again during naloxone-precipitated withdrawal [Wang et al. 1997b]. Because ½11 Craclopride is sensitive to changes in endogenous dopamine [Dewey et al. 1993], this strategy enabled us to test whether we could document in humans dopaminergic reductions reported in animal models of opiate withdrawal. Although there were decreases in D2 receptors in opiate-dependent subjects, there were no significant changes in striatal DA concentration during acute withdrawal. PET investigations in our own laboratory have demonstrated that the addictive liability of opiate drugs is associated with increased dopamine activity in the striatum of primates (unpublished results), consistent with in vivo microdialysis studies [Leone et al. 1991; Pothos et al. 1991; Rada et al. 1991].

F.

PET Studies of Phencyclidine (PCP) and Ketamine (‘‘Special K’’) Abuse

PCP and related dissociative anesthetics act by antagonizing the NMDA glutamate receptor. Although they are widely used as anesthetic drugs for children and animals, PCP has been a widely abused substance for over two decades, and ketamine is now in fashion. The use of PET to study PCP abuse is very preliminary. The uptake of ½11 Cketamine in primates, like cocaine, is very rapid in the striatum [Shiue et al. 1997]. A single report done in a group of PCP abusers who were studied with [18 FFDG indicated that, when compared with normal controls, PCP abusers demonstrate diminished glucose metabolism in frontal cortical areas, striatum, and thalamus [Wu et al. 1991b]. This is consistent with the applicability of NMDA antagonists as models of schizophrenia, since schizophrenic patients demonstrate a similar regional glucose pattern [Wolkin et al. 1985; Wu et al. 1991a], and stabilized schizophrenic patients given the NMDA antagonist ketamine experience an exacerbation of symptoms identical in content to those exhibited prior to clinical stabilization [Lahti et al. 1995]. Primate PET studies in our own laboratory have demonstrated that PCP and ketamine might share with cocaine the ability to block DAT proteins, thus increasing mesolimbic dopamine activity and producing a rewarding response in addition to a dissociative state. We used ½11 Ccocaine in both pretreatment and coadministration paradigms to demonstrate that the increases in subcortical dopamine produced by PCP in a related study (measured with ½11 Craclopride) can be attributed to occupancy of DAT sites (Fig. 3).


G.

PET Studies of Marijuana Abuse

Marijuana is the most widely used illegal drug of abuse in the United States [Goodman and Gilman 1990]. Although the mechanisms by which 9 -tetrahydrocannabinol (THC; the main psychoactive substance in marijuana) exerts its psychoactive effects are still not known, they may occur through an interaction of THC with regionally localized receptor sites in the human brain [Howlett 1990]. Attempts to investigate THC in the living brain with PET by labeling it with a positron emitter have been unsuccessful because of the highly lipophilic nature of THC. This was also a limitation for ()-5-18 F-8 THC, an analog of 9 -THC, which was labeled with fluorine-18 but did not show specific binding [Charalambous et al. 1991]. Although a promising alternative may be the use of THC antagonists with high receptor affinities [Gatley et al. 1996, 1997, 1998], this issue has yet to be resolved. Thus, imaging studies of chronic marijuana users have concentrated on the measurement of the effect of THC intoxication on cerebral blood flow and metabolism. For example, acute marijuana administration has been reported to decrease blood flow in subjects who were not experienced marijuana smokers, and to increase it in subjects who were experienced marijuana smokers [Mathew et al. 1997]. Chronic marijuana users demonstrated a temporary reduction in cerebral blood flow that reverted to normal with abstinence [Mathew et al. 1992, 1999] however, the measurement of the effects of THC and marijuana on blood flow may be confounded by the vasoactive properties of THC [Nahas 1986]. Since measures of brain glucose activity using [18 F]DG are insensitive to fluctuations in blood flow [Sokoloff et al. 1977], the acute effects of THC could be measured without confounding vasoactive effects. PET studies have been performed in nonabusing controls as well as in marijuana abusers, in which subjects received a baseline PET scan with [18 F]DG and a second scan after intravenous administration of THC. Though the whole-brain metabolic response to the effects of THC was variable among individuals, there appeared to be a consistent pattern of cerebellar activation paralleling the high cerebellar concentration of THC receptors [Volkow et al. 1996b]. Since the cerebellum is involved in motor coordination, proprioception, and learning, activation of the cerebellum by THC could explain the disruption of motor coordination and proprioception during THC intoxication.

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H.

PET Studies of Inhalant Abuse

While the rate of inhalant abuse continues to rise in this country, it remains one of the least-studied and least-discussed groups of abused substances [Brouette and Anton 2001]. Three groups of inhalants have demonstrated significant abuse liability in humans, especially children and adolescents: volatile solvents, nitrous oxide, and nitrites, among which glues, paints, and aerosol propellants are the most commonly abused [Howard et al. 2001; Howard and Jenson 1999; Kurtzman et al. 2001]. Recent studies suggest the existence of overlapping molecular sites of action for ethanol, inhalants, and volatile anesthetics like PCP on glycine receptors, and illustrate the feasibility of pharmacological antagonism of the effects of these drugs [Beckstead et al. 2001]. Since organic solvents have been implicated in a number of neuropsychiatric disturbances, neuroleptics have typically been used to treat inhalant abuse [HernandezAvila et al. 1998; Misra et al. 1999]. In a recent study, Tc-99m-hexamethylpropyleneamine oxime (Tc99m-HMPAO) brain SPECT scans along with psychiatric and biochemical tests were performed in 10 inhalant-dependent patients ranging from 16 to 18 years of age [Kucuk et al. 2000]. This study found that prolonged exposure to inhalants produced significant abnormalities in brain SPECT images, including hypo- and hyperperfusion in primarily temporal and parietal regions, respectively, demonstrated by nonhomogeneous radiotracer uptake. Direct assessment of the mechanism of action of solvents is often difficult to validate since these drugs are absent of the typical receptor binding kinetics of most abused drugs. Instead, organic solvents, like alcohol, have been classically related to a more generalized alteration in neuronal membrane function [Kurtzman et al. 2001]. Recent studies in our laboratory have demonstrated that toluene, which is found in adhesives, spray paint, glues, and paint thinners, possesses a regionally specific binding profile influencing in subcortical and cerebellar areas (Fig. 4). PET investigations of dopaminergic activity in patients receiving an acute dose of toluene demonstrated no significant effects of the drug on dopamine synthesis or postsynaptic receptor activity [Edling et al. 1997; Hageman et al. 1999]. This is especially perplexing in light of the moderate therapeutic efficacy of dopamine receptor antagonists in the treatment of inhalant abuse [Hernandez-Avila et al. 1998; Misra et al. 1999].

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Figure 4 Radioactivity distribution of ½11 Ctoluene in the primate brain, with (a) representing distribution at the striatal level and (b) representing radioactivity distribution at the level of the cerebellum. The color scale has been normalized to the injected dose of ½11 Ctoluene.

I.

alcoholic controls [Tiihonen et al. 1995]. Studies measuring D2 receptors and DAT sites in alcoholic patients either report decreases in DAT sites but no difference in D2 receptors [Repo et al. 1999], or decreases in D2 receptors but not DAT sites [Volkow et al. 1996c]. Changes in DAT sites and D2 receptors must be considered in light of the fact that dopamine transporters reflect dopamine neuron integrity, whereas dopamine receptors occur mainly on GABA-ergic neurons. In the absence of neurological impairment, [18 F]DG PET studies in alcoholic patients express abnormalities in frontal metabolism with [Volkow et al. 1992; Wik et al. 1988], consistent with studies of blood flow using xenon inhalation techniques [Mathew and Wilson 1986].

PET Studies of Alcohol Abuse J.

The neurochemical mechanisms by which alcohol produces its psychoactive effects, as well as the changes in the brain accompanying chronic alcohol abuse, are not well understood. In nonalcoholic people, alcohol decreases occipital and temporal cortex metabolism, producing a metabolic response similar to the benzodiazepine lorazepam [Wang et al. 2000]. These findings agree with evidence demonstrating alcohol and benzodiazepines share a binding site on the GABA-benzodiazepine receptor complex [Bosio et al. 1982; Burch and Ticku 1980; Hemmingsen et al. 1982; Ticku 1983; Ticku et al. 1983; Ticku and Davis 1981]. Neuroimaging studies using the benzodiazepine receptor ligands ½11 Cflumazenil or [123 I]iomazenil indicate that alcoholic patients express altered numbers of benzodiazepine receptors comared with healthy controls [Abi-Dargham et al. 1998; Litton et al. 1993]. Specifically, the DVR was significantly lower in several cortical regions and the cerebellum of alcoholic subjects compared to healthy comparison subjects. These results suggest either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism. In fact, children of alcoholics given lorazepam demonstrate a metabolic response similar to alcoholic patients, as well as a diminished sensitivity to both lorazepam and alcohol [Volkow et al. 1995c]. Dopaminergic systems are also altered in alcoholic patients. PET studies with ½11 Craclopride demonstrate reductions in dopamine D2 receptors in alcoholics relative to controls, which persisted over a 1- to 68-week detoxification period [Hietala et al. 1994]. DAT availability in alcoholics using the high affinity ligand, [123 I]-b-CIT, was increased in violent and decreased in nonviolent alcoholic patients as compared to non-

Conclusions

The above studies illustrate the use of PET in investigating the mechanisms of toxicity of drugs of abuse, as well as changes in brain chemistry that may account for the addictive actions of these drugs in the human brain. Although these studies remain preliminary, they have already documented neurochemical changes in the brains of individuals addicted to drugs, and provided a target for pharmacological intervention. Given the importance of radiotracer development in the advancement and application of neuroimaging techniques to the study of addiction, it is safe to say that basic research in labeling biomolecules with positron emitters has shaped the PET field as we know it today. Studies using carbon-11-labeled compounds can thus make significant contributions to our awareness of the many physiological and cognitive effects produced by chronic exposure to a number of different compounds [for review, see Kling et al. 2000; Sadzot et al. 1990; Sekine et al. 2001; Weinstein et al. 1998]. It is clear from studies presented above that PET has provided invaluable information on the addicted human brain that may be useful for developing new treatment strategies for addiction.

IV.

USING PET TO DEVELOP A TREATMENT FOR SUBSTANCE ABUSE

PET provides an ideal technique to probe a specific drug mechanism, and we have been able to use this technology to advance our understanding of the fundamental changes in neural activity and structure associated with chronic drug abuse. However, the development and clinical implementation of an ade-


quate therapy for addiction is not commensurate with our understanding of the neurochemical mechanisms of drugs of abuse. Given that prolonged exposure to drugs of abuse produces abnormalities in brain structure and function, potential pharmacotherapies that produce one response in the normal brain might produce quite another in an environment altered by prolonged drug exposure. The observation that chronic drug abuse produces changes in the dynamics of the dopamine system has provided an impetus for the development of many strategies targeting this system to weaken the initial stimulatory effects of rewarding drugs [O’Brien 1997]. It is possible that the most effective of these therapies might not act on dopaminergic systems directly, but on systems functionally related to dopamine. Thus, drugs that are already used in altered neural environments might prove more favorable to those experimental compounds which as of yet have no clinical target. For over a decade, we have been using PET and in vivo microdialysis techniques to study neurotransmitter interactions in the human, nonhuman primate and rodent brain [for review, see Schloesser et al. 1996]. The sensitivity of PET for detecting alterations in labeled D2 radiotracer binding (i.e., ½11 Craclopride or ½18 F]NMSP) has been demonstrated by pharmacologic agents that selectively increase or decrease synaptic dopamine concentrations by neurochemically different mechanisms like DAT blockade or increased synthesis of dopamine [Dewey et al. 1991, 1993; Innis et al. 1992). These findings suggest that this experimental approach is well suited for studies designed to investigate disease states that begin with, or result from, a loss in the ability to adequately regulate synaptic dopamine activity. The potential for PET paradigms clearly extends beyond the ability to measure changes in a single neurotransmitter system after a specific challenge. Studies in our laboratory [Dewey et al. 1988, 1990] and others [Hietala et al. 1997] have been exploring pharmacologic interventions outside the dopaminergic system that might subsequently inhibit the dopaminergic response to psychostimulants and other abused drugs. These studies are based on the premise that neurotransmitter systems do not work in isolation, and that healthy brain function depends on the ability of the system to maintain a functional state of homeostasis across a network of interacting neurotransmitter systems. In this, the inability of a specific neurotransmitter to be regulated by other etiologically relevant, and functionally linked systems, underlies the characteristic addictive state of tolerance and insensitivity. This, then, is

605

indicative of a lack of plasticity or an inability to respond to previously stimulating doses of the addictive compound. For example, the diminished euphoria experienced by chronic cocaine abusers over time may be related to other factors such as the integrity of other neurotransmitter systems that remain functionally linked to dopamine. Consequently, measuring the responsiveness of a specific neurotransmitter to a pharmacologic challenge may be more revealing than measuring changes in the more inherent static properties of these systems. Dopaminergic homeostasis is primarily maintained by the activity of excitatory amino acid (EAA) and inhibitory GABA-ergic systems [Kalivas 1993]. Thus, these neurotransmitters become promising targets to alter the functional homeostasis of the dopamine system, and in this, the responsivity of this system to a pharmacologic perturbation. Under the hypothesis that either a priori diminishing EAA neurochemical stimulation of dopamine or augmenting inhibitory GABA-ergic control over dopamine will reduce the reward-associated response to a drug challenge, our research team and others have been aggressively exploring the potential of these agents as therapies for drug abuse. However, while rodent and nonhuman primate studies suggest that antagonizing EAA glutamate receptors directly may reduce the dopaminergic response to drugs of abuse [Li et al. 1999, 2000; Wolf 1998], glutamate receptor antagonists are known to produce psychosis [Javitt and Zukin 1991]. The GABA-ergic system thus provides a more feasible approach to indirectly modulate the dopaminergic response to drugs of abuse. Since PET provides the most clinically relevant technique to explore the effects of drugs of abuse, we have relied largely on PET data to guide further behavioral and in vivo techniques. Our initial studies of GABA-ergic modulation of dopamine activity focused on the interaction between the anticonvulsant drug, g-vinyl GABA (vigabatrin, GVG, Sabril) and the dopaminergic response to psychostimulants [Dewey et al. 1992, 1997, 1998, 1999; Kushner et al. 1997b; Morgan and Dewey 1998]. GVG is a widely prescribed anticonvulsant with a particular mechanism of action designed specifically to act indirectly on GABA-ergic systems [Jung et al. 1977] in neurochemical environments altered by disease. Through irreversible inhibition of the enzyme responsible for the catabolism of GABA, GABA-transaminase (GABA-T), GVG increases GABA concentrations in both vesicular and cytosolic pools [Petroff and Rothman 1998]. Recent evidence suggests that the ability of GVG to increase cytosolic

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pools of GABA may contribute to its promise as a therapy for addiction. Drugs that depress dopaminergic function usually produce concomitant reductions in locomotor behavior [Swerdlow et al. 1986]. However, recent studies suggest that increases in cytosolic pools of GABA produced by GVG are only released in response to abnormal stimulation of the dopaminergic system [Jackson et al. 2000; Wu et al. 2001], such that normal locomotor activity and ‘‘natural’’ rewarding effects may be spared. This may explain findings suggesting that GVG does not diminish locomotor activity at clinically relevant doses [Bevins et al. 2001; Dewey et al. 1997; Stromberg et al. 2001]. Further, because the mechanism of GVG is through irreversible inhibition, the time required between doses depends on the ability of the system to synthesize new stores of GABA-T, implying that minimal dosing schedules might provide prolonged protection of dopaminergic systems. In this, the potential for pharmacologic tolerance within GABA-ergic systems is greatly reduced [Jung et al. 1977]. Moreover, rodent studies using prolonged GVG treatment have demonstrated no tolerance within related dopaminergic systems [Gardner et al. 1983; but see Neal and Shah 1990]. In addition to these mechanistic advantages, increasing GABA activity as a general strategy has demonstrated remarkable success in both behavioral and neurochemical paradigms [Roberts and Brebner 2000]. Inasmuch as the dopaminergic response to abused drugs diminishes the addictive liability of these drugs, PET studies are ideal for assessing the impact of potential therapies on the dopaminergic response to psychostimulants or other abused drugs. The success of indirect modulation of dopaminergic activity by augmenting inhibitory GABA-ergic tone is inherent in the many behavioral paradigms in animals demonstrating GVGs potential as a pharmacotherapy for addiction. GVG reduces the dopaminergic response to cocaine [Dewey et al. 1998], nicotine [Dewey et al. 1999], heroin (unpublished observations), PCP [Schiffer et al. 2000], and a cocaine/heroin combination (speedball) [Gerasimov and Dewey 1999] in rodents and nonhuman primates. Concomitantly, GVG reduces the effects of cocaine-induced brain reward stimulation [Kushner et al. 1997b] and cocaine self-administration [Kushner et al. 1997a], without affecting the reward associated with food [Kushner et al. 1997a] or water [Buckett 1981; Stromberg et al. 2001] intake. In addition, GVG reduces indices of craving and drug-seeking behavior to cocaine [Dewey et al. 1998], nicotine [Dewey et al. 1999], and heroin [Paul et al. 2001], as assessed by the conditioned place preference paradigm.

Schiffer et al.

Although animal models are typically designed to evaluate those factors maintaining drug-seeking behavior, little effort has been directed at developing animal models of polydrug use. However, evidence presented in Stromberg et al. [2001] suggests that it is possible to develop a successful model of cocaine/alcohol abuse. The clinical relevance of this issue, described above, along with the ability of GVG to modulate concurrent cocaine/alcohol intake [Stromberg et al. 2001], increases the promise of this strategy to treat drug abuse.

V.

SUMMARY OF FINDINGS AND THE STATUS OF TREATMENT OPTIONS

PET has made significant contributions to the development of several approaches for diminishing the initial dopamine-related reward produced by drugs of abuse. Strategies either directly interfere with the mechanism of a rewarding drug or indirectly approach the reward-related response from a different neurochemical perspective. Although, at present, the National Institute of Drug Abuse has > 30 compounds under preclinical investigation, several factors impede the clinical application of such therapies. Primarily, given the close ties between the mesolimbic dopamine system and locomotor activity, many drugs that appear to reduce the locomotor-activating properties of drugs of abuse merely inhibit the functioning of the basal ganglia and other systems related to movement. An example of this is the GABA-ergic compound baclofen, which reduces dopamine activity and selfadministration of psychostimulants [Roberts and Brebner 2000], but does not affect the subjective euphoria of cocaine in humans [Ling et al. 1998] or animal models [Munzar et al. 2000]. One conclusion is that, by diminishing global motor activity, baclofen also diminishes the actual act of drug self-administration in animals [Munzar et al. 2000]. Second, given a central reward system, antagonism of this entirety would also antagonize reward induced by ‘‘natural’’ appetitive events, such that these drugs would not be well tolerated in humans. Finally, since a great deal of drug addiction per se incorporates psychosocial variables, it is unlikely that isolating pharmacological targets alone will prove successful in the treatment of drug dependence. One should perhaps separate research with PET and what it can tell us about the brain and the use of PET as a clinical tool. Clinical PET, to some the end result of PET research, is no more than the routine applica-


tion of PET methods which prove clinically useful and can be converted to routine procedures, whether this be the reading of a PET scan generated by a specific labeled probe or a quantitative number reflecting a particular condition generated by mathematical modeling of PET data. There is little argument that simplification of kinetic models in interpreting PET is necessary for a clinical environment. The PET image itself, produced by a particular radiopharmaceutical, e.g., an ½11 Craclopride image, is already being used today in a purely clinical context. The outlook is particularly bright for methods of assessing physiologic vulnerability toward addiction, patients at risk in the case of hereditary factors which have not yet presented clinical symptoms, and the quantification of an addicted state relative to the potential for pharmacotherapeutic treatment.

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41 Genetics of Addictive Disorders TATIANA FOROUD and JOHN I. NURNBERGER, JR. Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

I.

INTRODUCTION

Alcoholism is a chronic or intermittent condition characterized by loss of control over drinking. It typically begins in adolescence or young adulthood and may be associated with medical, social, or legal sequelae at any stage. One of the most consistent observations in all epidemiologic studies of alcohol consumption is that women drink less than men [1,2]. Estimates of prevalence vary, but the condition may affect 5–10% of the male population and 1–3% of the females in many Western societies. Recent data suggest that prevalence may be increasing in younger cohorts [3] in the United States. There are 20 million Americans who have serious drinking problems. While alcohol remains the most commonly used drug in the United States, there is substantial use of other drugs, including tobacco, cocaine, amphetamines, and marijuana. About 5–10% of the U.S. population, or 10–25 million Americans, meet diagnostic criteria for nonalcohol substance dependence at some point in their lives. Uniformly, rates are at least two to three times greater in males than in females. Use of illicit drugs contributed to 20,000 deaths in 1990, the most common causes of death including overdose, suicide, homicide, motor vehicle accident injury, HIV infection, pneumonia, hepatitis, and endocarditis [4].

II.

GENETIC ASPECTS OF ALCOHOLISM

A.

Family Studies

Review of family studies has concluded that there is a concentration of alcoholics in the families of alcoholic probands [5,6]. Cotton reports an overall prevalence of 27.0% alcoholism in fathers of alcoholics and of 4.9% in mothers; 30.8% of alcoholics had at least one alcoholic parent. The same preponderance of alcoholism was not seen in the parents of comparison groups of patients with other psychiatric disorders. The studies of nonpsychiatric controls reviewed in the same study show a rate of 5.2% in fathers and 1.2% in mothers. A notable family study reported by Cloninger et al. [7] included 365 first-degree relatives of alcoholics selected from consecutive admissions to St. Louis hospitals. The particular question addressed was whether the predominance of males among alcoholic relatives of alcoholic probands was due to familial or nonfamilial factors. If it takes greater familial ‘‘loading’’ for a woman to become alcoholic, then it would be expected that there would be more alcoholic relatives of a female alcoholic than of a male alcoholic. If nonfamilial factors are responsible, then the risk in relatives should be comparable and independent of the sex of the proband. This latter was found to be the case. The authors suggested, therefore, that women do not become alco615

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holic as often as men because women are not ‘‘allowed’’ to drink as often or as much. An implication is that while the predisposition to alcoholism is largely genetic, the manifestation of the illness is dependent upon continued heavy drinking, which in itself is largely socioculturally conditioned. This is consistent with the study of grandsons of alcoholics by Kaij and Dock [8]; in that study, the rate of alcoholism in the sons of daughters of alcoholics was equivalent to the rate of alcoholism in the sons of sons of alcoholics, suggesting that the daughters passed on the genetic predisposition to alcoholism even though they did not manifest the illness themselves. Recent data from a multicenter study of the genetics of alcoholism show familial aggregation among female relatives of alcoholics as well as male relatives [9]. Hill and Yuan [10] examined a sample of children and adolescents between the ages of 8 and 18. These individuals came from either high-density multigenerational alcoholic families or from families without any history of alcoholism in first- or second-degree relatives. They found that the offspring from high-density families began drinking at a significantly earlier age than the individuals from low-risk families and tended to drink more heavily. Recently, Dawson [11] also found that a positive family history of alcoholism was associated with earlier initiation of alcohol drinking.

B.

Twin Studies

Twin studies have consistently found significant heritability of drinking behavior. The Finnish twin study of Partanen [12] included interview data on 902 male twins between 28 and 37 years of age. Heritability, or that proportion of the variance in a trait due to genetic factors, was estimated to be 0.39 for the phenotype defined as the frequency of drinking and 0.36 for the amount of alcohol consumed per session. A second Finnish study by Kaprio et al. [13] included data on several thousand pairs of twins in the state twin registry. Overall heritability for total alcohol consumption was 0.37 in males and 0.25 in females. Clifford et al. [14] report a study in which 572 twin families from the Institute of Psychiatry register were examined. Additive genetic factors were found to account for 37% of the variance in alcohol consumption among drinkers when pedigree data were considered together with twin data and the effect of shared environment on twin concordance is taken into account. The critical

data from these three large twin studies are strikingly similar, at least in males. Twin studies of alcoholism itself have also generally shown significant heritability. Kaij [15] studied registration of twin subjects at the Swedish County Temperance Boards. Such registration implies that a complaint was made about a person’s behavior while drinking, either by the police or a third party. This would not generally include alcoholics who were socially isolated, though they might be significantly impaired. The registration information was followed up with personal interviews of probands and cotwins. In a total of 205 twin pairs, probandwise concordance was 54.2% in monozygotic (MZ) and 31.5% in dizygotic (DZ) twins (P < :01). Concordance rates in MZ twins increased with the severity of the disturbance. A reanalysis of these data by Gottesman and Carey [16] shows heritability to vary from 0.42 to 0.98, with the more serious forms of alcoholism being more heritable. Hrubec and Omenn [17] examined medical records of 15,924 veteran male twin pairs in the National Academy of Sciences/National Research Council Twin Registry. Concordance for alcoholism was higher among MZ (82=312 ¼ 26:3%) than among DZ twins (56=472 ¼ 11:9%). Concordance for medical consequences of alcoholism (alcoholic psychosis, liver cirrhosis) is higher than that expected on the basis of concordance for alcoholism alone; that is, there is reason to postulate independent heritable effects that lead some alcoholics to manifest psychosis or cirrhosis while others do not. However, a recent reanalysis of these twin data supports a more important role for vulnerability factors for alcoholism per se in cirrhosis risk [18]. Kendler et al. [19] conducted a population-based study of female twin pairs from the Virginia twin registry. Personal interviews were completed on 1033 of 1176 pairs. MZ concordance rates varied from 26% to 47% (narrow to broad definition of alcoholism) while DZ concordance rates ranged from 12% to 32%. The heritability was estimated to be between 50% and 61%. This suggests substantial genetic influence in alcoholism in women in the populations studied. Subsequent studies by Prescott et al. [20] found that the genetic sources of vulnerability in males and females were partially, although not completely, overlapping. C.

Adoption Studies

Adoption studies have generally shown a relationship between alcohol problems in an adoptee and such pro-

Genetics of Addictive Disorders

blems in biologic relatives. Goodwin et al. [21] compared 55 adopted-away male children of an alcoholic parent with 78 adoptees without an alcoholic parent. The groups were matched by age, sex, and time of adoption. The principal finding was that 18% of the proband group were alcoholic compared with 5% of the controls (P < :02). This pattern does not hold true for adoptees designated as ‘‘problem drinkers’’ or ‘‘heavy drinkers.’’ There is no difference between groups if these categories are considered separately or if they are combined with the alcoholic group. It is only alcoholism itself that was heritable, with alcoholism defined as the presence of heavy drinking consisting of either 1 year of daily drinking with six or more drinks at least twice a month, or six or more drinks at least once a week for over a year. In addition, individuals also had problems in three out of the following four groups: (1) disapproval of drinking by friends, parents, wife; (2) trouble at job because of drinking, traffic arrests, or other police problem; (3) frequent blackouts, tremor, or serious withdrawal symptoms; (4) loss of control or repeated morning drinking. This result is consistent with Kaij’s finding [15] that heritability increases with the severity of the disorder. Goodwin also compared adopted-away sons of alcoholics with sons of alcoholics raised by the alcoholic parent [22], and found no differences. Twentyfive percent of the adopted sons became alcoholic compared with 17% of nonadopted sons. The sample sizes in each group were relatively small, with only 20 and 30 individuals, respectively. Additional studies in daughters of alcoholics did not show evidence for a heritable predisposition to alcoholism in women. These studies did show an increase in depression among daughters of alcoholic fathers, but only if the alcoholic father raised the daughter. This increase was not observed if the daughter was adopted away from the biological environment. These results are an apparent demonstration of an environmental cause of depression or perhaps a genetic-environmental interaction [22]. Bohman [23] used state registers in Stockholm to study 2324 adoptees born in that city between 1930 and 1949. Male adoptees whose fathers abused alcohol (excluding those who were also sociopathic) were more likely to be alcoholic themselves (39.4% vs. 13.6%; P < :01) compared with adoptees without an alcoholic (or sociopathic) father. The findings were similar, though not significant, for male adoptees with an alcoholic biologic mother. Cloninger et al. [24] then reanalyzed Bohman’s dataset, and postulated a familial

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distinction of alcoholics: the milieu-limited (type I) and male-limited (type II) groups. Type I alcoholics (as defined in Cloninger [25]) usually have onset after age 25, manifest problems with loss of control, and have a great deal of guilt and fear about alcohol use. Type II alcoholics are primarily males and have onset before age 25, are unable to abstain from alcohol, and have fights and arrests when drinking, but less frequently show loss of control and guilt and fear about alcohol use. Cloninger reanalyzed the Stockholm adoption data using these specific categories. This analysis showed that type I alcoholics were significantly increased in prevalence only among those adoptees with both genetic and environmental risk factors (alcoholism in both biologic and adoptive parents). Type I was the most common type of alcoholism, however, being present in 4.3% of the controls with no risk factors. Type II alcoholism was present in only 1.9% of the controls but 16.9–17.9% of adoptees with genetic risk factors, whereas the presence or absence of environmental risk factors (alcoholism in adoptive parents) did not appear to make a difference. Cloninger has further integrated these concepts with a personality typology based on behavioral and neurochemical data. The type I alcoholics, he theorizes, show low novelty seeking, high harm avoidance, and high reward dependence. The Type II alcoholics show high novelty seeking, low harm avoidance, and low reward dependence. As part of a more extensive, neurochemically based theory of personality, Cloninger associates novelty-seeking traits with dopamine pathways in the brain, harm avoidance with serotonin systems, and reward dependence with norepinephrine systems [25,26]. The Bohman-Cloninger analysis of the Stockholm sample is the largest adoption study in the field of alcoholism. However, the quality of the initial information (based on population registers) may not have been as complete as that gathered by Goodwin and colleagues, who performed personal interviews on the adoptees. Cloninger states that the population registers can identify 70% of alcoholics, without a bias for type I or type II, but it is not clear that there might not be a bias for the unregistered 30% of alcoholics to be found preferentially in one or another of the adoptee groups. However, the two studies reach essentially the same conclusion, heritable factors are important in the development of alcoholism in at least a subpopulation of heavy-drinking men. A variant on the usual adoption study format was reported by Schuckit et al. [27], who studied a population of half-siblings of alcoholic probands.

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Half-siblings with an alcoholic biologic parent had a high risk for alcoholism (46–50%) whether or not they were raised with an alcoholic parent figure. Those without an alcoholic biologic parent had a lower risk, regardless of environmental variables considered. D.

Disorders Possibly Genetically Related to Alcoholism

Winokur et al. [28] reported an increased prevalence of depression in the female relatives of alcoholics roughly comparable to the increased prevalence of alcoholism in male relatives. This was not found in the adoption study of Goodwin et al. [29] except in daughters brought up in the home of the alcoholic father; this may mean that the incidence of affective disorder and alcoholism in the same families may be related to environmental rather than genetic factors. A later study by Winokur and Coryell [30], showing increased alcoholism in the relatives of female depressive probands but not male depressive probands, is also compatible with that explanation. Some family studies in this area show an increase in risk for alcoholism in relatives of depressive probands, as well as an increase in depression in relatives of alcoholics; however, many other studies do not show this pattern [see review, 31]. It is clear that alcoholics themselves have an increased lifetime risk for depression [31]. The comorbidity between bipolar illness and alcoholism is particularly evident. If family studies are performed starting with probands with both disorders, then both disorders are found in relatives [32]. But family studies starting with bipolar probands or unipolar probands without alcoholism do not usually show an increase in alcoholism in relatives [33]. Similarly, family studies of primary alcoholics do not generally show an increase in relatives with major depression [31]. There may be some forms of illness that result from shared vulnerability factors. Recent studies suggest that comorbid disorders, including features of alcoholism and affective illness, may themselves run in families [34]. Bohman et al. [35] and Cloninger et al. [36] have observed that adopted-away daughters of type II (male-limited) alcoholics manifest no increase in alcoholism but do show an increase in somatization disorder. A major question is the relationship of alcoholism to sociopathy. Is there a genetic predisposition that may manifest as alcoholism in some and antisocial personality or criminality in others? The summaries of family studies by Goodwin [6] and Cotton [5] con-

clude that there is evidence for an increase in sociopathy in relatives of alcoholics in a number of family studies. The Swedish adoptee population studied by Bohman [23] showed a relationship between alcoholism and criminality in individual adoptees and their biologic fathers; however, this association was not demonstrated within the families. Thus, adoptees registered for alcohol abuse alone did not show an excess of criminality in relatives, and adoptees registered for criminality alone did not show an excess of alcoholism in relatives. Adoptees registered for both showed an excess of alcoholism only in relatives, but no more than adoptees registered for alcoholism alone. In the adoption data of Goodwin et al. [21], antisocial personality is not more common in adopted-away sons of biologic fathers with alcoholism. In the adoption study of Cadoret et al. [37], significant relationships were observed between alcoholism in adoptees and alcoholism in biologic relatives, and also between sociopathy in adoptees and sociopathy in biologic relatives. This relationship was not observed for alcoholism in adoptees and sociopathy in biologic relatives, or vice versa; however, there were nonsignificant trends, suggesting that a larger study might also show a positive relationship. Cadoret et al. summarize data from adoption studies of antisocial personality, also leading to the conclusion that the disorders are separable. It is not possible to conclude at this time that a single genetic predisposing factor may be manifest as either alcoholism or sociopathy. However, some sociopathic alcoholics may transmit both alcoholism and sociopathy as part of the same syndrome. A series of studies have shown an increased prevalence of alcoholism in parents of children with hyperactivity. Earls et al. [38] report an increase in DSM-III behavior disorder in general (attention deficit disorder with hyperactivity, oppositional disorder, and conduct disorder) in offspring of alcoholic parents. The risk was greater for offspring of two alcoholic parents than for those of one alcoholic parent. Merikangas et al. [39] examined a series of 165 probands selected for alcoholism and/or anxiety disorder and compared them with a sample of 61 unaffected controls. First-degree relatives of the probands completed a structured diagnostic interview. In this sample, rates of alcoholism were higher among relatives of the alcoholic probands, regardless of the presence or absence of anxiety disorder in the proband, as compared with the relatives of controls. There was also a twofold increase in the risk of anxiety disorder among the relatives of the probands with anxiety. The rate of comorbidity of alcohol dependence and anxiety dis-


orders was higher among female relatives than among male relatives of alcoholic probands.

III.

GENETIC ASPECTS OF DRUG ABUSE

There is a growing body of evidence confirming the familial aggregation of drug abuse. Numerous family history studies and systematic family studies of substance abusers in treatment settings [40–46] reveal a significantly increased risk of drug abuse among relatives of the addicted proband when compared to population estimates. In the first controlled family study of drug use disorders, Merikangas et al. [47] reported a strong familial aggregation of drug use disorders in families. The lifetime prevalence of drug disorders in the first-degree relatives of probands with drug abuse was 17.7% compared to 4.9% in relatives of unaffected controls, yielding a population relative risk of 3:6. Several twin studies have provided evidence that genetic factors play a major role in the familial aggregation of substance use and abuse with heritability estimated between 30% and 80 [48–53]. In the first study, using diagnostic criteria for drug abuse and dependence, Pickens et al. [51] reported far greater heritability for drug dependence than for abuse. In the largest twin study to date, Tsuang et al. [53] found that substance abuse in general was highly heritable, and that the contribution of genetic factors was more significant for frequent use or abuse than for nonproblematic use. Grove et al.’s [50] study of a small set of MZ twins who were reared apart yielded significant estimates of heritability for drug-related problems (0.45). The prevalence of drug abuse is far greater among males than females, with approximately fourfold greater rates of drug disorders among males. There is some evidence in the literature that the genetic factors underlying drug disorders in women differ from those in men. The twin study of Pickens et al. [51] suggested that whereas drug disorders in males are attributable to both common genes and common environmental factors, unique environmental factors play a major role in drug disorders in women (e.g., events specific to each person, but not to family members). Subsequent analyses of these twin data [54] suggested that heritability for substance abuse was much greater (heritability ¼ 0:73) for males with early age of onset, compared to males with later onset (heritability ¼ 0:30) or females (heritability ¼ 0:0). The results of some family studies suggest that the relatives of female

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drug abusers have an elevated risk of drug disorders compared to male drug abusers, thereby suggesting that females may manifest a more severe form of drug abuse than males or may have greater accumulation of underlying genetic and environmental risk factors for drug abuse [47]. The classic adoption studies of Cadoret [55] and Cadoret et al. [56,57], which employed an optimal study paradigm for discriminating the joint influence of genetic and environmental factors, have been highly informative in elucidating the role of genetic factors in the development of drug use and abuse in a U.S. sample. The results of their studies revealed the importance of the role of genetic factors in the development of drug disorders, with a far greater impact on the transition from drug use to abuse than on drug use itself. Most studies have consistently reported a higher concordance rate for cigarette smoking among MZ than among DZ twins. The mean heritability estimate for tobacco use is 53%, although there is a wide range of reported estimates, from 28 to 84% [58– 62]. Family studies have also found an increased risk of nicotine dependence among siblings of individuals who are nicotine dependent, with recurrence risk estimates of 2.1–3.5, depending on the instrument used to evaluate nicotine dependence [63]. Studies have found that genetic factors play a role not only in the initiation of smoking, but also contribute to the age of onset of smoking, the number of cigarettes smoked per day, and the persistence and intensity of smoking [60,64].

IV.

FAMILIAL RELATIONSHIPS BETWEEN ALCOHOLISM AND DRUG ABUSE

Among alcohol-dependent individuals, the rate of other mental disorders has been estimated to be as high as 47%, with a substantial proportion of this comorbidity due to other drug dependencies [65,66]. Family history of alcoholism contributes to an increased risk of drug use. In a sample of male college students, McCaul and colleagues [67] found the greatest level of alcohol and drug use among the students with a high density of alcoholism in their families. Intermediate levels of alcohol and drug use were noted among those students with lower rates of alcoholism and the least amount of alcohol and drug use among those students without a family history of alcoholism. Studies among opiate-dependent individuals have found an increased rate of alcoholism among

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relatives, even after controlling for the presence of alcoholism in the proband [46]. Cadoret et al. [56,68] also found higher rates of drug and alcohol use among male adoptees with an alcoholic parent as compared to those whose biological parents were not alcoholics; the same effect was not observed in a sample of female adoptees [57]. These results suggest that a general predisposition for addictive disorders might be inherited [62,69,50], although other studies have not supported this conclusion [40]. Support for this hypothesis was found in a large sample of World War I male veteran twins where the development of both heavy alcohol use and smoking was found to be due to both unique and shared genetic factors [62]. Analyses of a sample of Vietnam veteran twins found substantial genetic correlation between nicotine and alcohol dependence among middle aged male twins [61], suggesting a common genetic susceptibility to both dependencies. Kendler et al. [69] also found that common familial factors predispose to alcohol abuse/dependence and drug abuse/dependence. In a large study designed to address the contribution of genetic factors to substance use disorders, Merikangas et al. [47] identified a sample of 299 probands with drug (nonalcohol) dependence or alcohol dependence. Among the 149 individuals with nonalcohol drug dependence were probands with opioid, cocaine, and cannabis dependence. In addition, a sample of 61 control probands without any lifetime history of any diagnosis in DSM-III-R was also ascertained. Individuals and their first-degree relatives completed a structured diagnostic interview to identify any drug dependencies. There was an eightfold increased risk of drug and alcohol disorders among relatives of probands with drug disorders across a wide range of specific substances (including opioids, cocaine, marijuana, and sedatives) as compared with that of relatives of controls. There was also a sixfold increase in drug or alcohol disorders among relatives of the alcoholic probands, although this effect was largely due to the increase in alcoholism among the relatives of the alcoholic probands. The findings from Merikangas et al. [47] suggest that there may be some specificity in the familial aggregation of the predominant drug disorder with increasing rates of more ‘‘serious’’ drug disorders among probands with more ‘‘serious’’ substance disorders. Specifically, rates of opioid disorders were highest among probands with opioid dependence as compared with probands with marijuana dependence.


V.

STUDIES TO IDENTIFY GENES UNDERLYING ALCOHOLISM SUSCEPTIBILITY

These and other studies suggest that, rather than being a disorder due to a single gene, alcoholism is more likely a complex genetic disorder resulting from the action of multiple, possibly interacting, genes, as well as environmental factors. In the search for such genes, researchers have pursued a two-pronged strategy. Some investigators have focused on the evaluation of the role of known functionally polymorphic genes with alcoholism while others have used anonymous markers distributed throughout the genome to detect linkage of alcoholism susceptibility to chromosomal regions wherein such genes might reside.

A.

Candidate Gene Studies

Efforts to identify the genetic loci underlying alcoholism susceptibility in human subjects have primarily relied on the evaluation of candidate genes, but the only consistently replicated findings are those involving the protective effects of certain functional polymorphisms of the alcohol metabolizing enzymes alcohol dehydrogenase (ADH) and the mitochondrial aldehyde dehydrogenase (ALDH2) [70–76]. Most ingested alcohol is metabolized to acetaldehyde by ADH and by microsomal cytochrome P450IIE1 (CYP2E1) present in the liver. The acetaldehyde is in turn metabolized to acetate by ALDH. Alcohol dehydrogenase exists as a polygene family on chromosome 4 consisting of seven genes two of which, ADH2 and ADH3, are functionally polymorphic. The ADH2 gene encodes the b subunit of the dimeric enzyme, and there are polymorphic forms called b1 , b2 , and b3 . They differ by single nucleotide exchanges and one amino acid differences. The enzyme variants, however, are quite different in catalytic properties. The enzyme with the b1 subunit has low activity and high affinity for ethanol, whereas the b2 and the b3 forms have higher activity and lower affinity for ethanol. The prevalence of the variant enzyme forms varies in different ethnic populations. Among Caucasians, 95% have the b1 enzyme form, while in the Pacific rim Asian populations, such as Chinese, Japanese, and Korean, 90% have the b2 form. Among Africans and African-Americans, 24% have the b3 form. There is another ADH, ADH3, which is also functionally polymorphic, and encodes the g-subunits; however,


the two forms differ only twofold in their activity. Ninety percent of Asians have the g 1 form and 50% of Caucasians have the g2 form. Aldehyde dehydrogenases (ALDH) are found in the cytosol and mitochondria of liver cells. The mitochondrial form is called ALDH2 and has the highest affinity for acetaldehyde and is the enzyme most responsible for acetaldehyde oxidation. The form that is found in most populations around the world is a highly active enzyme, encoded by the ALDH2*1 allele. Among Asians, especially the Chinese, Japanese, and Koreans, a high prevalence of a variant form, ALDH2*2, has been observed, which encodes a protein subunit that confers very low or absent activity to the tetrameric enzyme. Individuals who are homozygous for the ALDH2*2 allele have virtually no enzyme activity in the liver, while those who are heterozygous have considerably lower activity than ALDH2*1 homozygotes. Therefore, the ALDH2*2 allele is functionally dominant. Studies have consistently demonstrated that functional polymorphisms in the ADH and ALDH2 enzymes in Asian populations [70–76] result in lower risks for alcoholism. The ALDH2*2 allele remains the single most powerful known genetic factor that reduces alcohol consumption. Individuals with this allele have elevated levels of acetaldehyde and experience a flushing reaction after drinking even small amounts of alcohol [77]. This reaction, similar to the alcohol-disulfiram reaction, is aversive, thereby discouraging alcohol ingestion. The ADH2*2 allele, which codes for the b2 subunit, has also been shown to be at lower frequency among alcoholics than in the general population, supporting a protective effect [70]. Recently, Neumark and colleagues [78] found that the ADH2*2 allele was present in about 20% of individuals of Jewish ancestry, and those individuals with the ADH2*2 allele had lower peak weekly alcohol intake than individuals without the allele. No association of the microsomal P450IIE1 (CYP2E1) polymorphism with alcoholism has been found. The dopamine D2 receptor (DRD2) gene on chromosome 11 is considered a candidate for involvement in alcoholism as well as the personality trait of novelty seeking and central nervous system reward [79,80]. It has been studied extensively by a number of research groups following the report of an association between the TaqI-A1 polymorphism in the DRD2 gene and alcoholism [81]. A number of positive reports [82–87] and many more negative reports have appeared [88– 102]. The bulk of evidence does not favor a major role in alcoholism vulnerability for DRD2 at this time, but a minor role can not be excluded.

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The serotonin transporter gene (HTT) has also been actively studied as a candidate gene for alcoholism due to the numerous roles of serotonin as a neurotransmitter. A functional polymorphism (5HTTLPR) was reported in the HTT promoter, with the two common alleles resulting in either a long, 528-bp allele or a short, 484-bp allele [103]. The short allele was initially reported to be associated with an increase in anxietyrelated traits, including harm avoidance [104]. This finding was not confirmed following examination in another study population [105]. A recent populationbased association study found the phenotype of severe alcoholism, marked by withdrawal seizure or delirium, to be associated with the 5HTTLPR promoter polymorphism, with alcoholics having an excess of the shorter allele as compared to population controls [106]. However, this finding was not confirmed in a large sample of alcoholic families using a more powerful, family-based association analysis [107]. B.

Family-Based Linkage Studies

To more efficiently identify genetic loci contributing to alcoholism susceptibility, recent studies have focused on a genomewide approach, which would allow novel genetic loci to be identified. After the collection of extended pedigrees with multiple members diagnosed with alcoholism, genetic analysis techniques can be employed to evaluate the evidence for linkage throughout the genome. Such a strategy was employed by the Collaborative Study of the Genetics of Alcoholism (COGA) which ascertained, evaluated, and genotyped 105 pedigrees as part of an initial genome screen [75,108]. The initial linkage analyses used only one definition of alcoholism with individuals defined as affected if they fulfilled criteria for alcoholism based on DSM-III-R and Feighner criteria (termed ‘‘COGA’’ criteria). Using 382 affected sibling pairs, regions on chromosomes 1, 2, and 7 were identified as harboring genes that predispose an individual to alcoholism [108]. The most significant finding of the study was on chromosome 7, with a LOD score of 3.5 near the marker D7S1793. On chromosome 1, a peak LOD score of 2.9 was found near the marker D1S1588. A second locus on chromosome 1, 60 cm from the initial linkage finding, had a LOD score of 1.6. A LOD score of 1.8 was found on chromosome 2, near the marker D2S1790. Additional analyses using individuals without a diagnosis of alcoholism, who were part of families with multiple alcoholic members, supported a protective locus on chromosome 4 near the ADH genes.

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Linkage to chromosome 4 was particularly interesting since the COGA sample has few Asian families, but rather consists primarily of non-Hispanic Caucasian and African-American families. This linkage result on chromosome 4 suggests that the protective effects of ADH might not be limited to the Asian population. Subsequently, linkage analyses were completed in a replication dataset of 157 pedigrees ascertained and evaluated using criteria identical to those used in the initial sample [109]. Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD ¼ 1:6) in the replication dataset as well as in a combined analysis of the two samples (LOD ¼ 2:6). Evidence of linkage to chromosome 7 increased in the combined data (LOD ¼ 2:9). The LOD score on chromosome 2 in the initial dataset increased following genotyping of additional markers; however, combined analyses of the two datasets resulted in overall lower LOD scores (LOD ¼ 1:8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD ¼ 3:4). Thus, analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also identified possible susceptibility loci on chromosomes 2 and 3 that require further confirmation. A genome screen has also been completed in a sample of alcoholics from a southwestern American Indian population [110], which is likely to be genetically more homogeneous than a sample of U.S. Caucasian families. Linkages to chromosomes 4 and 11 were reported. Further analyses of a chromosome 11 candidate gene, tyrosine hydroxylase, supported linkage of this locus in a sample of Finnish offenders with alcoholism and comorbid antisocial personality [111]. Another approach to the identification of genes contributing to alcoholism is to identify novel phenotypes that may have greater genetic contribution and may reduce genetic heterogeneity. A study by Kendler et al. [112] found a genetic correlation of 0.4–0.6 between major depression and alcoholism. Based on these data, a novel phenotype was developed in the COGA sample in which individuals were considered affected if they had either alcoholism (both DSM-IIIR alcohol dependence and alcoholism by Feighner criteria) or depression (either DSM-III-R major depression or depressive syndrome). Using this phenotype, strong evidence of linkage was observed on chromosome 1 with a LOD score of 5.12 in the same region previously reported linked to alcoholism alone in this sample [34, 113]. Importantly, using the phenotype of


alcoholism or depression, the strength of the linkage finding increased both in terms of the LOD score and the proportion of alleles shared identical by descent.

VI.

STUDIES TO IDENTIFY GENES UNDERLYING DRUG DEPENDENCE

A.

Candidate Genes for Drug Dependence

Because of the convincing evidence [53,39] regarding the specificity of the familial aggregation of opioid dependence, the genes encoding key proteins in central nervous system opioid systems have been given extensive study as plausible candidate susceptibility genes. In the coding region of the mu opioid receptor gene (OPRM1), two relatively frequent amino acid substitutions have been identified, an A6V substitution [114], and an N40D substitution [115,116]. The A6V variant has been reported by Berrettini et al. [114] and by Bond et al. [116] to be marginally overrepresented among opioid-dependent individuals (P ¼ :05 in each study). A common exon 1 SNP variant of the OPRM1, N40D, increases the affinity by severalfold of a POMC gene product, beta-endorphin, for the OPRM1 receptor [116]. Since POMC is an endogenous ligand of the OPRM1 receptor, this finding raises the possibility that variation in POMC expression may be important for the risk to opioid dependence in the presence of the OPRM1 N40D polymorphism. Additional studies by Kranzler et al. [117] reported minimal evidence for association of substance abuse with a microsatellite polymorphism located near OPRM1. Not all studies have confirmed an association between OPRM1 and opioid dependence [118]. For the delta-opioid receptor gene (OPRD1), there is a common, silent coding SNP (C ! T at bp 307) which has been found to be associated with opioid dependence using a case-control design. A follow-up study in a larger sample found no evidence for association of the OPRD1 gene with opioid dependence [119]. Gelernter and Kranzler [120] performed a family-based association study of the OPRD1 SNP in a sample of 72 opioid-dependent kindreds and found evidence for an association with opioid dependence, but no evidence for an association with cocaine dependence or alcoholism. There are several reports of association between opioid or cocaine dependence and nonfunctional variants of the DRD2 gene [96,121,122]. O’Hara et al. [96] reported an association between DRD2 and polysubstance dependence among Caucasian, but not African-


American individuals. Noble et al. [121] also observed this association in a group of Caucasian cocaine dependent individuals. Berrettini and Persico [122] confirmed the observation of O’Hara et al. [96] that there was no association for opioid or cocaine dependence among African-Americans. The D4 dopamine receptor gene (DRD4) is characterized by one to eight copies of a 48-bp imperfect exonic repeat [123]. The number of repeats determines the affinity with which some ligands bind DRD4 [124]. Novelty-seeking behavior [125–127] has been associated with larger alleles (seven copies) of the 48-bp repeat in DRD4. Elevated scores in novelty-seeking behavior may be characteristic of cocaine- and opioid-dependent persons [128,129]. There is a reported association of this DRD4 polymorphism with opioid dependence [130], but this has not been confirmed by Franke et al. [119], who studied > 800 persons, using both case control and trio designs. B.

Genetic Studies of Nicotine Use

Only a few studies have attempted to elucidate the genes contributing to the underlying genetic susceptibility to tobacco use. Recently, Spitz and colleagues [131] reported an association with DRD2 among individuals who had ever smoked, defined as > 100 cigarettes in their lifetime. The initial study reported an increased frequency of the A1 allele, either in the homozygous or heterozygous state, among individuals who smoked. A similar association had been previously reported [83,86]. However, a larger study, utilizing a family-based association method, did not find evidence of an association of the DRD2 alleles among individuals who had ever smoked, were habitual smokers or even individuals who were habitual smokers and alcohol dependent [132]. Only one genome screen has been reported to date to identify genetic loci underlying nicotine dependence. Using a sample from New Zealand, Straub and colleagues [133] reported linkage to several chromosomal regions with modest results. To further examine these regions, a second sample collected in the United States was analyzed, and consistent, though still modest, evidence of linkage was found on chromosomes 17 and 18.

VII.

ETIOLOGIC MARKER STUDIES

Major areas of concentration in the search for a potential biologic trait marker of alcoholism include (1)

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EEG and evoked potentials before and after alcohol, (2) psychologic/psychophysiologic measures, and (3) behavioral and neuroendocrine responses to alcohol. A poorly synchronized resting EEG (lower alpha) has been thought to be related to a predisposition for alcoholism [134]. Change in alpha rhythm following alcohol is more concordant in MZ than DZ twins, as are multiple other EEG parameters [135,136]. A relationship was found between resting EEG of the unselected twins and drinking behavior, with less alpha in the twins who drank more. In subsequent work, Propping et al. [137] found that relatives of alcoholics with poorly synchronized resting EEGs demonstrated the same characteristic themselves. Change in alpha rhythm following alcohol was also found to differentiate young adult subjects at high risk for alcoholism from controls [138]. Measurements of event-related potentials (ERP) have shown decreased amplitude of the P300 wave following visual stimuli in 7- to 13-year-old sons of alcoholics compared to controls [139], lessening the likelihood of previous alcohol exposure. Similar findings using an auditory stimulus had been reported in an older group (age 21–26) both before and after alcohol administration [140]. These findings have been confirmed in other populations, including the families from the Collaborative Study on the Genetics of Alcoholism (COGA) [141]. Hill et al. [142] found a significant increase in P300 latency in adolescent and adult relatives of alcoholics compared to controls. The EEG/ERP area remains one of the more promising in the field of pathophysiologic markers for alcoholism. In a study by Tarter et al. [143], sons of alcoholics performed more poorly than sons of nonalcoholics on 8 out of a series of 47 neuropsychological measurements. The authors discuss possible explanations including physical abuse by the father, psychiatric illness in the mother, and perinatal injury, as well as predisposition to alcoholism. Other investigators have not found such deficits, suggesting that they may not be a general feature of alcoholic populations [144]. A number of investigators report increased static ataxia in children of alcoholics [see summary in Hill et al., 145]. Finn and Pihl [146,147] have demonstrated increased cardiovascular reaction to unavoidable shock in sons of alcoholics, especially those with multigenerational family histories of alcoholism. Hill et al. [148] have found increases in the MMPI psychopathic deviance scale in alcoholics, and some evidence indicates this may be predictive of alcoholism. Von Knorring et al. [149] found increases in a personality factor related to impulsivity, sensation seeking, and

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psychopathy in type II alcoholics compared with controls. Schuckit [150–152] has studied behavioral and neuroendocrine responses to alcohol administration in a series of high-risk populations; offspring of alcoholics displayed less subjective intoxication than controls. A follow-up study by Schuckit and Smith [153] shows that decreased subjective intoxication is correlated with later development of alcoholism in sons of alcoholics. Using a 12-item questionnaire that measures an individuals level of response to alcoholism, the Self Rating of the Effects of Alcohol (SRE) instrument, data from 745 individuals from COGA was used to identify chromosomal regions linked to an individual’s level of response to ethanol [154]. From these data, several chromosomal regions were identified which appear to contribute to this phenotype. In particular, the region on chromosome 1 that is linked to a low level of response to alcohol is also linked in the same sample to alcohol dependence [108,109].

VIII.

ANIMAL MODELS OF ADDICTIVE DISORDERS

The use of animal models with similar or related behaviors may provide important genetic clues that will improve the efficiency of identifying genes underlying human addictions. Well-characterized animal lines with phenotypes related to certain aspects of human addictive behaviors can be used as an approach to study more homogeneous populations in which isolation of candidate regions and loci should be faster and more efficient. Most mouse studies have utilized B6 and D2 progenitors and a variety of breeding schemes. Unique quantitative trait loci (QTLs) have been identified in each experiment, but there are some consistent linkage findings that appear to replicate across these studies. While definitive QTL identification is certainly not yet available, several chromosomal regions show great promise for gene identification, especially murine chromosome 2 [155–160]. Selective breeding based on the phenotype of high and low alcohol consumption has resulted in the development of selected rat lines. Genome screen studies using the inbred alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines have resulted in strong evidence of linkage to rat chromosome 4, in the region near the neuropeptide Y gene [161]. The use of animal models has also proven to be successful in the identification of QTL contributing to the observed differences among the B6 and D2

mice in oral voluntary morphine consumption. Two major loci have been identified [162]. A locus on proximal murine chromosome 10 [162] explained 50% of the genetic variance in morphine consumption. Subsequently, the murine OPRM1 gene was localized to this interval [163–165]. Two groups of investigators have produced OPRM1 knockout mice [166,167]. These mice are indifferent to the analgesic and rewarding properties of morphine, suggesting that these opioid effects are mediated mostly through OPRM1. The second major locus that was identified was on mouse chromosome 6. IX.

SUMMARY

There is substantial evidence that genetic factors play a major role in the susceptibility to alcohol, opiate, and other drug abuse as well as nicotine use. Studies of extended pedigrees suggest that there may be a subset of genetic loci that nonspecifically increase the predisposition to various addictions. Ongoing studies have also identified chromosomal regions that may harbor susceptibility loci influencing addiction to specific drugs. ACKNOWLEDGMENTS This work was supported by U.S. Public Service grants AA10707, AA08403, and AA00285. REFERENCES 1.

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42 Biological Basis of Eating Disorders WALTER H. KAYE and NICOLE C. BARBARICH Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

I.

INTRODUCTION

food intake, an extreme fear of weight gain, and often a distorted view of their actual body shape. Loss of control over food intake usually occurs intermittently and typically only some time after the onset of dieting behavior [2]. Episodes of binge eating also develop in a significant proportion of people with AN [3], whereas a smaller percentage of those with BN will eventually develop AN [4]. Considering that restrained eating behavior and dysfunctional cognitions relating weight and shape to self-concept are shared by patients with both of these syndromes, and that transitions between AN and BN occur in many, it has been argued that AN and BN share at least some risk and liability factors. The etiology of eating disorders is still unknown; however, it seems clear that multiple factors may be linked to the pathogenesis of AN and BN, with current research focused on identifying the relative pathophysiological contributions of genetic, biological, psychological, and social factors [2]. While it has been argued that cultural attitudes toward standards of physical attractiveness have relevance to the psychopathology of eating disorders, it is unlikely that cultural influences in pathogenesis are very prominent. For one thing, dieting behavior and drive for thinness are quite commonplace in industrialized countries throughout the world, yet AN and BN affect only an estimated 0.3–0.7% and 1.7–2.5%, respectively, of females in the general population. Moreover, numer-

Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by abnormal patterns of feeding behavior and weight regulation, with disturbances in perceptions and attitudes toward shape and weight [1]. The characteristic feature of AN is an inexplicable fear of weight gain and an unrelenting obsession with fatness even in the face of increasing cachexia. In BN, the onset of binge eating usually emerges after a period of dieting, which may or may not have been associated with weight loss. In addition, binge eating is followed by the use of inappropriate behaviors such as selfinduced vomiting; misuse of laxatives, diuretics, or enemas; excessive exercise; or fasting as a means of compensation for the excess food ingested. Although individuals with BN are typically at a normal body weight, some 25–30% presenting to treatment centers have a prior history of AN. In certain respects, both diagnostic labels are misleading. In AN, weight loss is rarely associated with a true loss of appetite, but rather a volitional, and more often than not, ego syntonic resistance to feeding drives with an eventual preoccupation with food and eating rituals to the point of obsession [2]. In addition, binge eating in BN is not associated with a primary pathological increase of appetite. Individuals with BN have a seemingly relentless drive to restrain their 633

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ous clear descriptions of AN date back to the middle of the 19th century [5] suggests that factors other than a cultural emphasis on thinness play an etiologic role. In addition, these syndromes, particularly in the case of AN, have a relatively stereotypic clinical presentation, sex distribution, and age of onset, which provides support for the possibility of some biologic vulnerability to the disorders. This chapter provides a brief overview of the illness phenomenology and behavioral traits characteristic of AN and BN. Current knowledge of the potential etiological significance of genetic and neurobiological risk and vulnerability factors in the development of AN and BN is also discussed.

II.

ILLNESS PHENOMENOLOGY AND COURSE

A.

Phenomenology

Variations in feeding behaviors have been used to distinguish individuals with AN into two meaningful diagnostic subgroups that differ in other psychopathological characteristics. In the restricting subtype of AN, weight loss and an ongoing malnourished state are accomplished primarily through unremitting food avoidance and/or excessive exercise. In the binge-eating/purging subtype of AN, there is comparable weight loss and malnutrition, yet the course of illness is marked by supervening episodes of binge eating, usually followed by inappropriate compensatory behaviors such as self-induced vomiting or laxative abuse. Compared to the restricting subtype of AN, individuals with the binge-eating/purging subtype are also more likely to exhibit histories of behavioral dyscontrol, substance abuse, and overt family conflict. Marked perfectionism, conformity, obsessionality, constriction of affect and emotional expressiveness, and reduced social spontaneity are personality traits that are particularly common in individuals with AN. These traits appear to be premorbid and persist even after long-term weight restoration, indicating the presence of disturbances that are not merely the result of acute malnutrition and disordered eating behavior [6,7]. Although many individuals with BN aspire to ideal weights far below the range of normalcy for their age and height, most remain at normal body weight. The core features of BN include repeated episodes of binge eating followed by inappropriate compensatory behaviors including self-induced vomiting, laxative abuse, or pathologically extreme exercise, as well as abnormal

concerns with shape and weight. The DSM-IV [1] has specified two distinct subgroups of BN to distinguish between those individuals who engage in self-induced vomiting or abuse of laxatives, diuretics, or enemas (purging type), and those who exhibit other forms of compensatory behaviors such as fasting or excessive exercise (nonpurging type). Beyond these diagnostic categories, it has been proposed [8] that there are two clinically divergent subgroups of individuals with BN differing significantly in psychopathological characteristics: a multi-impulsive type, in whom BN occurs in conjunction with more pervasive difficulties in behavioral self-regulation and affective instability; and a second type, whose distinguishing features include self-effacing behaviors, dependence on external rewards, and extreme compliance. Individuals with BN of the multi-impulsive type are far more likely to have histories of substance abuse and display other impulse control problems such as shoplifting and self-injurious behaviors. Considering these differences, it has been postulated that multiimpulsive-type BN individuals rely on binge eating and purging as a means of regulating intolerable states of tension, anger, and fragmentation. In contrast, individuals with the latter type of BN may have binge episodes precipitated through dietary restraint with compensatory behaviors maintained through reduction of guilty feelings associated with fears of weight gain. B.

Course

The mean age of onset of AN is 17 years, with some data suggesting bimodal peaks at ages of 14 and 18 years [1]. Although childhood onset of AN has been reported, it is not clear whether prepubertal onset of the illness confers a less ominous prognosis. Recovery from AN tends to be protracted, but studies of longterm outcome reveal a highly variable course: roughly 50% of individuals will eventually have reasonably complete resolution of the illness, whereas another 30% will have lingering residual features that fluctuate in severity long into adulthood. In 10% of individuals, AN will pursue a chronic, unremitting course, and the remaining 10% of those affected will eventually die from the disease. Compared to AN, the age of onset of BN is more variable, with most cases developing during the period from middle to late adolescence through the mid-20s [9]. It is usually precipitated by dieting and weight loss, yet it can occur in the absence of apparent dietary restraint. There is considerable variation among indi-

Biological Basis of Eating Disorders

viduals in the frequency of binge episodes, their duration, and the amount of food consumed during any one episode. Follow-up studies of clinic samples 5–10 years after presentation showed a 50% rate of recovery while nearly 20% continued to meet full criteria for BN [9]. Following onset, severity of disturbed eating behavior will fluctuate over the course of several years in a high percentage of clinic cases. Approximately 30% of women who had been in remission experienced relapse into bulimic symptoms, although the risk of relapse appeared to decline 4 years after presentation [9].

III.

BEHAVIORAL TRAITS

Eating disorders are associated with a number of psychological symptoms aside from pathological eating behaviors. Recent studies in AN [10–12] have consistently found elevated scores of harm avoidance (the tendency to inhibit behavior to avoid punishment) and persistence (perseverance without intermittent reinforcement). In addition, decreased scores have been reported on measures of novelty seeking (behavioral activation to pursue rewards), self-directedness (the degree to which the self is viewed as autonomous and integrated), and cooperativeness (the degree to which the self is viewed as a part of society [10,11]. Personality styles of women with AN are characterized by marked rigidity, overcontrol, obsessionality, and perfectionism [7,13]. Studies in BN have reported increased scores on measures of impulsivity, disorganization, and affective lability [14]. Additional psychological disturbances in AN and BN include depression, anxiety, substance abuse, and personality disorders. Theories regarding a shared vulnerability between AN and obsessive compulsive disorder have also received a substantial amount of attention [15,16]. A major methodological issue in the study of these disorders is determining whether such symptoms are a consequence or a potential cause of pathological feeding behavior and malnutrition. Owing to the young age of onset and difficulty in premorbid identification of people who will develop an eating disorder (ED), it is impractical to study AN and BN prospectively. Instead, subjects can be studied after long-term recovery under the assumption that in the absence of confounding nutritional influences, persistent psychobiological abnormalities might be trait related and potentially contribute to the pathogenesis of the disorder. While the definition of recovery from an ED has not been formalized, the limited number of studies that have investigated people who have recov-

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ered from an ED tend to include people formerly ill with AN after they were at a stable and healthy body weight for months or years and had not been malnourished or engaged in pathologic eating behavior during that period of recovery. In studies of BN, investigators tend to include subjects who have been abstinent from binging and purging for months or years. In addition, some studies have included criteria of normal menstrual cycles and a minimal duration of recovery, such as 1 year, for inclusion in the study. Studies have reported that women who were longterm recovered from AN had a persistence of obsessional behaviors as well as inflexible thinking, restraint in emotional expression, and a high degree of self- and impulse control [6,7,17,18]. In addition, they have social introversion, overly compliant behavior, limited social spontaneity, and greater risk and harm avoidance. In terms of core ED symptoms, individuals who are longterm recovered from AN had residual disturbances, such as ineffectiveness, a drive for thinness, and significant psychopathology related to eating habits. Similarly, individuals who have recovered from BN continue to be overly concerned with body shape and weight, and have abnormal eating behaviors and dysphoric mood [19–23]. Both recovered AN and BN women have increased scores on measures of perfectionism with the need for symmetry and ordering/arranging as their most common obsessional target symptoms. Overall, these residual behaviors can be characterized as overconcerns with body image and thinness; obsessionality with symmetry, exactness, and perfectionism; and dysphoric/negative affect. Pathological eating behavior and malnutrition during the acute phase of syndromes appear to exaggerate the magnitude of these concerns. Thus, while target symptoms are the same in both ill and recovered individuals, the intensity of the symptoms is greater during the acute illness. The persistence of these symptoms after recovery raises the possibility that the disturbances are premorbid traits that contribute to the pathogenesis of AN and BN.

IV.

FAMILY/GENETICS

Despite the lack of empirical evidence, traditional theories of etiology have often viewed eating disorders as sociocultural in origin. However, emerging evidence suggests that both AN and BN are familial, and that clustering of the disorders in families may result from genetic transmission of risk. Family studies provide guidance as to whether a disorder is possibly genetic

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by establishing whether it clusters among biologically related individuals. Results from the largest and most systematic studies suggest a 7- to 12-fold increase in the prevalence of AN and BN in relatives of eatingdisordered probands compared to controls [24,25]. However, given that first-degree relatives share genes and environment, these studies are unable to definitively differentiate genetic versus environmental causes for the familial clusters. In contrast, twin studies are able to provide a better estimate of genetic versus environmental effects of a disorder by comparing similarities for a trait between identical (monozygotic; MZ) and fraternal (dizygotic; DZ) twins. Data from a large epidemiological sample of twins obtained via the Virginia Twin Registry [26,27] found evidence for a strong association between AN and BN. The cotwin of a twin affected with AN was 2.6 times more likely to have a lifetime diagnosis of BN compared to the cotwins of unaffected twins. There are several reports of greater pairwise concordance rates of eating disorders in MZ than in DZ twin pairs [28,29]. Studies reported that 58–76% of the variance in AN [30,31] and 54–83% of the variance in BN [26,32] can be accounted for by genetic factors. These heritability estimates are similar to those found in other psychiatric disorders, such as schizophrenia and bipolar disorder, suggesting that eating disorders may be as genetically influenced as disorders traditionally viewed as biological. Several family and twin studies have examined the covariation between eating disorders and a range of other psychiatric conditions that occur with comorbidity in AN and BN individuals [see reviews, 24,33]. Studies of AN probands have yielded familial risk estimates in the range of 7–25% for major affective disorder, with relative risk estimates in studies employing normal controls in the range of 2.1–3.4. Similar studies of BN probands have shown, with rare exception, that their first-degree relatives are several times more likely to develop affective disorders than relatives of control subjects. Most studies considering the effects of proband comorbidity on familial risk have shown that affective illness is more likely to be transmitted by probands with the same diagnostic comorbidity. In short, although AN and BN often co-occur with major mood disorders, particularly unipolar depression, the two conditions do not appear to express a single, shared transmitted liability. Evidence from family studies suggests a relatively low prevalence of substance abuse disorders among relatives of restricting-type AN probands. These rates are elevated in relatives of probands with BN.

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However, recent studies have consistently shown [34,35] that the genetic variation influencing susceptibility to alcoholism was independent of those genetic factors underlying risk to BN. Tentative evidence of independent familial transmission of obsessive-compulsive disorders (OCD) and AN and BN have been reported. However, preliminary data from other investigators suggest a common familial transmission of AN and obsessive-compulsive personality disorder (OCPD), suggesting the existence of a broad, genetically influenced phenotype with core features of rigid perfectionism and propensity for extreme behavioral constraint. Consequently, in spite of the formidable challenges encountered in the biological study of malnourished individuals, efforts to better understand the pathophysiology of AN and BN continue to have clinical and heuristic value.

V.

NEUROTRANSMITTER

The role of biological determinants in the etiology of AN has been proposed for the past 60 years [5]. An increased knowledge of the neurotransmitter modulation of appetitive behaviors has raised the question whether some disturbance of neurotransmitter function causes AN and/or BN [36–38]. Although it is possible that the monoamine disturbances found in patients with eating disorders could be a consequence of dietary abnormalities, it is equally important to consider that these disturbances may be premorbid traits that contribute to a vulnerability to develop AN or BN. To understand the relative effects of starvation and malnutrition, individuals are studied while symptomatic and after recovery. A.

Serotonin

There has been substantial interest in the role that serotonin (5HT) may play in AN and BN. In part this is related to evidence that has found alterations in the metabolism of 5HT both during the acute phase of eating disorders and after long-term recovery. These disturbances are of particular interest to eating disorders since 5HT has been implicated in a wide number of systems including feeding, mood, impulse regulation, anxiety, and obsessionality. Serotonin is a neurotransmitter that is widely distributed in the brain. It is synthesized from its amino acid precursor tryptophan (TRP), which is taken up by the brain and hydroxylated by the enzyme tryptophan5-hydroxylase [39]. The product of this reaction, 5-


hydroxytryptophan, is then decarboxylated by the aromatic amino acid decarboxylase to the compound 5hydroxytryptamine. Monoamine oxidase further metabolizes 5HT to the metabolite product known as 5hydroxyindoleacetic acid (5HIAA), which may be measured as a means of assessing serotonin turnover or metabolism [39]. Measuring the concentration of 5HIAA in cerebrospinal fluid (CSF) provides an index of presynaptic activity in serotonergic pathways [40] and has been utilized as a measure of 5HT metabolism in a number of psychiatric disorders. Diminished 5HT function is associated with an impulsive-aggressive behavioral style [41], and low concentrations of CSF 5HIAA are associated with a significant increase in aggressive behavior and suicide risk [42,43]. It has been argued that the region-specific increase in 5HT2 receptors in the brains of suicide victims may be increased in number secondary to decreased 5HT and/or 5HIAA levels. Therefore, decreased 5HT neurotransmission as a function of impulsivity has important implications for studying patients with AN since the core symptoms of the disorder are typically at the opposite extreme. During the acute phase of the illness, individuals with AN have a significant reduction in basal levels of CSF 5HIAA compared to healthy controls [44]. In addition, a blunted plasma prolactin response to drugs with serotonin activity and reduced 3 H-imipramine binding suggests reduced serotonergic activity in underweight AN, although these findings may be secondary to reductions in dietary supplies of the amino acid precursor TRP. In contrast, CSF 5HIAA activity in long-term weight recovered AN was reported to be significantly elevated, which may be correlated with the persistent behavioral traits characteristic of the disorder [45]. In particular, evidence suggests a possible association between the overly inhibited, anxious, and obsessional behavior of individuals recovered from AN with increased levels of 5HT activity. Several recent studies have reported alterations in binding of 5HT1A and 5HT2A receptors in AN. Frank [46] reported an association between increased frontal-limbic-temporal postsynaptic 5HT1A receptor binding and the anxious, harm-avoidant traits characteristic of AN. In particular, high correlations were found between anxiety or harm avoidance and binding in the medial temporal region of the brain, which includes the structural center responsible for the modulation of anxiety. Considerable evidence also exists for a disturbance of serotonin regulation in BN. During the acute phase, individuals with BN have a blunted prolactin response

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to 5HT receptor agonists m-chlorophenylpiperazine (m-CPP), 5-hydroxytryptophan, and dl-fenfluramine, and an enhanced migrainelike headache response to m-CPP challenges [47,48]. In addition, similar to individuals with AN, women with long-term recovery from BN have elevated levels of CSF 5HIAA and a dysphoric response to m-CPP administration [22]. The relative contribution of a disturbance in 5HT function to specific human behaviors remains indeterminate. Serotonin has been postulated to contribute to temperament or personality traits, such as harm avoidance [49] and behavioral inhibition [50], or to categorical dimensions such as OCD [51], anxiety and fear [52], and depression [53], as well as satiety for food consumption. It is possible that separate components of 5HT neuronal systems (i.e., different pathways, receptors) are coded for specific behaviors. However, that may not be consistent with the neurophysiology of serotonin neuronal function. All of the monoamine neuronal systems, including 5HT, have a diffuse, widespread distribution and, it can be argued, have a threshold function for information processing, independent of specific behaviors. According to Spoont [54], 5HT regulates or stabilizes the flow of information through a neural system. 5HT neuronal activity prevents overshoot of other neurotransmitter systems and thus attenuates signal amplitude. In addition, it controls the sensitivity of the system to perturbations by new stimuli entering the system. Decreased 5HT neurotransmission would impair the ability of neural networks to maintain the integrity of signal flow pattern. This would result in increased switching, unstable, amplified signal passage, and impulsive, exaggerated stimulus reactivity. In contrast, with increased 5HT neurotransmission, the brain would be insensitive to new stimuli entering the brain, and there might be redundant signal propagation or maintenance of prepotent response patterns. One point of interest in studying 5HT in eating disorders is that since the enzyme tryptophan hydroxylase is not normally saturated by TRP, the rate of 5HT synthesis can be influenced by changes in brain TRP concentration [55]. This concentration is dependent on the plasma concentration of TRP, in addition to the ratio of TRP to other large neutral amino acids (LNAA) with which it competes for uptake [56]. Since TRP is an essential amino acid that must be obtained through the diet, one important factor in determining the relative concentration of TRP available for 5HT synthesis is dietary intake. Numerous studies on dieting in healthy individuals have reported a decrease in plasma TRP after short-term food restriction [57]. In

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addition, a marked increase in prolactin response was found following intravenous administration of L-tryptophan in dieting women, but not men [58]. This finding has important implications for studying possible biological risk factors for AN, since approximately 90–95% of AN individuals are women [1]. In most people, food restriction is not an inherently reinforcing behavior. However, persistent dieting to the point of starvation raises the possibility that food restriction might have some benefit for people with AN. A recent study [59] found that the ratio of TRP to other LNAAs was significantly decreased in AN patients. Since starvation decreases the levels of TRP through a reduction in dietary TRP, less precursor is available for 5HT synthesis. Based on premorbid rates of anxiety, it has been argued [60] that patients with AN may initially have higher levels of 5HT in the synapse which contributes to a dysphoric state. Through dieting, the levels of TRP decrease leading to smaller amounts of the amino acid available for 5HT synthesis. Since less 5HT is available in the synapse, anxiety diminishes and mood in AN patients is elevated. A recent study supports the theory that a diet-induced reduction of TRP is associated with decreased anxiety in people with AN [60]. Based on this evidence, alterations in dietary TRP levels may represent a mechanism through which patients with AN attempt to regulate a dysphoric mood. BN, a more common eating disorder, may be the prototypic expression of a disturbance of 5HT activity which contributes to the pathogenesis of eating disorders. Clinically, people with BN have extremes of eating and behavior. They tend to either diet or overeat, with infrequent consumption of normal meals. Behaviorally, they tend to fluctuate between minimization and inhibition of mood states and extremes of mood and catastrophic overconcerns. These clinical observations, coupled with data from studies in ill and recovered BN, lead to the speculation that the 5HT system in people with BN is inherently unstable and poorly modulated. Certain traits, such as restricted eating and high harm avoidance, perfectionism, and exactness, appear consistent with increased 5HT transmission in the nondieting state. In contrast, a dietinduced reduction in synaptic 5HT release could result in a reduction of behavioral inhibition and might, in turn, lead to extremes of unstable mood and binge eating. It is possible that people with such an inherent modulatory defect in 5HT function may be prone to develop BN. They cannot respond appropriately and precisely to stress or stimuli, or modulate their affective states owing to their modulatory 5HT defect. They

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may learn that extremes of dietary intake, by effects on plasma TRP, are a means by which they can crudely modulate their brain 5HT functional activity. Several investigators [47,61] have proposed a model in which individuals with BN may restrict eating or overeat as a means of self-modulating 5HT activity. Dieting or binge episodes could alter the TRP/LNAA ratio in plasma, which in turn alters TRP availability to the brain changing 5HT synthesis and release [62]. Tryptophan depletion causes ill BN women to have an increase in labile and dysphoric mood and overeat compared to control women [63]. These changes in mood and feeding behavior support the possibility that individuals with BN have a fragile and dysregulated serotonin system that is vulnerable to dietary manipulations. The possibility of a common vulnerability for AN and BN may seem counterintuitive given the differences in 5HT disturbances and feeding behavior in these disorders. However, recent studies suggest that AN and BN have a shared etiologic vulnerability. There is a familial aggregation of a range of eating disorders in relatives of probands with either AN or BN, and these two disorders are highly comorbid in twin studies. Both disorders respond to serotonin-specific medications, and both disorders have high levels of harm avoidance [12,18,64,65], a personality trait hypothesized to be related to increased serotonin activity. These data raise the possibility that a disturbance of 5HT activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN. Other factors independent of a vulnerability for the development of eating disorder may contribute to the development of eating disorder subgroups. For example, people with restrictor-type AN have extraordinary self-restraint and self-control. The risk for obsessive-compulsive personality disorder is elevated only in this subgroup and in their families and shows a shared transmission with restrictor-type AN [24]. In other words, an additional vulnerability for behavioral overcontrol and rigid and inflexible mood states, combined with a vulnerability for an eating disorder, may result in restrictor-type AN. Overall, the evidence for a disturbance of serotonin presented above suggests a differential response for individuals with AN and BN. It appears that manipulations which decrease 5HT levels, such as the serotonin agonist m-CPP, produce euphoria in individuals recovered from AN and dysphoria in BN. Challenges such as ATD which lower plasma tryptophan levels, and consequently brain 5HT synthesis, decrease anxiety in both ill and recovered AN and increase depres-


sion and eating-disordered symptoms in BN. Thus, although a disturbance of 5HT is apparent in both AN and BN and the specific mechanism appears to be fundamentally different between syndromes, it is possible that a predisposition to a disturbance of 5HT creates a vulnerability for the expression of a cluster of symptoms common to both AN and BN. B.

Dopamine

Additional evidence has been reported for a disturbance of dopaminergic function in patients with eating disorders. Dopamine neuronal function has been associated with motor activity, reward, and novelty seeking. In a recent study, women who were recovered from restricting-type AN had significantly lower levels of CSF HVA than women who were recovered from BN [66]. Thus, altered dopamine activity could potentially account for some behavioral traits characteristic of AN. VI.

CONCLUSION

Phenomenological and etiologic research of AN and BN has found that eating disorders are characterized by protracted courses of illness, a persistence of psychological disturbances after recovery, and significant genetic contributions to their development and maintenance. Emerging evidence also raises the possibility that a disturbance of serotonergic activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN. However, to what extent abnormalities detected are consequences of pathological eating behavior, malnutrition, or premorbid traits remains somewhat speculative. Clearly, some of the atypicalities in monoaminergic function in eating disorders are state dependent; however, given the effects of these systems on mood, anxiety, memory organization, and body physiology, they may well have significant pathogenic influence, both sustaining and exacerbating certain psychological and cognitive elements of these syndromes. Future research should continue to explore the biological and genetic underpinnings of these disorders to develop more effective approaches to prevention and treatment. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Washington: American Psychiatric Association, 1994.

639 2. U Schweiger, M Fichter. Eating disorders: clinical presentation, classification and etiologic models. In: DC Jimerson, WH Kaye, eds. Balliere’s Clinical Psychiatry. London: Balliere’s Tindall, 1997, pp 199–216. 3. KA Halmi, E Eckert, P Marchi, V Sampugnaro, R Apple, J Cohen. Comorbidity of psychiatric diagnoses in anorexia nervosa [see comments]. Arch Gen Psychiatry 48:712–718, 1991. 4. LKG Hsu, TA Sobkiewicz. Bulimia nervosa: a four- to six-year follow-up study. Psychol Med 19:1035–1038, 1989. 5. J Treasure, I Campbell. The case for biology in the aetiology of anorexia nervosa [editorial]. Psychol Med 24:3–8, 1994. 6. NM Srinivasagam, WH Kaye, KH Plotnicov, C Greeno, TE Weltzin, R Rao. Persistent perfectionism, symmetry, and exactness after long-term recovery from anorexia nervosa. Am J Psychiatry 152:1630–1634, 1995. 7. M Strober. Personality and symptomatological features in young, nonchronic anorexia nervosa patients. J Psychosom Res 24:353–359, 1980. 8. K Vitousek, F Manke. Personality variables and disorders in anorexia nervosa and bulimia nervosa. J Abnorm Psychol 103:137–147, 1994. 9. PK Keel, JE Mitchell. Outcome in bulimia nervosa. Am J Psychiatry 154:313–321, 1997. 10. KL Klump, CM Bulik, C Pollice, KA Halmi, MM Fichter, WH Berrettini, B Devlin, M Strober, A Kaplan, DB Woodside, J Treasure, M Shabbout, LR Lilenfeld, KH Plotnicov, WH Kaye. Temperament and character in women with anorexia nervosa. J Nerv Ment Dis 188:559–567, 2000. 11. EI Kleifield, S Sunday, S Hurt, KA Halmi. The Tridimensional Personality Questionnaire: an exploration of personality traits in eating disorders. J Psychiat Res 28:413–423, 1994. 12. TD Brewerton, LD Hand, ER Bishop, Jr. The Tridimensional Personality Questionnaire in eating disorder patients. Int J Eat Disord 14:213–218, 1993. 13. PJ Beumont, GC George, DE Smart. ‘‘Dieters’’ and ‘‘vomiters and purgers’’ in anorexia nervosa. Psychol Med 6:617–622, 1976. 14. RC Casper, D Hedeker, JF McClough. Personality dimensions in eating disorders and their relevance for subtyping. J Am Acad Child Adolesc Psychiatry 31:830–840, 1992. 15. WH Kaye. Anorexia and bulimia nervosa, obsessional behavior, and serotonin. In: WH Kaye, DC Jimerson, eds. Eating Disorders. London: Balliere’s Tindell, 1997, pp 319–337. 16. N Barbarich. Is there a common mechanism of serotonin dysregulation in anorexia nervosa and obsessive compulsive disorder? (In Press.)

640 17. RC Casper. Personality features of women with good outcome from restricting anorexia nervosa. Psychosom Med 52:156–170, 1990. 18. AM O’Dwyer, JV Lucey, GF Russell. Serotonin activity in anorexia nervosa after long-term weight restoration: response to D-fenfluramine challenge. Psychol Med 26:353–359, 1996. 19. S Collings, M King. Ten-year follow-up of 50 patients with bulimia nervosa. Br J Psychiatry 164:80–87, 1994. 20. BA Fallon, BT Walsh, C Sadik, JB Saoud, V Lukasik. Outcome and clinical course in inpatient bulimic women: a 2- to 9-year follow-up study. J Clin Psychiatry 52:272–278, 1991. 21. E Johnson-Sabine, D Reiss, D Dayson. Bulimia nervosa: a 5-year follow-up study. Psychol Med 22:951– 959, 1992. 22. WH Kaye, CG Greeno, H Moss, J Fernstrom, M Fernstrom, LR Lilenfeld, TE Weltzin, JJ Mann. Alterations in serotonin activity and psychiatric symptomatology after recovery from bulimia nervosa. Arch Gen Psychiatry 55:927–935, 1998. 23. CE Norring, SS Sohlberg. Outcome, recovery, relapse and mortality across six years in patients with clinical eating disorders. Acta Psychiatr Scand 87:437–444, 1993. 24. LR Lilenfeld, WH Kaye, CG Greeno, KR Merikangas, K Plotnicov, C Pollice, R Rao, M Strober, CM Bulik, L Nagy. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in firstdegree relatives and effects of proband comorbidity. Arch Gen Psychiatry 55:603–610, 1998. 25. M Strober, R Freeman, C Lampert, J Diamond, W Kaye. Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J Psychiatry 157:393–401, 2000. 26. KS Kendler, C MacLean, M Neale, R Kessler, A Heath, L Eaves. The genetic epidemiology of bulimia nervosa. Am J Psychiatry 148:1627–1637, 1991. 27. EE Walters, KS Kendler. Anorexia nervosa and anorexic-like syndromes in a population-based female twin sample. Am J Psychiatry 152:64–71, 1995. 28. AJ Holland, A Hall, R Murray, GF Russell, AH Crisp. Anorexia nervosa: a study of 34 twin pairs and one set of triplets. Br J Psychiatry 145:414–419, 1984. 29. AJ Holland, N Sicotte, J Treasure. Anorexia nervosa: evidence for a genetic basis. J Psychosom Res 32:561– 571, 1988. 30. KL Klump, KB Miller, PK Keel, M McGue, WG Iacono. Genetic and environmental influences on anorexia nervosa syndromes in a population-based twin sample. Psychol Med 31:737–740, 2001. 31. TD Wade, CM Bulik, M Neale, KS Kendler. Anorexia nervosa and major depression: shared genetic and environmental risk factors. Am J Psychiatry 157:469– 471, 2000.

Kaye and Barbarich 32. CM Bulik, PF Sullivan, KS Kendler. Heritability of binge-eating and broadly defined bulimia nervosa. Biol Psychiatry 44:1210–1218, 1998. 33. M Strober. Family-genetic studies of eating disorders. J Clin Psychiatry 52 (suppl)9–12, 1991. 34. WH Kaye, LR Lilenfeld, K Plotnicov, KR Merikangas, L Nagy, M Strober, CM Bulik, H Moss, CG Greeno. Bulimia nervosa and substance dependence: association and family transmission. Alcohol Clin Exp Res 20:878– 881, 1996. 35. MA Schuckit, JE Tipp, RM Anthenelli, KK Bucholz, VM Hesselbrock, JI Nurnberger Jr. Anorexia nervosa and bulimia nervosa in alcohol-dependent men and women and their relatives. Am J Psychiatry 153:74– 82, 1996. 36. M Fava, PM Copeland, U Schweiger, DB Herzog. Neurochemical abnormalities of anorexia nervosa and bulimia nervosa. Am J Psychiatry 146:963–971, 1989. 37. SF Leibowitz. Brain monoamines and peptides: role in the control of eating behavior. Fed Proc 45:1396–1403, 1986. 38. JE Morley, JE Blundell. The neurobiological basis of eating disorders: some formulations. Biol Psychiatry 23:53–78, 1988. 39. F Petty, LL Davis, D Kabel, GL Kramer. Serotonin dysfunction disorders: a behavioral neurochemistry perspective. J Clin Psychiatry 57(suppl 8):11–16, 1996. 40. DC Jimerson, MD Lesem, AP Hegg, TD Brewerton. Serotonin in human eating disorders. Ann NY Acad Sci 600:532–544, 1990. 41. EF Coccaro, ME Berman, RJ Kavoussi, RL Hauger. Relationship of prolactin response to d-fenfluramine to behavioral and questionnaire assessments of aggression in personality-disordered men [see comments]. Biol Psychiatry 40:157–64, 1996. 42. KR Jamison. Night Falls Fast. New York: Vintage Books, 1999. 43. GL Brown, MH Ebert, PF Goyer, DC Jimerson, WJ Klein, WE Bunney, FK Goodwin. Aggression, suicide, and serotonin: relationships to CSF amine metabolites. Am J Psychiatry 139:741–746, 1982. 44. WH Kaye, MH Ebert, M Raleigh, R Lake. Abnormalities in CNS monoamine metabolism in anorexia nervosa. Arch Gen Psychiatry 41:350–355, 1984. 45. WH Kaye, HE Gwirtsman, DT George, MH Ebert. Altered serotonin activity in anorexia nervosa after long-term weight restoration. Does elevated cerebrospinal fluid 5-hydroxyindoleacetic acid level correlate with rigid and obsessive behavior? Arch Gen Psychiatry 48:556–562, 1991. 46. WH Kaye, GK Frank, CC Meltzer, JC Price, WC Drevets, CA Mathis. Enhanced pre- and postsynaptic 5HT1A receptor binding after recovery from anorexia nervosa: relationship to anxiety and harm avoidance. (Submitted.)

Biological Basis of Eating Disorders 47. DC Jimerson, MD Lesem, WH Kaye, TD Brewerton. Low serotonin and dopamine metabolite concentrations in cerebrospinal fluid from bulimic patients with frequent binge episodes. Arch Gen Psychiatry 49:132– 138, 1992. 48. TD Brewerton, DL Murphy, EA Mueller, DC Jimerson. Induction of migrainelike headaches by the serotonin agonist m- chlorophenylpiperazine. Clin Pharmacol Ther 43:605–609, 1988. 49. CR Cloninger. A systematic method for clinical description and classification of personality variants. A proposal. Arch Gen Psychiatry 44:573–588, 1987. 50. P Soubrie. Reconciling the role of central serotonin neuroses in human and animal behavior. Behav Brain Sci 9:319–363, 1986. 51. LC Barr, WK Goodman, LH Price, CJ McDougle, DS Charney. The serotonin hypothesis of obsessive compulsive disorder: implications of pharmacologic challenge studies. J Clin Psychiatry 53(suppl):17–28, 1992. 52. DS Charney, SW Woods, JH Krystal, GR Heninger. Serotonin function and human anxiety disorders. Ann NY Acad Sci 600:558–572, 1990. 53. DG Grahame-Smith. Serotonin in affective disorders. Int Clin Psychopharmacol 6(suppl 4):5–13, 1992. 54. MR Spoont. Modulatory role of serotonin in neural information processing: implications for human psychopathology. Psychol Bull 112:330–350, 1992. 55. JD Fernstrom, RJ Wurtman. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173:149–152, 1971. 56. JD Fernstrom, RJ Wurtman. Brain serotonin content: physiological regulation by plasma neutral amino acids. Science 178:414–416, 1972. 57. IM Anderson, M Parry-Billings, EA Newsholme, CG Fairburn, PJ Cowen. Dieting reduces plasma tryptophan and alters brain 5HT function in women. Psychol Med 20:785–791, 1990.

641 58. GM Goodwin, CG Fairburn, PJ Cowen. The effects of dieting and weight loss on neuroendocrine responses to tryptophan, clonidine, and apomorphine in volunteers. Important implications for neuroendocrine investigations in depression. Arch Gen Psychiatry 44:952–957, 1987. 59. A Favaro, L Caregaro, AB Burlina, P Santonastaso. Tryptophan levels, excessive exercise, and nutritional status in anorexia nervosa. Psychosom Med 62:535– 538, 2000. 60. WH Kaye, NC Barbarich, K Putnam, KA Gendall, J Fernstrom, M Fernstrom, CW McConaha, A Kishore. Anxiolytic effects of acute tryptophan depletion (ATD) in anorexia nervosa. (In Press). 61. WH Kaye, HE Gwirtsman, DT George, DC Jimerson, MH Ebert. CSF 5-HIAA concentrations in anorexia nervosa: reduced values in underweight subjects normalize after weight gain. Biol Psychiatry 23:102–105, 1988. 62. JD Fernstrom, DV Faller. Neutral amino acids in the brain: changes in response to food ingestion. J Neurochem 30:1531–1538, 1978. 63. TE Weltzin, JD Fernstrom, C McConaha, WH Kaye. Acute tryptophan depletion in bulimia: effects on large neutral amino acids. Biol Psychiatry 35:388–397, 1994. 64. CM Bulik, PF Sullivan, TE Weltzin, WH Kaye. Temperament in eating disorders. Int J Eat Disord 17:251–261, 1995. 65. EI Kleifield, S Sunday, S Hurt. Psychometric validation of the Tridimensional Personality Questionnaire: application to subgroups of eating disorders. Compr Psychiatry 34:249–253, 1993. 66. WH Kaye, GK Frank, C McConaha. Altered dopamine activity after recovery from restricting-type anorexia nervosa. Neuropsychopharmacology 21:503– 506, 1999.

43 Biological Basis of Personality Disorders CUNEYT ISCAN University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.

CHARLOTTE L. ALLPORT and KENNETH R. SILK University of Michigan Health System, Ann Arbor, Michigan, U.S.A.

I.

OVERVIEW

Prior to the 1980s, most explorations into the cause of personality disorders were relegated to the area of psychological theories [3]. These theoretical propositions were based on appreciating fully the developing individual in his/her environment and the reaction of that individual to interpersonal experiences [4,5]. While it was believed that axis I disorders would eventually be found to have significant etiologic roots in biologic predispositions and mechanisms, personality disorders were viewed as resulting primarily as a response to external factors [3]. These assumptions with respect to differences between DSM axes in the importance of the role of biology in etiology and treatment persisted despite evidence and argument to the contrary [6]. Papers published in the late 1980s and early 1990s proposed biologic theories for explaining some of the underlying pathologic processes found in personality disorders [7], and there was a growing body of empirical research to begin to support some of the biologic theories. The early biological theories and studies focused on comparisons between a specific personality disorder with what was thought to be a near-neighbor axis I disorder, e.g., borderline personality disorder (BPD) and mood disorders, specifically major affective

As we move beyond the 1990s, past the decade of the brain and into a new millennium, there has been an exponential increase in knowledge into understanding the biological basis of human psychology and behavior. Freud’s original concept of the biological basis of behavior, expressed in the ‘‘Project’’ [1] at the close of the 19th century, may become reality in the early parts of the 21st century. Yet to achieve complete understanding the task before us remains enormous. As we continue research into understanding the etiology of psychiatric disorders, the complexity of the human brain and behavior demands integrating different theoretical approaches and applying reductionism whenever necessary without losing perspective. Our current level of knowledge in the area of behavioral sciences compels us to bring together data at many levels of analysis. Those data include molecular genetics, neurochemistry, neurophysiology, cognitive science, and developmental psychology/psychopathology [2]. We now appear to possess the technology and the means to improve upon the technology to provide ever more sophisticated data from these fields that will facilitate our understanding of behavior at the molecular level. 643

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disorder and currently bipolar II disorder, cyclothymic disorder, or posttraumatic stress disorder (PTSD); schizotypal personality disorder (SPD) and schizophrenia; avoidant personality disorder and social phobia; histrionic personality disorder and somatization disorder; paranoid personality disorder and delusional disorder or schizophrenia, paranoid type. Early biological studies in BPD focused on biologic indices such as the dexamethasone suppression test (DST) or time of onset of REM sleep to try to discover similarities and differences that might help delineate more carefully the relationship between these BPD patients and patients with mood disorders [8–12]. While there were a decent number of studies in these areas, these studies failed to produce consistent results to support strongly the axis I–axis II spectrum hypothesis or to distinguish clearly the axis II disorder as a separate biological entity from the putative axis I disorder [7]. The interest in studying the similarities and differences between a specific personality disorder and a near-neighbor axis I disorder waned to be replaced by an interest in studying the biological underpinnings of the personality and personality disorders in general. Researchers began to look at types of behaviors or traits that were thought to cut across a number of personality disorders and the biological mechanisms that might be responsible or related to these behaviors or traits. These ‘‘second-generation’’ biological studies looked across personality disorders in contrast to earlier studies that tried to compare a specific axis I disorder with a specific axis II disorder [7]. Any given dimension of psychopathology can be disturbed in different degrees of severity across many of the personality disorders. Studying these dimensions has led to new research methodologies that have expanded our appreciation of the role of biology in the personality disorders. Most of the studies that have been done in recent years focused on this biological dimensional approach. The only exception to this generalization is SPD. There is considerable amount of research, especially in the area of neuroimaging, targeted to appreciating the specific link between schizophrenia, SPD in particular, and cluster A personality disorders in general. Several dimensional classifications have been put forth in recent years in an attempt to define a ‘‘phenotype’’ or trait which not only will appropriately reflect an underlying biological mechanism but also will hopefully provide us with a link to causality. These classification systems or dimensional models include Cloninger’s [13] seven-factor model of personality, Siever and Davis’s [14] four-dimensional psychobiological model, the five-factor model of Costa and

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McCrae [15], and Livesley’s [16] studies that employ factor analysis to define dimensional traits to be researched biologically. Understanding personality in a dimensional framework is a long-standing practice in the field of psychology, and two traditional domains of the personality have been defined as temperament and character [13,17]. Temperament refers to inborn and constitutional differences in the automatic responses of individuals to emotional or affect-laden stimuli; these responses are fortified under the influence of associative conditioning. Character and its corresponding traits are reflections of differences in early learning and self-teaching about life that stem from intuition and are shaped and modified by the learning individuals have absorbed from parents and important others [18]. Cloninger [13] conceptualizes temperament as involving individual differences in habit learning whereas character involves differences in higher cognitive processing. This conceptualization proposes a higher level of organization in terms of brain functions and aims to sort out the biological foundations of the personality. According to this perspective, character development is defined along the lines of abstract symbolic processes that are most highly developed in humans and include self-directed behavior, empathic social cooperation, and creative symbolic invention. These dimensions call for higher brain functions in the prefrontal and frontal brain regions, whereas temperament is defined along the lines of habit learning which does not utilize the cerebral neocortex and is well developed at an early age in almost all vertebrates. Based on this model, Cloninger et al. [17] defined four dimensions under temperament (harm avoidance, novelty seeking, reward dependence, and persistence) and three dimensions under character (self-directedness, cooperativeness, and self-transcendence). Siever and Davis [14] have proposed a ‘‘psychobiological model’’ based on four dimensions: cognitive/ perceptual organization, impulsivity/aggression, affective instability, and anxiety/inhibition. According to their model, core features of clusters of axis I disorders reflect disturbances in fundamental psychobiological dimensions: cognitive/perceptual organization disturbances and schizophrenic disorders; impulsivity/ aggression and impulse control and perhaps conduct disorders; affective instability and major affective disorders; and anxiety/inhibition and anxiety disorders. Based on these dimensions, Siever and Davis [14] classify odd cluster (cluster A) axis II disorders as being linked to schizophrenia through disturbances along a

Biological Basis of Personality Disorders

dimension in the area of cognitive/perceptual organization. Using the same reasoning, they link impulsivity/ aggression and affective instability to the dramatic cluster (cluster B) as well as to axis I disorders of impulsivity and affective lability, and anxiety/inhibition to cluster C (anxious cluster) as well as to axis I disorders of anxiety and inhibition. Costa and McCrae’s five-factor model of personality proposes five dimensions: neuroticism (versus emotional stability) (N), extraversion (E), openness to experience (O), agreeableness (A), and conscientiousness (i.e., disciplined adherence to goals, and strict adherence to principles) (C). Much work, particularly in the field of psychology, has been forth to explain this particular model further [19]. Studies that have been done in the area of personality disorders can be categorized in several ways. We have chosen to organize this chapter around the different methodological (and technological) ways in which researchers are exploring the biology of personality disorders and the data that have been gleaned from these studies. Thus we have organized this chapter around (1) neurotransmitter functions, (2) family-genetic techniques, and (3) neuroimaging techniques that study structural alterations in the brain and functionally assess brain activity via measurements of blood flow or metabolic activity with certain cognitive tasks. We will also discuss briefly the research on life events (trauma, especially childhood abuse and early development/attachment) and the possible alterations in the central nervous system’s functioning as a result of trauma.

II.

NEUROTRANSMITTER STUDIES

As stated above, early research into the biology of personality disorders focused on comparisons, particularly with respect to neurotransmitters and neurotransmitter function, between a specific personality disorder with what was thought to be a near-neighbor axis I disorder. Current trends in biologic research on personality disorders have now moved from exploring what particular substrate might be disturbed in a particular personality disorder to the idea of which neurotransmitter might be most closely related to a particular behavioral manifestation of a certain dimension of psychopathology that reveals itself as disturbed across a number of personality disorders [4]. The most heavily researched neurotransmitter with regard to personality and personality disorders is 5HT (serotonin). Over the course of more than two decades, research in this area has continually supported a strong

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role for 5HT in aggression and impulsivity [20]. These studies repeatedly reveal that 5HT levels are inversely related to aggression and impulsivity. The first evidence of an inverse relationship in humans between 5HT and aggression was reported by Asberg et al. [21]. Dysfunction in the 5HT system has been associated with self-directed and non-self-directed impulsive aggression. Evidence for this association continues to emerge from studies of violent suicide attempters and of individuals who had committed violent acts [22]. In a study of violent offenders, Linnoila et al. [23] found that cerebral spinal fluid (CSF) 5HIAA (a metabolite of 5HT) levels were significantly lower in violent offenders who committed impulsive crimes but not in violent offenders who committed premeditated crimes. A decrease in CSF 5HIAA level was noted among people who had murdered their own children [24]. Pharmacologic challenge studies also support this inverse relationship between 5HT levels and impulsive aggression. In pharmacological challenge studies, a physiological response (hormonal-prolactin, cortisol, thermal changes, blood pressure, heart rate) is monitored after an agent that stimulates a specific neurotransmitter system (in this instance the serotonergic system) is administered to the subjects. A variety of 5HT pharmacological challenge studies have been performed in subjects with personality disorders. Most common agents that have been used for this purpose are the 5HT-releasing agent and reuptake inhibitor d,lfenfluramine (d,l-FEN), the direct 5HT agonist metachlorophenylpiperazine (m-CPP), and ipsapirone (IPS), which is a potent 5HT-1A agonist. In a comprehensive review [20], Coccaro summarized six studies using the prolactin response to d,l-FEN. These studies reveal a blunted prolactin response of 5HT to the d,l-FEN challenge (infusion) in subjects with personality disorders who engage in some sort of self-mutilative or suicidal behavior. A recent study revealed blunted prolactin response to d-fenfluramine in depressed patients who had made suicide attempts. Furthermore, there was a negative correlation between change in prolactin levels and lethality of suicide attempts [25]. Blunted prolactin response to d-fenfluramine has correlated with aggression in personality-disordered patients as well [20]. Other pharmacologic challenge studies have been done with ipsapirone (IPS), a 5HT-1A agonist. IPS has been shown to be a useful probe of serotonin function in normal subjects. IPS acts both pre- and postsynaptically, and the response to IPS has been shown to be blunted in unipolar depressed patients. Other studies, however, reveal a blunted response to IPS associated with self-reported aggression. In an IPS

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challenge study by Reynolds et al. [26], subjects with BPD were compared with normal controls. There was an inverse correlation between the physiologic response to IPS and impulsivity, whereas cortisol response to IPS was correlated positively with scores of depression. Again, then, we find an inverse relationship between concentration of 5HT and aggression, in particular, impulsive aggression. Other neurotransmitters of interest are norepinephrine, dopamine, acetylcholine, gamma-aminobutyric acid (GABA), and arginine vasopressin (AVP). Based on animal studies that suggested a positive correlation between aggression and CSF vasopressin level, Coccaro et al. [27] found in humans that central AVP levels correlated positively with life history of aggression and inversely with the prolactin response to fenfluramine. It is possible that central AVP plays role in aggression independent of the serotonin system or by interacting with it [27]. Diminished activity in the GABA-minergic pathways has been proposed as playing a role in affective instability especially in patients with cluster B personality disorders [22]. GABA may have a damping effect that is triggered as a response to rapid surges of strong affect. Affective instability appears to show some response to anticonvulsants that are now used as mood stabilizers. Some anticonvulsant drugs are known to increase the GABA-minergic transmission [28]. Acetylcholine is another neurotransmitter that probably plays some role in affective instability. Limbic structures that are implicated in emotion regulation, such as the amygdala, hippocampus, and cingulate cortex, have rich cholinergic innervation [22]. Based on observations that depressive symptoms can be generated by the administration of cholinomimetics such as arecholine and physostigmine [29], similar studies have been performed with patients with personality disorders. In a study by Steinberg et al. [30], subjects with BPD responded to intravenous physostigmine infusion with a shift into depressive affect that was significantly more rapid in onset, greater in intensity, and more persistent than the response of healthy controls. The rapid shift in mood correlated with clinical measures of affective instability. The catecholamines (dopamine and norepinephrine) have not received as much attention and interest from personality disorders researchers as has serotonin. The norepinephrine (noradrenergic) system (NE) is believed to modulate arousal and reactivity to the environment through the locus ceruleus. NE is thought to play a role in heightened reactivity to environmental stimuli and contributes to affective instability in people

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with BPD [20]. The behavioral correlates of dopamine fall into two main areas: schizotypy and aggression. Coccaro reports at least two studies that support a positive correlation between schizotypy and higher CSF homovanillic acid (HVA, a dopamine metabolite) concentrations [20]. Cloninger [13], in his seven-factor model, has proposed that dopamine would be the principal neuromodulator for the novelty-seeking dimension, including thrill-seeking behavior, extravagant spending, binge eating, sexual hedonism, and substance abuse. According to this model, harm avoidance is associated with GABA and serotonin (dorsal raphe), reward dependence with norepinephrine and serotonin (medial raphe), and persistence with glutamate and serotonin (dorsal raphe). Another neurotransmitter system that has drawn interest because of its possible relationship to behavior found in personality disorders, particularly self-injurious behavior (SIB), is the opioid or endorphin system [31]. SIB is a common phenomenon in the cluster B group and especially in BPD. One model proposes that SIB is a result of a state of pain insensitivity and sensory depression that stem from a physiological (congenital) excess of B-endorphin or another endogenous opioid. Then SIB could be driven by an addiction to a relative excess of opioid activity. The individual goes through adaptive changes and becomes tolerant to high levels of circulating opioid transmitters, and experiences shortages if endogenous opioid levels fall, which in turn reinforces the SIB behavior. According to the model proposed by Sandman et al. [32] congenital conditions could result in a permanent upregulation of opiate receptors. A permanent upregulation of opiate receptors may have diverse effects with an elevation in pain threshold as one of the consequences. Based on this model, opiate blockers (e.g., naloxone and naltrexone) may attenuate SIB by making these behaviors more painful (aversive conditioning). Opiate peptides also affect the catecholamine systems. Although opiates exert an inhibitory effect on catecholamine systems, they potentiate dopaminergic neuron-firing rates in the hippocampus. Stein and Belluzi [33] suggest that increased dopaminergic firing may be responsible for reinforcement of the behavior that would be consistent with the ‘‘addiction’’ model. Another model proposes that a birth defect results in permanent attenuation of b-endorphin release that may ultimately result in a need to perform behaviors that stimulate endogenous opioid release. Though not a neurotransmitter, cholesterol along with its level in the blood and its relationship to aggression has also been studied. There is a possible intercon-


nection among serum cholesterol levels, central serotonergic activity and impulsive-aggressive behavior. In a study by Novotny et al. [34], a trend toward an inverse correlation between serum cholesterol levels and prolactin response to fenfluramine was found. Another study also supports the association between low plasma cholesterol, low blood serotonin concentrations, and a history of violent suicide attempts in psychiatric inpatients [35]. In one study, patients with BPD were found to have significantly lower serum cholesterol levels than patients with other personality disorders [36]. While the above summarizes studies done with some neurotransmitters that are currently thought to play a role in some of the dimensions of psychopathology discussed above, it is important to keep in mind that more than 70 neurotransmitters have been identified to date [37]. The role of most of these endogenous substrates in brain neurochemistry and function remains a mystery to be disentangled in future studies.

III.

FAMILY-GENETIC STUDIES IN PD

Psychiatric genetics involves a variety of research strategies, from family studies focusing on the increased frequency of certain disorders among family members on one end of the spectrum to studies on a molecular level on the other end of the spectrum. These latter studies are designed to look at certain gene loci and polymorphism at these loci and the relationship between the polymorphism and certain behaviors or phenotypic expressions or endophenotypes. Endophenotypes are phenotypic traits that are believed to be ‘‘closer’’ to the genes, and it is these endophenotypes that affect susceptibility to disease. For example, genes causing high cholesterol levels predispose the individual to myocardial infarction. Hence high cholesterol level can be considered an endophenotype enabling a closer link between the gene (high cholesterol) and the phenotypic trait (myocardial infarction). Advances in neuroscience combined with a better understanding of changes that occur on a molecular level allow us to speculate about gene-environment interaction and to appreciate the reciprocity that occurs between genes and environment since there are data to suggest that environment affects genes and alters the expression of genes [2,4,38,39]. This interaction hypothesis of mutual effects of genes and environment on each other should lead one to be cautious in interpreting studies of genes on a molecular level, because a particular gene may not necessarily reflect the inheritability of a specific trait since envir-

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onmental factors have the potential to impinge on genes or gene expression. Studies of genes pose other problems. Genes function at a molecular level, and there are several levels in the hierarchy of the functioning of the behavior of the organism. Thus, traits and behavior are complex constructs, and most likely what we see and measure in terms of behavior both clinically and in the laboratory may be far too distant from genes in this hierarchy [2] to draw immediate conclusions or to conclude direct relationships. Keeping these possible drawbacks in mind, we will examine the major findings in this area beginning with the family studies. Family studies in personality disorders can be categorized as studies done in probands with personality disorders, where personality disorders can be viewed as variants of axis I disorders or personality disorders are an extreme variant of a personality trait [40]. Familygenetic studies in probands with personality disorders are very limited. Antisocial personality disorder (ASPD) is the most-studied personality disorder in this group. Adoption studies suggest that criminal behavior in biological parents is associated with criminality and ASPD in adopted-away children. ASPD has also been proposed as a variant of substance abuse disorder based on adoption and family studies showing excess risk for ASPD among biological relatives of probands with substance abuse [41]. Studies that look at the coaggregation of certain personality disorders and axis I disorders in certain families (particularly cluster A disorders and schizophrenia) support only SPD and ASPD as sharing familial and genetic risk factors with specific axis I disorders (schizophrenia and substance-related disorders, respectively) [40]. This does not mean that other axis II disorders do not share ‘‘risk’’ factors with other axis I disorders; it means that at the moment we only have evidence related to SPD and ASPD. Family studies in the area of cluster A personality disorders focus on a possible genetic link between schizophrenia and SPD. In the famous Copenhagen adoption studies, Kety et al. [42,43] looked at mental illnesses in the biological and adoptive families of adoptees with schizophrenia. Adopted-away children of subjects with schizophrenia had a higher incidence of SPD. Kendler and Gruenberg [44] reported a similar finding in another Danish adoption study involving schizophrenia. Future studies in this area are necessary to shed light on which features (formal thought disorder, affective flattening, idiosyncracies in social interactions, etc.) of these disorders are genetically more transmissible or heritable than others.

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It is too early to say to what extent genes play a role in BPD, but because personality traits generally show a substantial genetic influence, there should certainly be aspects or symptoms of BPD for which this holds true. BPD reflects the interactional complexity between environmental conditions and genetic predisposition [45]. Only one study of BPD inheritance using twin methodology has been published. In a Norwegian sample of seven MZ and 18 DZ twin pairs, BPD was found to have zero concordance in MZ and 11% concordance in DZ twins. Although this study might seem to suggest that environmental factors are of greater importance than genetic factors, the sample size is too small to make real conclusions. Additional studies both large and small are needed to reach firmer conclusions about the relationship of genetic features and functions on the symptoms of BPD [46]. What is transmitted between generations in borderline patients has been a question that has interested researchers for more than a decade. Some studies have suggested that it is the affective component (affective lability, propensity to major affective episodes) that is transmitted; other studies suggest it is impulsive aggression that is transmitted, and still other suggest the borderline ‘‘syndrome’’ itself [38,47–49]. Studies of twins reared apart using the five-factor model showed that neuroticism, to a lesser extent conscientiousness, and to a moderate degree agreeableness, are influenced by genes [50]. On a molecular level, genes related to serotonin synthesis and metabolism have been of interest to researchers. The serotonin-related gene best studied for its relationship to impulsive aggressive behavior is the gene coding for tryptophan hydroxylase (TPH), the first enzyme involved in the synthesis of serotonin [51]. A polymorphism on chromosome 11 coding for TPH has been identified, and the two alleles have been designated L and U. In a Finnish cohort of violent offenders, the L allele was associated with reduced CSF 5HIAA concentrations and a history of suicide attempts [52]. A recent study with a nonpatient sample revealed individual differences in aggressive disposition associated with an intronic polymorphism of the TPH gene [53]. Other studies involving this polymorphism reveal that the LL genotype appears to be associated with significantly higher total scores on the BussDurkee hostility inventory when compared with UL or UU genotypes [51,54]. Other genetic loci have been studied that target receptors and neurotransmitters that are thought to be involved in behavior related to personality psycho-

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pathology. These loci are serotonin receptor 1B (HTR1B) genotype, serotonin receptor 2A (HTR2A) genotype, serotonin transporter (SLC6A4), and D4 dopamine receptor gene (DRD4). Preliminary studies suggest a relationship between HTR1B genotype and suicide attempts and between HTR2A genotype and suicidality and self-mutilation. The serotonin 1B receptor gene has also been studied for its association with alcoholism and aggression. Antisocial alcohol consumption and antisocial behavior showed significant evidence of linkage to this gene’s polymorphism [55]. Also, a polymorphism at the serotonin 1B locus reveals a significant relationship between the presence of the Hincll() allele and positive measures of aggression in patients with personality disorders. Though the results are not always consistent across different studies, these preliminary studies do point to the fact that allelic variability or polymorphisms in serotonin related genes are probably associated with impulsive aggression [56]. This is logical because, as reviewed above, known clinical and laboratory work has repeatedly shown a relationship between low levels of circulating serotonin and impulsive aggression as well as blunted 5HT responses among impulsive and aggressive patients when challenged with pharmacologically active agents that should provoke substantial release of serotonin or serotonin-related compounds. Another gene implicated in susceptibility to impulsive aggression is the gene coding for the serotonin transporter, SLC6A4. A polymorphism in the promoter region of the serotonin transporter was also found to be associated with a high degree of harm avoidance [57]. Sander et al.’s [58] study in ‘‘dissocial alcoholics’’ revealed an association between S allele of the 5 0 regulatory SLC6A4 polymorphism that confers susceptibility to a temperamental profile of high novelty seeking and low harm avoidance [58]. Additional studies of gene polymorphisms reveal other interesting relationships between specific genes and behavior often seen in personality disorder patients. A preliminary study suggests a linear relationship between harm avoidance and the presence of the S allele for a polymorphism in the serotonin transporter. The association between novelty seeking and DRD4 polymorphisms has also been studied with some preliminary and at this point controversial findings [59]. Despite the elegance of these studies, research in this area is in its very early phase. Obviously, as more data accumulate, we will be able to define more specific relationships.


IV.

NEUROIMAGING STUDIES

Neuroimaging methodologies offer the opportunity first to identify structural alterations in the brain that may be associated with certain dimensions or traits in personality disorders and, second, to assess brain activity functionally via measurements of blood flow or metabolic activity [51]. Continued technological advances enable better visualization of the brain structures and functionality in different brain areas. Computed tomography (CT) and magnetic resonance imaging (MRI) enable observation of the brain structures. Positron emission tomography (PET), singlepositron emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) enable the visualization of regional patterns of brain activation during different tasks or emotional states. In recent years, neuroimaging studies in the area of personality disorders focused on structural differences, comparing regional brain size and activity between normal subjects and people with personality disorders and particular personality dimensions. Functional neuroimaging has allowed the study of changes in brain activity associated with specific cognitive and emotional tasks. This techonology should enable us to pursue certain positive findings (impulsivity and serotonergic system, antisocial personality disorder and prefrontal cortex dysfunction, and proposed similarities between schizophrenia and SPD). Most of the neuroimaging studies in recent years have focused on SPD. There are several studies in ASPD and BPD. One area of focus in neuroimaging studies is impulsivity and aggression. From a neuroanatomic viewpoint, aggression and impulsivity have been thought to reside primarily in the frontal cortex. The prototype for frontal lobe activity and aggression is railroad worker Phineas Cage, who in the 1800s sustained an injury to his frontal cortex and subsequently underwent personality changes with increased aggressiveness and impulsivity [60]. PET studies in murderers revealed decreased use of glucose in prefrontal cortical areas, but the decrease in glucose use was found among impulsive murderers and not among murderers who planned the crime [61]. Goyer et al. [62] found decreased rates of glucose metabolism in BPD patients when compared with controls. In a fenfluramine mediated PET study, subjects with BPD had diminished response to serotonergic stimulation in areas of prefrontal cortex [63]. In an MRI study in subjects with BPD, Lyoo et al. [64] showed decreased frontal lobe volume. Raine et al. [65] studied gray and white matter volumes in the prefrontal cortex in subjects with

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antisocial personality disorder (ASPD). The ASPD group showed an 11% reduction in prefrontal gray matter volume in the absence of ostensible brain lesions, and also reduced autonomic activity during stress. The researchers conclude that this prefrontal deficit may underlie the low arousal, poor fear conditioning, lack of conscience, and decision-making deficits. Thus, overall, studies support the relationship between decreased metabolic activity and decreased volume and increased impulsivity and aggression. Biologic research in the area of SPD appears to be targeting two purposes. A better understanding of the differences and similarities between the SPD and schizophrenia holds the hope of disentangling the multiple pathophysiologic pathways to schizophrenia. Considering both SPD and schizophrenia as two phenotypic expressions (i.e., clinical expressions) of the same core pathology has led to studies to try to answer the fundamental question of what causes the difference in the expression. The second purpose of research in this area would be to understand better the core features in SPD, namely cognitive impairment and social deficits and/or eccentricity, as a dimension of personality. SPD patients, like schizophrenic patients, demonstrate volume reductions in temporal cortex and thalamus that are associated with severity of social deficits and cognitive impairment [66]. A recent study supports larger brain CSF volumes in subjects with SPD [67]. Overall, findings from the neuroimaging studies in SPD are consistent with decreased volume in frontal and temporal regions (especially superior temporal lobe reduction), decreased posterior corpus callosum size, and some evidence for the involvement of thalamus and putamen. In most of the studies, individuals with SPD fall in the gray area between patients with schizophrenia and normal controls. This finding lends support to the long-standing hypothesis that SPD is a ‘‘mild’’ or ‘‘subclinical’’ expression of the pathology underlying schizophrenia. Pharmacological and/or cognitive activation techniques during functional brain imaging will most likely lead to more sophisticated studies in the future. This should eventually provide more interesting results about brain activity and functions of certain areas in the brain [68].

V.

LIFE EVENTS AND BIOLOGY

The nature-nurture debate into the etiology of psychiatric disorders has been a long-standing one with little

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resolution. Based on early observations that childhood abuse and early emotional trauma were present in the histories of individuals who were diagnosed with personality disorders (especially cluster B disorders), studies have been conducted to shed light on the role of life events, upbringing, and early trauma in the etiology of personality disorders. These studies supported a higher incidence of early-childhood trauma. Childhood sexual abuse and neglect in childhood have been found to be significantly higher in patients with BPD [69–71]. These findings have led to hypotheses such as BPD being a form of PTSD, specifically a chronic PTSD [72]. It appears that patients with BPD may experience a range of different types of abuse that could all be categorized under the umbrella of childhood trauma. Figueroa and Silk [73] reviewed the biological underpinnings of BPD while attempting to integrate the biology of stress and trauma. According to McEwen [74] there is a point at which stress is reversible, but prolonged exposure to stress can produce permanent changes in the biochemistry of the brain. It becomes clear that significant traumatic experiences can be an influencing factor in our biological makeup. According to van der Kolk [75], Nigg et al. [76], and Sabo [77], childhood abuse and neglect are significant trauma for a developing child, particularly if they are ongoing. Caregivers who are supposed to protect become dangerous and threatening, and this then affects attachment to others and other aspects of object relationships [75,76]. Sabo adds: ‘‘Early childhood experience, including separation/neglect and trauma, may contribute to alterations in neurotransmission for BPD patients. Thus the constitutional vulnerability in BPD patients could derive from genetic or environmental experiences early in development’’ [77, p 62]. The biological changes in these patients cause a broad array of problems. The effects of prolonged stress produce changes in the neurochemistry of the brain; the effects of an overwhelming and inescapable trauma probably affect the brain in many of the same ways: Autonomic activation is necessary to cope with the major stress, so a diminished capacity to activate appropriated autonomic stress reactions causes impaired physiological adaptation to stress. In many traumatized people this adaptive mechanism has been disturbed by the trauma; they continue to respond even to minor stimuli with an intensity appropriate to emergency situations [78, p 66].

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Trauma and stress, then, certainly can lead to difficulties in attachment. Studies done based on attachment theory seem to open new avenues in understanding the underlying biological vulnerabilities in individuals and the closely interwoven dance between the environment and the evolving or shaping brain in its early developmental stages. Fonagy et al. [79] emphasize the importance of reflective function in the infant and the mother, defined as the capacity to reflect on one’s own mental state. They describe the person with BPD as someone who has likely been a victim of childhood trauma, who has low reflective functioning, and who has a preoccupied attachment style. In that study, parents who rated high in reflective function were about four times more likely to have children with secure attachment than parents who rated low in reflective function. Yet despite having parents who had high ratings in the reflective functioning scale, some children had insecure attachment, indicating that they were innately more vulnerable to psychopathology [18,79]. It thus appears that it is impossible to ignore the complex two-way interaction between life events/environment and the individual’s genetic makeup or constitutional predispositions. The role of the attachment process and the initial phases of infant-mother interaction in shaping and/or affecting permanently the limbic system and higher cortical areas (prefrontal and fontal cortex) is a fertile area that awaits further studies.

VI.

FREUD’S PROJECT: BIOLOGY AND ITS CLINICAL IMPLICATIONS

To return to where we began, we look to Freud’s ‘‘Project,’’ which predicted a biological or neurological underpinning to all mental processes. Yet through most of this century, the followers of Freud turned away from consideration of biological mechanisms and paid most attention to the psychotherapeutic process, particularly the psychoanalytic process. Yet today we are beginning to appreciate that psychotherapy and the changes that occur in psychotherapy appear to have biological ramifications as well [80,81], and that the symptom picture attributed to object relations deformities in personality disordered patients is a combination of biological predispositions and parental rearing or reaction to these dispositions [18,82,83]. Therapies can focus on the biological issues within the context of psychodynamic understanding, a process which is evident in the work of Kernberg et al.’s [18] Transference Focused Therapy and its spotlight on


attachment and the biology of attachment and aggression and its impact on the early developmental stages. This can also be seen in the psychodynamic work of Fonagy as well [79,84]. A better understanding of underlying biological mechanisms can help the clinician, the patient, and the family to consider the vulnerabilities without being critical or judgmental. Thus, as more data accumulates from ‘‘biological’’ laboratories as well as from consulting rooms, we should be able to refine our links from the biology behind personality traits to the clinical picture and behavioral symptoms. This increased knowledge should help us better organize our clinical approach in working with patients who suffer from personality disorders. This idea of considering biology in psychotherapeutic work can be found in Linehan’s Dialectical Behavior Therapy (DBT) [85]. DBT has gained significant popular support over the past decade, particularly in the treatment of BPD, and it is one of the few forms of psychotherapeutic intervention that has been empirically studied, though recently Bateman and Fonagy [84] have begun to systematically study their intervention. DBT integrates proposed underlying biological vulnerabilities—namely, affective instability, impulsivity, and stress intolerance—in BPD with behavioral strategies designed to help the patient modify disordered behavior resulting from these vulnerabilities. One of the significant advantages of DBT theory is that it incorporates both aspects of constitution (predisposition) and environment in defining the etiology of BPD [77,82]. It also correlates symptoms with the growing knowledge of the biology of the personality

Table 1

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disorders. The five key areas of dysfunction that Linehan identifies are emotion, interpersonal, self-, behavior, and cognitive dysregulation. Table 1 presents the key areas of each dysfunction with the possible corresponding underlying biological dysfunction. This model allows the clinician to define a patient’s symptoms, then, in terms of both its biological basis and the behavioral components or clinical symptoms that these deficits produce. Referring to a patient’s symptoms as evolving from a biological basis helps a patient to consider her illness in terms of deficits that can be compensated for by learning new skills and behavioral adaptations. It also helps a clinician in using pharmacological interventions. This process can be compared to the situation in a patient with diabetes who must learn new behaviors around types and timing of food intake as well as use (at times) of medication to compensate for the lack of insulin production. The skills training manual for DBT presents skills that address these deficits or dysfunctions and helps patients to view their illness from a more empowering stance, as opposed to the role of victim [86]. The most immediate result of these biological studies would be a more rational and biologically informed approach to the psychopharmacological treatment of patients with personality disorders as well as better biological information to pursue the development of new medications. While most of our current pharmacological treatment of the personality disorders remains essentially empirical, there have recently been developed for BPD a series of pharma-

DBT Identified Areas of Dysregulation and Possible Underlying Biology

Dialectical behavior therapy Emotion dysregulation Affective instability Anger Interpersonal dysregulation Self-dysregulation Behavior dysregulation Parasuicidal behavior Impulsive behavior Cognitive dysregulation Irrational thoughts Paranoid ideation

Proposed biological dysregulation Serotonin leading to impulsivity Acetylinecholine leading to rapid-onset affective states GABA leading to lack of inhibitory actions Dopamine and norepinephrine leading to increased reactivity to environment including to people Genetic factors Emotional dysregulation leading to a lack of consistent self Genetic as in high novelty seeking or low harm avoidance Serotonin; opioids and endorphin system Dopamine

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cologic algorithms that may ultimately be able to provide us with a better and more organized approach to our current empirical one [87]. Hopefully, then, the study of the biology of the personality and its disorders allows the clinician to construct an understanding of the sufferings and difficulties of the patient with more empathy and less stigma, both of which are needed in the treatment of these difficult conditions. This would allow a true synthesis to occur in the treatment of these patients, a synthesis of psychodynamically informed sociotherapies [45,82] with behavioral therapies and techniques that improve daily coping and functioning accompanied by medication to reduce immediate biological risk. A full, thoughtful synthetic approach can be achieved when psychoeducational elements, designed to inform patient and family, are added to the above strategies and interventions [45,88].

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Iscan et al. 68. PF Goyer, PE Konicki, SC Schulz. Brain imaging in personality disorders. In: KR Silk, ed. Biological and Neurobehavioral Studies of Borderline Personality Disorder. Washington: American Psychiatric Press, 1994, pp 109–127. 69. JL Herman, JC Perry, BA van der Kolk. Childhood trauma in borderline personality disorder. Am J Psychiatry 146:490–495, 1989. 70. MC Zanarini, AA Williams, RE Lewis, RD Reich, SC Vera, MF Marino, A Levin, L Yong, FR Frankenburg. Reported pathological childhood experiences associated with the development of borderline personality disorder. Am J Psychiatry 145:1101–1106, 1997. 71. MC Zanarini. Childhood experiences associated with the development of borderline personality disorder. Psychiatr Clin North Am 23(1):89–101, 2000. 72. JL Herman, BA van der Kolk. Traumatic antecedents of borderline personality disorder. In: BA van der Kolk, ed. Psychological Trauma. Washington: American Psychiatric Press, 1987, pp 111–126. 73. E Figueroa, KR Silk. Biological implications of childhood sexual abuse in borderline personality disorder. J Pers Disord 11:71–92, 1997. 74. BS McEwen, E Stellar. Stress and the individual mechanisms leading to disease. Arch Intern Med 153:2093–2101, 1993. 75. BA van der kolk. The separation cry and the trauma response: developmental issues in the psychobiology of attachment and separation. In: BA van der Kolk, ed. Psychological Trauma. Washington: American Psychiatric Press, 1987, pp 31–62. 76. JT Nigg, NE Lohr, D Westen, LJ Gold, KR Silk. Malevolent object representations in borderline personality disorder and major depression. J Abnorm Psychol 101:61–67,1992. 77. A Sabo. Etiological significance of associations between childhood trauma and adult psychopathology. J Pers Disord 11:50–70, 1997. 78. BA van der Kolk, MS Greenberg. The psychobiology of the trauma response: hyperarousal, constriction, and addiction to traumatic reexposure. In: BA van der Kolk, ed. Psychological Trauma. Washington: American Psychiatric Press, 1987, pp 63–87. 79. P Fonagy, M Target, G Gergely. Attachment and borderline personality disorder. Psychiatr Clin North Am 23(1):103–122, 2000. 80. PS Wong, E Bernat, S Bunce, H Shevrin. Brain indices of nonconscious associative learning. Conscious Cogn 6:519–544, 1997. 81. JM Schwartz, PW Stoessel, LR Baxter Jr, KM Martin, ME Phelps. Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 53:109–113, 1996. 82. J Paris. Significance of biological research for a biopsychosocial model of the personality disorders. In:

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44 Iatrogenic Sexual Dysfunction MARLENE P. FREEMAN and ALAN J. GELENBERG University of Arizona College of Medicine, Tucson, Arizona, U.S.A.

I.

INTRODUCTION

for sexual function has not typically been incorporated into psychiatric research methodology. Analyses from clinical trials reveals that the incidence of sexual side effects is higher in studies which included systematic inquiries about sexual dysfunction, rather than those that rely on spontaneous patient reports [2]. Sexual side effects often interfere with quality of life, and, if unaddressed, may affect compliance. In this chapter, sexual dysfunction associated with different classes of psychotropic medications will be addressed and mechanisms for sexual side effects discussed. Finally, we present treatment options for iatrogenic sexual dysfunction.

Sexual dysfunction, usually defined by subjective dissatisfaction, is common in the general population and even more in psychiatric patients. Sexual dysfunction may involve any aspect of normal sexual function, including desire, arousal, and orgasm. Causes of sexual dysfunction include psychiatric disorders, nonpsychiatric causes (including medical conditions), and medications [1]. With many psychotropic medications, men and women often experience sexual side effects. Arousal may be affected, with women having decreased vaginal lubrication, and men erectile dysfunction. Orgasmic problems, including inhibition or delay, occur in both males and females, with men experiencing ejaculatory dysfunction. Menses and fertility also can be disturbed. Since the etiology of sexual dysfunction may be complicated, clinicians need to assess baseline sexual function, as well as incorporating a sexual and reproductive history into routine psychiatric evaluation. Many patients are hesitant to discuss sex, or may not realize its relevance. So it is imperative that psychiatrists regularly inquire nonjudgmentally about sexual symptoms and side effects. Many psychotropic medications impact sexual function. However, the study of iatrogenic sexual dysfunction has been historically limited, as formal screening

II.

ANTIDEPRESSANTS AND SEXUAL DYSFUNCTION

Dissatisfaction with sex is a frequent complaint. The most common symptoms in community surveys are low libido (34%) and orgasmic dysfunction (24%) in women, and premature ejaculation (29%), inhibition of orgasm (10%), and erectile dysfunction (10%) in men [3]. Mathew and Weinman [4] reported higher rates of sexual dysfunction in depressed men: decreased libido (31%), erectile dysfunction (35%), and delayed ejaculation (47%) versus nondepressed controls (6%, 0%, 6% respectively). Sexual dysfunction due to major 657

658

depression might be more common than the sexual side effects caused by medication. In one study, more than half of both female and male patients said that depression had negatively affected their sexual function, whereas only 14% of females and 26% of males had sexual side effects with clomipramine [5]. Sexual dysfunction from antidepressants is well documented. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) cause sexual side effects. Harrison et al. [6] conducted a doubleblind study of the effects of imipramine, phenelzine, and placebo on sexual function in depressed outpatients, assessed before and 6 weeks after treatment. Both drugs were associated with a significantly greater incidence of sexual side effects than placebo. Dysfunction of orgasm and ejaculation occurred more often than erectile dysfunction, and men had more sexual side effects than women. The degree of a TCAs’ effect on serotonergic neurotransmission may determine its impact on sexual dysfunction. Tricyclics with greater impact on serotonin reuptake blockade, such as clomipramine and imipramine, seem to cause more sexual dysfunction. Some patients who have had anorgasmia with imipramine improved when switched to desipramine [7,8]. In another study, clomipramine caused sexual side effects in as many as 14% of females and 26% of males [9]. Moclobemide, a reversible monoamine oxidase A inhibitor (RIMA) not approved for use in the United States, may be associated with fewer sexual side effects. No difference was found in response to a sexual function questionnaire between subjects who received either moclobemide, 300 mg/day, or placebo (N ¼ 60) in a 3-week trial [10]. Sexual side effects with moclobemide may differ between men and women. Kennedy et al. [11] found that while women reported significantly more sexual dysfunction with selective serotonin reuptake inhibitors (SSRIs) than with moclobemide, rates of sexual dysfunction between the drugs did not differ in men. The underlying psychiatric disorder may affect these side effects. In a naturalistic study of patients with panic disorder, rates of sexual impairment with tricyclics and SSRIs were 56.6% and 45%, respectively, higher than most reports of antidepressant-induced sexual side effects [12]. As over half of the patients also met criteria for another mental illness, the presence of more than one diagnosis, or the diagnosis of panic disorder itself, might have contributed to high rates of sexual dysfunction. Although trazodone has a well-known side effect of priapism, other types of sexual dysfunction may occur

Freeman and Gelenberg

with its use. Ejaculatory inhibition has been reported [13], and trazodone might decrease pathological sexual behavior. Decreased exhibitionism occurred in a male patient taking trazodone [14]. Some new antidepressants may be less likely to produce sexual side effects. Segraves et al. [15] conducted a double-blind comparison of sustained-release bupropion and sertraline in depression. Subjects were in stable relationships and had normal sexual functioning. Efficacy was comparable, but patients who received bupropion experienced less sexual dysfunction: only 15% in men and 7% in women, significantly less than with sertraline. Coleman and colleages [16] found similar results with sustained-release bupropion versus sertraline. Anecdotes, however, suggest some patients may have sexual dysfunction with bupropion [17]. Mirtazapine also appears to cause a lower incidence of sexual side effects. Boyarsky et al. [18] treated male and female patients with depression with open-label mirtazapine; sexual function measured by the Arizona Sexual Experiences Scale (ASEX) improved significantly with treatment. Also, patients who have experienced sexual side effects during treatment with SSRIs may benefit from treatment with mirtazapine instead. Koutouvidis et al. [19] reported on 11 patients who had poor compliance while receiving treatment with SSRIs due to sexual dysfunction. When treated with open-label mirtazapine, all experienced improvement in depressive symptoms without sexual side effects. Also, Gelenberg and colleagues [20] treated 19 patients with mirtazapine who had experienced remission from depression and SSRI-induced sexual dysfunction. When mirtazapine was substituted for the SSRI, 11 (58%) had return of normal sexual function with mirtazapine treatment, and all maintained remission from depression. Nonetheless, a case has been reported of sexual dysfunction associated with the use of mirtazapine [21]. Nefazodone is another new antidepressant that may produce low rates of sexual dysfunction. When 681 outpatients with chronic major depressive disorder were randomized to 12 weeks of nefazodone, cognitive behavioral therapy, or the combination, sexual function in males and females improved across all groups as depression improved [22]. In another study, Ferguson et al. [23] randomly assigned 105 patients with sertraline-induced sexual dysfunction to receive either nefazodone or sertraline. After 8 weeks, sexual dysfunction reemerged only 26% in the nefazodone group, compared with 76% of those treated with sertraline.

Iatrogenic Sexual Dysfunction

While SSRIs have been mostly associated with decreased libido and sexual function, some patients may experience heightened sexual parameters. Paradoxical sexual excitement has been reported. Morris [24] reported a case in which a patient treated with fluoxetine had an intermittent and dose-dependent increase in sexual stimulation. Elmore and Quattlebaum [25] similarly described two cases of women treated with SSRIs who experienced undesirable sexual arousal and one who experienced had sexual desire, arousal, and hypersexuality. Also, SSRIs benefit men with premature ejaculation and paraphilias [26,27]. III.

ANXIOLYTICS AND SEXUAL DYSFUNCTION

In an open-label study of buspirone in patients with generalized anxiety disorder, Othmer and Othmer [28] noted improved sexual function in eight of nine patients, all but one of whom had experienced sexual dysfunction at study entry. Patients were treated for 4 weeks after washout of other medications, with an average buspirone dose of 45 mg/day. The investigators acknowledged that improved sexual function may have resulted from the discontinuation of other medications. Benzodiazepines, including alprazolam, chlordiazepoxide, diazepam, and clonazepam, have been reported to cause sexual dysfunction [28–35]. Concomitant benzodiazapine use was associated with greater sexual dysfunction than the use of lithium alone or with other medications in bipolar patients [36]. The risk of sexual dysfunction with benzodiazepines appears to be lower than with SSRIs. IV.

ANTIPSYCHOTICS AND SEXUAL DYSFUNCTION

As with depression, sexual dysfunction may result from the disorder of schizophrenia and may precede treatment with antispychotic medications [37,38]. Possible mechanisms include hormonal or neurologic abnormalities or social awkwardness. Sexual side effects are common with older (typical) antipsychotic medications. Sexual side effects are estimated to occur in 30–60% of both men and women taking typical antipsychotics and may include erectile and ejaculatory dysfunction, decreased libido, orgasmic dysfunction, and menstrual disturbances [39]. In men, the most prevalent sexual side effects of antipsychotics are erectile

659

and ejaculatory dysfunction [40]. While all typical antipsychotics may be associated with sexual dysfunction, it is most prevalent with the use of thioridazine, which causes high rates of retrograde ejaculation [41]. Sexual side effects have been reported to differing degrees with virtually all typical antipsychotics [42,43]. Priapism also has been reported and may require emergency surgical intervention [44,45]. Menstrual irregularities, including amenorrhea, are common in women receiving treatment with traditional neuroleptics, presumably related to elevated levels of prolactin. In one random sampling of outpatients with schizophrenia, more men than women reported sexual dysfunction while receiving treatment with neuroleptics (54% vs. 30%), yet 91% of women reported menstrual changes while receiving treatment with neuroleptics [46]. Hence, in women, neuroleptics may impact fertility as well as sexual function. Aizenberg et al. [47] conducted a pilot study in which eight male patients with schizophrenia experienced ejaculatory dysfunction and decreased sexual satisfaction while taking thioridazine. The addition of low-dose imipramine, 25–50 mg qhs, resulted in resolution of sexual side effects in four patients (50%) and partial improvement in one other. Except for risperidone, the newer antipsychotic medications have been associated with less hyperprolactinemia than the older antipsychotics and have also been associated with less sexual dysfunction [48]. Standard doses of clozapine and quetiapine do not seem to cause hyperprolactinemia, and normal menstrual function has returned in women switched from typical antipsychotics to clozapine [49,50]. Switching to clozapine also has been associated with improved libido, possibly as a result of successful treatment of negative side effects [51]. Between increased libido and fertility, the risk of pregnancy rises when a woman is switched from a traditional antipsychotic to an atypical. Lack of elevation of serum prolactin with clozapine has been demonstrated also in the pediatric population [52]. Switching patients from traditional neuroleptics to clozapine has resulted in lowering of serum prolactin levels [53]. However, in a prospective systematic study of side effects, no significant differences in sexual side effects were found between patients receiving haloperidol and patients receiving clozapine during the first 6 weeks of treatment [54]. Sexual side effects with clozapine treatment decreased with longer duration of treatment. Sexual side effects significantly decreased in men from 53% (first 6 weeks) to 22.2% (18 weeks), and in women from 23% to 0%, respectively.

660

Risperidone, on the other hand, seems to increase prolactin levels. Breier et al. [55] conducted a 6-week double-blind, parallel-group comparison of risperidone and clozapine in patients previously treated with fluphenazine. Patients receiving clozapine had decreases in plasma prolactin, but those who took risperidone had increases. The investigators did not report sexual side effects during the trial. Markianos et al. [56] also reported increases in prolactin levels in patients switched from treatment with a traditional antipsychotic to risperidone. Kapur et al. [57] have suggested that since prolactin elevation is related to the extent of D2 receptor occupancy, increases in prolactin with risperidone and other medications may be related to dosage. The clinical relevance of risperidoneinduced prolactin increases is unclear. Guille et al. [58] reported that in patients with bipolar disorder treated with atypicals, including risperidone, retrospective chart reviews (N ¼ 42) failed to elicit prolactin-related side effects. However, Kim et al. [59] described five cases which risperidone treatment was associated with elevated serum prolactin levels and amenorrhea, and Popli et al. [60] reported a case of risperidoneinduced galactorhea. Kleinberg et al. [61] analyzed data from all randomized, double-blind studies of risperidone in patients with schizophrenia to assess the relationship between risperidone, serum prolactin levels, and clinical sequellae. Dose-related increases in prolactin levels were observed in both men and women. In male patients, the incidence of adverse events associated with hyperprolactinemia (including erectile dysfunction, ejaculatory dysfunction, gynecomastia, and decreased libido) was positively correlated with risperidone dose, but this was not demonstrated in female patients. While related to risperidone dose, adverse effects in men were not related to prolactin level. Also, at risperidone dose of 4–10 mg, adverse events were not experienced at significantly higher rates than seen with placebo. Risperidone-induced sexual side effects reported by Montejo et al. [62] reversed when patients were switched to treatment with olanzapine. Olanzapine may produce less hyperprolactinemia and associated effects than risperidone. David et al. [63] found that patients switched from haloperidol to olanzapine had decreases in serum prolactin, although serum prolactin was moderately elevated by olanzapine in general. They found that prolactin was more strongly elevated by risperidone than by haloperidol or olanzapine. Wudarsky et al. [64] also reported prolactin elevation occurring in pediatric patients with olanzapine, but at rates lower than with haloperidol.


Antipsychotics may cause sexual dysfunction through a variety of mechanisms. They obviously affect central neurotransmission, but they may also act by interfering at a peripheral level—e.g., through blockade of cholinergic and alpha-adrenergic receptors [65]. Thioridazine’s calcium channel antagonist activity could impact sexual function [66]. Alpha-adrenergic receptors are important in sexual function in the autonomic nerous system, with the parasympathetic system responsible for arousal and erection, and the sympathetic responsible for ejaculation and orgasm. Antipsychotics’ influence on hormones, particularly by increasing prolactin levels via blockade of pituitary dopamine receptors, also may account for sexual dysfunction [67]. Sequellae of increased prolactin levels can include galactorrhea, breast tenderness, ejaculatory and orgasmic disturbances, and menstrual irregularities. Ghadirian et al. [68] found that in a random sample of outpatients with schizophrenia, sexual dysfunction was more strongly associated with high prolactin levels in men than in women. Androgens also can be affected by antipsychotics. Haloperidol decreases serum testosterone levels in male rats [69]. A patient experienced sexual dysfunction, lowered testosterone levels, and hyperprolactinemia during risperidone treatment [70]. Hyperprolactimemia may also decrease estrogen levels in reproductive-age women [71].

V.

MOOD STABILIZERS AND SEXUAL DYSFUNCTION

It is unclear whether lithium influences sexual function. In a study of sexual function in euthymic male patients (N ¼ 35) with bipolar or schizoaffective disorder who were treated with lithium monotherapy, Aizenberg et al. [72] administered a questionnaire of sexual function. Most frequently reported were reduction in sexual thoughts (22.9%), diminished waking erection (17.1%), and loss of erection during coitus (20%). Thirty-one percent reported sexual dysfunction on at least two items, but overall patients reported a high degree of sexual satisfaction. Lithium levels were not related to sexual function. Additionally, cases of decreased libido and erectile dysfunction have been attributed to lithium [73]. However, Ghadirian et al. [74] studied sexual function using a self-rated scale in 104 outpatients with bipolar disorder. Concomitant benzodiazepine use was associated with sexual dysfunction. Sexual dysfunction was more commonly reported with patients treated with a combination of


lithium and benzodiazepines (49%) than those treated with either lithium alone (14%) or lithium with other concomitant drugs (17%). Lithium treatment may increase serotonergic neurotransmission [75], possibly accounting for some sexual side effects. Less evidence is documented regarding carbamazepine and sexual function. A case has been reported in which a man developed ejaculatory and orgasmic dysfunction after beginning treatment with carbamazepine for trigeminal neuralgia [76]. When carbamazepine was discontinued, sexual function returned to baseline. Anticonvulsants are often utilized to treat bipolar disorder. Sex hormone binding globulin (SHBG) increases during pharmacotherapy with carbamazepine, and acute decreases in free and total testosterone levels have occurred with initiation of carbamazepine treatment [77]. Free testosterone may be decreased as a result of the induction of hepatic synthesis of SHBG [78], but the clinical importance of this is not clear, and there are few data on the impact of anticonvulsants on sexual function in psychiatric patients. Valproate, although not implicated in sexual dysfunction, may possibly interfere with endocrine function, such as increased androgen levels and polycystic ovarian syndrome (PCOS) [79]. While the question of valproate’s role in the development of PCOS in psychiatric patients is controversial, elevation of androgens could theoretically protect against sexual side effects of concomitant psychotropic medications. Also, there are three cases of men with epilepsy and erectile dysfunction whose sexual function improved when they were started on lamotrigine [80].

VI.

STRATEGIES TO TREAT PSYCHOTROPIC-INDUCED SEXUAL DYSFUNCTION

661

VII.

(Please see Table 1 at the end of this section.) A.

Buspirone

Buspirone, a partial 5-hydroxytryptamine-1A (5HT1A) agonist, has shown some benefit in treating antidepressant sexual side effects. For example, Othmer and Othmer [84] conducted an open-label study of buspirone for sexual function in patients with generalized anxiety disorder. All but one had complained of sexual dysfunction from other medications. Patients were treated with buspirone, average 45 mg/day, after a washout of other psychotropic medications. After 1 month, eight of nine men and women returned to normal sexual function, without correlation with reduction in anxiety. In another study, patients with depression who had previously failed to respond to an SSRI were treated with added buspirone, up to 60 mg/day, or placebo in double-blind fashion [85]. There were no differences in antidepressant response between buspirone and placebo, but of 119 patients, 39.5% had SSRI-related sexual dysfunction prior to study entry. Significantly more patients in the buspirone group reported remittance of sexual dysfunction than in the placebo group. Improved sexual function occurred within the first week of treatment and was more pronounced in women than men, with benefits in both libido and orgasmic function. In a negative study, Michaelson et al. [86] conducted a double-blind, placebo-controlled trial of buspirone, amantadine, and placebo in women who had been successfully treated with fluoxetine but had experienced fluoxetine-associated sexual dysfunction. All groups reported improved sexual function, highlighting the importance of including placebo groups in such studies. B.

Sometimes lowering the dose of a drug may reverse or improve sexual dysfunction [81,82]. However, many patients need to discontinue a drug to reverse sexual side effects. Taking a 3-day ‘‘drug holiday,’’ an interruption in use of medication, improved SSRI-induced sexual function in approximately half of patients, with improved orgasmic function, sexual satisfaction, and libido [83]. Drug holidays work better with shorter half-life SSRIs, sertraline and paroxetine, than fluoxetine. The addition of or switching to a different medication with less sexual dysfunction is an alternative strategy.

PHARMACOTHERAPY FOR SEXUAL DYSFUNCTION

Bupropion

Bupropion has been associated less with sexual dysfunction than other antidepressants [87,88]. As a result, clinicians often augment with or switch to bupropion from an SRI when sexual side effects have occurred. Additionally, Clayton et al. [89]) conducted an 8-week study of patients (N ¼ 11) who had had depression successfully treated with SSRIs but experienced sexual dysfunction. For each patient, the SSRI was tapered as open-label treatment with sustained-release bupropion was initiated. Overall, patients experienced improved sexual function, with no significant change in depres-

662


sive symptoms. However, five patients dropped out of the study, likely owing to a discontinuation syndrome secondary to tapering the SSRI. Of the dropouts, most reported symptoms associated with SSRI discontinuation syndrome—including agitation, gastrointestinal distress, sweating, flushing, headache, dizziness, and dysphoria. Gitlin et al. [90] also demonstrated improvement in SSRI-associated sexual dysfunction with the addition of open-label bupropion (150–300 mg/day). However, Ashton et al. [91] did not find that SSRI-associated sexual dysfunction improved significantly more with bupropion, 150 mg/day, than with placebo in a double-blind trial. C.

Mirtazapine

Substituting mirtazepine may be an effective strategy for treating SRI-induced sexual dysfunction. As previously mentioned, Gelenberg and colleagues [92] treated patients experiencing SSRI-induced sexual dysfunction with mirtazapine. Eleven (58%) had return of normal sexual function with mirtazapine treatment, and all maintained remission from depression. D.

antidepressant efficacy when cyproheptadine was used either daily or PRN for SSRI-induced sexual dysfunction. While there are positive reports on cyproheptadine for sexual dysfunction associated with MAOIs [104,105], Kahn [106] wrote of one patient experienced visual hallucinations, fear, and irritability when 2 mg QHS was added to his medication regimen; symptoms resolved with the discontinuation of cyproheptadine. E.

Mianserin

Another serotonin antagonist, the ICA mianserin, has been tried as an antidote for SRI-induced sexual dysfunction. Aizenberg et al. [107] added mianserin 15 mg to 15 male patients with SRI-induced sexual side effects for 4 weeks. Patients generally experienced improved orgasmic function and sexual satisfaction, with marked improvement in sexual function in nine of 15, partial improvement in two, and no improvement in four. In an open-label trial of mianserin, 15 mg/day for 3 weeks, two-thirds of women with SRIinduced sexual side effects (N ¼ 16) reported significant improvement in sexual function, with no major adverse effects or psychiatric decompensation [108].

Cyproheptadine F.

Cyproheptadine, an antiserotonergic and antihistaminergic agent, has been used adjunctively to treat SSRIinduced sexual dysfunction. In some case cyproheptadine, 4–12 mg, is used PRN 1–2 h before sexual activity [93–95], while others employ daily dosing, 12–16 mg [96–98]. In a single case, single-blind crossover study, a woman with sexual dysfunction induced by imipramine took cyptroheptadine, diphenhydramine, or placebo 2 h before intercourse, then recorded the ease of achieving orgasm [99]. She reached orgasm 40% of the time with cyproheptadine 4 mg, which was significantly more effective than diphenhydramine and nonsignificantly more effective than placebo. Sedation is common in patients receiving cyproheptadine for sexual side effects [100]. However, more serious side effects have been reported. Goldbloom and Kennedy [101] reported the reversal of therapeutic effects of fluoxetine in two patients with bulimia who were treated with cyproheptadine 4–8 mg/day for sexual dysfunction. Bulimic symptoms subsided after cyproheptadine was discontinued. Price and Grunhaus [102] described a man with increased depressive symptoms and the emergence of suicidal ideation after he started cyproheptadine for clomipramine-induced anorgasmia [102]. Feder [103] also found diminished

Amantadine

Amantadine, a dopamine agonist, has been used to counteract SSRI-induced sexual side effects. Balon [109] described a woman whose fluoxetine-associated anorgasmia improved with amantadine, 100 mg PRN 5–6 h before sex. Prior to the PRN use, she was treated with 100 mg BID, which resulted in anxiety. Balogh et al. [110] reported on seven patients who experienced fluoxetine-induced anorgasmia. Of the four men and three women who were treated with amantadine, 100 mg QD or BID, all but one man and one woman had resolution of anorgasmia. In a randomized, placebocontrolled study for the treatment of fluoxetine-associated sexual dysfunction in women, Michaelson et al. [111] administered either amantadine, buspirone, or placebo for 8 weeks. Patients who received amantadine had greater improvements in energy, while all groups reported improvement in sexual function. G.

Yohimbine

Adjunctive yohimbine is another strategy to combat psychotropic-induced sexual dysfunction. Yohimbine is an indole alkaloid from the bark of the yohimbine tree, with alpha-2 adrenoceptor antagonist activity, central blockade of alpha-2 receptors, and noradrener-


gic activity [112]. In a meta-analysis of all placebo-controlled trials of erectile dysfunction (not specifically related to psychotropic use), yohimbine has been shown to be superior to placebo and well tolerated in doses of 5–10 mg TID [113]. Jacobsen [114] reported an open trial of yohimbine, 5.4 mg TID for at least 3 weeks for fluoxetine-induced sexual dysfunction. Eight of nine patients had improved sexual function with yohimbine, although five had side effects, leading to discontinuation in two. Side effects included nausea, anxiety, insomnia, and urinary frequency. In a double-blind placebo-controlled crossover study, a patient who had previously not responded to cyproheptadine had successful treatment of clomipramine-induced anorgasmia with yohimbine [115]. Initially the patient experienced headache with yohimbine, which subsided after he received several doses. While 10 mg yohimbine 90 min before sex resulted in restoration of orgasmic function after each administration, 15 mg resulted in premature ejaculation. After placebo the patient experienced orgasm only one of seven times. Segraves [116] reported successful treatment of all of 10 cases of SSRI-induced anorgasmia with yohimbine, 5.4 mg 1–2 h prior to sexual intercourse. Similarly, Hollander and McCarley [117] reported that yohimbine, 5.4–10.8 mg 2–4 h before sex, successfully counteracted SSRI-induced anorgasmia in five of six patients. Investigators found that if the dosage was too low, patients experienced no results, but if too high, patients complained of feeling ‘‘wired or wound up,’’ and insomia, fatigue, anxiety, and excessive sweating. Yohimbine has also been combined with trazodone for sexual dysfunction [118]. Fifty-five male patients were diagnosed with at least 3 months of psychogenic erectile dysfunction, determined after physical examinations, laboratory analyses, Doppler sonography of the cavernosal arteries, and polysomnographic recording of nocturnal erections. Each patient underwent two courses of treatment, 8 weeks with a combination of yohimbine (5mg TID) and trazodone (50 mg/day), then 8 weeks of placebo. Partial and complete response to placebo totaled 22%, compared with 71% with the yohimbine-trazodone combination. The study was complicated by the use of both yohimbine and trazodone, which is a triazolopyridine derivative and influences alpha-adrenergic and dopamine function. However, since trazodone alone was no more effective than placebo for erectile dysfunction in another double-blind study [119], the benefits were likely due to yohimbine.

663

H.

Stimulants

Stimulants may be beneficial in treating sexual side effects of psychotropics. Bartlik et al. [120] reported on five cases in which either methylphenidate, 15–25 mg or 5–10 mg PRN 1 h prior to sex, or dextroamphetamine, 5 mg 1 h before sex, reversed sexual side effects in patients treated with SSRIs.

I.

Sidenafil

Sildenafil appears to be a useful antidote. It is a phosphodiesterase-5 (PDE-5) inhibitor, and affects the corpus cavernosum and systemic vasculature. Fava et al. [121] conducted an open trial of sildenafil in nine men and five women, 12 of whom were being treated with SSRIs, and two of whom were receiving mirtazapine. After 4 weeks, patients experienced statistically significant improvement in sexual functioning, measured by the Arizona Sexual Experiences Scale (ASEX). Both men and women reported improvements in libido, arousal, orgasm, and sexual satisfaction, and men reported improved erectile function. Efficacy is also supported by a case report of a woman with fluoxetine-induced sexual dysfunction, successfully treated with sildenafil 50 mg 1 h prior to sexual intercourse [122]. She experienced return of normal arousal and orgasm in seven of seven trials. She had not responded to cyproheptadine and buproprion, and had only partial response to dextroamphetamine in previous trials to counteract the sexual side effects. In a larger report of cases, Salerian et al. [123] described 92 patients (31 women and 61 men) with psychotropic-induced sexual dysfunction, treated with sildenafil. Significant improvement was noted with all classes of psychotropic medications, and men and women responded equally well to sildenafil. Nurnberg et al. [124] conducted a double-blind placebo-controlled trial of sildenafil 50–100 mg for SRI-induced sexual dysfunction in 90 men. Sildenafil resulted in significantly greater improvements in erectile and orgasmic function, intercourse satisfaction, and overall satisfaction than placebo. Open-label extension in nonresponders also demonstrated the efficacy of sildenafil in SRIassociated sexual dysfunction. A case has also been reported of a male patient with schizoaffective disorder who experienced erectile dysfunction induced by haloperidol, successfully treated with sildenafil 50 mg PRN [125]. The patient did not experience any side effects secondary to the use of sildenafil.

664


While most evidence suggests that sildenafil is a safe medication, it is contraindicated in patients taking organic nitrates, as synergistic decreases in arterial pressure have been demonstrated to occur [126]. J.

Ginkgo Biloba

Ginkgo biloba has been used to treat antidepressantassociated sexual dysfunction. Cohen and Bartlik [127] reported on an open trial of ginkgo biloba 60–240 QD in patients experiencing sexual dysfunction while being treated with antidepressants. They found a positive effect on all four phases of the sexual response cycle: desire, excitement, orgasm, resolution. In that trial, women (n ¼ 33) responded better than men (n ¼ 30), 91% vs. 76%. Some patients experienced gastrointestinal side effects, headache, and general CNS activation. In a letter critical of that trial, Balon [128] expressed concern over lack of pretreatment evaluation prior to starting antidepressant treatment, and inconsistencies of data interpretation and reporting of side effects. A case report supports a possible role for gingko biloba extract in the treatment of a woman with fluoxetine-induced sexual dysfunction [129]. However, in another open trial, Ashton et al. [130] treated 22 consecutive patients with SSRI-induced sexual dysfunction for 1 month with ginkgo biloba 300 mg TID. They found little improvement in sexual function, with only three patients (13.6%) reporting at least partial improvement. K.

Ginseng

Ginseng is another potential treatment for sexual dysfunction, but data are lacking in the treatment of psychotropic-associated sexual dysfunction. In a study of male patients with erectile dysfunction, 90 patients were randomized to receive Korean red ginseng, trazodone, or placebo [131]. With ginseng, patients experienced signifiant increases in sexual satisfaction, libido, and penile rigidity. The overall efficacy was 60% for ginseng, 30% each for placebo and trazodone. While this study was not specific for the treatment of iatrogenic sexual dysfunction, results merit further study.

VI.

CONCLUSIONS

Sexual side effects are common with many psychotropic medications. Clinicians must actively inquire about sexual function in order to make accurate assessments. Women in particular may be reticent on this topic.

Baseline assessments of sexual function are necessary to determine whether or not sexual dysfunction is attributable to medication. Psychiatric and medical disorders can impact sexual function, independent of medication. A medical differential diagnosis and use of a standardized scale, such as the ASEX, may be helpful. Several mechanisms could account for iatrogenic sexual dysfunction from psychotropic medications. Sites of action leading to side effects may be central or peripheral. Several neurotransmitter systems are likely involved. Medications that increase serotonergic activity and/or decrease noradrenergic or dopaminergic activity have been implicated in sexual dysfunction. Increased dopaminergic activity in the medial preoptic area has been associated with increased sexual activity, and the administration of serotonin in this area may cause decreased sexual activity [132]. More specifically, activation of 5HT2 receptors can inhibit dopaminergic activity, and some antidotes for sexual dysfunction increase noradrenergic transmission by inhibition of autoreceptors. Hormones might be involved in the etiology of iatrogenic sexual dysfunction. Increased prolactin from antipsychotics can produce clinically troublesome side effects. Older antipsychotic medications tend to increase prolactin levels. Atypicals, with the exception of risperidone, do so to a lesser degree. Testosterone might mediate psychotropic-induced sexual dysfunction. Animal models have demonstrated suppression of serum gonadal steroids with serotonin reuptake inhibitors [133]. A case report has demonstrated the occurrence of low testosterone levels in a patient during treatment with venlafaxine; the testosterone level increased after the venlafaxine was discontinued [134]. Testosterone has been traditionally thought of as a male hormone. Low levels of testosterone have been associated with sexual dysfunction in men, and testosterone supplementation has been demonstrated to improve sexual function in hypogonadal men [135,136]. Testosterone deficiency in women also has been associated with decreased libido and sexual responsiveness [137]. Combination hormonal replacement, using both estradiol and testosterone, results in greater improvement in sexual function than estrogen therapy alone in postmenopausal women [138]. Androgens increase sexual desire and arousal in women after surgical menopause [139,140]. Testosterone increases sexual desire in premenopausal women also [141]. As the neurobiological basis for mental illnesses becomes better understood, we should be able to

Iatrogenic Sexual Dysfunction Table 1

665

Pharmacotherapy for Iatrogenic Sexual Dysfunction

Treatment for sexual dysfunction

Dosages reported

Supporting data

Buspirone

45–60 mg/d

Double-blind, placebocontrolled; open label

Cyproheptadine

4–12 mg PRN 1–2 h before sexual activity 100–200 mg/d

Open label; case reports

Amantadine

Yohimbine

5–10 mg PRN 2–4 h before sexual intercourse or 5 mg TID

Sildenafil

5–100 mg PRN 1 h before sexual intercourse 150–300 mg/d 60–240 mg/d 15 mg/d 15–25 mg 25 mg/d 5 mg 45 min prior to sexual activity (PRN) 5–10 mg methylphenidate PRN 1 h prior 5 mg PRN 1 h before sexual activity

Bupropion Gingko biloba Mianserin Methylphenidate

Dextroamphetamine

Inhibition of phosphodiesterase-5 Increased dopaminergic activity Unknown Serotonin antagonism Increased dopaminergic activity

Case reports

Increased dopaminergic activity

4. 5. 6.

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Serotonergic blockade, enhancement of dopaminergic noradrenergic activity Serotonergic blockade; may interfere with efficacy of SRIs Dopamine agonist

Case reports suppose use, one double-blind trial showed improvement but not significantly different from placebo group Open label, case reports; double-blind data not specific for antidepressant-induced sexual dysfunction Double-blind, open label, case reports Double-blind, open label Open label Open label Case reports

develop more rational pharmacotherapies with fewer side effects. Currently, choosing from our arsenal of psychotropic mediations involves balancing benefits with unwanted effects, including sexual dysfunction. We have described strategies to treat sexual dysfunction, but most importantly, clinicians must discuss sexual function with their patients openly and consider the impact of psychotropic medications on this important aspect of their lives.

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45 Neurobiology of Violence and Aggression MICHAEL S. MCCLOSKEY, ROYCE J. LEE, and EMIL F. COCCARO University of Chicago, Chicago, Illinois, U.S.A.

I.

INTRODUCTION

these behaviors are not generally seen as being pathological. In contrast, premeditated or ‘‘instrumental’’ aggression is planned aggressive behavior used to obtain a specific goal that is typically not culturally sanctioned. Premeditated behavior may occur in the absence of significant anger or hostility, and is under the person’s volitional control. Impulsive aggression is similar to premeditated aggression in that is often seen as pathological. However, unlike premeditated aggression, impulsive aggression is usually unplanned, accompanied by feelings of anger and hostility, and often described by the individual as being beyond their control. Just as there are multiple forms of aggression, there are also multiple factors that influence ones decision to engage (or not engage) in aggressive behavior. Cultural norms, economic factors, past aggressive experiences, and parental modeling are but of few of the environmental influences that help determine one’s propensity for aggression [2]. A growing body of literature suggests that neurobiological factors [3] also affect one’s tendency to behave aggressively, and that pathological aggression may reflect in part a neurobiological abnormality. This chapter will examine research aimed at identifying the neurobiological substrates that underlie aggression and violence.

Aggression, defined as a verbal or physical act with the intent to cause emotional, psychological, or physical harm, is ubiquitous. Individuals are continually exposed, directly or indirectly, to the aggressive acts of others. Not surprisingly, violence, typically conceptualized as physical aggression with injurious intent, has become increasingly endemic in American society. Estimates suggest that upwards of 10,000 violent crimes are committed in America each day [1], with this number representing only a proportion of the more severe acts of aggression. The effects of aggression have cost our society billions of dollars, to say nothing of the human cost. Accordingly, the importance of determining factors that contribute to aggressive behavior in order to better predict and prevent such behavior cannot be overstated. Aggression has multiple forms. It may be culturally sanctioned, premeditated, or impulsive. Culturally sanctioned aggression, as its name suggests, pertains to aggressive behavior that is viewed as acceptable and often necessary by the society in which the individual lives. The use of force to protect oneself, one’s family, or one’s country from imminent harm are examples of culturally sanctioned aggression, and

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II.

NEUROCHEMICAL CORRELATES OF AGGRESSION

A.

Serotonin

Serotonin (5HT) is the neurotransmitter most often associated with aggression, particularly impulsive aggression. Early research by Sheard et al. [4] found that compared to placebo, treatment with lithium resulted in a reduction of impulsive aggression among prison inmates. It was hypothesized that the 5HT-enhancing properties of lithium were responsible for the decrease in aggression. This finding coincided with Asberg et al.’s [5] study showing that among depressed individuals, lower lumbar cerebral spinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) levels correlated with violent suicide attempts and completed suicide. Additional research on personality disordered adults [6,7] showed that frequency of aggression and past suicidal behavior were each inversely related with CSF-5HIAA levels, formalizing the trivariate relationship between aggression, suicidal behavior and reduced CSF-5HIAA. Linnoila et al. [8] hypothesized the trivariate relationship between aggression, suicidal behavior, and reduced 5HT was mediated by impulsivity. In a study of violent criminals, they found that violent offenders whose crimes were ‘‘impulsive’’ (i.e., not an a priori plan) showed significantly lower CSF-5HIAA levels than violent offenders whose crimes were premeditated. Violent criminals with a history of attempted suicide had the lowest CSF-5HIAA levels. Other studies of violent offenders by Lidberg et al. [9] and Virkkunen et al. [10] obtained similar results. Furthermore, Virkkunen et al. [11–13] extended these findings by showing that individuals who engaged in acts of impulsive fire setting also had CSF-5HIAA levels that resembled those of impulsive offenders and were significantly reduced compared to healthy controls. These results have been paralleled by research on CSF-5HIAA and impulsive aggression among primates [14,15]. More recent research suggests the relationship between impulsive aggression and reduced CSF5HIAA is not as clear as was originally believed. A number of studies have failed to produce the hypothesized relationship between reduced CSF-5HIAA and increased aggression [16–20]. A meta-analysis [21] also failed to link aggression and reduced CSF5HIAA. Negative findings such as these have led some to suggest that the evidence for the role of 5HT in aggression is more equivocal than originally believed

[22]. Others have noted that the failed replications were on populations with less severe forms of aggression (e.g., personality disorder populations or healthy volunteers), and have suggested that reduced CSF5HIAA levels may only be related to severe levels of aggressive behavior. An alternative hypothesis by Coccaro [23] is that increased 5HT, which was found in a number of the failed replications, may also lead to decreased 5HT receptor responsiveness via a compensatory reduction in postsynaptic 5HT function. Concerns about the sensitivity and interpretability of CSF-5HIAA among individuals exhibiting less severe forms of aggressive behavior fostered the development of alternative methodologies to examine 5HT function, including neuropharmacological challenges. Fenfluramine is a challenge agent that, for most adults, leads to a robust activation of 5HT. This in turn results in the release of prolactin [24], which can be measured in the blood. The specific 5HT receptors believed to be activated by fenfluramine are the 5HT2c and possibly the 5HT2a receptors [25,26]. 5HT1a receptors do not appear to be involved in the fenfluramine induced prolactin response [27], though they may still have some involvement with aggression [28– 30]. Thus, differences in prolactin response to fenfluramine indicate a role not only for serotonin, but for specific 5HT receptor sites. Using 60 mg of d,l-fenfluramine as the challenge agent, Coccaro et al. [31,32] found an inverse correlation between prolactin response and history of impulsive aggression among personality-disordered individuals. Furthermore, an inverse correlation was also found between prolactin response and past suicidal behavior across both mood- and personality-disordered participants. No relationship between impulsive aggression and prolactin response was found for mood-disordered patients. The authors felt this last finding was consistent with animal research showing that reduced NE levels (common among mooddisordered individuals) partially inhibits the aggression-facilitating effects of 5HT [33]. The relationship between blunted prolactin response and increased history of aggression has been replicated in studies using personality-disordered subjects [27,34–36], alcoholic subjects [37,38], sociopaths [39], and healthy volunteers [40]. A reduced prolactin response has also been found among individuals with histories of suicidal and other self-injurious behaviors [41]. However, some populations have not shown the predicted relationship between prolactin response and history of aggressive behavior. Both Fishbein et al. [42] and Bernstein and Handlesman [43] found a positive

Neurobiology of Violence and Aggression

relationship between prolactin response to fenfluramine and past instances of aggression among nonalcoholic drug abusers. The reason for these findings is unclear. One speculation is that the habitual drug abuse may have sufficiently altered the neurochemistry of the brain to modify the relationship between 5HT indices and impulsive aggression. Neuropharmacological 5HT challenges using children as subjects has also yielded inconsistent results, with some studies showing prolactin response positively correlating with aggression [44,45], one study showing an inverse correlation between prolactin response and aggression [46], and other studies showing no significant relationship between the two [47,48]. Again, the reason for the disparity is unclear. It is possible that systems that regulate 5HT’s effect on aggression are not fully developed in prepubescent children. However, this is only speculative. More research is needed to elucidate the relationship between 5HT and aggression among both children and adult substance abusers. The majority of findings from the neuropharmacological challenges support the conceptualization that reduced 5HT activity is associated with increased aggression. In contrast, results from CSF-HIAA studies were equivocal. To resolve this discrepancy, Coccaro et al. [20] examined prolactin responses to d,l-fenfluramine and m-CPP (a 5HT2 agonist) in addition to measuring basal CSF-5HIAA levels in personality-disordered subjects. Results indicated that prolactin response to d,l-fenfluramine and m-CPP were each inversely correlated with history of aggression. However, basal CSF-5HIAA levels did not correlate with aggression, and inversely correlated with prolactin response to d,l-fenfluramine. This suggests that receptor sensitivity rather than basal CSF5HIAA levels may be key in modulating aggression, particularly among individuals without acts of severe aggression. Most studies of aggression, including the majority of studies cited in this chapter, rely on self-report questionnaires and/or interviews to provide an index of aggression. Retrospective self-report measures are subject to multiple sources of error including social desirability, over- or underreporting, lying, and response set issues [49], and thus may not provide a valid estimate of aggression. Fortunately, behavioral measures of aggression exist that provide a directly observable sample of aggressive responding. The two most commonly used laboratory measures of aggression are the Point Subtraction Aggression Paradigm [50] and the Taylor Aggression Paradigm [51]. Both occur in the context of

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a (faux) social interaction, and use provocation as a means to elicit aggression. The PSAP operationalizes aggression as the number of times a participant chooses a response, which he believes will to cause his opponent to lose money. The TAP operationalizes aggression as the level of electrical shock administered to an opponent. Both measures have been shown to correlate highly with aggressive behavior in naturalistic settings [52]. Laboratory measures of aggression have generally supported the hypothesis that 5HT functioning modulates aggressive behavior. Studies using healthy volunteers showed that short-term reduction in brain 5HT via dietary tryptophan depletion resulted in increased aggressive responding on laboratory aggression measures, whereas dietary tryptophan supplementation had an inhibiting effect on aggression [53–56]. Acute increase of 5HT levels through the use of the 5HT agonists d.1fenfluramine [29], eltoprazine [57], and paroxetine [58] also resulted in a reduction in aggressive responding on laboratory aggression tasks compared to placebo. These results support the CSF5HIAA and neuropharmacological challenge studies implicating 5HT in the regulation of aggression. Furthermore, they suggest that the use of medications that increase 5HT (e.g., lithium, SSRIs) may be beneficial in reducing aggressive behavior. Lithium was the first psychotropic agent to have empirically supported antiaggressive properties, showing that it reduced impulsive (but not premeditated) aggression among prison inmates [4]. These findings have been replicated and extended to children with conduct disorder, and other mentally ill populations [59,60]. It has been hypothesized that lithium enhances 5HT function [61], though other studies suggest that 5HT may not be responsible for lithium’s antiaggressive effects [62]. Selective serotonin reuptake inhibitors (SSRIs), the first line of treatment for most forms of unipolar depression, are believed to exert their effect by increasing the levels of 5HT in the synaptic terminals, resulting in increased 5HT functioning. As SSRIs predominantly affect 5HT, they should theoretically be effective in treating individuals with recurrent impulsive aggression. Controlled studies using personality-disordered patients with a history of impulsive aggression [63], borderline personalitydisordered patients [64], depressed patients with a history of anger attacks [65], and adults with autism [66] all have shown reduced physical and/or verbal aggression in response to SSRIs as compared to placebo. Furthermore, a number of atypical antipsycho-

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tics that are believed to affect 5HT2 receptors have been found to reduce aggressive behavior over and above their palliative effects on psychotic symptoms [67–70].

B.

Other Neurotransmitters

Compared to 5HT, few studies have examined the role of norepinephrine (NE) and dopamine (DA) in the expression of aggressive behaviors. Some animal research has suggested that increased NE facilitates aggression [71]. One of the earliest studies in neurotransmitter function and aggression [6] found that history of aggressive behavior positively correlated with the CSF-MHPG, the major metabolite of NE. Though the magnitude of this relationship was very small in comparison to the variance accounted for by CSF5HIAA, it still suggest that NE may have at a minimum an auxiliary role in the regulation of aggressive behavior. Other studies using CSF-MHPG [11], NE plasma concentrations [34], and NE neuropharmacological challenges [72] have also suggested a relationship between increased NE and increased impulsive aggression and irritability, though failed attempts at replication have also occurred [12,13]. Additional evidence indicates that NE facilitates aggression comes from pharmacological trials, which have shown that beta-noradrenergic blockers propanolol or nadolol reduce aggressive behavior in patients with traumatic brain injuries [73,74], dementia [75], and chronic psychiatric inpatients [76–78]. The role of NE in aggression has yet to be fully determined, though the current findings suggest that NE may serve a supportive function in the regulation of aggression. Research evaluating the role of DA in the regulation of aggression has also been lacking. The few studies that examined DA and aggression have yielded inconsistent results. Some studies have documented an inverse relationship between aggression and level of homovanillic acid (HVA) in the CSF among violent offenders [12], individuals with antisocial personality disorder [8], and abstinent alcoholics and healthy volunteers [79]. However, other studies were unable to find any relationship between CSF-HVA and aggression [6,11]. Adding to the confusion, it has been postulated that the significant findings were secondary to 5HT’s regulation of both aggression and CSF-HVA [80]. However, this is still a matter of debate [81], and the role of DA in the expression of aggression remains undefined.

C.

Neuropeptides and Neurosteroids

Neuropeptides and neurosteriods have multiple functions in the central nervous system (CNS). They may act as neurohormones, as neuromodulators, or even as neurotransmitters alone or in conjunction with other neurotransmitters. Because of their role in, among other things, social behavior, sexual behavior, stress, and pain, they are of interest in studies of aggression. Vasopressin is a neuropeptide that has been shown to facilitate aggressive behavior in lower animals [82]. Among humans the evidence mixed. Coccaro et al. [83] found that increased levels of CSF vasopressin positively correlated with past aggressive behaviors in a sample of personality-disordered men. In contrast, Virkkunen et al. [13] found no difference in CSF vasopressin levels among impulsive and nonimpulsive violent offenders. Coccaro et al. [83] suggested the inconsistency between his finding and those of Virkkunen et al. [13] may be a function of the different populations sampled. Without additional research, any conclusions are speculative. Increased levels of endogenous opiates have been linked to aggressive and self-aggressive behavior. Suicide victims have been found to have increased mu-opioid receptors [84], circulating metenkephalin levels have correlated with acts of self-aggressive behaviors [85], and opiate blockers appear to reduce selfaggression [86]. Participants receiving oral morphine also showed increased aggressive behavior when compared to a participant’s receiving placebo [87], and increased levels of CSF opiate binding proteins were found among healthy volunteers with higher levels of ‘‘assaultiveness’’ [88]. Testosterone levels have often been associated with increased aggression [89], particularly in men [90]. Plasma testosterone levels have been reported to be higher in populations characterized by aggressive behavior. Alcoholic men with a history of domestic violence were found to have higher levels of plasma testosterone than a comparison group that did not engage in domestic violence [91]. There may be an interaction between testosterone level and type of aggression. One study found that CSF free testosterone was related to aggression only among criminal offenders who exhibit both violent behaviors that are both antisocial and impulsive [13]. Anecdotal reports have suggested that ingestion of exogenous testosterone produces an increase in impulsive violence. Unfortunately, no controlled studies have been able to experimentally examine this relationship.


Cortisol is believed to be associated with decreased aggression, though the actual evidence appears mixed. Cortisol has been negatively correlated with testosterone in healthy volunteers [92]. Furthermore, plasma cortisol was decreased among alcoholics with a history of repeated domestic violence [91], and decreased levels of free cortisol were also found among a group of antisocial violent offenders [93]. However, the same study found that cortisol levels were unrelated to nonantisocial aggression. Nonhuman primate studies have actually shown increased cortisol levels in association with aggressive competition for alpha status. Furthermore, studies of children have shown that both increased [94] and decreased [95] cortisol levels were associated with aggressive or disruptive behavior. D.

Cholesterol

Decreased cholesterol has been implicated in the facilitation of impulsive aggressive and self-aggressive behaviors. Virkkunen [96,97] demonstrated that impulsive violent offenders have reduced levels of serum cholesterol. These results were also extended to include individuals with a history of suicidal behavior [98–101]. A meta-analysis of cholesterol reducing agents associated them with increased likelihood of death as a result violence or suicide [102]. One study did find that among adolescents admitted to a psychiatric inpatient unit, serum cholesterol was positively correlated suicidal ideation [103]. Despite this contradictory finding, the majority of evidence reviewed seems to favor an inverse relationship between aggression/selfaggression and serum cholesterol. E.

Neurochemical Correlates of Aggression: Summary

Serotonin has been hypothesized to exhibit inhibitory control over aggressive impulses. The studies reviewed generally support this hypothesis. Aggression is associated with blunted responses to 5HT challenges and, at least among the very violent, decreased CSF-5HIAA levels. Laboratory measures show increased aggression in response to 5HT deprivation and reduced aggression in response to use of SSRIs or tryptophan loading, and controlled studies indicate that SSRIs have also been successfully used to treat pathological aggression. Pharmacological challenges and clinical drug trials suggest that NE may also affect aggression by facilitating its expression. Among the other neurochemicals reviewed, endogenous opiates have been found to facilitate aggressive

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behavior. Testosterone has also been associated with increased aggression, particularly in men who demonstrate antisocial and impulsive violence. In contrast, serum cholesterol levels were inversely related to aggression. Once some of the neurotransmitters and other neuromodulaters associated with the regulation of aggression have been identified, emphasis can switch to locating the cortical and subcortical structures where these neurochemicals exert their effect.

III.

NEUROANATOMICAL CORRELATES OF AGGRESSION

Neuropsychological and neuroimaging studies suggest that a number of specific brain structures are involved in the regulation of aggressive behavior. Among these, the prefrontal cortex area, including the orbitofrontal and ventral medial cortex, appears to be of particular importance. Research has also implicated the temporal cortex, cingulate cortex, and amygdala in the regulation of aggression. A.

Prefrontal Cortex

The prefrontal and orbitofrontal cortex has been associated with the modulation of aggressive impulses since the case of Phineas Gage [104]. Since then numerous clinical studies have found an association between lesions in the prefrontal-orbitofrontal cortex and dysregulation of aggressive impulses [e.g., 105–109]. Neurologic patients with orbitofrontal cortex damage also show irritability and aggressiveness [110,111]. The orbitofrontal cortex is also involved in olfactory identification, and it was recently shown that combat veterans diagnosed with PTSD were less proficient at olfactory identification than a combat-exposed control group [112], suggesting involvement of the orbitofrontal cortex in PTSD, a disorder often accompanied by anger dyscontrol. PET studies have shown reduced metabolic activity in the prefrontal-orbitofrontal cortex of violent criminals [113,114], and among personality-disordered individuals, regional glucose metabolism to the orbitofrontal cortex was negatively correlated with life history of aggression. B.

Amygdala

The amygdala is involved with evaluations of potential threat [115]. Stimulation of the amygdala has been associated with aggressive attacks in both humans and animals [116], and amygdalotomy has

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been found to reduce aggressive attacks among patients with intractable aggression [117]. Rich connections exist between the amygdala and prefrontal cortex. It has been suggested that one way in which the prefrontal cortex may modulate aggression is via inhibition of the amygdala. No direct imaging studies of the amygdala have been performed. However, Raine et al.’s [118] PET study of murderers found both reduced glucose metabolism in the prefrontal cortex and increased glucose metabolism in subcortical areas, which could include the amygdala.

C.

Temporal Lobe

Temporal lobe dysfunction has also been linked to aggression. Aggressive outbursts have been associated with seizure activity among patients with temporal lobe epilepsy [119]. Temporal lobe lesions have also been associated with violent behavior in criminal [120,121] and noncriminal [122] populations. Furthermore, PET studies have repeatedly shown reduced metabolic activity in the temporal lobes for psychiatric patients with recurrent acts of violence [123,124]. One study also showed that temporal lobe metabolic activity was inversely correlated with life history of aggression among personality-disordered patients [125].

E.

Neuroanatomical findings suggest that areas of the brain richly innervated with 5HT neurons (e.g., the orbitofrontal cortex, limbic cortex, temporal lobe) appear to regulate aggression. This is consistent with the neurobiological research showing a primary role for 5HT in the regulation of aggression. If abnormalities in 5HT functioning in temporal, limbic, and/or prefrontal cortex contribute to pathological aggression, the question remains to what extent are these abnormalities are heritable, developmental, or acquired.

IV.

GENETIC STUDIES OF AGGRESSION

As stated earlier, aggression is a complex, multidetermined behavior whose expression is likely affected by numerous environmental and biological factors, as well as the exponential interactions between the two. Behavioral genetic studies are useful in that they provide a rough estimate of the extent to which inherited biological factors may influence expression of a behavior.

A. D.

Neuroanatomical Correlates of Aggression: Summary

Twin Studies

Brain Structures and 5HT

Prefrontal, temporal, and limbic structures all appear to play a role in the regulation of aggression. All of these areas are heavily innervated by 5HT neurons, suggesting that decreased 5HT transmissions in these areas are largely responsible for the biological component of aggression dysregulation. There is empirical support for this theory. Siever et al. [126] compared brain metabolic activity of personality-disordered patients with impulsive aggression to nonaggressive controls after administration of d,l-fenfluramine. Compared to the control group, individuals with impulsive aggression showed reduced cerebral glucose metabolism in the orbitofrontal, ventral medial, and cingulate cortex. Both groups showed increased metabolic activity in the inferior parietal lobe in response to the neuropharmacological challenge, suggesting some structural specificity for reduced 5HT in aggressive individuals. These results were replicated comparing a sample of patients with borderline personality disorder to normal controls [127].

Twins studies examine the relative concordance rates of monozygotic (MZ) and dizygotic (DZ) siblings in the expression of a behavior to estimate the heritability for that behavior. Twin studies have generally yielded varible results ranging from findings that genetic influences account for close to 50% of the variance in aggression [128,129], to failing to find a significant increase in the concordance of MZ twins as compared to DZ twins for aggressive behavior [130,131]. One study that examined aggression amongst a population of male twins found that the heritability of aggression is a function of the type and severity of the aggressive acts committed [132]. Life history of verbal aggression, often considered a milder form of aggression was shown to have a heritability estimate of 28%. In contrast, life history of direct physical aggression (e.g., fist fights) had a heritability estimate of 47%. This suggests that tendencies toward physical aggression may be significantly influenced by biological factors, whereas verbal outbursts are less so.


B.

Molecular Genetics

Evidence for abnormalities at the gene level which could transmit traits of increased aggression has been somewhat confusing. The most studied DNA polymorphism is within the noncoding region of the tryptophan hydroxylase (TPH) gene. TPH is the ratelimiting enzyme in the synthesis of serotonin, putatively involved in the expression and regulation of impulsive aggression. Nielson et al. [133] reported that impulsive violent offenders with one or two copies of the TPH ‘‘L’’ allele had significantly lower CSF concentrations of CSF 5HIAA than to impulsive violent offenders with two copies of the ‘‘U’’ allele. The ‘‘L’’ allele in impulsive and nonimpulsive violent offenders was associated with a greater frequency of past suicide attempt (LL 65% vs. LU 53% vs. UU 17%, P < :02). In fact, almost all of the offenders who attempted suicide had either the LL or UL genotype, independent of CSF 5HIAA levels. TPH genotype was not associated with psychiatric diagnosis such as affective or anxiety disorders. Although Nielsen et al. [134] replicated his finding in a study of 804 Finnish alcoholic offenders, and there has been an independent replication by New [41], there have been nonreplicating studies published as well [135–137], correlating the more common U allele with suicidality and/or aggression or not finding a correlation [Coccaro, unpublished data]. The reason for these failures to replicate the original findings may be related to the fact that the polymorphism is on the noncoding region of the TPH gene. Hence, it may be in linkage dysequilibrium with an unknown polymorphism in some study populations, but not in others [138]. An association between antisocial alcoholism and the C allele biallelic polymorphism of the 5HT-1d-beta receptor has been found [139]. Antisocial alcoholism is alcohol abuse along with antisocial personality disorder or intermittent explosive disorder. Violence in schizophrenics has been associated with a ‘‘low-activity’’ allele of a biallelic polymorphism for COMT in schizophrenics by Strous [140] with replication by Lachman [141].

C.

Genetic Studies of Aggression: Summary

Though results are inconsistent, is appears that 30– 50% of variance in aggressive behavior may be attributable to biogenetic factors, with more severe forms of aggression having a stronger heritability. Future advances in molecular genetics may lead to the identi-

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fication of specific combination of genes that account for these biogenetic factors.

V.

CONCLUSIONS

Findings from neurobiological studies have increasingly implicated serotonin in the regulation of aggressive behavior. Data from CSF studies, neuropharmacological challenges, 5HT depletion studies, and controlled pharmacological treatment trials, all provide evidence that decreased levels of 5HT is associated with increased acts of aggression, especially impulsive aggression. Decreased 5HT receptor responsivity may also be implicated in pathological aggression. Finally, neuroanatomical research data suggest 5HT exhibits its antiaggressive effects via synapses in the orbitofrontal, prefrontal, temporal, and limbic cortex. Information about the role of other neurochemicals is still limited, but evidence is emerging that other neurotransmitters and modulators may also assist in the regulation of aggression.

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Coccaro EF, Bergeman CS, Kavoussi RJ, Seroczynski AD. Heritability of aggression and irritability: a twin study of the Buss-Durkee aggression scales in adult male subjects. Biol Psychiatry 1997; 41:273–284. Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M. Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry 1994; 51:34–38. Nielsen DA, Virkkunen M, Lappalainen J, Eggert M, Brown GL, Long JC, Goldman D, Linnoila M. A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch Gen Psychiatry 1998; 55:593–602. Buresi C. Association between suicide attempt and the tryptophan hydroxylase (TPH) gene. Am J Hum Genet 1997; 61:A270. Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry 1997; 154:1451–1453. Manuck SB, Flory JD, McCaffery JM, Matthews KA, Mann JJ, Muldoon MF. Aggression, impulsivity, and central nervous system serotonergic responsivity in a nonpatient sample. Neuropsychopharmacology1998; 19:287–299. Coccaro E, McNamee B. Biology of agresssion: relevance to crime. In: Skodol AE, ed. Psychopathology and Violent Crime. Washington: American Psychiatric Press, 1998:99–128. Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL, Naukkarinen H, Virkkunen M, Linnoila M, Goldman D. Linkage of antisocial alcoholism to the serotonin 5HT1B receptor gene in 2 populations. Arch Gen Psychiatry 1998; 55:989–994. Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM. Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res 1997; 69:71–77. Lachman HM, Nolan KA, Mohr P, Saito T, Volavka J. Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder. Am J Psychiatry 1998; 155:835–837.

46 Pathological Gambling Clinical Aspects and Neurobiology MARC N. POTENZA Yale University School of Medicine, New Haven, Connecticut, U.S.A.

I.

INTRODUCTION

casinos has been witnessed following the passing of legislature such as the Indian Gaming Regulatory Act in 1988 and that allowing for the introduction of riverboat casinos on the Mississippi in 1989 [5,6]. From 1976 to 1997, legalized gambling revenues in the United States have increased 1600% [6–8], and gambling ventures currently gross more than the motion picture, music, and theme park industries combined ($50 billion in 1998, with predictions of further increased growth in the near future) [5,8]. With the growth in legalized gambling there has been a concurrent increase in the prevalence rates of individuals with gambling disorders [9]. As such, there exists an increasing need for understanding the spectrum of gambling behaviors, the biological processes underlying the behaviors, the potential for associated adverse health consequences, and the ways in which prevention and treatment efforts can be utilized to promote improved clinical care [10].

Gambling is a human behavior that has persisted throughout millennia and been documented in diverse cultures. Early records document gambling in ancient Egyptian, Japanese, and Persian societies [1,2], and similarly early accounts can be found of problematic gambling behaviors [3]. For example, in the Mahabharat, a central book of Hinduism, one character is described as gambling away his kingdom and his wife [4]. Historically, gambling has gone through periods of expansion and restriction. For example, in the 1700s and 1800s, it was not uncommon for public works (construction of bridges, roads, schools, hospitals, or churches) to be financed in part through lotteries or for travelers to resort in large, elegant European casinos [2]. In contrast, in the early 1900s, many forms of gambling were illegal or largely restricted in the United States. Throughout these periods, although gambling was generally considered a moral vice, it remained a popular activity within the general population. Over the past several decades, many regions of the world, including the United States, have witnessed a rapid growth in legalized gambling. The introduction of state lotteries in New Hampshire in 1964 has been followed by a progressive growth in state-run and interstate lotteries such as Powerball [5]. A growth in

II.

DEFINTIONS

A.

Gambling

Gambling by definition is placing something of value at risk in the hopes of gaining something of greater value. Gambling, like many routine daily processes, 683

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involves decision making based on the assessment of risk and reward. The centrality of risk- and rewardbased decision-making processes to gambling might in part explain its persistence throughout time. In most forms of gambling, the risked item is money, and traditional forms of gambling include wagering on lotteries, card games, horse and dog racing, sports, and slot machines. Newer forms of gambling, such as Internet gambling, appear to be growing in popularity, with current estimates suggesting Internet gambling revenues to reach $2.3 billion by the end of 2001 [11]. Internet gambling might present an increase risk for abuse given the ready access, rapidity of action, ability to be used in isolation, and difficulties in regulating usage.

B.

Problem Gambling and Pathological Gambling

Excessive gambling has been described by multiple terms including compulsive, addictive, or disordered gambling. Only in 1980 was a gambling-related disorder, pathological gambling (PG), introduced into the Diagnostic and Statistical Manual of Mental Disorders (DSM) [12]. The diagnostic criteria have undergone several revisions since their original inclusion, and a current listing is included in Table 1 [13]. The criteria for PG are similar to those for substance dependence, and include features of diminished control over the self-destructive behavior, aspects of tolerance and withdrawal, and interference in major areas of life functioning due to the behavior.

Table 1

A. Persistent and recurrent maladaptive gambling behavior as indicated by five (or more) of the following: (1) is preoccupied with gambling (e.g., preoccupied with reliving past gambling experiences, handicapping or planning the next venture, or thinking of ways to get money with which to gamble) (2) needs to gamble with increasing amounts of money in order to achieve the desired excitement (3) has repeated unsuccessful efforts to control, cut back, or stop gambling (4) is restless or irritable when attempting to cut down or stop gambling (5) gambles as a way of escaping from problems or of relieving a dysphoric mood (e.g., feelings of helplessness, guilt, anxiety, depression) (6) after losing money gambling, often returns another day to get even (‘‘chasing’’ after one’s losses) (7) lies to family members, therapist, or others to conceal the extent of involvement with gambling (8) has committed illegal acts such as forgery, fraud, theft, or embezzlement to finance gambling (9) has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling (10) relies on others to provide money to relieve a desperate financial situation caused by gambling B. The gambling behavior is not better accounted for by a Manic Episode Source: Ref. 13.

conjunction with the adult rates are consistent with a cohort effect [9]. 2.

1.

Prevalence Rates of Problem Gambling and PG

Although the majority of people gamble, a relatively small proportion develops problems with gambling. For example, 86% of the general population is thought to have engaged in traditional forms of gambling at some point in their lives [6]. In contrast, a meta-analysis of prevalence studies performed in North America over the past several decades estimates lifetime rates of problem and PG of 3.85% and 1.60%, respectively [9]. The same study found more recent studies generating higher estimates, suggesting an increase in the number of individuals with problem and PG concurrent with the increase in access to legalized gambling [9]. Consistently higher lifetime prevalence rates of problem gambling (9.45%) and PG (3.88%) have been found in adolescents and young adults, data which in

Diagnostic Criteria for Pathological Gambling

Comorbidities

PG is often observed in setting of other mental health disorders [14–16]. High rates of comorbidity between substance use disorders (SUDs) and PG have been described, with individuals with SUDs reported as having 4- to 10-fold higher rates of PG (rates of 5–15%, depending on the substance and the study) [14,17–19]. Studies have also revealed high rates of SUDs in groups of individuals with PG; e.g., rates of alcohol abuse or dependence have been found in the range of 45–55% [20,21], and nicotine dependence in the range of 70% [14]. Given the phenomenological similarities and the high rates of comorbidity between SUDs and PG, PG has been described as ‘‘an addiction without the drug’’ [22]. Emerging data suggest common genetic factors contributing to the development of PG and certain SUDs, suggesting in part a common etiology [23,24].

Pathological Gambling

PG also shares comorbidities with non-substancerelated mental health disorders. Some studies suggest high rates of attention deficit and bipolar disorder in individuals with PG [14,25–27]. Studies of the relationship between obsessive-compulsive disorder (OCD) and PG have been mixed, with some studies reporting elevated rates [21,28] but most larger studies reporting nonelevated or low rates [15,29,30]. Data from the St. Louis Epidemiologic Catchment Area Study found problem gamblers as compared with nongamblers to have elevated odds ratios for major depression (3.3; 95% confidence interval [CI] 1.6, 6.8), schizophrenia (3.5; CI 1.3, 9.7), phobias (2.3; CI 1.2, 4.3), somatization syndrome (3.0; CI 1.6, 5.8), and antisocial personality disorder (6.1; CI 3.2, 11.6) [15]. The study also provided additional data on the relationship between problem gambling and SUDs, with problem gamblers as compared with nongamblers reported as having elevated odds ratios for alcohol use (7.2; CI 2.3, 23.0), alcohol abuse/dependence (3.3; CI 1.9, 5.6), nicotine use (2.6; CI 1.6, 4.4), and nicotine dependence (2.1; CI 1.1, 3.8) [15]. Recreational gamblers as compared with nongamblers were also observed to have elevated odds ratios for psychiatric disorders and related behaviors, including major depression (1.7; CI 1.1, 2.6), dysthymia (1.8; CI 1.0, 3.0), ‘‘somatization syndrome’’ (1.7; CI 1.1, 2.8), antisocial personality disorder (2.3; CI 1.6, 3.4), alcohol use (3.9; CI 2.4, 6.3), alcohol abuse/dependence (1.9; CI 1.3, 2.7), nicotine use (1.9; CI 1.6, 2.4), and nicotine dependence (1.3; CI 1.0, 1.7) [15]. These and other data support the notion that gambling behaviors can be conceptualized along a spectrum ranging from nongambling to recreational to problem to pathological gambling [6,9,23,24]. A need exists for naturalistic studies to identify the course over time of gambling behaviors within individuals and their movement from one group to another, as well as for better identifying and defining the health and disease factors associated with the respective patterns of gambling [31]. 3.

High-Risk Groups

As described above, (1) adolescents and young adults and (2) individuals with SUDs represent two high-risk groups for developing problem or PG. Given the comorbidities detailed above, individuals with other specific mental health disorders (e.g., depression, schizophrenia, anxiety disorders, antisocial personality disorder) likely also represent high-risk groups. Males also represent a high-risk group, with most studies reporting an 2 : 1 male : female ratio [32].

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Nonetheless, given the recent increase in accessibility to legalized gambling, particularly forms which appear more problematic for women (e.g., slot machines), the male:female ratio may diminish in the near future [32]. Studies have suggested that minority groups, particularly African-Americans, represent a high-risk group for PG [15,16]. For example, African-Americans comprised 31.0% of the group of problem gamblers as compared with 15.2% of the recreational and 21.4% of the nongamblers in the St. Louis Epidemiologic Catchment Study [15]. Limited data exist examining carefully the gambling patterns of other racial and ethnic groups, although it has been suggested that Hispanic, Asian-American, and Native American groups might be at elevated risk for developing problem or PG [16]. Data support the notion that lower socioeconomic status is associated with higher rates of problem and PG [16]. However, given the complex relationship between socioeconomic status and race and ethnicity and the limited data currently available, more work needs to be done in this area to clarify the relationship [16]. As with other potential at-risk populations, more research is needed to investigate whether older adults might represent a high-risk group, particularly as there has been an increase in the gambling rates of older adult Americans in the past 25 years: lifetime gambling rates in adults 65 years of age or older have risen from 35% in 1975 to 80% in 1998, and past-year rates from 23% in 1975 to 50% in 1998 [6].

III.

CONCEPTUALIZATION AND CLASSIFICATION OF PG

The two most prominent theories regarding the conceptualization of PG describe the disorder as: (1) an addiction without the drug-bearing similarities to SUDs; or (2) a disorder lying along an impulsive/compulsive spectrum [22,33,34]. These classifications are not mutually exclusive, and there exist data to support each view [10,22]. PG is currently included in the DSM-IV-TR in the category of Impulse Control Disorders Not Elsewhere Classified with such disorders as pyromania, intermittent explosive disorder, trichotillomania, and kleptomania [13]. Additional nonsubstance-related disorders that share similar features but are either formally included in DSM-IV-TR or are classified elsewhere have been grouped with PG and include compulsive buying, compulsive sexual behaviors, and compulsive computer use [35]. These disorders share a difficulty in controlling impulse to engage

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in a behavior which, although often hedonic in nature at some point in the disorder, ultimately leads to interference in major areas of life functioning. Neurobiological similarities appear to explain some of the common elements among these disorders [35].

IV.

NEUROBIOLOGY

A.

Serotonin Systems

1.

Neurochemical Studies

Serotonin (5HT) is arguably the most widely-implicated neurotransmitter system in impulse control. A role for 5HT in PG and other impulse control disorders has been suggested, particularly in behavioral initiation and cessation [35,36]. Low levels of the 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been observed in multiple groups of individuals with poor impulse control, including those attempting suicide, alcoholic criminals, and fire setters [37–41]. In a study of ten males with PG, Nordin and Eklundh observed decreased cerebrospinal fluid (CSF) levels of 5-HIAA when correcting for CSF flow parameters [42]. 2.

Pharmacological Challenge Studies

Additional support for a role for 5HT in PG comes from pharmacological challenge studies. A study using the 5HT and norepinephrine transporter inhibitor clomipramine (CMI) at a dose thought to preferentially target the 5HT transporter has been performed [43]. PG as compared with control subjects demonstrated lower prolactin levels at baseline and exhibited significantly blunted prolactin increases 60 min following CMI administration [43]. The blunted prolactin response raises the possibility of diminished 5HT transporter binding in individuals with PG. An independent challenge study employed the agent metachlorophenylpiperazine (m-CPP), which was administered to 10 males with PG and 10 healthy male control subjects [44]. A metabolite of the antidepressant trazodone and a partial 5HT1 and 5HT2 receptor agonist, m-CPP binds with high affinity to 5HT1A , 5HT1D , 5HT2A , 5HT2C , and 5HT3 receptors, and has particularly high affinity for 5HT2C receptors [45–47]. 5HT2C receptors are localized to brain regions including the cortex and caudate and have been implicated in mediating aspects of mood, anxiety, appetite, behavior (including sexual activity), and neuroendocrine function [48,49]. Individuals with PG as compared with

controls were more likely to report a euphoric effect or ‘‘high’’ following m-CPP administration, a finding which has been described in other individuals with disorders or behaviors characterized by impaired impulse control—e.g., antisocial personality disorder [50], borderline personality disorder [51], trichotrillomania [52], and alcohol abuse/dependence [53]. In addition, the group of individuals with PG as compared with the controls exhibited an increase in prolactin levels following m-CPP administration, and greater prolactin increases correlated with increasing gambling severity [44]. 3.

Genetic Studies

Genetic studies support the notion that 5HT systems might be involved in mediating the pathophysiology of PG [24,54,55]. One report did not find a statistically significant association between PG and allelic variants of the tryptophan 2,3-dioxygenase gene, whose gene product regulates 5HT metabolism [54]. A variant of the 5HT transporter (5HTT) promoter region [56] has been associated with altered protein expression [57] and was previously implicated in anxiety [57] and depression [58]. Specifically, individuals with at least one copy of the short variant, associated with decreased protein levels, have been found to have higher measures of anxiety or depression [57,58]. An increased association between the short (less functional) variant and PG in the group of males but not females studied has been reported, with increasing association observed with increasing severity of PG [59]. These findings further support a role for 5HT dysregulation in PG, and suggest the direct target of 5HT reuptake inhibitors (SRIs), drugs with apparent efficacy in the treatment of PG (see below, Sec. V.C.1), might be differentially regulated in certain groups with PG. Further studies are warranted to replicate and extend these findings. 4.

Monoamine Oxidase Studies

Additional support for a role for 5HT in PG comes from studies of monoamine oxidase (MAO) function. The MAOs, subtypes MAOA and MAOB , are enzymes responsible for metabolizing 5HT, norepinephrine (NE), and dopamine (DA) [60]. Peripheral MAO derived from platelets is of the MAOB subtype and has been suggested to be an indicator of 5HT function [61,62], although MAOB also binds with high affinity to and catabolizes DA [60]. Low levels of platelet MAO activity have been found in association with impulsive behaviors (e.g., suicidality and alcohol


abuse) [63,64], high levels of sensation seeking [65–67], and disorders involving impaired impulse control, including eating disorders [68]. Low platelet MAO activity has also been observed in males with PG, although no clear pattern of a relationship between MAO levels and measures of sensation seeking emerged [69,70]. Additionally, an association between an MAOA gene polymorphism and PG in males has been reported [71]. B.

Dopamine Systems

1.


The neurochemical dopamine has been widely implicated in mediating rewarding and reinforcing behaviors. In particular, the mesocorticolimbic dopamine pathway, extending from the ventral tegmental area in the midbrain to the nucleus accumbens in the ventral striatum with additional neuronal connections to cortical and subcortical brain areas, is thought to underlie many aspects of the initiation and maintenance of selfadministration of drugs with addictive potential [72– 74]. A role for dopamine in the rewarding and reinforcing aspects of PG has been proposed [44,75]. One study consistent with such a relationship, published by Bergh et al. [76], reported decreased levels of ceberospinal fluid levels of dopamine and elevated ceberospinal fluid levels of the dopamine metabolites 3,4dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) in males with PG. The authors concluded these findings to be consistent with an increased rate of dopamine neurotransmission, although more recently the same group did not find decreased HVA levels when correcting for CSF flow rate [42]. A separate study investigated peripheral levels of DA under gambling conditions [77]. Plasma levels of dopamine were measured when playing Pachinko, and following a winning streak or machine payout described as a ‘‘Fever,’’ six males who were regular Pachinko players were found to have elevated levels of DA. It was suggested that the DA changes may be related to the motivational processes underlying repeated Pachinko playing. 2.

Neuroimaging Studies

One study investigated the role of the mesocorticolimbic dopamine system in video tank game in which participants were paid increasing amounts of money

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depending upon the skill level reached [78]. Positron emission tomography (PET) studies using 11 C-labeled raclopride, a ligand with high affinity for D2 -like dopamine receptors (D2Rs), found decreased levels of striatal binding in eight male subjects playing the tank videogame as compared to when they viewed a gray screen image [78]. The authors concluded the observed 13% reduction in 11 C-raclopride signal during the gaming condition is consistent with at least a twofold increase in levels of extracellular dopamine [78]. As the game involved increasing monetary reward associated with each skill level reached during the video game, the paradigm is similar but not identical to actual gambling. Another gambling-related study of healthy subjects involved a paradigm in which subjects viewed a spinner which would ultimately land on one of three varying, seemingly random outcomes, each associated with a specific monetary reward or punishment (79). As assessed by blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), individuals exhibited changes in brain activity in specific brain circuitry (e.g., in DA pathways originating in the ventral tegmental area and projecting to the nucleus accumbens, orbitofrontal cortex, amygdala, sublenticular extended amygdala, and hypothalamus) in anticipation of and response to rewarding and punishing outcomes [79]. These findings suggest similar brain circuitry as being involved in processing monetary rewards and punishments as are activated in response to cocaine [80]. Additionally, preliminary findings suggest abnormal function of similar limbic and cortical brain regions as mediating gambling urges in subjects with PG to those involved in cocaine cravings in subjects with cocaine dependence [81,82]. Together, these findings further support a relationship between the SUDs and PG, perhaps as mediated by abnormalities in functioning of neural pathways involved in the assessment of the risks of potential reward and punishment associated with specific behaviors [83]. An independent study investigated for specific dopamine and 5HT abnormalities in individuals with PG [84]. Using PET, the researchers found decreased striatal binding in PG subjects of 11 C-n-methylspiperone, a ligand with high affinity for D2Rs and 5HT2A and 5HT2C receptors [85]. The striatal signal, corresponding to D2R-receptor occupancy, could be explained by multiple, nonmutually exclusive possibilities including decreased numbers of available D2Rs,

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decreased affinity of D2Rs for the tracer, or increased synaptic concentrations of dopamine. 3.

Genetics Studies

Genetic studies also suggest a role for dopamine systems in PG. A study was performed investigating the D2 A1 allelic variant of the D2R, an allele previously reported by the same research group to be implicated in multiple compulsive/addictive behaviors such as cocaine and other drug abuse, compulsive eating, and smoking [86,87]. In a group of 171 Caucasians with PG, 50.9% carried the D2 A1 allele as compared with 25.9% of the control group (odds ratio ½OR ¼ 2:96; P < 0000001) [88]. Gambling severity was also found to correlate with an increased likelihood of carrying the D2 A1 allele, and the group of individuals without compared to those with a history of a major depressive episode were more likely to carry the D2 A1 allele [88]. This latter finding suggests differences in underlying motivations for gambling and comorbidity may be important factors in relation to the genetics of PG. The authors have postulated a reward deficiency theory based on their findings [86,87], although additional studies appear warranted to more precisely identify specific genetic factors contributing to the pathophysiology of PG and related disorders. Associations of polymorphic variants of the D1 , D3 , and D4 dopamine receptors with PG have also been explored [54,89,90]. The frequency of the Dde I allele of the D1 dopamine receptor (D1R) has been reported to be significantly higher than controls in each of three groups: pathological gamblers, tobacco smokers, and Tourette’s syndrome probands [89]. A negative association for heterozygosity at the Dde I polymorphism was observed for all three disease groups. Given the roles of the D1R and D2R in modulating rewarding/ reinforcing behaviors [91], the authors proposed heterosis as an reason for the distribution of the genetic variants of the D2R and D1R in PG [90]. Heterosis, with regard to populations, refers to a situation where the progeny (hybrid) has a significantly greater effect on phenotype than either parental strain (e.g., certain hybrid strains of corn exhibiting increased vigor) [90]. Allelic variants of the dopamine D4 receptor (D4R) have been described which differ in the number of 48base-pair (BP) nucleotide repeats and generate proteins with functional differences, a finding which lends support to the idea that the allelic variants might contribute directly to differences in D4R function and human behavior [92]. These allelic variants have been implicated in some studies of novelty-seeking behavior

[93,94] but not others [95–98]. One group reported a significant positive association between PG and the longest allele of the D4R (D7), with a stronger association observed in the female group and a nonsignificant relationship seen in the male group [99]. An independent group found no significant association between the D7 allele carriers and PG, although a significant positive association was found with regard to the number of individuals with a high number of 48-BP repeats [5–8] and PG [90]. The second group also reported an increase in heterozygosity at the D4R allele in association with PG, invoking the notion of heterosis. Discrepancies in the findings of the two groups might be explained by genetic heterogeneity, or by the fact that the genetic contributions from these loci might be only modest or additive. Comings et al also described a decrease in heterozygosity of the Msc I allele of the D3 dopamine receptor individually in groups with PG or Tourette’s syndrome [54]. Together, the findings from association studies support a potential role for dopamine receptor allelic variants in PG; however, further studies are warranted to replicate the findings, identify specific functional correlates to the genetic findings, and clarify the relationship to the underlying pathophysiology of PG. C.

Norepinephrine Systems

1.


Norepinephrine has been hypothesized as mediating aspects of arousal, attention and sensation seeking in individuals with PG [44,100–102]. In support of this notion, male subjects with PG were found to have higher cerebrospinal fluid levels of the norepinephrine metabolite 4-hydroxy-3-methoxyphenyl glycol (HMPG) and higher urinary measures of norepinephrine [100]. Scores of extraversion were found to correlate positively and significantly with cerebrospinal fluid and plasma levels of HMPG, urinary measures of vanilylmandelic acid (VMA), and the sum of urinary levels of norepinephrine and norepinephrine metabolites [101]. Increased cerebrospinal fluid levels of NE and HMPG were also found in an independent group of males with PG [76], although a subsequent report from the same research team reported findings of decreased HMPG in males with PG when correcting for cerebrospinal fluid flow [42]. 2.

Neurochemical Studies and Stress

A study of male Pachinko players found changes in norepinephrine during gambling [77]. Blood levels of


norepinephrine were found to increase from baseline over time during Pachinko play, with statistically significant changes noted at the onset and end of the machine payout period. Levels of norepinephrine remained significantly elevated 30 min following the end of payout periods. Alterations in heart rate, a physiological measurement associated with arousal and noradrenergic activity, was also observed, with peak heart rate measured at the onset of payout. Changes in immune function, including alterations in levels of T-cells and natural killer cells, were noted concurrently [77]. Consistent with these findings, two independent groups found physiological changes in association with gambling. Meyer et al. [103] described elevated heart rate and salivary measures of cortisol persisting over a several hour period of gambling in males who gambled regularly on casino blackjack. Schmitt et al. [104] described higher epinephrine and cortisol levels and blood pressure differences approaching statistical significance in Aboriginal individuals on days in which gambling behavior was concentrated. Together, these findings suggest that alteration in norepinephrine and related stress-response pathways might explain some of the pathophysiology associated with PG [105]. D.

Opioid Systems

A role for endogenous opioids in PG has been investigated given: (1) their mediation of levels of pleasure; (2) modulation of mesocorticolimbic dopamine activity via gamma-aminobutyric acid (GABA) input to dopamine neurons in the VTA; and (3) efficacy of the mopioid receptor antagonist naltrexone in targeting urges/cravings in alcohol and opioid dependence [106–109]. Blood levels of beta-endorphins, endogenous agonists for the -opioid receptor, were found to become elevated during Pachinko play, peaking during the period of machine payout [77]. Recent pharmacological investigations into the potential of naltrexone in the treatment of PG further substantiate a role for opioid systems in PG (see below, Sec. V.C.2) [110–113]. E.

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past-year high-action forms of gambling (e.g., casino cards, lottery, or gambling machine) [114]. No statistically significant differences were observed in the two groups of males with regard to measures of low action forms of gambling or in female MZ versus DZ groups with regard to past-year participation in either high- or low-action forms gambling [114]. The VietNam Era Twin Registery has served as the basis for several additional investigations into the heretibility of gambling disorders in a large group of male MZ (n ¼ 1869 pairs) and DZ (n ¼ 1490 pairs) twins [23,24,115]. The authors found that faimilial factors accounted for 50% of the liability to report one or two symptoms of PG, and that familial factors (genetic and/or environmental) explained 60% of the liability for reporting three or four symptoms [24,115]. The results are comparable to findings derived from the same sample for the heritability of drug use disorders, with 34% and 28% of the variance accounted for by genetic and shared environmental factors, respectively [116]. Additional analyses on the same dataset suggest significant shared proportion of genetic factors, accounting for 12–20% of the variance, contributing to the development of gambling and alcohol use problems [23]. These estimates are similar to those for the shared genetic contributions for marijuana and alcohol use disorders, and less than those for shared genetic contributions for nicotine and alcohol use disorders [23]. Additional analyses suggest that the high rates of comorbidity for PG, antisocial personality disorder, and conduct disorder to be determined largely by genetic factors, with between 61% and 86% of the variance for these behaviors to be determined by shared genetic factors [24]. Together, these findings support significant roles for genetic and common and unique environmental factors in the development of PG, and suggest both common and unique elements for the development of PG and other psychiatric disorders like alcohol dependence, conduct disorder and antisocial personality disorder.

V.

TREATMENT

A.

Self-Help

Genetic Studies

Historically, twin studies, allowing for comparison of rates of disorders in monozygotic (MZ) and dizygotic (DZ) twins, have been informative in investigating for genetic influences. Twin studies investigating disordered gambling behaviors have recently been published [23,24,114,115]. One study observed significantly greater rates of similarities in male MZ as compared with male DZ twins with regard to participation in

Arguably the most widespread form of help over the past several decades for individuals with problem or pathological gambling has been Gamblers Anonymous (GA). GA, founded in 1957, is based on the 12-step principles originally developed for Alcoholics Anonymous and currently has chapters throughout the world. Although reported to be effec-

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tive and life-saving for many individuals, GA’s efficacy in general has not been systematically explored in detail. One study reported that only 8% of patients entering GA remained at 1 year, with the majority leaving after one or two meetings [117], findings not dissimilar from structured investigations of other selfhelp programs [118]. Further information regarding GA can be obtained by telephone at 1-800-266-1908 or on the internet at http://www.gamblersanonymous.org. B.

Behavioral Treatments

Although behavioral treatments for PG have been explored for many decades with varying degrees of success, few well-controlled studies of significant magnitude have been performed to date [119]. One group has reported positive outcomes using imaginal desensitization, with individuals randomly assigned to that treatment reporting less gambling and fewer urges to gamble at 1 month and up to 9 years after treatment as compared with individuals assigned to aversion therapy [120–122]. Given the relatively small sample size (20 subjects) and inpatient population used in the study, further investigations are warranted to confirm and extend these results. Several groups have been examining the applicability of cognitive behavioral therapy to PG [119]. Gambling-related interventions focusing on skills training, cognitive restructuring, problem solving, and relapse prevention were reported to be helpful in an initial study of three subjects, and a more extensive trial found the active treatment superior to wait-list control in reducing gambling and increasing perceptions of control over the behavior [123,124]. In a majority of cases, gains were maintained one year after treatment in the actively treated group. Although promising, the study included only a total of 29 subjects. Currently, a large scale controlled trial of cognitive behavioral therapy for PG is being conducted with promising initial findings [119]. C.

Pharmacotherapies

3.

SSRIs

Given the efficacy of serotonin reuptake inhibitors (SRIs) in targeting obsessive-compulsive behaviors in obsessive compulsive disorder [125] and the data supporting 5HT dysregulation in PG (see above, Secs. IV.A.1–4), trials of SRIs in the treatment of individuals with PG have been undertaken. A double-blind, pla-

cebo-controlled, crossover case study of clomipramine was described [126]. Although only minimal improvement was observed after 10 weeks of placebo treatment, gambling behavior was discontinued at week 3 with abstinence from gambling persisting at 38 weeks following initiation of active drug at 25 mg/day with an increase up to 175 mg/day [126]. Increased irritability observed during treatment was effectively treated with a temporary decrease in dose. As selective SRIs (SSRIs) are often better tolerated than nonselective SRIs, many recent studies have examined the tolerability and efficacy of SSRIs in the treatment of PG [112]. A single-blind crossover study of the SSRI fluvoxamine has been reported [127]. Sixteen subjects entered the 16-week trial (8-week placebo lead-in, 8-week active), and seven of 10 completers were determined to be responders by scores on the Clinical Global Impression score for gambling severity (PG-CGI) and PG modification of the Yale-Brown Obsessive-Compulsive Scale (PG-YBOCS) [127]. The medication was well tolerated, and the average dose for completers was 220 mg/day at endpoint, with responders receiving a slightly lower average dose of 207 mg/day. Two of the three completers who were deemed nonresponders had histories of cyclothymia, suggesting that individuals with comorbid cycling mood disorders may respond preferentially to alternative pharmacotherapies (see below, Sec. V.C.3). More recently, randomized, double-blind, placebocontrolled studies have been performed for two SSRIs: fluvoxamine and paroxetine (Table 2) [112]. Hollander and colleagues [128] have recently performed a randomized double-blind, placebo-controlled 16-week crossover study of fluvoxamine in the treatment of PG. Fifteen subjects with PG were enrolled, and 10 participants (all male) completed the study. Study drug dosing was initiated at 50 mg/day, increased incrementally to 150 mg/day, and adjusted based on clinical response and drug tolerance, with a maximum of 250 mg/day and a minimum of 100 mg/day. Mean endpoint dose of fluvoxamine was 195 50 mg=day. Adverse effects were minimal, and active drug was found to be superior to placebo, as measured by PG-CGI and PGYBOCS scores, in reducing gambling and related symptomatology. However, there was a significant placebo response observed. Both groups (those receiving active medication and those receiving placebo) showed improvement during the first 8 weeks of the study regardless of group assignment, and the most significant difference in response was observed at the end of the second 8-week block. These findings suggest acute trials of longer duration than 8 weeks might be impor-

Sample size

Duration

89 Subjects enrolled, 12 weeks with 1-week placebo lead-in 45 completed (20 naltrexone, 25 placebo)

8 weeks with 1-week placebo lead-in

188

Naltrexone group significantly improved as compared with placebo as determined by CGI, G-SAS; risk of LFT abnormalities with analgesics

7 of 10 Completers determined to be responders by PG-CGI and PGYBOCS scores; fluvoxamine superior to placebo, particularly at end of 16 weeks of treatment Paroxetine group significantly improved as compared with placebo as determined by CGI, G-SAS

195>

51

Outcome

Dose, mg/day

Average

Legend: PG-CGI ¼ Clinical Global Impression Scale for Gambling Behavior; PG-YBOCS ¼ Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling; CGI ¼ Clinical Global Impression Scale; G-SAS ¼ Gambling Symptom Assessment Scale; LFT ¼ Liver Function Test.

Naltrexone (ReVia)

41 Subjects (20 paroxetine, 21 placebo)

Fluovoxamine 15 Subjects enrolled, 16 weeks (crossover design, (Luvox 10 completed 8 weeks each of active/ placebo) with initial 1-week (10 male) placebo lead-in

Drug

Kim and Grant Paroxetine 2000 (Paxil)

Hollander, et al. 2000

Reference

Opioid Kim et al. antagonists 2001

SSRIs

Category

Table 2 Major Placebo-Controlled, Double-Blind Drug Trials in the Treatment of PG

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tant in distinguishing responses to active drug as compared with placebo, and indicate that open-label trials, such as those reported for fluoxetine and citalopram, should be interpreted cautiously in this patient population [129,130]. A longer-term, placebo-controlled trial of fluvoxamine in the treatment of PG has been performed by an independent group [131]. Patients were treated for 6 months with placebo or fluvoxamine at 200 mg/day, and outcome was measured by quantification of time and money spent on gambling. Although the authors found no statistically significant differences in response rates to placebo as compared with active drug for the overall sample, they described fluvoxamine as being superior to placebo for the male and younger-age pathological gamblers. However, the large proportion of individuals for whom follow-up was not available significantly limits the interpretation of the data, which suggests that long-term compliance with drug treatment may be a concern for the PG patient population. The findings of a recent parallel-group, 8-week (following 1 week single-blind placebo lead-in), flexible dosage, randomized, placebo-controlled, double-blind trial of paroxetine are the basis of the first multicenter drug treatment trial for individuals with PG [112]. Dosing, initiated at 20 mg/day, was adjusted up to 60 mg/day as clinically indicated. Forty-one patients with PG completed the study (20 paroxetine, 21 placebo), with a significant proportion dropping out of treatment. Adverse effects were mild in nature (mainly headache, fatigue, and dry mouth) and were observed with greater frequency in the paroxetine-treated group (2.3 treatment-emergent symptoms per patient in the paroxetine group as compared with 1.2 in the placebo). Outcome as measured by scores on the patient- and clinician-rated CGI and the Gambling Symptom Assessment Scale (G-SAS) showed paroxetine to be superior to placebo. Together, the initial findings from studies of SSRIs suggest that they are well tolerated and efficacious drugs in the treatment of PG. Larger-scale (e.g., multicenter), placebo-controlled trials of these drugs are necessary to confirm and extend these initial results and better define the short- and long-term efficacies and tolerabilities of the SSRIs in specific groups of individuals with PG, particularly those with co-occurring disorders. 2.

Opioid Anatagonists

Naltrexone, a mu-opioid antagonist, has FDA approval for the treatment of alcohol dependence

and opiate dependence. Case reports of individuals with PG treated with naltrexone suggested a role for the drug in PG [110,111]. Recently, a randomized, flexible-dosage, double-blind, placebo-controlled study of naltrexone was performed [113]. The trial was of 12 weeks duration (1 week placebo lead-in followed by an 11-week treatment phase), and 89 subjects were enrolled and 45 completed week 6 or later (20 naltrexone, 25 placebo). Average end-of-study dosages of naltrexone were 187:50 96:45 mg=day and 243:18 31:98 mg=day for the active drug and placebo groups, respectively. Approximately onequarter of the group receiving naltrexone experienced increased liver function enzyme elevations, a finding that appeared most frequently in individuals taking concurrent nonsteroidal anti-inflammatory drugs. Statistically significant improvement as measured by the patient-rated and clinician-rated CGIs, and the GSAS was observed in the active drug as compared with the placebo group. Although encouraging, the clinical potential of naltrexone in the treatment of PG requires further study to determine better the long-term clinical efficacy and tolerability given the short-term nature of the study, high doses of naltrexone used, and increased rate of liver function abnormalities observed in the present study. 3.

Mood Stabilizers

Given that mood lability is not infrequently observed in individuals with PG and that a history of cyclothymia may be related to poor outcome with SSRI treatment (see above), the use of mood stabilizers in the treatment of individuals with PG has been described. Lithium, a salt with mood-stabilizing properties believed to modulate 5HT systems [132], has been examined in the treatment of PG [133]. Open-label treatment of three males with PG and comorbid cycling mood disorders with lithium at daily doses up to 1800 mg/day was found to be at least partially effective in controlling gambling, cycling mood, hypomania/mania, and risk-taking behaviors. Many treatment-related factors (specific duration of treatment, structured outcome measures) were not described, and larger controlled studies are being performed to investigate the efficacy and tolerability of lithium in the treatment of individuals with PG and cycling mood disorders [134,135]. A placebo-controlled, double-blind case report trial of carbemazepine in the treatment of a male with PG has been reported [136]. Although no improvement was noted in gambling behavior over a 12-week


placebo phase, a decease in gambling behavior was observed 2 weeks into active treatment with carbemazepine, with gains maintained at 30 months. The drug was introduced at 200 mg/day and increased to 600 mg/day (reaching blood levels of 4.8–9:5 g/mL). Additional larger studies are needed to confirm these findings. Studies of valproic acid in the treatment of PG are also under way [134,135]. 4.

Atypical Antipsychotics

Limited data are available on the tolerability and efficacy of antipsychotic drugs in the treatment of individuals with PG. One open-label case report found olanzapine administration in conjunction with behavioral intervention targeting gambling behaviors to be effective in decreasing gambling and thought disorder symptoms in an individual with comorbid schizophrenia and PG [137]. However, a larger, placebocontrolled, double-blind study of olanzapine in the treatment of inpatients with PG did not find a difference in outcome in the groups treated with active drug or placebo [138]. D.

Future Directions

Although treatment trials to date are limited by small sample sizes and often relatively short durations, encouraging reports of behavioral and pharmacological treatments are emerging. Future efforts should be directed at determining: (1) which treatment strategies will be efficacious and well tolerated over the long term; (2) whether interventions combining behavioral and pharmacological elements will be more effective than either alone; (3) if specific groups of individuals with PG (e.g., those with comorbid disorders, specific age groups, or other typologies [139,140]) might respond preferentially to specific treatment strategies; and (4) whether gambling-specific interventions (e.g., debt restructuring) might represent important therapeutic components. VI.

CONCLUSIONS

As described above (Secs. V.A–D), well-tested, effective, and well-tolerated treatment strategies appear to be emerging. Many areas have professional clinicians and self-help programs available. Currently, suggested interventions for general practitioners or other health care providers include: (1) routine screening for problem gambling and PG; (2) sensitive broaching with the patient of a suspected gambling problem; (3) moti-

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vating the patient to contact a self-help group (e.g., GA: 1-800-266-1908 or http://www.gamblersanonymous.org), a local gambling treatment program, and/ or a gambling helpline (e.g., National Council on Problem Gambling helpline: 1-800-522-4700 or http:// www.ncpgambling.org) to facilitate engagement in locally available gambling treatment; and (4) following up with the patient and gambling treatment facility regarding the status of the patient’s gambling problem [10]. The availability of a brief questionnaire for problem gambling and PG, like the CAGE for alcoholism [141], will be helpful in the screening process, and such instruments are under development, testing, and use [105,142,143]. Additionally, help for family members affected by a relative’s gambling problems is available (e.g., Gam-Anon: http://gamblersanonymous.org/ gamanon.html or 1-718-352-1671), and these interventions can be helpful even in the absence of recovery of the individual with PG. As the availability of legalized gambling has increased in many areas over the past decade, so have the prevalence rates of problem gambling and PG [9]. As such, there is a growing need for the identification of efficacious, well-tolerated treatments for individuals with gambling disorders. As effective treatments emerge, it will become increasingly important to develop, enact and modify education and prevention strategies in the areas of problem gambling and PG [144]. ACKNOWLEDGMENTS Supported in part by NIDA grant K12-DA00366, the National Alliance for Research on Schizophrenia and Depression, the National Center for Responsible Gaming, and Women’s Health Research at Yale. REFERENCES 1. 2.

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47 Neurobiology of Suicide LEO SHER and J. JOHN MANN Columbia University, New York, New York, U.S.A.

I.

disorders, present in 60% of cases [5–9]. Suicide is also associated with schizophrenia, cluster B type personality disorders, alcoholism, substance abuse, Huntington’s disease, and epilepsy [10–22]. The lifetime mortality due to suicide is estimated at 20% for bipolar disorder, 15% for unipolar depression, 10–17% for alcoholism, and 5–10% for personality disorders [10–13]. These numbers apply to sicker patients associated with teaching hospitals. Bostwick and Pankratz [23] recently reported that for affective disorder patients hospitalized without specification of suicidality, the lifetime risk of suicide was 4.0% compared with 0:5% for the nonaffectively ill population. Murphy and Wetzel [24] also calculated a lower suicide rate in alcoholism in general. Nevertheless, the lifetime rates of suicide attempts and suicide are still much higher in these disorders than in the general population. Most patients with psychiatric disorders do not commit suicide, indicating that other factors influence risk. Suicide attempters have a tendency to make more than one suicide attempt, sometimes with increasing lethality in succeeding attempts [25]. At the same time, other persons with the same level of objective severity of major depression may never make a suicide attempt, suggesting that some individuals have a predisposition to suicidal behavior. Malone et al. [25] reported that most vulnerable individuals with a

STRESS-DIATHESIS MODEL OF SUICIDAL BEHAVIOR

There are approximately 30,000 deaths per year by suicide in the United States [1,2]. In 1999, suicide was the eighth leading cause of death, ranking ahead of AIDS and liver and kidney disease [1]. Despite the decrease in the death rates from leading causes such as myocardial infarction and AIDS, rates of suicide have remained stubbornly high. Suicide is a very extreme type of behavior. We have proposed a stress-diathesis model to explain what is different in people who are at risk for suicide compared to people who are relatively protected [3]. Over the past two decades, there has been increasing evidence that part of diathesis for suicidal behavior has a biological component. The study of neurobiology of suicide can yield new understanding of the diathesis or what contributes to vulnerability for suicide, may eventually assist in improved screening of high-risk patients and permit development of new treatment modalities to prevent suicide. Thus, the neurobiologic studies of risk for suicide, may not only potentially improve identification of patients at high risk for suicide, but also suggest new approaches for therapeutic intervention. Suicide is usually a complication of a psychiatric disorder, a stressor that is present in > 90% of suicides [1–4]. Suicide is most commonly associated with mood 701

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mood disorder who make a suicide attempt, do so early in the course of illness. Mann [3] has suggested that suicide is not simply a logical response to extreme stress, and proposed a stress-diathesis model of suicidal behavior. Typical stressors associated with suicidal acts include the psychiatric disorder, and often also acute use of alcohol or sedatives that may disinhibit patients, sometimes an acute medical illness especially affecting the CNS, and finally adverse life events. Mann [3] suggests that the diathesis or predisposition to suicidal behavior is a key element that differentiates psychiatric patients who are at high risk versus those at lower risk. Although the objective severity of the psychiatric illness does not assist greatly in distinguishing patients at high risk for suicide attempt or suicide from those who are at low risk, suicide attempters react differently to the same objectively determined level of severity of depression and life events. Suicide attempters experience more subjective depression, hopelessness, and suicidal ideation than psychiatric controls. The vulnerability or diathesis for suicidal behavior is influenced by genetic factors [26–28], parenting [29]; medical illness, especially affecting the brain, e.g., epilepsy [20]; migraine [30,31]; Huntington’s disease [21,22]; alcoholism and substance abuse [14–19]; and cholesterol level [32–39]. Some of these factors may be interrelated. Diathesis (vulnerability) determines how an individual reacts to a given stressor, and depends on factors that mold personality such as environmental and genetic factors, childhood experiences, etc. The neurobiologic findings can represent a combination of state- and trait-related effects [40]. The trait-related effects may represent the diathesis, whereas the statedependent effects may reflect acute psychiatric conditions or stressors.

II.

GENETIC STUDIES OF SUICIDAL BEHAVIOR

It has long been recognized that psychiatric disorders run in families. In 1621 Robert Burton wrote in his book The Anatomy of Melancholy that the ‘‘inbred cause of melancholy is our temperature, in whole or part, which we receive from our parent,’’ and ‘‘such as the temperature of the father is, such is the son’s, and look what disease the father had when he begot him, his son will have after him’’ [41]. Genetic factors also play an important role in the diathesis for suicidal behavior. Evidence that suicidal behavior has a genetic component comes from differ-

ent types of studies including studies of families, twin and adoption studies, and molecular genetic research. Genetic studies demonstrate that suicidal behavior has a genetic component that is independent of the genetic component of major psychiatric disorders [26–28,42– 44]. A.

Family History

Suicidal behavior can be transmitted familially by learning, by genetic transmission, by environmental influences, etc. A number of studies suggest that individuals at risk for suicidal behavior have a higher than statistically expected family history of suicide. Murphy and Wetzel [45] in their review of existing literature noted that 6–8% of those who attempted suicide have a family history of suicide. Roy [46] also reviewed the literature and found that a family history of suicide was more frequent in the families of suicide victims than controls. Egeland and Sussex [47] reported on the suicide data obtained from the study of affective disorders among the Older Order Amish community in southeastern Pennsylvania. Twenty-six people committed suicide in this community over the 100 years from 1880 to 1980. Almost three-quarters of the 26 suicide victims were clustered in four family pedigrees, each of which contained a heavy loading for affective disorders and suicide. The converse was not true: there were other family pedigrees with an equally heavy loading for affective disorders but without a single suicide in 100 years. A familial loading for affective disorders was not itself a sufficient predictor for suicide. Some examples will illustrate the point. Shafii et al. [48] performed psychological autopsies on 20 adolescent suicide victims in Louisville, KY. The authors reported that significantly more of the suicide victims as compared to the controls had a family history of suicide. Linkowski et al. [49] found that 123 of 713 depressed inpatients (17%) had a first- or seconddegree relative who had committed suicide. A family history of suicide increased the probablility of a suicide attempt among the depressed patient, especially the risk for a violent suicide attempt. Brent et al. [44] conducted a family study of adolescent suicide victims (suicide probands) and community control probands (controls). The rate of suicide attempts was increased in the first-degree relatives of suicide probands compared with the relatives of controls, even after adjusting for differences in rates of probands and familial axis I and II disorders. The

Neurobiology of Suicide

authors concluded that liability to suicidal behavior might be familially transmitted as a trait independent of axis I and II disorders. B.

Twin Studies

Twin studies help to address the question of whether suicidal behavior may be genetically transmitted. If suicide is a genetically transmitted behavior, then concordance for suicide should be greater among identical twins (monozygotic, MZ) than fraternal (dizygotic, DZ) twins. Twin studies support the presence of a substantial genetic component in suicidal behavior. Roy [43] reported a much higher concordance rate for MZ twins than for DZ twins (13.2% vs. 0.7%). Roy et al. [27] also found a higher rate of concordance for suicide attempts in MZ compared to DZ twins surviving the cotwin suicide. Roy et al. [27] reported that the rate of concordance for attempted suicide (38%) was higher than for completed suicide (13.2%). This indicates that both attempted and completed suicide are heritable, and that they are both components of the phenotype of suicidal behavior. Statham et al. [50] reported a 23.1 concordance rate for serious suicide attempt in MZ twins, over 17-fold greater risk than in the total sample. The authors reported that the heritability for serious suicide attempts was 55%. Twin studies do not rule out effects of a common environment, and do not explain the basis of the heritability such as psychopathology. C.

Adoption Studies

Adoption studies provide the strongest evidence that there may be a genetic factor for suicide and that it is independent of the genetic transmission of major psychiatric disorders. Schulsinger et al. [28] reported results from an adoption study conducted in Denmark. A screening of the adoption register in Copenhagen for causes of death revealed that 57 adoptees had committed suicide. They were matched with 57 adopted controls for age, sex, social class of the adopting parents, and time spent both with their biological relatives and in institutions before being adopted. Twelve of the 269 biological relatives (4.5%) of the adopted suicides had themselves committed suicide, compared with only 2 of the 269 biological relatives (0.7%) of the adopted controls. This difference was statistically significant even allowing for the transmission of major psychiatric illnesses. None of the adopting relatives of either the suicide

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adoptee group or the control adoptee group had committed suicide. The examination of the type of affective disorder suffered by the suicide victim is of particular interest. Wender et al. [51] reported that adoptee suicide victims with the diagnosis of ‘‘affect reaction’’ had significantly more biological relatives who had committed suicide than controls. The diagnosis of affect reaction has been used in Denmark to describe a patient who had mood symptoms accompanying a situational crisis, triggering what may have been an impulsive suicide attempt. Perhaps part of the genetic predisposition to suicide may be related to a tendency for impulsive behavior. D.

Molecular Genetic Research

Molecular genetic analyses attempt to identify the specific alleles which may be responsible for the observed familiality and heritability of phenotype. Two techniques that are usually used to identify genes for complex diseases such as psychiatric disorders are positional cloning (linkage) and case/control association methods using candidate gene markers [52–54]. Both types of study have advantages and disadvantages. Positional cloning is systematic and allows coverage of the whole genome but is not powerful, whereas association methods are powerful but not systematic. In positional cloning the coinheritance of a disorder and a DNA marker is studied in large families or related pairs. Another key approach is linkage disequilibrium (marker/disease gene association) in populations. With most clinical samples, linkage studies are frequently not very powerful for common complex diseases in which no single gene accounts for much of the variance in vulnerability. However, case/control association methods work on a different principle and do not suffer the same vulnerability. All humans have considerable genetic variation or polymorphism. A gene is called polymorphic if no single form of the gene has an abundance of > 99% in a population [54]. Gene variants, including polymorphisms, are related to the development of diseases which are genetically influenced. Association studies search for correlations in the population between a DNA marker and a disorder. If persons with a disorder have an increased frequency of a specific allele, or genotype, it may mean that the gene contributes to vulnerability to the disease. The candidate gene approach is frequently used in association studies. When biological investigations have provided some clue as to the possible involvement of known genes, these genes may become candidates for

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studies. If a biochemical pathway leading to a mental disorder has been identified, proteins that participate in this pathway indicate candidate genes that may give results in association tests. Most candidate gene studies of suicidal behavior have involved the serotonergic system. Serotonergic neurons are located in the brainstem from where they project to virtually every part of the brain, often modulating neuronal responses to other neurotransmitters [55]. As a result of this widespread projection pattern, serotonin plays a key role in the regulation of many different functions and behaviors. Multiple lines of evidence suggest that major depression and suicidal behavior are independently related to abnormalities in serotonergic system [3,56–58]. There is a serotonergic abnormality that contributes to the diathesis or vulnerability to suicidal acts [3]. The risk for suicidal behavior, aggressive acts, alcoholism, and substance abuse appear to have in part a common underlying genetic or biological predisposition mediated by serotonergic activity [3]. Thus, genes related to serotonergic pathways became a focus of attention of genetic researchers studying mood disorders and suicidal behavior. 1.

TPH Gene

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis. Several candidate gene studies demonstrated an association between a polymorphism of the TPH gene and suicidal behavior, and there is one positive linkage study [59]. An association between a polymorphism in the TPH gene in intron 7, A779C, and suicidal behavior was first reported by Nielsen et al. [60]. The results of this study were replicated by Nielsen et al. [61] in a larger sample. The L allele (equivalent to the C allele) was found to be more common in the impulsive alcoholic criminal offenders who attempted suicide (LL 72%, UL 59%, and UU 31%). In serious or multiple suicide attempters, this finding was even more striking. Mann et al. [62] studied the distribution of the same polymorphism in 29 depressed attempters and 22 depressed nonattempters. The U allele was shown to be more common (41% vs. 20%) in attempters than in depressed nonattempters. Buresi et al. [63] investigated the prevalence of the A218C TPH polymorphism in a large sample of suicide attempters and healthy controls and found that rarer A (or U) allele was more common among the suicide attempters (46.4% vs. 35.7%, P ¼ :003). The

frequency of A allele was even higher in serious suicide attempters. These results were recently replicated by Persson [64] but not by Bellivier et al. [65], Kunugi et al. [66], or Ono et al. (67). Consistent with the results of Mann et al. [62], Buresi et al. [63], and Persson et al. [64], Manuck et al. [68], and Joensson et al. [69] found lower serotonergic activity to be asssociated with the U allele. Further studies are necessary to clarify the role of the TPH gene in the etiology of suicidal behavior. 2.

5-HTTLPR Allele in the Serotonin Transporter Gene

A 44–base pair deletion/insertion polymorphism in the 5 0 flanking regulatory region of the human 5HTT gene results in differential expression of 5HTT and serotonin reuptake in transformed lymphoblastoma cell lines [70]. The short allele (frequency 0.4 in Caucasians and 0.6 in some Asian populations) has reduced transcriptional efficiency, resulting in decreased 5HTT expression and 5HT reuptake and reduced 5HTT density in vivo in transformed lymphoblastoma cell lines [55]. The short form of the serotonin transporter promoter length repeat polymorphism (5HTTLPR) is associated with 40% fewer binding sites in homozygote (SS) and the heterozygote (SL) than the long form (LL). Mann et al. [58] hypothesized that fewer 5HTT sites on platelets of depressed patients, and fewer 5HTT sites in the prefrontal cortex of suicides, may be the consequence of an association of the short allele with suicide and major depression. In this study postmortem brain samples were genotyped for the 5HTTLPR polymorphism, and 5HTT binding was assayed. The 5HTTLPR was associated with major depression but not with suicide. However, the association was due to a difference in the rate of heterozygotes, and moreover, genotype was not associated with any difference in brain serotonin transporter binding. This finding indicates that the serotonergic transporter binding abnormalities abnormalities in the brain of suicide victims may be related to other genetic variants. Studies of the association of the 5HTTLPR and mood disorders, alcoholism, and certain personality traits have produced inconsistent results [71–74]. The differences in the number and function of the serotonin transporter may make a contribution to the development of certain psychiatric symptoms and personality traits, but additional are needed to determine whether other promoter alleles contribute to the etiopathogenesis of behavioral disorders.


3.

5-HT1B Gene

Several research groups have reported pathological aggressive behavior and increased alcohol and cocaine intake in 5HT1B receptor gene knockout mice [75–78]. This indicates that functional variants in the 5HT1B gene may contribute to human psychopathologies such as suicide, aggression, major depression, alcoholism, or substance abuse. However, Huang et al. [79] found no association of suicide, major depression, or pathological aggression with 5HT1B genotypes or allelic frequency for two identified polymorphisms in a postmortem study of the 5HT1B binding. The sample size was modest, and Huang et al. [79] could have missed an uncommon association. There was a suggestion of an association between alcoholism and lower 5HT1B binding that is consistent with reports of an association with a 5HT1B polymorphism [80,81]. 4.

5HT2A Gene

Zhang et al. [82] studied an association between the 102T/C polymorphism in the 5HT2A receptor gene and suicidal behavior and found a weak association of the TT genotype with suicide attempts in patients with mood disorders. However, Turecki et al. [83] found no association between suicide and the TT genotype. Moreover, Du et al. [84] found an association between suicidal ideations and the CC genotype. The role of 102T/C 5HT2A polymorphism in the etiology of suicidal behavior requires further investigation.

III.

IN VIVO BIOCHEMICAL STUDIES

5-Hydroxyindolacetic acid (5HIAA) is the major metabolite of serotonin [85]. A number of research groups studied cerebrospinal fluid (CSF) 5HIAA levels in the CSF of psychiatric patients [85–87]. About two-thirds of the studies that looked at suicide attempters with mood disorders compared with nonattempters with mood disorders found that suicide attempters have lower levels of CSF 5HIAA. However, about onethird of the studies do not confirm this. One of the factors that appears to determine whether or not CSF 5HIAA is low is the lethality or medical severity of the attempt. The more lethal the attempt, the lower the level of CSF 5HIAA [86]. Low CSF 5HIAA is also found in some, but not all, studies of suicide attempters with schizophrenia and personality disorders compared with patients who have the same diagnoses without a history of suicidal behavior [85,88–92]. Thus, it appears that the relationship between low CSF 5HIAA

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and suicide attempts is independent of the neurobiology of specific psychiatric disorders. CSF 5HIAA levels can predict future behavior. During the 12 months after hospital discharge, patients who had low levels of CSF 5HIAA had a higher rate of completed suicide than with patients who had higher levels of CSF 5HIAA [93]. Low CSF 5HIAA predicts future suicide attempts and suicide completion in mood disorders [93,94] and schizophrenia [88]. The prolactin response to fenfluramine is another index of serotonergic function [86,87]. Fenfluramine causes the release of serotonin and inhibits serotonin reuptake. A history of a highly lethal suicide attempt is associated with a blunted prolactin response to fenfluramine [95]. Patients with a history of a very lethal suicide attempt have a blunted prolactin response compared with individuals with major depression but no history of a ‘‘very lethal’’ suicide attempt [95], and, like low CSF 5HIAA, a blunted prolactin response to fenfluramine may be a biochemical trait. Both low CSF 5HIAA and a blunted prolactin response are related to severity of lifetime aggression [96,97]. The blunting of serotonergic function is independent of how long ago the suicide attempt occurred [95]. Serotonin is involved in a number of platelet functions [98–100]. Platelet 5HT2A receptor binding is increased in patients with suicidal behavior [98]. Upregulation of 5HT2A receptors on the platelets of suicide attempters correlates with the severity of the most recent suicide attempt [99,100]. In summary, three different indices of serotonergic function correlate with suicidal behavior in patients independent of psychiatric diagnosis: CSF 5HIAA, the prolactin response to fenfluramine, and platelet 5HT2A receptor binding. The results of these studies suggest that there is a link between genetics, serotonergic function, and suicidal behavior.

IV.

POSTMORTEM STUDIES

Interpretation of the results of postmortem studies is complicated by the presence of contradictory data, the variety of diagnoses included in samples of suicide victims, and methodological issues, such as postmortem delay [101]. For example, postmortem brain measurements of 5HT and 5HIAA are of limited value because of the rapid drop in the concentration of these compounds after death [102]. A number of research groups have found increased density of postsynaptic serotonin receptors in the cortex and, conversely, fewer postsynaptic serotonin

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transporter sites [103–107]. Decreased serotonin release is one possible cause of an increase in 5HT2A receptors in the prefrontal cortex of suicide victims. There may be some degree of regional specificity of the correlation between suicidal behavior, fewer serotonin transporter sites, and increased 5HT1A receptors [101]. Brain regions most involved in suicidal behavior are likely to be those areas where the changes in serotonin receptors are greatest in suicide victims. Considerable evidence suggests that there are alterations in serotonergic and noradrenergic receptor binding in membrane homogenates from the brain of suicide victims [101,106], independent of psychiatric diagnosis. This suggests that there is a biological substrate for the vulnerability to commit suicide. Alterations in binding to the serotonin transporter and the 5HT1A receptor were found primarily in the ventral and ventrolateral prefrontal cortex of suicide victims [101]. The ventral prefrontal cortex is of particular importance in relation to the risk for suicide. This brain region is involved in the executive function of inhibition, and injuries to this area of the brain can result in disinhibition [3]. The ventral prefrontal cortex may mediate an universal restraint mechanism that is suboptimal in some suicidal patients [3].

V.

LEVELS OF SERUM CHOLESTEROL AND SUICIDAL BEHAVIOR

Low levels of cholesterol or cholesterol-lowering treatments (particularly diet) increase the probability of suicidal behavior [37]. Cholesterol levels appear to have an effect on behavior involving aggression and suicidality. For example, a 12-year follow-up of a group of men found that that those with cholesterol levels < 160 mg/dL had a greater risk of suicide than those with levels of 160 mg/dL or higher [38]. Lindberg et al. [36] reported that a 7-year follow-up revealed that the relative risk for suicide was higher in men in the lowest cholesterol group compared to those in the highest cholesterol group. Kunugi et al. [39] found that cholesterol levels were significantly lower in suicide attempters when compared with both psychiatric controls and normal controls when sex, age, and psychiatric diagnosis were adjusted for. Kaplan et al. [34,35] reported evidence from nonhuman primates that a low-cholesterol diet was associated with more aggression and lower serotonergic function. It remains to be determined if such a mechanism operates in man and is the pathway whereby cholesterol influences suicide risk.

VI.

PSYCHOTROPIC MEDICATIONS AND SUICIDAL BEHAVIOR

Pharmacological treatments of suicidal behavior are based on two assumptions: (1) individuals with behavioral disorders such as depression, anxiety, impulsivity, alcohol or drug abuse or dependency, bipolar disorder, and schizophrenia, are at higher risk for suicidal behavior; and (2) there is a diathesis for suicidal acts related to biochemical alterations in the brain and psychotropic medications may correct these alterations. Based on these assumptions, psychotropic medications should reduce the symptoms that contribute to the expression of suicidal behavior. Mann and Kapur [108] and Baldessarini and Jamison [109] propose that some medications may prevent the onset of suicidal behaviors in at-risk persons. Another consideration is the toxicity of antidepressants after overdose. An American College of Neuropsychopharmacology Task Force suggested that ‘‘new generation low-toxicity antidepressants, including selective serotonin reuptake inhibitors, may carry a lower risk for suicide than older tricyclic antidepressants. This possible safety advantage may be a consequence of lower toxicity in the event of drug overdose’’ [110]. A considerable number of new and effective psychotropic medications have been developed over the past three decades. However, the reduction in suicide rate has been very little [3]. With the exception of lithium, which may be an effective treatment against suicide, little is known about specific contributions of moodaltering treatments to minimize mortality rates in persons with mood disorders. It has been suggested that long-term lithium treatment shows a protective effect against suicidal behavior in major affective disorder including both unipolar and bipolar disorders [111,112]. Isometsa et al. [113] found that only 10–14% of individuals who committed suicide in the context of major depression had received adequate doses of antidepressant treatment. Recently, Oquendo et al. [114] reported that a large majority of the depressed patients with a history of suicide attempts, who were at higher risk for future suicide and suicide attempts, received inadequate treatment. There may be a potential for more effective recognition of psychiatric conditions such as major depression, and the treatment of these conditions with adequate doses of medications in terms of reducing suicide rates. Rutz et al. [115] found that education of primary care physicians in the diagnosis and treatment of depression produced an increase in prescription rates of antidepressants and decrease in


suicide rates. Education at regular intervals has the potential for benefit in the diagnosis and treatment of depression, thereby lowering suicide rates. Rihmer et al. [116] studied the regional distribution of the suicide rate, rate of diagnosed depression, and prevalence of working physicians in Hungary. The authors found a strong and significant positive correlation between the rate of working physicians and the rate of diagnosed depression, and both parameters showed a strong and significant negative correlation with the suicide rate. The more physicians per 100,000 inhabitants, the better the recognition of depression and the lower the suicide rate. Isacsson et al. [117] reported the low rate of antidepressant use in suicide victims reflected insufficient diagnosis and treatment of depressive disorders. Marzuk et al. [118] reported similar data from a population of suicide victims in New York City. Eighty-four percent of these patients were not taking an antidepressant (or neuroleptic) medication at the time of suicide. More recently, Isacsson [119] reported that an increase in the use of antidepressants correlates with a substantially reduced a suicide rate in Sweden. Meltzer [120] reports that clozapine can reduce suicide by 80–85% in neuroleptic-resistant patients. More widespread treatment of depressed and psychotic patients with antidepressants and atypical antipsychotic medications may be effective in preventing suicide.

707

are at risk for suicide. This may create an opportunity for timely therapeutic interventions to prevent suicide. The advantages of a prospective study of a large number of subjects—imaging the brain, studying polymorphisms in many candidate genes, obtaining detailed clinical information in the living patient, and studying the changes using neuropharmacological challenges—allow determination of the relative importance and interrelationship of clinical, social, and biological risk factors for suicidal behavior.

ACKNOWLEDGEMENTS This work was partly supported by PHS grants MH62185, MH48514, MH56390, and MH40210.

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48 Sleep Disorders ERIC A. NOFZINGER Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

I.

INTRODUCTION

somnographically into NREM and REM sleep states based on three measures: (1) electroencephalography (EEG); (2) electromyography (EMG); and (3) electrooculography (EOG). With sleep onset, the EEG frequency slows, the amplitude increases and the EMG decreases. This sleep is classified as NREM stages 1, 2, 3, or 4, which are distinguished by increasing amounts of low-frequency, high-amplitude EEG activity, also known as ‘‘delta’’ activity. Delta sleep decreases across the night. REM sleep follows the first NREM period and is characterized by low-amplitude, mixed high-frequency EEG, the occurrence of intermittent REMs, skeletal muscle atonia, and irregular cardiac and respiratory events. Across the night, brain function oscillates between the globally distinct states of NREM and REM sleep about three or four times, approximately every 90 min. Across successive sleep cycles within a night, stages 3 and 4 sleep decrease, then disappear, while REM sleep and lighter NREM sleep stages increase. The lower-frequency EEG rhythms in NREM sleep represent widespread thalamocortical electrical oscillations. Slow oscillations in the 1–4 Hz delta range have both cortical and thalamic origins. The higher-frequency EEG rhythms (beta and gamma frequencies, roughly > 20 Hz) can be seen during waking and REM sleep [1–16]. They are associated with increased vigilance. Changes in these oscillations can result from state-dependent changes in modulatory systems such

A working knowledge of sleep and its various disorders is essential to psychiatric clinical care. Alterations in sleep are among the most common clinical disturbances in a broad range of mental disorders. Sleep disturbances may herald the onset of a new episode of a mental disorder. Misdiagnosis of sleep problems may be a cause of treatment failure in patients with mental disorders. And perhaps, most importantly, disturbances in sleep are among the most troubling symptoms for patients with mental disorders. This chapter will first provide a general overview of normal sleep to provide a context within which to understand sleep alterations in disease states. Then, sleep in neuropsychiatric disorders commonly encountered in a psychiatric practice will be reviewed. Finally, a review of nonpsychiatric general sleep disorders will provide a broader context within which to understand the more specific sleep disorders seen in patients with mental disorders.

II.

NORMAL SLEEP

Sleep propensity, or the need for sleep, is lowest shortly after awakening, increases in midafternoon, plateaus across the evening, is greatest during the night, and declines across sleep. Sleep has been subclassified poly713

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Nofzinger

as the brainstem, the hypothalamus, and the basal forebrain. Changes in low- or high-frequency EEG rhythms in neuropsychiatric disorders, may therefore result from functional changes at one or more brain system levels including the cortex, thalamus, and modulatory structures. Rapid eye movement, or REM sleep, represents a unique state of the central nervous system. Evidence from a variety of approaches suggests that REM sleep is generated at the level of the brainstem. Specifically, the laterodorsal and pedunculopontine tegmental cholinergic nuclei (LDT and PPT) in the pontine reticular formation underlie the phasic and tonic components of REM sleep [17–38]. These brainstem structures are under modulatory influence from other brainstem nuclei, including the noradrenergic locus coeruleus and the serotonergic raphe, as well as forebrain structures such as the amygdala [39–45]. Functional neuroimaging studies show that REM sleep is associated with a relative increase in function in limbic and paralimbic structures in relation to both waking and NREM sleep. Alterations in REM sleep in neuropsychiatric disorders may reflect alterations in limbic and paralimbic function in these diseases. During NREM sleep, there are decreases in relative brain function in heteromodal association cortical areas in relation to waking [35,46–56]. This includes the prefrontal, parietal and temporal association areas. The thalamus is another region where consistent reductions in relative brain function is found. III.

SLEEP DISORDERS

A.

Sleep in Neuropsychiatric Disorders

1.

Depression

The majority of patients with mood disorders describe difficulty falling asleep, difficulty staying asleep, and difficulty returning to sleep after early-morning awakenings [57]. Clinically, they report a paradoxical state of physical daytime fatigue, yet with persistent mental activity that makes it difficult for them to fall asleep at night. While insomnia characterizes the melancholia of middle-age and elderly unipolar depression, younger patients and bipolar depressed patients will often describe difficulty getting out of bed in the morning and hypersomnia during the daytime [58]. An extensive literature describes the changes in EEG sleep in patients with depression [59–73]. Measures derived from the EEG sleep recordings that have been found to differ between healthy and

depressed subjects include measures of sleep continuity, measures of visually scored EEG sleep stages, and automated measures of characteristics of the EEG waveform across the sleep period such as period amplitude or EEG spectral power measures. The changes in subjective sleep complaints are paralleled by EEG measures of sleep. These include increases in sleep latency and decreases in sleep continuity. In terms of EEG sleep stages or ‘‘sleep architecture,’’ depressed patients often show reduced stages 3 and 4 NREM sleep (also known as ‘‘slow-wave sleep’’ (SWS) because of the presence of slow EEG delta activity during these stages). Several changes in REM sleep have also been noted. These have included an increase in the amount of REM sleep, a shortening of the time to onset of the first REM period of the night, a shortened REM latency, and an increase in the frequency of eye movements within a REM period. In terms of quantitative EEG changes in sleep, many studies have reported reductions in delta sleep in depression. Increased high-frequency EEG activity has also been reported in depressed patients including alpha and beta. Importantly, sex differences have been found in these abnormalities. Depressed women appear to have relative preservation of delta sleep in relation to depressed men, despite elevations in higherfrequency EEG activity in both groups. Studies have shown that patients with psychotic depression have particularly severe EEG sleep disturbances and very short REM sleep latencies; that patients with recurrent depression have more severe REM sleep disturbances than patients in their first episode; and that sleep continuity and REM sleep disturbances are more prominent early in the depressive episode than later. Some studies suggest that patients with dysthymia and mania (surprisingly) have EEG sleep disturbances very similar to those observed in major depression. EEG sleep findings help to inform our understanding of the neurobiology of longitudinal course and treatment outcome in depression. Although severely reduced REM latencies, phasic REM measures, and sleep continuity disturbances generally move toward control values after remission of depression, most sleep measures show high correlations across the course of an episode. Reduced REM latency is associated with increased response rates to pharmacotherapy [74] but not to psychotherapy [75]. Depressed patients with abnormal sleep profiles (reduced REM latency, increased REM density, and poor sleep continuity) are significantly less likely to respond to cognitive behavior therapy and interpersonal therapy than

Sleep Disorders

patients with a ‘‘normal’’ profile. Other studies have indicated that reduced REM latency and decreased delta EEG activity are associated with increased likelihood of or decreased time until recurrence of depression in patients treated with medications or psychotherapy [76]. Each of the major neurotransmitter systems that have been shown to modulate the ascending activation of the cortex, i.e., the cholinergic, noradrenergic, and serotonergic systems, have been implicated in the pathophysiology of mood disorders. The role of additional brainstem neurotransmitter systems such as GABA-ergic, nitroxergic, glutamatergic, glycinergic, histaminergic, adenosinergic, dopaminergic, and various peptide systems, such as galanin, orexin, vasoactive intestinal polypeptide, and nerve growth factor in the sleep disturbances in depression, remain to be defined. Nearly all effective antidepressant medications show a pronounced inhibition of REM sleep including a prolongation of the first REM cycle and a reduction in the overall percent of REM sleep (exceptions include nefazadone [77] and bupropion, which do not suppress REM sleep [78,79]. Enhanced cholinergic function concurrent with reduced monoaminergic tone in the central nervous system has been proposed as a pharmacologic model for depression. In an exaggerated sense, the state of REM sleep mimics this formulation, i.e., a cholinergically driven state with reduced firing of noradrenergic and serotonergic neurons. Cholinergic agents such as the muscarinic agonist RS 86, arecoline, physostigmine, and scopolamine produce exaggerated REM sleep effects in depressed patients in comparison with patients with eating disorders, personality disorders, anxiety disorders, and healthy controls [80–82]. These studies suggest that there may be a supersensitivity of the cholinergic system driving REM sleep in mood disorders patients, although an alternative plausible hypothesis is that there may be reduced monoaminergic (5-HT and/or NE) inhibition of the brainstem cholinergic nuclei in mood-disordered patients [81]. Cholinergic activation may also play a role in the hyperactivity in the HPA axis and in the blunting of growth hormone secretion noted in depressed patients across the night, given the influence of cholinergic drugs on HPA activity and GH release [83]. Selective serotonin reuptake inhibitors are known to have prominent REM-suppressing activity, most notably early in the night when enhancements in REM sleep are most often seen in mood-disordered patients [60]. A tryptophan-free diet, which depletes central serotonin activity, is noted to decrease REM latency in

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healthy controls [84] and in depressed patients [85], and ipsaparone, a 5HT1a agonist, is noted to prolong REM latency in both normal controls and depressed patients [86,87]. Anatomically, 5HT1a receptors have been conceptualized as the limbic receptors given their high densities in the hippocampus, the septum, the amygdala, and cortical paralimbic structures. The action in these structures has been shown to be largely inhibitory (hyperpolarizing). Given the importance of limbic and paralimbic structures in REM sleep modulation, the influence of SSRI medications may be mediated by these limbic receptors. Importantly, in the brainstem LDT, a locus of cholinergic cells identified in the generation of REM sleep, bursting cholinergic neurons are inhibited by the action of 5HT on 5HT1a receptors. Finally, the effects of the 5HT1a antagonist pindolol on EEG sleep in healthy subjects were studied and noted to reduce REM sleep [88]. This was interpreted as supportive of a reduction in raphe serotonergic autoregulation, resulting in increased serotonergic input to pontine cholinergic centers and inhibition of REM sleep. Given the selective activation of limbic and paralimbic structures during REM sleep in healthy subjects, the study of the functional neuroanatomy during REM sleep in depressed patients may provide clues as to alterations in limbic and paralimbic function related to the pathophysiology of depression. In contrast to healthy controls [12], depressed patients fail to activate anterior paralimbic structures (sub- and pregenual anterior cingulate and medial prefrontal cortices) from waking to REM sleep. In contrast to healthy controls, depressed subjects show large activations in the dorsal tectum (superior colliculus and periaqueductal gray) during REM sleep. Finally, in contrast to controls, depressed subjects activate left sensorimotor cortex, left inferior temporal cortex, left uncal gyrus and amygdala, and left subicular complex during REM sleep. These findings suggest that depressed patients demonstrate uniquely different patterns of activation from waking to REM sleep than do healthy controls. In the context of neuroscience models relating forebrain function during REM sleep to attention, motivation, emotion and memory, these results suggest that prior REM sleep abnormalities in mood-disordered patients therefore likely reflect alterations in limbic and paralimbic forebrain function related to depression. One study reported on the reversibility of these findings following antidepressant therapy [89]. Depressed patients underwent concurrent EEG sleep studies and [18 F]fluoro-2-deoxy-D-glucose ([18 F]FDG) positron

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emission tomography (PET) scans during waking and during their second REM period of sleep before and after treatment with bupropion SR. Bupropion SR treatment did not suppress electrophysiologic measures of REM sleep, nor did it alter an indirect measure of global metabolism during either waking or REM sleep. Bupropion SR treatment reversed the previously observed deficit in anterior cingulate, medial prefrontal cortex, and right anterior insula activation from waking to REM sleep. In secondary analyses, this effect was related to a reduction in waking relative metabolism in these structures following treatment in the absence of a significant effect on REM sleep relative metabolism. Another study sought to clarify the neurobiological basis of variations in one aspect of central nervous system ‘‘arousal’’ in depression by characterizing the functional neuroanatomic correlates of beta EEG power density during NREM sleep [90]. First, nine healthy (n ¼ 9) subjects underwent concurrent EEG sleep studies and [18 F]FDG PET scans during their first NREM period of sleep in order to generate hypotheses about specific brain structures that show a relationship between increased beta power and increased relative glucose metabolism. Second, brain structures identified in the healthy subjects were then used as a priori regions of interest in similar analyses from identical studies in 12 depressed subjects. Regions that demonstrated significant correlations between beta power and relative cerebral glucose metabolism in both the healthy and depressed subjects included the ventromedial prefrontal cortex and the right lateral inferior occipital cortex. During a baseline night of sleep, depressed patients demonstrated a trend toward greater beta power in relation to a separate age- and gender-matched healthy control group. In both healthy and depressed subjects, beta power negatively correlated with subjective sleep quality. Finally, in the depressed group, there was a trend for beta power to correlate with an indirect measure of absolute wholebrain metabolism during NREM sleep. This study demonstrated a similar relationship between electrophysiologic arousal and glucose metabolism in the ventromedial prefrontal cortex in depressed and healthy subjects. Given the increased electrophysiological arousal in some depressed patients and the known anatomical relations between the ventromedial prefrontal cortex and brain-activating structures, this study raised the possibility that the ventromedial prefrontal cortex plays a significant role in mediating one aspect of dysfunctional arousal found in severely aroused depressed patients.

Nofzinger

Functional neuroimaging of NREM sleep in depressed subjects would be expected to provide evidence regarding the functioning of homeostatic mechanisms in mood-disordered patients since this is a time of nonselective nonactivation of the cortex in which the buildup of a sleep-dependent process, process S, is discharged and during which growth hormone secretion occurs. Ho et al. [91] demonstrated that whole-brain and regional cerebral glucose metabolism was elevated during the first NREM period of the night for depressed men in relation to healthy men. These findings are supportive of a deficiency of hemostatic mechanisms in mood-disordered patients, perhaps secondary to cortical hyperarousal. Clark et al. [92] reported that reductions in delta sleep in depressed patients was associated with reductions in afternoon waking relative and global blood flow. This suggests that the elevations in glucose metabolism during NREM sleep in depressed patients is not related to a waking hypermetabolic state. Studies across waking and NREM sleep are needed to clarify this notion. Wu et al. [93] characterized the functional neuroanatomic changes following sleep deprivation therapy in depressed patients. They found that depressed patients who demonstrated high pretreatment relative glucose metabolic rates in the medial prefrontal cortex were more likely to respond to sleep deprivation. Further, a reduction in relative metabolism in this region was found following sleep deprivation. 2.

Late-Life Depression

Assessments of the timing and quality of NREM and REM sleep cycles through EEG sleep studies have proven to be particularly useful indicators of hemostatic and adaptive physiological processes during successful and pathological aging in humans. In a study of healthy ‘‘old old’’ and ‘‘young old,’’ Reynolds et al. [94] reported: (1) a small, age-dependent decrease in slow-wave sleep, in contrast to the stability of REM sleep measures from ‘‘young old’’ to ‘‘old old’’; (2) much better preservation of slow-wave sleep among aging women than men, particularly in the first NREM period of the night, but no sex-related differences in REM sleep measures; (3) greater stability of sleep maintenance among aging men than among aging women; and (4) longer REM sleep latencies among aging women than men. In comparison with 20-year-olds, 80-year-olds have significant reductions in both REM sleep percent and REM sleep latency, as well as a slower recovery from the effects of acute sleep loss [95]. The elderly show

Sleep Disorders

greater rigidity in sleep patterns, with less intersubject and intrasubject variability in habitual sleep times compared to the young [96]. Therefore, while some loss of REM and slow wave NREM sleep characterize the aging process, successful aging is associated with a relative stability of sleep states over the later years. One explanation for these findings may be some mild losses in both hemostatic adaptive physiological mechanisms which result in NREM and REM sleep decrements, respectively. Alternatively, information processing related to both hemostatic and adaptive behavior may be more stable and efficient in the elderly, especially in those for whom the aging process has been bridged successfully. EEG sleep studies have also provided insights into the pathophysiology of disorders in which affective adaptation is significantly stressed in late life, i.e., in response to significant losses or in acute depressive episodes. In a study of elderly volunteers who had lost a spouse, Reynolds et al. [97] were able to distinguish EEG sleep changes discriminating subjects who did from those who did not develop an episode of major depression. Bereaved subjects with depression had significantly lower sleep efficiency, more early morning awakening, shorter REM latency, greater REM percent, and lower rates of delta wave generation in the first NREM period, as compared to nondepressed bereaved volunteers. These findings are similar to those of elderly patients with recurrent unipolar depression. In a subsequent longitudinal study of bereaved elders who did not become clinically depressed, only increases in phasic REM activity and density (compared to normal controls) were observed throughout the first 2 years of bereavement [98]. These findings are similar to those of Cartwright [99] for depressed vs. nondepressed divorcing women, suggesting that short REM latency and slow-wave sleep are correlates of depression during stressful life events, while increased REM activity may correlate with successful recovery from stress in the absence of major depression. 3.

Schizophrenia

Early sleep EEG studies sought to test the intriguing hypothesis that schizophrenia is a spillover of the dream state into wakefulness. No evidence has accrued to support this hypothesis. However, subtle alterations in architecture of REM sleep may occur. REM latency was found to be decreased in several studies [100]. It has been proposed that this may result from a deficit in SWS in the first NREM period leading to a passive

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advance, or early onset of the first REM period. An alternative explanation is ‘‘REM pressure.’’ However, studies of the amounts of REM sleep have been conflicting with increases, decreases, and no change being found [64,100]. Studies examining treatment-naive schizophrenia patients show no increases in REM sleep [101,102]; the increases in REM sleep observed in previously treated subjects may reflect effects of medication withdrawal, and/or changes related to the acute psychotic state [102]. It is therefore unlikely that the observed decreases in REM latency in some schizophrenia patients result from primary abnormalities in REM sleep. Slow-wave sleep is of particular interest to schizophrenia because of the implication of the prefrontal cortex in this disorder [103] and in generation of SWS [104]. Several studies have shown a reduction of SWS in schizophrenic patients; SWS deficits have been seen in acute, chronic, and remitted states; and in never-medicated, neuroleptic-treated, and unmedicated patients [100]. Studies that fail to find differences in SWS have generally used conventional visual scoring. Three studies that have quantified sleep EEG parameters have consistently shown reductions in SWS. Ganguli et al. [101] observed no change in visually scored SWS. Instead, drug-naive schizophrenic patients showed a significant reduction in delta wave counts. This suggested that automated counts may be a good marker of SWS deficiency in schizophrenia. The neurobiological correlates of the psychopathological dimensions are critical for our understanding of the pathophysiology of psychiatric disorders. Research during the past decade has focused increasingly on the positive and negative syndromes, a conceptual distinction of particular importance to pathophysiology of schizophrenia. A number of studies have examined the association between REM sleep parameters and clinical parameters. Tandon et al. [102] reported an inverse association between REM latency and negative symptoms. No association has been seen between sleep abnormalities and depressive symptoms [102] but two studies have shown that increased REM sleep may correlate with suicidal behavior in schizophrenia [105,106]. It is important to understand the longitudinal nature of sleep abnormalities in schizophrenia, in order to elucidate their significance for pathophysiology. Stage 4 does not appear to improve, whereas other sleep stages change following 3–4 weeks of conventional antipsychotic treatment [107]. In a longitudinal study, alterations of SWS appeared to be stable when polysomnographic studies were repeated at 1 year, but the

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Nofzinger

REM sleep parameters appeared to change. These observations suggest that SWS deficits in schizophrenia might be trait related [108]. Consistent with this view, delta sleep abnormalities have been found to correlate with negative symptoms [101,109–111] and with impaired outcome at 1 and at 2 years [112]. Some evidence, albeit modest, for decreased frontal lobe metabolism has been documented in schizophrenia using a variety of techniques, including PET, single-photon emission computed tomography (SPECT), [31 P]MRS, and xenon-133 inhalation technique. It may therefore be instructive to examine SWS deficits in the context of such physiological alterations. An association has been demonstrated between SWS deficits and reduced frontal-lobe membrane phospholipid metabolism as examined by [31 P]MRS [113]. 4.

Alzheimer’s Disease

Disturbances in sleep commonly accompany Alzheimer’s disease [114]. These disturbances are a significant cause of distress for caregivers, often leading to institutionalization of these patients [115,116]. The changes in sleep often parallel the changes in cognitive function in demented patients [117,118]. Also, daytime agitation has been associated with negative sleep quality at night [119]. A large-scale community-based study of Alzheimer’s patients reported that sleeping more than usual and early-morning awakenings were the most common sleep disturbances in noninstitutionalized patients [120]. Night-time awakenings, however, were more disturbing to caregivers. Nighttime awakenings were associated with male gender and greater memory and functional declines. Three groups of subjects were identified in association with nocturnal awakenings: (1) patients with only daytime inactivity; (2) patients with fearfulness, fidgeting, and occasional sadness; and (3) patients with multiple behavioral problems including frequent episodes of sadness, fearfulness, inactivity, fidgeting, and hallucinations. In terms of sleep laboratory–based evaluations, sleep continuity disturbances in these patients include decreased sleep efficiencies, increased lighter stage 1 NREM sleep, and an increased frequency of arousals and awakenings [121,122]. Sleep architecture abnormalities include decreases in stages 3 and 4 NREM sleep and some reports of decreases in REM sleep [123–131]. Loss of sleep spindling and K complexes have also been noted in dementia. Sleep apnea has been observed in 33–53% of patients with probable Alzheimer’s disease [132–140]. It is unclear if there is an increased prevalence of sleep apnea, however, in Alzheimer’s

patients in relation to age- and gender-matched controls. Nocturnal behavioral disruptions, or ‘‘sundowning’’ episodes are reported commonly in the clinical management of Alzheimer’s patients, although specific diagnostic criteria for a sundowning episode have been difficult to define [141–144]. Despite extensive clinical research in this area, the pathophysiology of sundowning, including its relationship with brain mechanisms that control sleep/wake and circadian regulation, remain unclear. Overall, the literature on sleep in Alzheimer’s disease suggests that the primary defect in this disease is the more general neurodegenerative changes that lead to the profound cognitive and functional declines of this disease, and that the sleep changes are secondary manifestations of the disorder. If sleep is viewed as generated by core sleep systems that then require an intact neural structure throughout the rest of the brain for expression of behavioral states, then the sleep changes in Alzheimer’s disease are most likely related to end-organ failure as opposed to pathology in key sleep or circadian systems themselves. 5.

Parkinson’s Disease

Light, fragmented sleep occurs frequently in Parkinson’s disease patients. Sleep problems have been reported in as many as 74–96% of patients [145–147]. Complaints include frequent awakenings, early awakening, nocturnal cramps or pains, nightmares, vivid dreams, visual hallucinations, vocalizations, somnambulisms, impaired motor function, myoclonic jerks, excessive daytime sleepiness, REM sleep behavior disorder, and sleep-related violence leading to injury [145–163]. These changes may result from the disease itself or to complication from treatment with dopaminergic agents [164–175]. Additionally, depression is common in Parkinson’s disease. The sleep disruption may in part be related to this comorbid disorder [147,153,167,176,177]. Sleep architecture abnormalities include increased awakenings and reductions in stages 3 and 4 sleep, REM sleep, and sleep spindles [175,178,179]. Reductions in REM latency have been observed. Increased muscular activity, contractions, and periodic limb movements may prevent SWS and foster light, fragmented sleep. Disorganized respiration is also found [180]. B.

Sleep Apnea Syndrome

Sleep apnea syndrome refers to episodes of transient cessation of breathing during sleep (for 10 sec) that

Sleep Disorders

disrupt sleep and thus lead to daytime sleepiness. In most cases, this cessation is related to the occlusion of the pharyngeal airway, and is referred to as obstructive sleep apnea syndrome. In other cases, there is abnormal ventilatory effort in the absence of any discrete airway obstruction. This is referred to as central sleep apnea syndrome. A third condition, the upper-airway resistance syndrome (UARS), consists of increased respiratory effort in the absence of discrete apneic events. This increased effort leads to nonrestorative sleep, which subsequently produces daytime sleepiness. These syndromes are most commonly found in obese, aging men although they are not restricted to these Pickwickian types. Epidemiologic studies suggest that 4% of men and 2% of women ages 30–60 will meet minimal diagnostic criteria for obstructive sleep apnea syndrome [181,182]. The most common clinical symptoms reported are daytime sleepiness in the presence of sleep-related snoring with occasional pauses in breathing or ‘‘gasping’’ for breath during sleep. Other daytime symptoms include fatigue, morning headaches, and cognitive changes such as reduced concentration and attention. The sleepiness of sleep apnea is differentiated from the sleepiness of narcolepsy by the constant, unrelenting nature of the sleepiness. In narcolepsy, the sleepiness is qualitatively more sudden in onset and offset. The constant sleepiness and fatigue need to be differentiated from similar sleep symptoms in psychiatric patients by the concurrent changes in mood or personality found in psychiatric disorders that are not found in the isolated apneic patient. The pathophysiology of obstructive sleep apnea syndrome is related to the neuroanatomical factors that maintain airway patency during sleep [183,184]. It is widely accepted that the site of airway obstruction in obstructive sleep apnea syndrome lies in the pharynx. Whether this airway will close during sleep is related to the balance between forces that narrow the airway, such as intrapharyngeal suction during inspiration, and forces that dilate the airway, such as the tone of pharyngeal airway muscles. Anatomical abnormalities in this area are often found in apneic patients related to obesity, enlarged tonsils, and facial bony abnormalities. Additionally, sleep itself is associated with a loss of tone in pharyngeal muscles that maintain the outward pressure necessary for airway patency. Alcohol is often an extrinsic suppressant of pharyngeal muscle tone that exacerbates apnea by reducing the outward pressure on the pharyngeal airway. Central sleep apnea syndrome refers to the periodic loss of ventilatory effort with associated cessation of breathing during sleep. This is differentiated from

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obstructive-type apneas in which there is a loss of breathing despite persistent attempts at ventilation. These patients constitute < 10% of apneic patients. The pathogenesis of central sleep apnea is likely diverse given the broad conditions that produce this type of breathing during sleep such as central alveolar hypoventilation, congestive heart failure, nasal obstruction, and dysautonomias. In general, a final common pathway appears to be some disturbance in the respiratory control system that includes sensors for (1) hypoxia and hypercapnia and (2) brainstem and forebrain centers that influence respiratory function in response to metabolic and behavioral demands. Clinically, patients with alveolar hypoventilation present with signs of respiratory failure, whereas nonhypercapnic patients may present with insomnia, normal body habitus, and awakenings with gasping for breath. Diagnosis is definitively made by the use of an esophageal balloon. Treatment for the hypercapnic patient with hypoventilation during waking requires ventilation at night using a nasal mask and a pressure-cycled ventilator. For the nonhypercapnic patient, treatment consists of correcting the underlying problem (e.g., nasal obstruction, congestive heart failure) or watchful waiting, as 20 % may resolve spontaneously. Nasal CPAP can be tried if the patient is obese, snores, and has heart failure. Oxygen administration may be helpful if the apneic events are associated with hypoxemia. If persistent, acetazolamide, a carbonic anhydrase inhibitor, can be attempted.

C.

Primary Insomnia

Insomnia is the experience of inadequate or poor quality of sleep and is characterized by one or more of the following: difficulty falling asleep, difficulty maintaining sleep, and/or awakening earlier than one would like. Additionally, patients are bothered by daytime dysfunction that may include fatigue, mood symptoms, and difficulty with cognitive function that requires attention and concentration. Roughly 10% of the adult population will suffer from chronic insomnia, and 30–50% will experience transient insomnia at some point in their lives. Females appear to be more affected across the life span, and the elderly are particularly vulnerable. Consequences of insomnia may include poor daytime performance, an increased likelihood of subsequent development of a mental disorder such as depression or anxiety, and increased medical morbidity and mortality. Insomnia may be classified as either short-term (transient) or long-term (chronic) and

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as either primary or secondary to another general medical or mental disorder. Transient insomnias occur in otherwise healthy individuals who revert to normal sleeping as an outcome. These may be related to sleeping in an unfamiliar environment; an environment that is temporarily disrupted by noises, sounds, or temperature changes; the occurrence of a recent life stressor; a change in the timing of bedtime related to travel across time zones or shift work; or acute administration or withdrawal of a medication that affects the sleep/wake cycle. In each case, identification of the etiology is important. Shortterm (1–4 weeks) sedative hypnotic use may be indicated. Care should be taken to taper and discontinue this medication following resolution of the acute event to avoid the development of psychological or physiological dependence on a sleeping aid. Chronic primary insomnias are by definition primary and not secondary to other medical or mental disorders. Other terms that have been used to define this population include psychophysiologic insomnia, sleep state misperception, and idiopathic insomnia. The term psychophysiologic insomnia stems from a psychophysiology literature and suggests that insomnia patients suffer from psychophysiologic ‘‘hyperarousal.’’ A vicious cycle of precipitating event, increased arousal, difficulty sleeping, preoccupation with inability to sleep leading to even more arousal, and inability to sleep defines the pathophysiology of these patients. The neurobiology of the concept of ‘‘hyperarousal, however, remains poorly defined. In part, the presence of an excessive amount of high-frequency EEG activity within the sleep period is used in support of the concept of hyperarousal. Sleep state misperception refers to the subjective perception of being awake throughout the night, despite the presence of polysomnographically determined sleep. In general, primary insomnia patients tend to underestimate the actual amount of sleep they are getting in a night. These observations raise the likelihood that the sleep that insomniac patients experience may not represent the restorative sleep that noninsomniac patients receive each night. The presence of high-frequency EEG activity within polysomnographically determined sleep may represent a less differentiated behavioral state that includes components of both sleep and wakefulness in the same individual. Idiopathic insomnia refers to insomnia that is not secondary but that does not appear to involve the vicious cycle reported by patients with psychophysiologic insomnia. These individuals may simply have genetically less differentiated sleep that appears less restorative.

Nofzinger

Treatment of insomnia is multifaceted and includes behavioral and pharmacological approaches. Historically, there should be no evidence that the insomnia is secondary, and if so, the underlying disorder should be evaluated and treated. Several behavioral strategies are available. Relaxation techniques include progressive muscle relaxation, EMG biofeedback, meditation, and guided imagery. Stimulus control therapy follows from a learning model of insomnia. In this model, insomniacs develop negative associations to the bedroom, and the sleeping environment produces increased arousal and subsequent insomnia. Stimulus control instructions include ‘‘lie down only when you feel sleepy,’’ ‘‘use the bed and bedroom for sleep and sex only,’’ and ‘‘get out of bed and go to another room if you are not sleeping.’’ Along with these instructions include prescriptions to maintain the same clock times for going to bed and getting out of bed the next day as well as to avoid daytime napping irrespective of how much sleep had been obtained on the preceding night. Sleep restriction therapy refers to restricting the amount of time in bed to the time that a person believes he is actually sleeping. For example, a schedule for someone who believes he is sleeping for 6 h might be midnight to 6 am; for 4 h from 1 am to 5 am; or for 8 h from 10 pm to 6 am. Along with these instructions include avoidance of daytime napping. This counters the natural tendency of insomniac patients to prolong their times in bed in an effort to obtain more sleep. This is often counterproductive as it lightens the sleep that they do get, increasing the likelihood of middle-of-the-night awakenings and earlymorning awakenings. Cognitive therapy for insomnia includes questioning erroneous beliefs that an insomniac patient may have regarding the catastrophic consequences of insomnia and beliefs regarding the inadequacy of sleep that he is having. Studies are under way to test the relative merits of each of these treatment methods when used individually or in combination. D.

Narcolepsy

There are two independent clusters of symptoms that may require treatment in narcoleptic patients. The first is daytime sleepiness. Given the severity of the sleepiness, it would be unusual for behavioral interventions to be completely effective. Some patients find that adding periodic, brief daytime naps reduces some of the sleep attacks. Allowing for adequate sleep at night is advised. Occasionally, these patients will demonstrate insomnia, or nightmares that require the use of a seda-

Sleep Disorders

tive hypnotic medication. The primary treatment for the sleepiness, however, consists of the use of either a stimulant medication or a medication that relieves sleepiness. The commonly used stimulants include methylphenidate, dextroamphetamine, and pemoline, in descending order of stimulant potency. Short-acting preparations last 4 h, and longer-acting preparations extend this effect a few hours. Consequently, these medications are often prescribed at least in the morning and around lunchtime. Occasionally, a patient may need a late-afternoon dose if he anticipates being involved in activities during the evening that require his full attention. Often, tolerance to low doses builds, requiring escalation to effective levels. Side effects such as nervousness, affective symptoms, and nocturnal insomnia require monitoring. An alternative medication is modafinil. This medication may reduce the need for sleep and subsequently benefits some narcoleptic patients. Some patients, however, do not obtain full relief of their sleepiness with the use of this medication, or experience adverse effects which require switching to, or adding, a stimulant. The second cluster of symptoms that requires treatment includes cataplexy, hypnogogic hallucinations, and sleep onset paralysis. Of these, the cataplexy is the most significant symptom clinically, as it is associated with considerable limitation in psychosocial function and potential danger to the individual as a result of personal injury from falls. These symptoms are generally effectively managed with the use of antidepressant agents such as clomipramine, the selective serotonin reuptake inhibitors, or venlafaxine. Dosages that relieve cataplexy are generally lower than those used to treat depression. Tolerance to these agents can develop which may require switching to an alternative agent. E.

Restless Legs Syndrome/Periodic Limb Movement Disorder

The restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are related sleep disorders. Restless legs refers to a waking complaint that interferes with sleep onset, whereas periodic limb movements are found during sleep and may interfere with restorative sleep. The restless legs complaint is a dysesthesia described as an uncomfortable restless, or creeping and crawling sensation in the lower legs. This sensation is only relieved with vigorous movement of the legs, often requiring the patient to get out of bed. The disorder affects 5–10% of the population, beginning generally in midlife [185]. Periodic limb

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movements during sleep often occur with restless legs syndrome, but may be found in isolation. In this disorder, stereotypic periodic (every 20–40 sec) limb movements (0.5- to 5-sec extensions of the big toe and dorsiflexions of the ankle are often associated with signs of arousal from sleep, such as K complexes followed by alpha EEG waves. The degree to which PLMD is a disorder that either impairs sleep or that requires intervention remains unclear, however, since 11% of the normal population without sleep complaints, especially the aged, will demonstrate PLMD on polysomnographic assessment. The pathophysiology of RLS and PLMD has not been well defined. There is evidence to suggest that abnormal dopaminergic function in the CNS may play a role. The efficacy of opiates in the treatment of the disorder suggests a role for the endogenous opiate system. There is also thought to be a role for the spinal cord in RLS, and relations between RLS and peripheral neuropathies have been noted. Associated medical conditions for RLS include uremia, iron deficiency anemia, peripheral neuropathy, fibromyalgia, magnesium deficiency, rheumatoid arthritis, and posttraumatic stress disorder. Treatments that exacerbate RLS or PLMD include lithium, tricyclic and SSRI medications, and withdrawal from anticonvulsants, benzodiazepines, and barbiturates. Bupropion is one antidepressant that has been associated with a reduction in periodic limb movements, perhaps related to its dopaminergic activity. The treatment of RLS and PLMD primarily involves dopaminergic agonists. Pramipexole 0.125 mg and pergolide 0.1–0.5 mg QHS are often first-line recommendations. Levodopa/carbidopa 100-25 or 20050 is also helpful when given at bedtime. The short duration of action of this combination often requires a second, middle-of-the-night dose unless the sustained-release preparation is used. Benzodiazepines and traditional sedative/hypnotics consolidate sleep and may reduce arousals secondary to the PLMD. Opiate medications are very beneficial for the treatment of these disorders, although, given their abuse potential, they should be employed as a last resort. Less consistent information is available to support the use of other agents such as carbamazepine, clonidine, and gabapentin. F.

NREM Parasomnias

Three related sleep disorders, or sleep syndromes, fall into a category of NREM parasomnias: confusional arousals, sleep terrors, and sleepwalking. Each is

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thought to represent a ‘‘disorder of arousal.’’ As a group, these disorders tend to occur normally in children below the age of 5 when behavioral state regulation is not yet well differentiated. There appears to be a genetic tendency for these disorders as a group. Persistence into adulthood is not the norm, but when they do, they can interfere with psychosocial functioning. They each tend to occur out of a deeper NREM sleep stage (slow-wave sleep) early in the night, and each is associated with amnesia for the event. Confusional arousals refer to periods of partial sleep and partial waking behavior with amnesia for the events on full awakening. The individual will have the appearance of being confused, disoriented with incomplete responsiveness to their surroundings. These episodes may last from a few seconds to a few minutes with return to sleep. Sleep terrors refers to periods in which the individual seems to be in the midst of a paniclike state with crying out, sitting erect in bed with acute autonomic arousal such as increases in heart rate, respiration, and sweating. No recall of the event is noted. Sleepwalking refers to the appearance of motoric behavior during sleep that can lead to an individual getting out of bed and walking around his environment. Occasionally, the motoric behavior is isolated to the bed, with uncomplicated, brief, automatic behaviors. At other times, the behavior can be very complex, including walking around the bedroom performing some stereotypic act, or leaving the bedroom and walking around the house. Sleep-related eating episodes are not uncommon. On rare occasions, a sleepwalker may leave his immediate home, walk around in neighborhood, or even drive a car. In general, the individual returns to bed voluntarily, either on completion of the episode or after full awakening from the episode. The individual is often somewhat difficult to arouse and only partially responsive to environmental stimuli. Complete amnesia for the events is most common. The pathophysiology for all of the confusional arousals is unclear. A strong genetic component is recognized for both sleep terrors and sleepwalking. Aside from this, factors associated with increasing the depth of sleep, such as sleep deprivation, or dissociating sleep, such as acute toxic/metabolic changes, or stressing an individual may increase the likelihood that these episodes will occur in genetically predisposed individuals. Presumably, these episodes occur when there is a dissociation between the brain mechanisms that regulate cortical activation or behavioral arousal and those that regulate motoric behavior. It remains

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unclear whether there is an association between these events and psychopathology. Any association may simply be related to the observations that mental disorders are themselves associated with disruptions in sleep continuity, factors that would be expected to increase the frequency of such events in susceptible individuals. The diagnosis of each of these disorders is generally a clinical one. Reports of parasomnias in the first third of the night with specific features as described above support the diagnoses. Polysomnography can be performed, although it is only infrequently helpful given the difficulty of ‘‘capturing’’ one of the episodes in the sleep laboratory. Attempts to precipitate an episode in the lab by forced arousals from delta sleep may aid in diagnosis. In cases where a seizure disorder may be suspected, one or several daytime diagnostic EEGs and a full-scalp EEG during sleep may be performed to detect eleptiform EEG activity. Treatment of these disorders is largely conservative and educational in nature, informing the patient and his family about sleep and the generally benign longitudinal course of parasomnic behaviors. At the time of occurrence, the individuals should not be disturbed, but rather the parasomnic events should be allowed to self-terminate. Occasionally, forced arousals during an event can precipitate an unconscious aggressive attack. Minimizing sleep deprivation, stressors, and medications or dietary factors that may interfere with sleep integrity (e.g., alcohol, caffeine, antidepressant medications) is recommended. If there is reason to suspect that the behaviors may be interfering with either sleep integrity or with daytime functioning, occasional use of sleep-consolidating medications such as the benzodiazepines may be effective in preventing the escalation of these partial arousals into more complex behaviors during sleep. If an underlying mental disorder is present that appears to be interfering with sleep continuity, this can be referred for appropriate intervention, either psychotherapy or pharmacotherapy with nonalerting antidepressant medications. If there is a history of either self or other injury during the events, steps should be taken to ‘‘sleepwalkerproof’’ the bedroom and surrounding environment. This may include the removal of potentially dangerous objects, locking doors, and separating bed partners from the sleepwalker. G.

Nightmares

The term nightmare implies a vivid dream in which something catastrophic or frightening is happening

Sleep Disorders

either to the dreamer or to someone else. Often, this term also implies an awakening from the frightening dream in a fearful state. There is no clear distinction, however, between a nightmare and a dream. Nearly everyone has experienced a nightmare, suggesting that this is a normal phenomenon of sleep. In general, the casual occurrence of nightmares does not come to the attention of the medical community, and no interventions are required. Nightmares are more common in childhood than in adulthood and more common in girls than in boys. The prevalence of a nightmare disorder is difficult to define, however, given the difficulty in defining a separate disorder from the more common occurrence of having bad dreams. The pathophysiology of nightmares is unknown. Human brain imaging studies performed during REM sleep consistently reveal selective activation of anterior limbic and paralimbic structures, regions thought to play a significant role in emotional behavior, although no comparative studies have been performed to differentiate regional cerebral function during REM sleep in healthy subjects versus nightmare-disordered subjects. Elevations in autonomic arousal prior to awakening with a nightmare has been observed. Behavioral studies suggest that individuals with ‘‘thin’’ interpersonal boundaries, defined as more open, sensitive, and vulnerable to intrusions, are more susceptible to nightmares. Numerous drugs that affect sleep, and REM sleep specifically, such as many antidepressant medications, are known to precipitate nightmares. Alcohol withdrawal is particularly associated with bizarre, vivid dreaming. Subjects with posttraumatic stress disorder have recurrent intrusive nightmares related to their traumatic life experience, as part of their diagnostic criteria. Given the diverse etiologies of nightmares, there is no uniform therapy. Identification and removal of precipitating factors including toxic/metabolic or drug induced are often the simplest treatment. There have been no empirical medication trials to determine the efficacy of any medication treatment for nightmare sufferers, and clinical experience would suggest that response is highly individual. Psychotherapy may be of some benefit in cases where the nightmare appears to reflect an unsuccessful attempt at some type of emotionally adaptive behavior to a stressful life situation. H.

REM Sleep Behavior Disorder

Clinically, REM sleep behavior disorder (RBD) refers to a parasomnia in which there are sleep-related beha-

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viors associated with elaborate dream mentation. Depending on the elaborateness of the behavior and the aggressiveness of the dream, these behaviors can result in accidental self or other injury. In general, the nature of the dream enactments is out of character for the person’s waking behavior. Often, the presenting complaint comes from the bed partner, who is concerned about the behaviors, rather than the actual patient, who is often unaware that anything unusual has happened during sleep. The disorder most often occurs in men and is more common in aging. The pathophysiology of the disorder can best be understood based on an understanding of the normal physiology of REM sleep. REM sleep occurs periodically throughout the night, alternating with NREM sleep in roughly 90-min cycles. During REM sleep the brain is in an active behavioral state in which cerebral metabolism and other signs of cortical activation are comparable to those of waking. Two exceptions include the absence of conscious awareness and the near-complete immobilization of skeletal musculature via an active inhibition of motor activity by pontine centers in the perilocus coeruleus region. These exert an excitatory influence on the reticularis magnocellularis nucleus of the medulla via the lateral tegmentoreticular tract. In turn, this nucleus hyperpolarizes spinal motoneuron postsynaptic membranes via the ventrolateral reticulospinal tract. It is presumed that a defect in some aspect of this REM sleep atonia system is disturbed in patients suffering from REM sleep behavior disorder. Acute toxic/metabolic RBD has been associated with alcohol and benzodiazepine withdrawal, or an adverse effect associated with administration of tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors, and clomipramine. Chronic RBD is either idiopathic (estimated to be 40%) or associated with some form of neurologic insult. These can be from a variety of etiologies including vascular, malignant, infectious, and degenerative. The specific pathology in each case, although presumed to have a final common pathway on the REM sleep atonia system, is not known. Diagnosis is suspected based on a clinical report of potentially harmful sleep-related behaviors in which there appears to be an acting out of some dream sequence. Diagnosis is confirmed in a polysomnographic study that shows increased tone, or increased twitching in the chin EMG channel. Videotaping sleeprelated behaviors is helpful diagnostically when increased movements are seen during a polysomnographically identified REM sleep period.

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The most widely supported treatment for RBD is administration of clonazepam, 0.5 mg PO QHS titrating upward to achieve clinical benefit. In general, tolerance is not seen. This medication is reported to be helpful in > 90% of cases. At the present time, clonazepam is approved for the treatment of seizure disorders and panic disorders. A wide variety of case reports exist in which numerous other agents may be helpful, although controlled trials are lacking.

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ACKNOWLEDGMENTS Supported in part by grants MH30915, MH52247, MH37869, MH00295, MH01414, and MH45203 from NIMH, and by the Theodore and Vada Stanley Foundation.

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49 Perspectives in the Pharmacological Treatment of Schizophrenia LARRY ERESHEFSKY College of Pharmacy, University of Texas at Austin, Austin, Texas, U.S.A.

I.

SCHIZOPHRENIA

dard of care for patients with schizophrenia and make restored function to perform and enjoy life’s many facets our ‘‘bottom line’’ [7].

Schizophrenia is a chronic and disabling illness, which is usually characterized as a constellation of positive, negative, and cognitive symptoms or deficits (Fig. 1). Above all, schizophrenia is a disorder in which social, occupational, self-care, and interpersonal functions are severely reduced [1]. Schizophrenia is the fourth leading cause of disability worldwide; 60–70% of patients do not marry, 10% commit suicide, and 20–40% of patients make at least one suicide attempt during their illness [1–3]. Patients with schizophrenia have a 20% shorter life expectancy than demographically matched control subjects [4], and the combination of impoverished life styles, medical care, and risk factors including both the illness itself and drug therapy result in a 4.3-fold increased rate of mortality from unnatural causes and 1.6-fold increased rate of mortality due to natural causes [5]. Cigarette smoking, obesity, substance abuse and dependence (especially alcohol), poor diet, and limited access to medical services contribute to the increased mortality rate [6]. However, despite many of the medical management issues facing our patients, we have made tremendous progress in treating this tragic illness. Patients maintained long term on second-generation (or atypical) antipsychotics have recovered function and regained their lives and sense of purpose. We must raise the bar on our stan-

II.

INTRODUCTION TO ANTIPSYCHOTIC THERAPY

The serendipitous discovery of neuroleptic medications (from the French neuroleptique—meaning to clasp the neuron) revolutionized our treatments for persistent psychotic disorders. The observation that these agents almost invariably induced parkinsonian features, led to simple animal models to screen these putative medications. Antipsychotics were screened using rodent models which included antagonism of amphetamine’s excitatory effects and the causation of catalepsy, a form of extrapyramidal disturbance [8–10]. Compounds that did not cause catalepsy in animal models were not considered to be effective antipsychotic agents—e.g., clozapine [11]. The theory for dopamine’s primary role in mediating psychosis was supported by the pharmacological and neurochemical characterization of stimulant’s effects on behavior, Parkinson’s disease and its treatment, and neuroleptic activities in both human and animal models. Although dopamine type 2 receptor (D2) blockade is still a component of all marketed antipsychotic agents’ pharma731

732

Ereshefsky

Clozapine’s complex pharmacologic profile is illustrated in Figure 2. Neuroscience insights into brain function and the development of many novel antipsychotics with a wide array of pharmacological effects have led to a dramatic paradigm shift in our conceptualization of schizophrenia and other psychotic disorders [8–10]. Tables 1 and 2 list pharmacological effects of antipsychotic medications, including possible clinical implications and applications for the increasingly diverse selection of drug therapies available for schizophrenia [15–24]. Key pharmacological differences among atypical antipsychotics will be further discussed in this chapter. Figure 1 Relationship of symptoms to function in schizophrenia. The relative importance of changes in positive and negative symptoms, and of cognition deficits on functional capacity of patients with schizophrenia, is illustrated by the differently weighted arrows (cognition improvement being the most important predictor of functional change).

cological profiles, the modulation of other biogenic amines, indirect effects on excitatory aminoacids, and possibly peptidergic systems play a role in many second-generation antipsychotic therapies [12–14].

III.

OLDER TREATMENTS IN THE MANAGEMENT OF SCHIZOPHRENIA

The perceived advantages for the second-generation antipsychotics, e.g., superiority for relieving negative symptoms and their effectiveness in improving several domains of cognitive and social function [25–29], have resulted in the overwhelming majority of patients in the United States receiving these therapies. The goal for rapid calming of agitated or aggressive patients in emergency settings and acute care units poses a chal-

Figure 2 Complex pharmacological profile of clozapine. Clozapine’s pharmacologically diverse array of effects is illustrated. Clozapine remains the ‘‘gold standard’’ against which all other medications’ efficacies are judged. The unique combination of varied dopaminergic, serotonergic, and adrenergic effects across a wide array of receptor subtypes, along with significant effects on neuropeptide neurotransmission, results in a broad-spectrum medication for patients with persistent, treatment-resistant, psychotic and mood disorders.

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= No effect; þ to þ þ þþ represent increasing relative effects (though no single study evaluates all drugs in all dimensions); nt ¼ not tabulated in studies. Source: Ref. 18

1 -Adrenoceptor 2 -Adrenoceptor H1 histamine Serotonin transport Norepinephrine transport

D3 D4 5HT1a 5HT1d 5HT2a 5HT2c 5HT6 5HT7 Muscarinic M1

D1 D2

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cisThiothixene Fluphenazine Haloperidol Ziprasidone Risperidone Loxapine Chlorpromazine Olanzapine Thioridazine Clozapine Quetiapine Iloperidone Aripiprazole

Table 1 Antipsychotic Receptor Pharmacology—Relative Effect by Within-Drug in Vitro Receptor Binding

Pharmacological Treatment of Schizophrenia 733

734 Table 2

Ereshefsky Receptor Effects and their Possible Consequences on Antipsychotic Efficacy and Side Effects

Receptor

Efficacy

Adverse effects

D2

Reduction in positive symptoms of schizophrenia, relapse prevention

D3

Potential alteration in risk of tardive dyskinesia, interacting with genetic polymorphism for D3; possibly enhances efficacy Possible increased dopamine release from neuronal projections to frontal cortex, improving cognition, and reducing negative symptoms Regulation of serotonin release: anxiolytic, antidepressant, and antiaggressive effect Modest reductions in positive symptoms, improved cognition and functional status, improved negative symptoms, improved sleep latency, reduced sexual dysfunction Minimal effects on positive/negative/ cognitive symptoms Possibly enhances efficacy in parallel to 5HT2a effects Possibly enhanced efficacy, especially circadian rhythm disturbances, e.g., sleep. Improved cognition, reduced negative symptoms, and gains in functional status; secondary improvement in positive symptoms Possible indirect neuroprotective effect through glutamatergic system; Reductions in EPS

Extrapyramidal side effects, prolactin elevation worsened cognition at high dose, worsened negative symptoms at high dose Unknown

D4

5HT1a=d partial agonist/antagonist 5HT2a

5HT2c 5HT6 5HT7

Indirect augmentation of NMDA glutamate

Muscarinic M1

Noradrenergic alpha 1

Acute sedating effects may ameliorate aggressive impulses

Noradrenergic 2c

Increased dopamine release; improved cognition, reduced negative symptoms, reduced craving for substances of abuse Acute sedating effects may ameliorate aggression and agitation Antidepressant and anxiolytic effect; improvement in negative symptoms Antidepressant effect

Histamine H1 Serotonin transporter inhibitors (reuptake inhibitors) Norepinephrine transport inhibitors (reuptake inhibitors) Neuropeptide effects, Substance P (NK1, NK3), neurotensin, and CRF1 antagonists

Reduce stress mediated brain dysfunction; reduce cortisol and possible midbrain neurotoxicity

Unknown

Unknown

Excessive dosage results in worsening of obsessive compulsive symptoms

Weight gain, possible increased risk of seizures, reduced efficacy Unknown Unknown

Unknown

Dry mouth, constipation, sinus tachycardia, etc.; worsened cognition, sedation and withdrawal upon abrupt discontinuation Orthostatic blood pressure changes, reflex tachycardia, weight gain, nasal congestion Tachycardia, tremor, sweating, agitation

Weight gain, sedation (may be reduced with chronic dosing) Exacerbate EPS, akathisia, alter sleep pattern, cause sexual dysfunction, possibly increase prolactin May increase agitation, insomnia, and restlessness Unknown

Pharmacological Treatment of Schizophrenia

lenge when using atypical therapies. Rapid calming is not always evident in agitated patients treated with orally administered atypical medications at standard doses. There is a continuing need for intramuscular (IM) therapy using benzodiazepines, e.g., lorazepam, neuroleptics, or combinations of the two, during the crisis management phase for patients with psychotic disorders [30–32]. Second-generation short-acting intramuscular medications are in the final stages of development with olanzapine short-acting intramuscular pending marketing at the time of this chapter’s completion (pending resolution of manufacturing issues). Ziprasidone IM is approved as a medication to manage agitation. Ziprasidone IM 20 mg, rapidly reaches peak concentrations within 1-2 h comparable to an 80 mg ziprasidone oral dose and demonstrates comparable efficacy to modest doses of haloperidol, e.g. 5 mg IM. Whether higher doses of second-generation medications are used to facilitate calming of patients, or if they are combined with traditional neuroleptics, it is essential to recognize that these higher doses or combination therapies, driven by health care economic expedience, do not define appropriate maintenance strategies, where monotherapy at standard doses deliver maximal benefit vs. risk [33–35]. Despite the ongoing role for neuroleptic therapy as an emergency intervention in the agitated patient on atypical medications, it is important to remember that when the atypical medications are administered on a subchronic basis, they demonstrate equivalent or superior efficacy in reducing aggressive behavior and positive symptoms [36–38]. The use of adjunctive neuroleptic therapies should therefore be reserved for those patients requiring rapid reductions in these symptoms, or in those in whom there is only partial response despite optimization of the atypical medication’s dosage. If neuroleptics are used initially, they should not be continued as long-term therapy; rather, atypical agents should be utilized as front-line therapy. An exception to this would be either a history of treatment resistance to atypical agents with a robust response on neuroleptics, or in those where depot therapy is necessary. Moreover, despite the popularity of benzodiazepines as adjunctive calming agents, they are detrimental to cognitive and memory processes [39]. High-potency neuroleptic antipsychotic agents, when used in the acute setting, are also likely to incur EPS, hence the routine use of prophylactic anticholinergic antiparkinsonian therapies. These antimuscarinic agents also are detrimental for cognitive function [40]. Therefore, management of aggression with an antipsychotic that is less likely to incur EPS is highly desirable.

735

A.

SECOND-GENERATION ANTIPSYCHOTICS

Second-generation antipsychotics are characterized as more complex than high-potency neuroleptics and act beyond the single neurotransmitter focus on dopamine D2 receptors (Tables 1, 2). The clinical success of the first ‘‘atypical’’ antipsychotic, clozapine, renewed interest in the role of serotonin (5HT) and other neurochemical systems (noradernergic, peptidergic (i.e., neurotensin, substances P and K), and glutamatergic) in schizophrenia [11]. Clozapine is associated with reduced liability for extrapyramidal symptoms (EPS) and is effective in up to 50% of ‘‘treatment-resistant’’ patients. However, adverse effects including agranulocytosis, myocarditis, and seizures limit the widespread use of clozapine, despite its efficacy in treatment-resistant patients. Clozapine is characterized by weak and loose binding activity at D2 receptors (see below), activity at other dopamine receptors, and potent activity at serotonin 5HT2A ; histaminic; -adrenergic; and neurotensin (neuropeptide) receptors [41]. B.

Dopaminergic System

Many of the effects of antipsychotic medications are tied to their interaction with dopamine neurotransmission in four key brain regions: 1. Mesolimbic system. D2 blockade of the mesolimbic region, including amygdala and hippocampus, is associated with antipsychotic efficacy; all marketed first- and second-generation medications are active in antagonizing the effects of amphetamine or dopamine overactivity. 2. Frontal cortex. Increased dopamine release, mediated by atypical antipsychotics in frontal and prefrontal cortex, leads to improvements in negative symptoms and cognition. In contrast, excessive D2 blockade from high-dose neuroleptic therapy can lead to possible worsening of these symptoms via diminished dopamine firing and release in these brain regions, the result of sustained depolarization blockade. 3. Basal ganglia. Dysregulation resulting from sustained nigral-striatal D2 blocking effects lead to extrapyramidal symptoms, while atypicals reduce the incidence of EPS via a variety of mechanisms including enhanced dopaminergic neuronal firing and release. 4. Turberoinfundibular projections to the pituitary. Antagonism of dopamine’s inhibitory effects by potent D2 blockade results in increased pituitary secre-

736

tion of prolactin [42]. Figure 3 illustrates key dopamine pathways and their significance in the management of patients with psychosis [13]. All antipsychotic drugs have been found, to varying degrees, to antagonize dopamine D2 receptors. Traditional neuroleptic effectiveness has been associated with 65% occupancy of these receptors as demonstrated by positron emission tomography (PET) studies. Usual occupancies at clinically utilized dosages are typically > 75%, a range associated with a high likelihood of EPS. Even at the lower range of occupancies considered effective, the older highpotency neuroleptic drugs maintain a ‘‘tight,’’ longlasting blockade of the receptor, triggering changes in neuronal regulation that lead to dysregulation. Usual conservative doses of neuroleptics are above the threshold for extrapyramidal effects and prolactin elevation. In contrast, clozapine has demonstrated antipsychotic efficacy with only 50–60% occupancy of D2 receptors, even at the highest doses utilized 8–12 h

Figure 3 Dopamine pathways of interest in schizophrenia. The ideal antipsychotic medication for schizophrenia would have three distinct effects in different brain regions of interest. In the basal ganglia, no discernible effect on dopamine neurotransmission is wanted, thereby insuring no EPS. In the limbic midbrain, the classical dopamine hyperactivity (amphetamine) model is still considered applicable to drug mechanism of action, hence the need to block dopamine or counteract its effects. In the frontal cortex and dorsolateral prefrontal cortex, diminished cortical function is thought to result in negative symptoms and reduced cognitive capacity. Increasing cortical function by a variety of mechanisms, including increased dopamine release via 5HT2a blockade, D2 partial agonism and/or 5HT1a agonist effects appears to result in improvement in these non-psychotic manifestations of schizophrenia.

Ereshefsky

postdose, and is associated with very low risk of extrapyramidal side effects and transient, nonsustained hyperprolactinemia. Recent research has refined our awareness of the dopamine D2 receptor system. Work by Kapur and colleagues with 22 patients randomly assigned 2-week low-dose treatment with haloperidol (either 1 or 2.5 mg/d) offers elegant documentation for the threshold of D2 receptor occupancy by antipsychotic: a 65% D2 occupancy is associated with initial efficacy, while prolactin increases already occur at 72% D2 occupancy, and extrapyramidal side effects are observed if D2 occupancy exceeds 75% [41,42]. Atypical antipsychotics continue by a variety of mechanisms to modulate limbic midbrain regions while reducing their deleterious effects on striatal function. Increased cortical function and activity appears to be hallmark of the newer antipsychotics and is probably a result of non-D2 properties of these medications. Prolactin elevation can occur with those newer agents, e.g., risperidone, which potently block D2 receptors in a sustained, ‘‘tight’’ fashion. At high doses of risperidone, e.g., > 6 mg/day, the magnitude and duration of D2 binding begin to mitigate the benefits of the drug’s atypical profile derived principally from serotonin receptor blockade mediated release of dopamine (see the serotonin section). Current treatment guidelines recommend doses of risperidone of 6 mg/day as optimal [35,36]. The ‘‘more complete’’ atypicality observed with quetiapine and clozapine (freedom from EPS at any dosage used) may be in part be explained by low-affinity occupation (‘‘loose’’ binding with rapid dissociation) of the D2 receptor [41,43]. Their observations indicate that low-affinity antipsychotics have transient periods of occupancy of D2 receptors paralleling the drug’s pharmacokinetics (e.g., blood levels). At maximum concentrations postdose of quetiapine, for instance, higher than previously observed binding of 70% occurs perhaps accounting for ‘‘loose’’ bound drug’s antipsychotic effect. This less sustained D2 occupancy is insufficient to disrupt striatal transmission and precipitate extrapyramidal symptoms. Both clozapine and quetiapine demonstrate D2 receptor occupancy rates in the 60–70% range 2 h postdose, falling to 20–55% at 12–24 h postdose. Prolactin elevations are transient with those drugs, paralleling the time course of significant D2 occupancy, e.g., clozapine and quetiapine. The loose binding associated with quietapine, when coupled with its relatively short half-life, results in rapid receptor dissociation from the D2 receptor, explaining why twice-daily dosing is recommended for acute/initial effi-


cacy, and also explains the need for much higher doses than originally used in the management of acutely psychotic patients, e.g. > 800 mg day. Olanzapine has attenuated D2 blocking side effects in part due to its intermediate binding for the D2 receptor and due to pharmacological complexity that is most similar to clozapine. Normalization of hyperprolactinemia and related hormonal changes has been reported when patients are switched from neuroleptics or risperidone to olanzapine, clozapine, ziprasidone, or quetiapine [11,44,45]. Seeman and colleagues have suggested that the concept of loose versus tight binding can be used to predict clinical characteristics of antipsychotic medications (Table 3). Ziprasidone is considered intermediate in its binding tightness, as well, based on pilot PET data, with peak occupancies approaching 80% following a 60-mg dose (usually administered BID) and 12-h trough binding < 60%. This rapid fall in occupancy is in part due to ziprasidone’s shorter half-life (4–11 h) as well [46]. A novel approach to antipsychotic therapy is the development of D2 partial agonist/antagonist compounds. These partial agonists provide dopaminergic effects in systems where endogenous activity for dopamine is low, and antagonist effects in those areas where dopamine is hyperactive. If the balance point between effects is properly selected, it should be possible to obtain increased dopaminergic function in cortical structures, reduced activity in limbic midbrain regions,

Table 3

737

and no discernible effects in the striatum. If dopaminergic agonist effects are in excess, then restlessness, insomnia, psychosis, and cardiovascular effects— e.g., hypotension and tachycardia—are observed, while overly potent blockade can lead to hyperprolactinemia, EPS, and tardive dyskinesia risk [47,48]. Of the many dopamine partial agonist medications studied over the past 10 years, aripiprazole (NDA filed with the FDA, Bristol Myer Squibb/Otsuka Pharmaceuticals) seems to best approximate this needed balance [49–51]. [See Table 1 for a summary of receptor pharmacology (51–55).] In addition to partial agonist properties, aripiprazole shares effects on serotonin receptor subtypes, similar to ziprasidone. Aripiprazole is nonsedating and has shown efficacy comparable to risperidone 6 mg/day in short-term, 4week efficacy trials [50–52]. In contrast to risperidone, prolactin is either lowered or unchanged. Aripiprazole’s EPS rate except for akathisia is at a placebo-like level at effective doses. Looking toward future applications, a specific genetic polymorphism at D2 receptors leads to a significantly lower response rate to neuroleptic therapies. Work by Suzuki et al. [56] suggests that D2 receptor polymorphism (Taq1 A1 vs. A2) may modify D2 occupancy and account for early response rates in a subpopulation with one or two A1 alleles. Although the syndrome of schizophrenia may ultimately be refined into distinct disease states characterized by biological

Loose Versus Tight D2 Receptor Binding: Predicted Clinical Implicationsa Tight binding (high affinity, long duration)

Representative drugs

Haloperidol, risperidone, fluphenazine, chlorpromazine

Dissociation rate from D2 EPS and TD risk

Slow High

Hyperprolactinemia

High and sustained

Rapidity of receptor washout Weeks to months Rapid relapse upon cessation Low of long term therapy Need for initial divided Low dosing

Intermediate binding Ziprasidone, olanzapine, loxapine, (sertindole removed from worldwide markets) Intermediate Moderate to low, dose dependent Moderate to low, dose dependent, possibly transient Days to weeks Low Low; except ziprasidone, which has a short half-life

Loose binding (low affinity, short duration Clozapine, quetiapine (remoxipride removed from worldwide markets) Fast Low, dose independent Low, transient

Days High Moderate

a Predictions do not take account other relevant pharmacological effects, e.g., 5HT2a , which modify risk or efficacy parameters. Source: Ref.

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markers that are predictive of disease presentation, genetic evaluations have been inconclusive. In contrast, genetic polymorphisms which appear to predict response and adverse effects from antipsychotic therapy are demonstrating greater initial promise. Such biological markers could inform drug development and drug selection, potentially identifying subpopulations in which a drug’s benefits are maximized. Another illustration is the association between the risk of TD from antipsychotics and a specific homozygous D3 receptor polymorphism Ser9Gly. Twentytwo percent to 24% of patients with TD vs. 4–6% in patients without TD have this homozygous polymorphism [57]. Interestingly, newer antipsychotic agents have widely varying D2, D3, and D4 receptor affinities, which deserves further study and might form a basis for selecting a drug with differing side effects potential in subpopulations of patients [58,59]. Lastly, CYP2D6 polymorphisms play a role in risk for TD with phenothiazines and haloperidol. IV.

SEROTONIN

The success of clozapine for treatment-resistant patients also led investigators to seek plausible pharmacologic mechanisms for its atypicality. According to Meltzer and colleagues [60], the central pharmacologic profile for atypicality is a high serotonin 5HT2a /D2 occupancy ratio resulting in a functional antagonism of D2 blockade-mediated adverse effects in the striatum, as well as beneficial therapeutic effects in mesocortical circuits [60,61]. Refinement of Meltzer’s theory has been proposed by Kapur and Remmington [62]: 5HT2 occupancy and D2 occupancy as measured by PET are potentially independent (but interacting) dimensions of antipsychotic effect. This model partitions new-generation antipsychotics into three categories (Table 4). The dopamine neuron’s release from serotonergic inhibition by blockade of postsynaptic 5HT2a heteroreceptors leads to increased DA transmission in the

striatum (less EPS) and in the cortex (treatment of negative symptoms and improvement in cognitive function) [63]. The density of 5HT2a receptors in limbic midbrain is quite low, providing a rationale for the effectiveness of the second-generation drugs to treat, rather than worsen psychosis, while reducing EPS and negative symptoms. Alternatively, inhibition of serotonin firing with reduced serotonin 2 heteroreceptor activation can also increase dopamine transmission in these regions of interest [64]. Changes in serotonin firing rate can be achieved by activating pre- and postsynaptic 5 HT1a receptors. Antipsychotics that act as partial agoinclude aripiprazole ¼ nists at 5HT1a ziprasidone > clozapine quetiapine, and lead to increased dopaminergic release in cortical regions. Additionally, this serotonergic agonist effect when coupled with 5HT2a blockade mimics the antidepressant and anxiolytic actions of many commonly used psychotropics—e.g., SSRIs, nefazodone, and buspirone. The 5HT1a partial agonist buspirone is an effective anxiolytic, has been useful in managing aggression, and has been reported to have beneficial effects on symptoms of schizophrenia when used as an adjunct in patients treated with conventional antipsychotics [65]. Several of the newer antipsychotics have nonselective affinity for both 5HT2a and 5HT2c (clozapine, olanzapine) while others are more selective for 5HT2a (risperidone and quetiapine). While there does not appear to be a relationship between 5HT2c affinity and antipsychotic efficacy, there is a possible correlation between activity at this receptor and weight gain [64,65]. The propensity for antipsychotic medications to cause weight gain and possible adverse consequences on glucose and lipid regulation is in part tied to 5HT2c and other aspects of serotonin neuromodulation, as well as to H1 antihistaminic effects and changes in insulin receptor sensitivity and leptin levels. Switching medications in response to significant weight gain should be clinically indicated by a benefit vs. risk assessment. A recent meta-analyses for weight gain

Table 4 Classification of Antipsychotic Drugs by their 5HT2a and D2 Receptor Occupancy Characteristics PET occupancy: PET occupancy: PET occupancy: Combined serotonin PET occupancy: 5HT2 /dopamine high 5HT2 (> 80%), high 5HT2 (> 80%), high 5HT2 (> 80%), low 5HT2 ð< 80%Þ, D2 threshold model high D2 (> 70%) intermediate D2 (< 80%) low D2 (< 70%) low D2 (< 60%Þ Antipsychotics a

Risperidone Sertindole

Olanzapine Ziprasidonea

Clozapine

Quetiapine

Other effects such as serotonin transporter inhibition and 5HT1a blockade further modify this drug’s profile Source: Ref. 62.


potential for various antipsychotic medications ranked commonly used medications as follows: clozapine olanzapine > risperidone > haloperdol aripiprazole ziprasidone [66]. A robust patient treatment response should not be sacrificed for potential concerns about weight gain. Overall quality of life may be best served by maintaining the most effective medication. Nondrug interventions to manage weight in responding schizophrenic patients should be considered—e.g., exercise and diet. In patients who have gained significant weight, ongoing monitoring of lipids and fasting glucose are also necessary to forestall the development of dyslipidemia and diabetes mellitus. Genetic cloning of serotonin receptors has identified additional potential serotonergic targets of antipsychotic drug action. 5HT6 receptors pharmacologically resemble 5HT2 receptors and 5HT6 receptor mRNA is expressed extensively in the striatum. Clozapine and olanzapine have high affinity for the 5HT6 receptor which may also contribute to both efficacy and to improved cortical function via excitatory amino acid systems (see below). 5HT7 receptor modulation is thought to affect circadian rhythms and may be especially beneficial for patients with insomnia. Ziprasidone and risperidone each have high affinity for the 5HT7 receptor with intermediate and no affinity, respectively, for the 5HT6 receptor. Clozapine and olanzapine have moderate affinity for 5HT7 . Activity at one or both of these receptors may account for differential effects seen with some atypical antipsychotics, and could be considered as part of a ‘‘multidimensional’’ comparison when deciding upon switching antipsychotic drugs [67].

V.

GLUTAMATE EXCITATORY AMINO ACID SYSTEM

N-methyl D-aspartate (NMDA) glutamatergic antagonists such as phencyclidine (PCP) and ketamine can induce a psychosis and altered behavioral/cognitive state that mimics schizophrenia including hallucinations and disturbances of reality testing, autistic preoccupation, memory disturbances, negative symptoms, and reductions in prepulse inhibition (cognitive function) [68–72]. This NMDA hypofunctioning state, characterized by hypofrontality with midbrain overactivity, has been proposed as a model of schizophrenia. This model hypothesizes that hypofunction of the glutamate receptors may be genetically or environmentally mediated early in life, and expressed with maturational changes in the adolescent brain.

739

Hypofunction of the NMDA receptors causes compensatory excessive release of the excitatory neurotransmitters acetylcholine and glutamate in the cerebral cortex. Overstimulation of postsynaptic receptors then causes disturbances of thought and behavior and may also cause excitotoxic damage if exposure is prolonged [73]. This model has been of great heuristic value as it provides a testable hypotheses across a spectrum of investigational technologies. Most of the newer antipsychotic agents by modulating serotonin 5HT2a and/or 5HT6 receptors appear to normalize and improve glutamate function in a variety of animal and human models for schizophrenia and cognitive function. This is demonstrated in studies using the glutamate antagonist ketamine, and supports a model where glutamatergic receptor hypofunction translates to hypofrontality, cognition deficits, and negative symptoms. Investigations using glycine, an allosteric modulator of the NMDA receptor or d-cycloserine, a full agonist at the glycine site, as augmenting agents for antipsychotics have demonstrated beneficial effects for negative symptoms and cognition, but they do not improve positive symptoms [74–76]. Moreover, clozapine’s effects are not augmented by the addition of glycine. This indirect evidence has been interpreted as support for a direct clozapine-mediated effect on NMDA that is not a feature of conventional antipsychotic treatment. Atypical antipsychotics, especially olanzapine, clozapine, and quetiapine, have clearly demonstrated the ability in a dose-related fashion to antagonize the deleterious effects of ketamine administration in either or both animals and patients with schizophrenia, while risperidone does not uniformly cause this effect (low doses protect, high doses do not) [76–78]. Whether clinically meaningful differences in glutamate activity exist among atypical antipsychotics is unclear, but could form the basis for selecting a particular agent when cortical hypofunction, e.g., negative symptoms and cognition deficits dominate the clinical picture. There does appear to be a significant difference among neuroleptics as a class in comparison to atypical therapies, further reinforcing the preference for the second generation medications [79]. Additional treatment implications arise from the glutamatergic hypothesis including: 1. Genetic linkages to schizophrenia are more likely to be discovered in the genes modulating neuroprotection and neurotoxic processes [80–82]. 2. Drug development is being guided in a new and novel direction away from ‘‘classical’’ D2 and 5HT2a antagonists [81].

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3. Augmentation strategies for partially responding schizophrenics include medications which modulate glutamatergic systems (serine, glycine; see above) as well as anticonvulsants with activity in the excitatory aminoacid systems, e.g., lamotrigine [83]. A.

Adrenergic

Side effects mediated by 1 -adrenoceptor antagonism include reductions in blood pressure, with associated orthostatic hypotension and acute sedation. Tachyphylaxis to these effects occurs, so tolerance to orthostasis occurs within a few days, resulting in little need to switch from one therapy to another (except in debilitated or fragile elderly patients). Switching from one 1 blocking agent to another, in the stable and tolerant patient, is usually uneventful, provided the dose of the current therapy is reduced sufficiently to offset the effects of the new therapy. If an 1 -blocking medication is stopped for more than a week, it is necessary to reinstitute dosage back at the recommended starting dose, since tachyphylaxis abates rapidly following discontinuation of drug [2,8,10,11]. Clozapine, for instance, should be started at 12.5 mg QD or BID, even though maintenance doses as high as 900 mg/day are safely utilized [35]. The 2 -adrenoceptor has been the subject of recent interest as a possible mediator of antipsychotic effect with specific interest focused on the role 2C antagonism plays in augmentation of dopamine output in the cortex [84]. One investigator has demonstrated that administration of an 2 antagonist (idazoxan) to rats treated with a strong dopamine D2 antagonists (raclopride) led to increased dopamine release in the prefrontal cortex compared to raclopride alone [85]. In a behavioral model of antipsychotic efficacy, 2 antagonism resulted in significantly lower doses of raclopride for response than with raclopride alone. The ratio of 2C /D2 receptor affinities has been suggested as an important new consideration in identifying drugs with potential atypical properties. Iloperidone (Phase III, Zomaril, Novartis Pharmaceuticals), clozapine, and quetiapine appear to have the greatest selectivity in in vitro receptor antagonist studies [86]. Iloperidone has a prominent effect on dopaminergic neurotransmission via 2C , complementing its favorable impact on negative symptoms and cognition deficits in patients with schizophrenia. Interestingly, it may also stabilize dopamine reward circuits involved in drug ‘‘craving,’’ potentially providing clinicians with a new strategy for reducing substance dependence in patients with schizophrenia [87]. Future research is required to

clarify the role of the 2 -adrenoceptor subtypes in treating schizophrenia and psychosis (Tables 1, 2). B.

Muscarinic

There is an inverse relationship between affinity for the muscarinic receptors and potential for causing extrapyramidal symptoms. Blockade of muscarinic type 1 (M1) receptors is associated with decreased extrapyramidal side effects with antipsychotic drugs [14]. Blockade of M1 is also associated with anticholinergic side effects typified by classical atropinelike symptoms. More significantly, for patients with schizophrenia, antimuscarinic effects can result in memory disturbances and other cognitive adverse effects (Tables 1, 2). Predicting antipsychotic medications’ M1 blockadeinduced clinical effects solely by in vitro receptor binding affinity is misleading, since muscarinic effects are modulated by serotonergic and other cholinergic receptors potentially affected by medications. Hence the in vitro M1 potency of olanzapine does not accurately predict clinical side effects. In vivo in patients with schizophrenia it may more potently bind to the M2 receptor, explaining its low anticholinergic sideeffects profile [88]. Muscarinic rebound can occur when an antipsychotic agent with M1 antagonist effects is either abruptly discontinued or tapered too quickly. These symptoms include GI cramping, diarrhea, insomnia, nightmares, and nervousness. This is more likely to occur when the antipsychotic being switched to has little or no M1 blocking effects, e.g., risperidone, ziprasidone, or quetiapine. A slower taper of the first agent is warranted.

VI.

NEUROPEPTIDES: NEUROTENSIN AND SUBSTANCE P

Neuropeptide systems including neurotensin, enkephalins, and substance P have been implicated in the clinical manifestations of schizophrenia [89–92]. The relevance of these neurotransmitters to the clinical setting and specifically to antipsychotic switching has not been clarified, but future research may identify differential effects for available drugs mediated through one or more of these systems. Neurotensin agonist effects in particular are observed with antipsychotic agents, and appear to be differentially affected by atypical vs. typical antipsychotics. Neurotensin is colocalized on dopaminergic neurons and haloperidol, but not clozapine or olanzapine increase neurotensin concentrations in the striatum, yet both drugs affect nucleus


accumbens neurotensin levels [14]. Neurotensin modulators with agonist activity and NK-3 antagonists are in clinical development for schizophrenia, and pivotal trials have demonstrated efficacy and safety. Basic science and behavioral models strongly support neurotensin neurotransmission as a viable target for antipsychotic drug effect [93–96]. Substance P antagonists have been tried in schizophrenia without success [97], but appear to reduce stress reactions under a variety of conditions.

VII.

BIOGENIC AMINE TRANSPORTER

The antipsychotic ziprasidone inhibits in vitro both the serotonin and norepinephrine transporter. Ziprasidone’s pharmacological similarity to antidepressants may be one of the mechanisms, explaining its beneficial effects on depressive symptoms in double-blind, placebo-controlled studies in schizophrenic patients [98]. Clozapine, olanzapine, and loxapine have moderately potent adrenergic transporter inhibitor effects, potentially contributing to their efficacy for depressive symptoms in patients. Most atypical antipsychotics have demonstrated beneficial effects on mood, but potential significant differences in these effects between various atypical antipsychotics have not been tested in head-to-head clinical trials [99] (Tables 1, 2). However, both clozapine and olanzapine have been demonstrated to reduce the rate of suicide attempts when compared to standard neuroleptic therapy and to risperidone, respectively [100–102]. Comparing and contrasting the pharmacological properties of first- and second-generation agents, and similarly differentiating between atypical therapies, can assist in determining best treatment for the patient. Considerations include potential differences in target symptom responses, risks for adverse effects, and rebound withdrawal reactions upon abrupt discontinuation. Table 2 lists possible clinical consequences of these medications’ neurochemistry. These differences can be exploited in both partially responding patients, as well as guide the clinician in selecting a medication likely to reduce adverse effects. These pharmacological differences are consistent with recent treatment guidelines and algorithms on antipsychotic selection [25,26,34,35]. A pharmacologically based evaluation of the atypical agents can facilitate the selection of best therapy for patients with schizophrenia. To illustrate, for negative symptoms, switching from a neuroleptic to an atypical agent, or downward titration of typical antipsychotics

741

toward the lowest possible dose should be considered. In the case of poor or inadequate negative symptom response: 1. Consider if these are primary versus secondary (i.e., adverse drug effect) negative symptoms. 2. Choose a drug that minimizes the impact of EPS (e.g., loose to intermediate D2 binding antagonists, or lower doses of risperidone) which can result in apathy and reduced volition. 3. Select an agent that ameliorates depressive symptoms (i.e., ziprasidone, olanzapine, clozapine) if present. 4. Improve cortical and prefrontal function by selecting a medication which increases dopamine and demonstrates glutamate effects. As discussed above, cortical activation can be accomplished by selecting atypical antipsychotics with 5HT2 activity, 2c antagonism (risperidone, clozapine, quetiapine), 5HT1a agonist effects (ziprasidone quetiapine), and/or D2 partial agonist effects (aripiprazole). 5. Add an adjunctive drug, with differing pharmacological actions from the antipsychotic being used, that may yield an improvement in negative symptoms [25,26,34,35,99]. These differences between medications provide clinicians and patients with more choices, and increase the chance of finding the right drug for the patient with schizophrenia. Hence, if one drug does not provide the desired benefit for a patient, then switching to another atypical medication is appropriate, and has a good chance of working!

VIII.

DOSAGE GUIDANCE

The determination of minimum dosage for drugs with potent D2 receptor antagonist properties is of great interest, though few placebo-controlled trials with fixed-dose paradigms utilize neuroleptic threshold dosing. One recent study incorporated three fixed-dose treatment arms for haloperidol (4, 8, and 16 mg/day) against placebo and sertindole (potent 5HT2a antagonist/D2 antagonist withdrawn from testing/marketing in the US due to QTc prolongation and cases of ‘‘sudden death’’). These doses of haloperidol demonstrated excellent clinical efficacy based on the mean change from baseline on the PANSS. The modest improvements observed in negative symptoms using the SANS, rather than worsening, underscore the need for lower than previously appreciated doses of neuroleptic. However, even at these lower doses, e.g., 4 mg/ day of haloperidol, significant extrapyramidal symp-

742

Ereshefsky

toms were present when compared with sertindole [103]. Recently, sertindole has been re-introduced into the european marketplace. Loxapine’s intermediate potency for D2 blockade is associated with lower rates of EPS than haloperidol, when utilized in dose ratios of 10 mg loxapine equivalent to 2 mg haloperidol [104–106]. Moreover, it’s possible beneficial effects on negative symptoms via 5HT2a blockade deserve further clinical exploration. The importance of dosage for drugs with 5HT2A/ D2 ratios in an intermediate range, e.g., 10–15 as listed in Table 1, is illustrated by two recent comparative trials with risperidone and olanzapine. Risperidone at an average dose of just over 8 mg/day has been demonstrated to have significantly greater EPS (and other adverse effects) when compared in a double-blind trial with olanzapine at an average dose of 18 mg/day [100]. Efficacy as demonstrated by mean change from baseline on the PANSS suggested some advantages for the olanzapine treatment group. In contrast, a different study’s results evaluating risperidone at an average dose of 4.8 mg/day demonstrated no statistically significant differences in EPS or response when compared to olanzapine [107]. The nature of clinical trials, including use of placebo controls, and analyses using intent-to-treat with last observation carried forward, leads to a highly conservative approach to ensure rejection of false positive treatment results. However, this leads to distortions in best dosage and in a clear picture of effectiveness in the real world. Table 5 lists recommended dosage ranges from product labeling, and also lists revised dosage ranges based on after-market experience and studies [25,26,34,35,99].

IX.

PHARMACOKINETIC AND DRUG INTERACTION CONSIDERATIONS

The pharmacokinetics and drug interaction potential for selected antipsychotics are summarized in Table 6 [108]. In general, half-life is not by itself an important consideration, since plasma concentrations do not always mirror receptor binding, e.g., loose vs. tight binding at D2. However, medications with a short half-life and/or looser D2 binding, e.g., quetiapine, clozapine, and ziprasidone, can require additional care when titrating upward or downward during a transition from one drug to another. Divided daily dosing is recommended during the transition For patients being withdrawn from high-dose neuroleptic therapy longer cross tapers are needed when switch-

ing therapies. It may take several weeks or longer to completely wash out the D2 receptor effects and residual EPS. Substituting a weak/loose D2 receptor atypical agent can result in gradual positive symptom worsening over months of time after depot therapy discontinuation as well as withdrawal dyskinesias [109]. Drug interactions from switching are most likely to occur when either haloperidol or phenothiazines are tapered or started (potent CYP2D6 inhibitors). However, since switching entails the gradual decrease in the first drug as the replacement drug is started, drug interactions pose minimal problems. Monitoring for changes in clinical effects and adverse drug effects are necessary whether drug interactions are present or not. Drug interactions can significantly increase or decrease the levels of a drug already titrated to effect resulting in adverse events or treatment failure. Illustrative drug interaction considerations include: 1. Fluvoxamine (to increase levels) with cigarette smoking (to decrease levels) for drugs which are a CYP1A2 substrates (Table 6). 2. Carbamazepine, rifampin, and phenytoin (to decrease levels); or erythromycin, protease inhibitors, grapefruit juice, macrolide antibiotics (erythromycin), and nefazodone (to increase levels) affect drugs metabolized by CYP3A4. Of particular note is the marked sensitivity of quetiapine to CYP3A4 drug interactions explained by its high first-pass metabolism via gut wall. 3. Paroxetine, fluoxetine, haloperidol, and phenothiazines (to increase levels) of drugs metabolized via CYP2D6 (Table 6) [108,110–118]. Drugs with a single identified major metabolic pathway (depicted as þ þ þ in the table) are more sensitive to drug-drug interactions at that metabolic enzyme than those medications which have more than one pathway. For drugs with a major (þ þ þ) noncytochrome P450 metabolic pathway, drug interactions at CYPs are infrequent; i.e., ziprasidone concentrations are only modestly elevated when combined with ketoconazole, due to the major pathway via aldehyde oxidase [119]. Additionally, drugs that have active metabolites of roughly comparable clinical effect are far less likely to undergo significant drug interactions. Risperidone is converted to 9-OH-risperidone, a 5HT2 and D2-blocking drug of roughly equivalent effect to the parent drug. Therefore, even though the ratio of risperidone to 9-OH-risperidone dramatically shifts in the presence of an CYP2D6 inhibitor, the sum of the ‘‘active moiety’’ remains constant.

1 mg BID 20 mg BID

Risperidone

Ziprasidone (Geodon)

40–160 mg/day in divided doses

2–16 mg/day

150–800 mg/day in divided doses

25 mg BID/TID

Clozapine (Clozaril, generics) Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Label maintenance dose

Investigational dosing 15–30 mg 15 mg QAM 12.5 mg first dose 200–900 mg/day in divided doses 10 mg HS 5–20 mg/day

Label Starting dose

Aripiprazole (Abilitat)

Drug

Table 5 Dosing Recommendations in Adults with Schizophrenia

10–30 mg/day; rapid reverse titration in acute settings from 30 mg downward Inpatient: 50–100 mg BID; rapid titration in acute setting to 400–600 mg/ day Evaluate 4 mg/day, prior to titrating to 6 mg/day 40 mg BID; rapid titration in acute setting to 120– 160 mg/day

None

Modified starting dose

30 mg

Maximum dose

8 mg/day 200 mg/day

80–160 mg

1000 mg/day

2–6 mg/day

400–800 mg/day

300–400 mg/day 900 mg/day in divided in divided doses doses 15–20 mg/day 40 mg/day

20 mg

Usual dose

Pharmacological Treatment of Schizophrenia 743

744

Ereshefsky Table 6

Antipsychotic Pharmacokinetics: Half-Life and Metabolic Pathways

Drug

Half-life (hours) CYP 1A2 CYP 2C CYP 2D6

Haloperidol Clozapine

14–30 18–36

þþ þþþ

Risperidone 9-OH risperidone Quetiapine Olanzapine

3–4 18–36 2–4 24–40

— — — þþþ

Ziprasidone Aripiprazole Iloperidone

4–10 72 9–22

þ — —

— þ/— (2C9/10) — — — þ/— (2C19) — — —

CYP 3A Other pathways

þðred HL) þ þ þ þ/— þþ

Reductase 2E1, FMO

þþþ — — þ

—? — þþþ þ/—

Conjugation 20 metabolites FMO Glucuronidation

— þþþ þþþ

þþ þþþ þþ

þ þ þ Aldehyde oxidase Reduction; black-oxidation via 2D6?

þ þ þ Major pathway; þþ significant pathway; þ minor pathway; þ/— possible pathway; — not a pathway; FMO ¼ flavin-containing mono-oxygenase system; CYP ¼ cytochrome P450 (heme-containing mono-oxygenase).

X.

REASONS TO SWITCH PATIENTS [18,25,26,34,35,99]

A decision to switch therapy from one antipsychotic to another should be informed by evaluating the available literature for evidence of differential antipsychotic effectiveness, patient safety, medication tolerability, and patient preference. A thorough patient history is essential to identify both potential response patterns and to assess dosage (sensitivity to adverse effects). However, a data-driven approach to decision making is difficult since research lags behind the needs of our patients, and many new therapies have only limited comparative data. As a result, information to guide clinical decisions must be derived in part from an awareness of the more basic sciences: the neurochemistry and pathophysiology for schizophrenia and other persistent psychotic disorders, and pharmacodynamic and pharmacokinetic characteristics of the medications. Best-practice guidelines should be developed based on an evidence-based literature review and use of an expert consensus panel when treatments ‘‘beyond’’ controlled studies are to be considered. This is the approach used in the development of the Texas Medication Algorithm Project: Figure 4 illustrates the current revision of the Texas Implementation of Medication Algorithm’s strategies flow sheet http://www.mhmr.state.tx.us/centraloffice/ medicaldirector/timascz1algo.pdf) [35]. Failure to

respond to one antipsychotic at an appropriate dose and duration should result in the systematic sequential use of other novel antipsychotic therapies. Neuroleptic therapy should be viewed, unless prior history suggests otherwise, as third- to fourth-line therapy, if it is to be tried at all. An exception is in the nonadherent patient where first-generation depot therapy can be necessary, while we await the introduction of long-acting second-generation therapies [120–122]. Moreover, when more than one antipsychotic is considered a comparable choice, then and only then, should cost enter into the decision making process.

XI.

POSITIVE SYMPTOMS AND AGGRESSION [18,25,26,34,35,99]

In selecting a new treatment for positive symptoms, numerous pharmacologic approaches are possible. First, maximize current therapy including evaluation of the patient for akathisia and other forms of EPS. If significant EPS is present, increasing the dosage of the current agent is not recommended. If on a neuroleptic agent where plasma concentration monitoring might have meaning, e.g., haloperidol or fluphenazine, then consider an 8- to 12-h postdose level [120–122]. Additionally, consider if impulsive and aggressive symptoms deserve treatment with mood stabilizers or


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Figure 4 Revised Schizophrenia Texas Medication Algorithm. Revised Texas Medication Algorithm Project, developed by consensus conference for the Texas Implementation of Medication Algorithms. Note that ziprasidone has been added as a firstline second-generation antipsychotic. The role of neuroleptic therapy is relegated to third-line status, while clozapine therapy is recommended following two trials of second-generation antipsychotics of adequate duration and dosage. Legend: FGA, firstgeneration antipsychotic (AP); SGA, second-generation AP.

behavioral therapies. For persistent positive symptoms consider: 1. If currently on neuroleptic therapies, switch to second-generation agents. All of the newer medications demonstrate significant antiaggressive, mood-stabilizing, and antipsychotic effects via D2 and 5HT2a blocking effects comparable or superior to neuroleptics. 2. If already on an atypical agent with beneficial effects for symptoms other than the positive ones, then consider increasing the dose of the current therapy (increasing D2 effect), ‘‘topping off’’ with low-dose neuroleptic, or switch to an agent with a more balanced D2/5HT2a effect, e.g., risperidone or loxapine. 3. Choose an agent with activity at 5HT1a (clozapine, quetiapine and ziprasidone) potentially useful in diminishing impulsivity and symptoms of anxiety and irritability.

4. Consider the importance of individual drug therapy’s unique effects on 5HT6 , 5HT7 , neurotensin, substance P, and glycinelike NMDA activity. 5. Use clozapine if at least two other atypical agents have been tried first.

XII.

NEGATIVE SYMPTOM [18,25,26,34,35,99]

In general, switching from a typical neuroleptic to an atypical agent, or downward titration of typical antipsychotics toward the lowest possible dose, should be considered. In the case of continuing poor or inadequate response: 1. Consider if these are primary versus secondary (drug ADEs) negative symptoms. Choose a drug that minimizes the impact of EPS (e.g., low/intermediate-

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affinity D2 antagonists) and/or ameliorates depressive symptoms (ziprasidone, olanzapine, clozapine). 2. Improve cortical and prefrontal function by increasing dopamine and/or glutamate effects. This can be accomplished by selecting atypical antipsychotics with 5HT2a and/or 5HT6 activity (increased prefrontal dopamine), 2c antagonism (risperidone, clozapine, quetiapine) and/or 5HT1a agonist effects (ziprasidone, quetiapine). 3. Add an adjunctive drug or therapy, with differing pharmacological actions than the antipsychotic being used, that may yield an improvement in negative symptoms (e.g., cycloserine, glycine, SSRIs, bupropion, low-dose psychostimulants, or psychosocial treatment).

XIII. COGNITIVE SYMPTOMS/ DISORGANIZED BEHAVIOR [18,25,26,34,35,63,99] Atypical antipsychotics are preferred in comparison to conventional agents. In long-term studies of > 3 months and up to 12 months’ duration, atypical antipsychotic agents appear to improve cognition and functional attainment of patients, whereas typical neuroleptics demonstrate little to no benefit. Based on empirical data from investigations of cognitive performance in the laboratory in both humans and animals, improvement is probably related to increased dopamine release and/or increased neuronal activity in prefrontal cortex and other mesocortical structures. Choose agents with minimal anticholinergic activity (order of M1 potency: clozapine low-potency conventionals > olanzapine quetiapine ¼ risperidone ¼ ziprasidone. Additionally, avoid adjunctive anticholinergics for EPS and benzodiazepines for akathisia, which can worsen cognitive performance. Switch patients to agents with lower EPS potential if abnormal motor function persists. It is also important to note that reducing neuroleptic dosage also appears to improve congnitive test performance. In many patients an effective therapy, which begins to reduce negative symptoms and improves cognition, can be accompanied with an accompanying worsening in psychic tension, depressive symptoms, insomnia, and even hallucinations. The ‘‘awakening’’ phenomenon, which can sometimes be dramatic in a patient now receiving the ‘‘right’’ therapy, can lead to intense dysphoria as the patient realizes how terrible their life has been, and acknowledges their losses (personal and occupational). Adjunctive psychosocial interventions

Ereshefsky

are a critical part of the successful therapy of patients with schizophrenia [7,123].

XIV.

AFFECTIVE SYMPTOMS [18,25,26,34,35,99]

Manic, depressive, or mixed-mood states can be treated either using monotherapy second generation drugs or in combination with mood-stabilizing or antidepressant therapies. Atypical antipsychotic drugs are strongly preferred over typical antipsychotic agents in these patients. Some considerations include: 1. Depressive symptoms are more commonly observed in patients receiving neuroleptics (especially at excessive dose) than with atypical agents. If depressive symptoms are present on risperidone or neuroleptics, consider lowering the dosage prior to switching, since D2 blockade can lead to inadvertent secondary symptoms. 2. Olanzapine and clozapine in monotherapy, and risperidone, quetiapine, and ziprasidone as adjunctive therapies, have all demonstrated utility in acutely manic patients with bipolar affective disorder. 3. Combined 5HT2a blockade along with 5HT1a agonist effects should result in potent anxiolytic and antidepressant effects. 4. Olanzapine and clozapine have data demonstrating reduced rates of suicide attempts, further illustrating potential benefits on mood. 5. Ziprasidone’s significant effects as a dualmechanism, noradrenergic and serotonergic transporter-importer imparts antidepressant effects at higher doses, e.g., 120–160 mg/day. If manic excitement occurs dosage reduction (20–40 mg/day) is usually sufficient to manage these symptoms. A.

Cardiovascular Safety and Tolerability

The cardiovascular safety of antipsychotics, especially the concerns about cardiac conduction disturbances, leading to torsades de pointes arrhythmias, ventricular fibrillation, and to sudden death, is not new. The rare occurrence of sudden death in patients on sertindole was a reminder of an issue initially raised for lowpotency phenothiazine agents such as thioridazine in the 1970s [124–132]. Most antipsychotic therapies appear, at least in vitro, to demonstrate some capacity to block IKr (potassium rectifier fast channel) in the myocardium, potentially causing prolongation of QTc. In June of 1998, the FDA issued to Pfizer Pharmaceuticals a nonapprovable letter for ziprasi-


747

Figure 5 Change in QTc from baseline for various antipsychotic medications. This dose-controlled study utilized normal maximum daily doses of each antipsychotic listed administered to achieve steady state (SS). EKGs were obtained at peak plasma concentration, and the graphic displays the mean change from baseline for QTc along with the 95% confidence intervals (CI). If the CI passes through 0, there is no statistically significant change in QTc. The QTc was calculated, correcting for heart rate, by use of the baseline method ¼ QT=RR0:40 . Note that the lower CI for thioridazine passes above the upper CI for ziprasidone 160 mg/day. Metabolic inhibitors (MI) were added to each drug at full dosage, and administered until steady state was reachieved. The confidence intervals associated with these observations for each antipsychotic medication’s change in QTc represent a worstcase scenario.

done based on ‘‘the judgment that ziprasidone prolongs the QTc and that this represents a risk of potentially fatal ventricular arrhythmias that is not outweighed by a demonstrated and sufficient advantage of ziprasidone over already marketed antipsychotics.’’ Haloperidol and droperidol (black box warning recently added to label) also prolong QTc in a concentration-dependent fashion [129,130]. To address these concerns Pfizer conducted an open-label parallel randomized study (#054), as a head-to-head safety evaluation (to maximal doses) against haloperidol (15 mg/ day), thioridazine (300 mg/day), olanzapine (20 mg/ day), risperidone (16 mg/day), and quetiapine (750 mg/day). These data were presented at the FDA Psychopharmacological Drugs Advisory Committee Meeting on July 19, 2000 [133] Figure 5 summarizes the data from this seminal evaluation. EKGs were obtained at the time of the presumptive postdose maximum concentration. A metabolic inhibitor phase of the study was employed to ensure the maximal concentrations likely to be observed in real-world practice were evaluated: Ketoconazole (CYP3A4) was added to the quetiapine and ziprasidone treatment arms; paroxetine (CYP2D6) to thioridazine and risperidone treatment arms; and fluvoxamine (CYP 1A2) to olanzapine therapy. Compared to baseline, ziprasidone

demonstrated an average 10- to 20-msec prolongation in QTc, depending on the heart rate correction equation utilized. Moreover, although QTc changes with risperidone and olanzapine were basically unchanged from baseline, haloperidol and quetiapine demonstrated significant increases in QTc, though the magnitude of the change was considered not clinically significant. Thioridazine demonstrated a 30-msec increase in QTc from baseline, prompting a black box warning in labeling, and new contraindications regarding concomitant medications. The label for thioridazine further warns that CYP2D6 inhibitors (e.g., paroxetine and fluoxetine) are contraindicated with this antipsychotic. In the presence of each antipsychotic’s specific metabolic inhibitor, the following rank order for mean change from baseline in QTc is reported: Thioridazine (29.6 msecÞ Ziprasidone (16.6 msecÞ Haloperidol (13 msecÞ > Quetiapine (8 msec> Olanzapine (3.0 msec) and Risperidone (2.6 msec) [131]. Since marketing, ziprasidone has been used in > 200,000 patients, with 250,000 new prescriptions written through October 2002. No cases of torsades de pointes arrhythmias have been attributed to ziprasidone, and all-cause mortality is no different from that with other second-generation antipsychotic agents. Although use to date cannot preclude a rare but real

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risk, the magnitude of the risk is now sufficiently low as to justify ziprasidone’s use as a front-line agent in the management of schizophrenia [35,134]. In April 2002 (Pfizer Pharmaceuticals, Geodon product labeling), the labeling for ziprasidone was modified to more clearly define potentially dangerous combinations of drugs that might add to the QTc prolongation potential. Significantly, most psychotropics (except thioridazine and mesoridazine) are no longer warned against in combination with ziprasidone. B.

Other Cardiovascular Considerations

1.

Weight Gain

Weight gain with atypical antipsychotics is variably observed. As discussed previously, a meta-analysis appears to accurately place the atypicals from least likely weight gain potential, ziprasidione (and also aripiprazole), to olanzapine and clozapine, having the greatest potential [66]. Weight gain itself increases the risk of cardiovascular disease and diabetes mellitus as a primary risk factor. Additionally, weight gain is directly related to changes in lipid regulation leading to hyperlipidemia. The current literature and evaluations of atypical medications in patients cannot determine etiologic sequence of events; rather, there is an interrelationship of these three components of cardiovascular risk [135–138]. In schizophrenia, the prevalence of diabetes is higher, and estimated to be 9% higher in younger patients receiving atypical antipsychotics than in matched controls [139,140]. Hyperglycemia and an increased rate of diabetes mellitus have been associated with long-term hospitalized patients with psychotic disorders, as well as in patients on traditional neuroleptic agents [141–144]. Despite this apparent disease treatment effect, atypical antipsychotics appear to more frequently, as a class, increase glucose levels and/or insulin concentrations [145–147] and are infrequently associated with diabetic ketoacidosis and hyperosmolar coma [148–152]. Although most cases of diabetes mellitus are associated with weight gain, there have been several incidents of ketoacidosis, hyperosmolar coma, or diabetes mellitus in patients without weight gain. In addition to weight mediated insulin resistance, there is likely to be a more direct effect on insulin responsivity. Whether the insulin resistance causes weight gain, or weight gain precipitates insulin resistance, or both, is unclear. In either case, dyslipidemia is also more frequently associated with atypical antipsychotics, which cause weight gain and insulin resistance [145,153].

2.

Glucose Dysregulation

Of the front-line atypical antipsychotics, olanzapine appears to be most frequently implicated in hyperglycemia, increases in plasma insulin concentrations, weight gain, and dyslipidemia. Onset of hyperglycemia occurs typically within 3–6 months [138,150,152–154]. Elevations in glucose and insulin levels normalize after discontinuation of olanzapine, and in part are paralleled by weight loss [151,154,155]. Clozapine is the antipsychotic most associated with causing diabetes. Given the current concerns, it is recommended that baseline laboratory, weight/dietary, and cardiac assessments be made in patients prior to starting any antipsychotic therapies. The EKG can be done one time to rule out rare congenital causes of prolonged QTc in patients aged < 45 years, and repeated only if dizziness or a syncopal episode occurs when on antipsychotic therapy. If weight gain 7% of body weight occurs, then glucose and lipid monitoring should be instituted every 6 months. A risk-benefit analysis is needed prior to stopping effective treatments in order to reduce the potential adverse consequences associated with diabetes, dyslipidemia, and obesity. If effective treatment is continued, the medical consequences of the medication must be addressed. In the final cost-benefit analysis, the cost of medication, the potential benefits of effective therapy, and the medical monitoring and treatment costs, e.g., lipid-lowering drug therapy, all need to be factored into the ultimate decision [156– 158]. In patients at high risk for medical complications from antipsychotic therapies, risperidone or ziprasidone may be preferred over olanzapine. Quetiapine might be an acceptable choice as well, but lags in well-controlled studies evaluating weight gain, lipid effects, and hyperglycemia. XV.

DRUG THERAPY SELECTION VIA GENOTYPING

Selecting therapy by genotyping patients may eventually become commonplace. As previously discussed, the work of Kinon and Lieberman illustrates that D2 receptor polymorphism may predict response to typical neuroleptics [9]. In an evaluation of clozapine and genetic predictors of response, a more complex multifactoral analysis is necessary. Assay of 19 candidate genetic polymorphisms in clozapine responders (n ¼ 133) and nonresponders (n ¼ 67) was used to identify a combination of genetic features which are predictive of response. These most significant polymorphisms were two 5HT2A genotypes: T102/- and His452/His452


associated with good response in 80% of patients while about 50% of nonresponders had this genotype. A more complex model with six allele pairs mapping to four receptor/transmitter systems (5HT2a , 5HT2C , 5HT transporter and histamine H2 receptors) resulted in 76.7% success in the prediction of clozapine response (P ¼ :0001) and a sensitivity of 95% (0:04) [159].

XVI.

SPECIAL CONSIDERATIONS FOR DEPOT NEUROLEPTICS

The time to steady state for depot medications is based on the rate-limiting absorption half-life rather than the metabolic rate constant. For flupenthixol, fluphenazine, and haloperidol decanoate based on its absorption characteristics, therapy can be administered every 3 –4 weeks in the majority of patients [121,160,161]. Taking all depot antipsychotics as a class, if we utilize an average apparent terminal phase half-life of approximately 2–3 weeks, then the time to steady state following repeated injections will be 8–16 weeks. An understanding of the clinical implications resulting from these pharmacokinetic differences between depot and oral therapy is critical for the safe and effective use of these drugs. If depot neuroleptic therapy, i.e., fluphenazine or haloperdol decanoate, is initiated at a clinically effective dosage, e.g. no overlapping therapy is needed, then over the course of repeated injections and several months of time, the concentrations will increase two- to fourfold above these effective levels, resulting in adverse effects and toxicity. Conversely, an initially subtherapeutic dosage of depot antipsychotic, if repeatedly administered over time, will result in concentrations accumulating to steady state, eventually resulting in therapeutic effects. In stable individuals where dosage reductions are desired, 2–3 months should elapse between dosage adjustments to allow sufficient time for Cp to approximate the new steady state. Overly aggressive changes in dosage (either up or down) can result in improper dosage titration. In many chronically ill patients, where a greater delay in pharmacodynamic responsiveness is expected, 4 months or longer may be necessary between dosage changes to optimize the titration of the depot antipsychotic. In chronically medicated, stable patients, dosage intervals as infrequent as 4–6 weeks can be successfully employed for haloperidol decanoate [162]. Tightly bound drugs with long apparent half-lives, e.g., depot neuroleptics such as haloperidol decanoate, can be discontinued abruptly and the replacement

749

medication initiated and titrated upward as the neuroleptic washes out. For haloperidol decanoate, approximately one-half of the drug will wash out in 1 month’s time, and a minimum effective dose of the new agent should be administered by the time the next injection would have been administered. It will require up to 4–6 months to completely wash out the depot neuroleptic from systemic circulation. Interestingly, for fluphenazine decanoate, a deep compartment distribution of the drug results in washout times exceeding 6 months, despite a shorter initial terminal half-life than haloperidol decanoate [163]. Atypical antipsychotic therapies in long-acting formulations are finally approaching the marketing stage. Risperidone in a long-acting microspheres formulation (Risperdal Consta, Janssen Pharmaceutica) is closest to marketing [164,165]. Its pharmacokinetics are ratelimited by the slow erosion and disintegration of polylactide-glycolide copolymer microspheres ‘‘loaded’’ with risperidone. The initial dissolution of the microspheres is slow, leading to a latency period of 2–3 weeks until clinically relevant plasma concentrations are detected. Peak concentrations are observed 5–6 weeks after the injection. The dosing interval studied to date is every 2 weeks, and this product, unlike fluphenazine and haloperidol depot preparations, requires the use of overlapping oral risperidone for at least 2 weeks following the first long-acting IM injection. The clinical data and in vitro studies suggest that risperidone concentrations are relatively higher than 9OH risperidione levels in patients on long-acting therapy. Risperidone penetrates the CNS better and may have slightly greater activity [166]. Olanzapine pamoate, ziprasidone depot, iloperidone microspheres, and 9-hydroxyrisperidone palmitate are other long-acting second-generation antipsychotic therapies now in clinical development.

XVII.

CONCLUDING COMMENTS

Disease models for schizophrenia now focus on neurodegenerative changes and functional impairment. New therapies address more directly these deficits by increasing cortical activity via dopaminergic augmentation (by 5HT2a , a2c , or partial D2 agonism) and indirect effects which enhance glutamate function (antagonism of phencyclidine or ketamine in animal and human evaluations). Treatment to ultimately prevent the prenatal and/or perinatal diathesis by stabilizing excitatory amino acid systems is possible based on animal neurotoxicity and neuroprotection studies.

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More immediately, providing the best possible prenatal care for at-risk pregnant women is necessary. Newer therapies for schizophrenia are safe enough to consider as early treatment, e.g., pre-first-break psychosis. Shortening the time of acute psychosis during ‘‘first-episode’’ can also lead to long-term improved prognosis and function, justifying more aggressive identification and treatment of adolescents as they begin to deteriorate into first-break psychosis. Chronic patients at one point thought to be permanently impaired now have hope for partial to substantial recovery. Improved cognition, self-care, and overall functional capacity occur when second-generation therapies are taken consistently for extended lengths of time. Novel therapies, which more directly prevent stress-mediated neurochemical processes and structural damage, as well as novel treatments designed to increase brain function, are in development, suggesting that the beginning of a new era in the management and treatment of schizophrenia is dawning.

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50 Multiple Mechanisms of Lithium Action ALONA SHALDUBINA, ROBERT H. BELMAKER, and GALILA AGAM Ben-Gurion University of the Negev, Beer-Sheva, Israel

I.

INTRODUCTION

and regeneration of axons in the mammalian brain [4,5]. Long-term, but not acute, lithium treatment of cultured cerebellar granule cells induces a concentration dependent decrease in mRNA and protein levels of proapoptotic factors p53 and Bax; conversely, mRNA and protein levels of the cytoprotective factor Bcl-2 (B-cell lymphoma/ leukemia-2 protein) are markedly increased [4,6] (Fig. 1). Manji et al. [7] also demonstrated that chronic lithium treatment robustly increases Bcl-2 level in rat frontal cortex, hippocampus, and striatum. The mechanism of the lithium effect is not known. Manji et al. [7,8] proposed that lithium affects Bcl-2 via alteration of gene expression; however, it is also possible that classic effects of lithium on cyclic AMP or inositol mediate effects on Bcl-2 expression. Over-expression of Bcl-2 has recently been shown to prolong cell survival and attenuate motor neuron degeneration, and to promote growth and regeneration of axons in the mammalian CNS [5]. Lithium’s neuroprotective effect, induced by increasing brain Bcl-2 levels, may be relevant in the long-term treatment of mood disorders for the prevention of neurodegeneration [7,8]. It is hard to understand how Bcl-2 effects could explain lithium’s effect on acute mania within 10–21 days, however. Moreover, neuronal cell loss in affective disorder, while possible, is not thought of as a

Lithium has therapeutic and prophylactic effects on both the manic and depressive phases of bipolar affective disorder, yet the mechanism of lithium’s therapeutic action is not clear. Numerous biochemical effects of lithium have been identified and some of these may be a component of the therapeutic response. One of the current challenges is to distinguish critical effects from the many known biochemical actions of lithium, many of which may contribute to side effects or lead to toxicity [1]. We will summarize six theories of lithium action that have emerged in the last decade.

II.

APOPTOSIS PREVENTION

Multiple neuroimaging and postmortem morphology studies have demonstrated reduced brain volume and cell number in mood disorders [2]. These findings may represent neurodevelopmental abnormalities, disease progression, or biochemical changes secondary to changes in neurotransmitter levels in chronic affective disorders [3]. Chronic lithium administration at therapeutically relevant concentrations has been recently found to protect neurons against apoptotic cell death, to prolong cell survival, and to promote growth 757

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Figure 1

Consequences of Bcl-2 upregulation by lithium.

central feature compared to neurodegenerative disorders where Bcl-2 is usually studied or even compared to schizophrenia.

III.

PHOSPHOADENOSINE PHOSPHATE PHOSPHATASE

3 0 ð2 0 ÞPhosphoadenosine 5 0 -phosphate (PAP) phosphatase is a ubiquitous enzyme, highly conserved during evolution [9]. PAP phosphatase specifically catalyzes the hydrolysis of 3 0 -phosphate from PAP, thereby converting PAP to adenosine 5 0 -phosphate (AMP) and inorganic phosphate [9,10]. Lithium inhibits PAP phosphatase in an uncompetitive manner well within therapeutic concentrations (Ki ¼ 0:3 mM). The human PAP phosphatase (HsPIP) has dual specificity, acting both on PAP and on inositol-1,4-bisphosphate [10,11]. Thus, PAP phosphatase may play a role in inositol recycling and phosphoinositide metabolism [10], and in this sense lithium inhibition of PAP phosphatase may reinforce inositol depletion by inhibition of inositol phosphate dephosphorylation. Lopes-Coronardo et al. [10] have found high PAP phosphatase expression in rat heart, brain, and kidney, but Spiegelberg et al. [11] demonstrated that among human tissues the expression of PAP phosphatase is highest in kidney and lowest in lung and brain. PAP phosphatase activities in rat brain and kidney were recently compared in our lab and were found to have significantly higher activity in brain (1:15 0:15 nmoles/min mg protein [SE]) than in kidney (0:51 0:25 [SE]), with no signifi-

cant difference between frontal cortex and hippocampus or between the medulla and cortex in the kidney. Furthermore, a moderate difference in PAP phosphatase protein levels between postmortem human frontal cortex specimens from bipolar patients versus control subjects were recently observed by Shaltiel et al. [12]. This study was the first to measure PAP phosphatase in tissue derived from bipolar patients. A 24% significantly lower PAP phosphatase protein level in the frontal cortex of bipolar patients vs. normal subjects was observed (two-tailed paired t-test, t ¼ 2:21, P < :05) [12]. Several other lithium-related biochemical measures in bipolar disorder have been reported to be altered in the direction of their response to lithium treatment, as it was found for PAP phosphatase rather than in the more intuitive opposite direction. For instance, brain inositol is reported to be reduced postmortem [13], although lithium inhibits IMPase. Lithium’s effects to counter the underlying abnormality in bipolar illness might involve gene upregulation [14] rather than simply counteracting enzyme expression because of the direct inhibitory effect on the enzyme’s activity. The relationship of PAP phosphatase function to brain neurochemistry underlying emotion is not known. The accumulation of PAP upon PAP phosphatase inhibition affects several cellular systems (Fig. 2). PAP acts as competitive inhibitor of a variety of enzymes that use PAPS (3 0 -phophoadenosine 5 0 -phosphosulfate) as sulfate donor, mainly PAPS reductase and sulfotransferases that catalyze sulfation of a large number of substrates [15]. Sulfation plays an impor-

Multiple Mechanisms of Lithium Action

Figure 2

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Possible physiological effects of PAP accumulation.

tant role in biotransformation of many exogenous and endogenous compounds, including deactivation of drugs. In addition, some neurosteorids, which can be synthesized de novo in the nervous system, are known to exist not only as free compounds but also as sulfated derivatives. Pharmacological studies indicate that unconjugated and sulfated steroids, such as pregnenolone and pregnenolone sulfate, may have opposite effects on GABA(A) receptors [16]. Thus, pregnenolone acts as a potent positive allosteric modulator of gamma-aminobutyric acid action at GABA(A) receptors, whereas pregnenolone sulfate acts as a potent negative modulator [16]. Recent experiments also suggest that dehydroepiandrosterone and dehydroepiandrosterone sulfate may have distinct effects on growth of neurites from embryonic neocortical neurons in vitro [17]. Thus, regulation of steroid sulfation may have profound behavioral and morphological effects on the nervous system. In yeast, PAP accumulation interferes with RNA processing enzymes. In particular, two 5 0 ! 3 0 exoribonucleases were found to be inhibited, affecting the processing of subspecies of ribosomal RNA and small nucleolar RNA, resulting in inhibition of mRNA turnover [18]. Since Li was found to affect gene expression [8], PAP accumulation due to PAP phosphatase inhibition could represent one of the mechanisms of lithium action. An attractive aspect of the hypothesis is the very low Ki of lithium effect, which would cut off a very large percentage of PAP phosphatase activity during chronic lithium therapy in vivo. It is not clearly

related (other than via its secondary effect on inositol polyphosphate phosphatase) to any known signal transduction system. Sulfation per se is perhaps more relevant to solubilization and detoxification in the periphery than to brain function.

IV.

THE INOSITOL DEPLETION HYPOTHESIS

A widespread hypothesis explaining lithium’s therapeutic and prophylactic effect in affective disorder is that inhibition of inositol monophosphatase impairs the operation of the phosphatidylinositol cycle (PI cycle). The membrane phospholipid, phosphatidylinositol (PI), is sequentially phosphorylated to form phosphatidylinositol bisphosphate (PIP2 ). Agoniststimulated phospholipase C (PLC) cleaves PIP2 to two second messengers: inositol 1,4,5-trisphosphate (IP3 ) and diacylglycerol (DAG). IP3 releases calcium sequestered in endoplasmic reticulum. IP3 may be phosphorylated to form inositol penta- and hexaphosphates, which are subsequently dephosphorylated to inositol monophosphate (IP), which is dephosphorylated by inositol monophosphatase to free inositol. Lithium inhibits the last step in this process. DAG, the second derivative of PIP2 activates protein kinase C. DAG is converted sequentially to cytidine disphosphate—diacyl glycerol (CDP-DG), which is combined with free inositol by PI synthase to re-form PI (Fig. 3).

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Figure 3 Effect of lithium on the PI cycle.

With discovery of the importance of the cycle as a second-messenger system, the lithium-induced reduction of inositol immediately assumed potential importance as a key mechanism of lithium action [19]. Lithium was first shown to affect the system in 1971, when it was found that lithium decreased free inositol concentrations and increased inositol monophosphate (IP) concentration in brain [20]. Del Rio et al. [21] demonstrated that lithium also reduced intracellular concentration of inositol trisphosphate (IP3 ). Hallcher and Sherman [22] showed that lithium at therapeutic doses inhibits bovine brain inositol monophosphatase, thereby explaining the reduction in inositol and accumulation of inositol monophosphate. Inhibition is uncompetitive with a Ki of 0.8 mM, thus within therapeutically effective serum concentrations in the range of 0.5–1.4 mM [22]. Berridge [19] proposed that the Li-induced shortage of inositol in the brain, an organ to which plasmaborne inositol is essentially unavailable, leads to depletion of substrate for phosphatidylinositol resynthesis only in overactive neurons. This theory could explain lithium’s specific therapeutic activity in psychopathological states with minimal effects on normal behavior [23]. An intriguing possible interaction with the findings of Maes et al. [24,25], who reported lowered prolyloligopeptidase activity during depression but raised dur-

ing mania, with the PI signal transduction system and lithium’s inhibitory effect on IMPase has been suggested by Williams et al. [26]. They have shown that a Dictyostelium mutant lacking the prolyl oligopeptidase gene has elevated IP3 levels, which, apparently, protected it from lithium’s interferance with cell aggregation during development. IP3 elevation was found to result from increased dephosphorylation of IP5 in the mutant [26]. Kofman and Belmaker [27] found that ICV inositol administration reversed a behavioral effect of lithium in rats, supporting the concept that inositol depletion mediated the behavioral effect. However, it has been difficult to demonstrate that lithium in vivo indeed reduces PIP2 concentrations, and some scientists have claimed that, especially in primates, inositol concentrations are in excess of those needed to saturate PI synthase [28]. Belmaker et al. [29] showed that chronic dietary lithium administration, in rats reduced inositol level in hypothalamus by 27%, compared to control group. Furthermore, Moore et al. [30] did find in a small group of patients that 7 days but not 21 days of lithium reduced frontal cortical myoinositol levels in vivo using magnetic resonance spectroscopy. This ambiguity raised the possibility that lithium exerts its effect on inositol monophosphatase at the level of gene expression. To elucidate this supposition, lymphocyte-


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derived cell lines were treated in vitro with 1 mM lithium. A 40% increase of mRNA levels of one of the two genes coding for inositol monophosphatase was observed [31]. A critical test of the inositol depletion hypothesis will be whether inositol depletion diet in patients augments clinical lithium response [32].

V.

LITHIUM AND SEROTONIN

Serotonin (5HT) is released by presynaptic serotonergic neurons and activates specific postsynaptic receptors (mostly 5HT2 ). Serotonin also activates presynaptic autoreceptors (5HT1A or 5HT1B ), which decrease the availability of 5HT by feedback inhibition of serotonin release. The serotonin reuptake channel is another mechanism for regulation of serotonin level in synaptic cleft. This system is a specific target for serotonin-specific reuptake inhibitors. The use of lithium in combination with antidepressant drugs has been reported to rapidly improve antidepressant response in otherwise treatment-resistant patients [33]. Electrophysiological studies demonstrated that lithium has a capacity to increase the release of 5HT to the synapse, perhaps by inhibiting 5HT1A autoreceptors [34]. 5HT1A autoreceptors are localized on the soma and dendrites of 5HT neurons and control their firing (Fig. 4). A very recent finding concerns 5HT1B autoreceptors, which are localized on presynaptic neuron terminals and control 5HT release. Activation of the 5HT1B autoreceptor decreases release of serotonin to the synaptic cleft. Redrobe and Bourin [35] demonstrated that lithium induced antidepressant effects in the mouse forced swimming test, and this lithium effect

Figure 4

was shown to be mediated by 5HT1B receptors. Massot et al. [36] demonstrated that lithium, but not other metallic cations, causes specific inhibition of 5HT1B receptor binding in membrane preparation. This effect occurs at relevant therapeutic concentrations. The lithium-induced desensitization of 5HT1B autoreceptors decreases the efficacy of the negative retrocontrol of 5HT release at neuron terminals, leading to an enhancement of the availability of 5HT in the synaptic cleft. Massot et al. [36] also demonstrated that acute lithium can block 5HT1B -mediated mouse behavior in vivo and 5HT1B inhibition of forskolin-stimulated adenylate cyclase in CHO cell homogenates. Thus, lithium effects on 5HT autoreceptors could be demonstrated at the molecular, physiological, and behavioral levels, which makes for an exciting finding whose replication and extension are worth waiting for. However, it seems to explain mostly lithium’s antidepressant effects and it would be hard to connect the above mechanism with its antimanic effects.

VI.

EXCITATORY AMINO ACIDS

The possible involvement of glutamate in the mechanism of lithium’s therapeutic effect was suggested by Dixon and Hokin [37]. The group was studying the effects of lithium on the PI cycle. Kennedy et al. [38] and Lee et al. [39] found that in the presence of lithium, cholinergic stimulation of rat and mouse cerebral cortex slices resulted in decreased accumulation of IP3, as would be expected from the inositol depletion hypothesis (see above). However, in guinea pig, rabbit, and rhesus monkey, cerebral cortex slices in the presence of lithium, Dixon et al. [40] and Lee et al. [39] showed

Effect of lithium on 5HT autoreceptors.

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Shaldubina et al.

increased IP3 accumulation. Species differences in baseline inositol levels were suggested to account for this contrast [39]. Lithium-induced IP3 accumulation in rhesus monkey brain slices was independent of agonist stimulation or inositol supplementation [40]. Involvement of an endogenous neurotransmitter in this lithium effect was postulated, and indeed lithium was found to stimulate glutamate availability in the synaptic cleft [41]. Activation of the N-methyl-Daspartate (NMDA) receptor by glutamate resulted in IP3 accumulation (Fig. 5). Lithium-induced glutamate accumulation may be mediated either by increasing its release or by inhibiting its reuptake. Dixon and Hokin [37] examined the effect of lithium administration on the uptake of radioactively labeled glutamate by presynaptic nerve endings in mouse cerebral cortex. Acute lithium inhibited glutamate uptake in a dose-dependent manner, with maximal effect at 20 mM lithium. The maximal lithium effect occurred at very high concentration (20–25 mM) and after a short period of 2 h, and therefore seems to be irrelevant for lithium’s therapeutic action, which occurs at lower concentration and after 1–2 weeks of treatment. It may, however, be related to lithium’s toxicity. Dixon and Hokin [37] also studied the effect of chronic lithium treatment on glutamate reuptake. Mice were fed lithium-containing chow for 2 weeks, which led to lithium blood levels of 0.7–1.0 mM, and glutamate uptake by cerebrocortical synaptosomes was measured. A small but significant increase of glutamate uptake was obtained. Moreover, lithium also narrowed

Figure 5

the range of glutamate uptake (reduced the variance from 0.42 to 0.18), an effect interpreted as stabilization of the uptake and thus perhaps relevant to lithium’s mood-stabilizing effect in bipolar disorder [37]. Since glutamate is an excitatory neurotransmitter, upregulation of its uptake may exert an antimanic effect because more glutamate would be removed from the synaptic cleft.

VII.

GLYCOGEN SYNTHASE KINASE-3

Glycogen synthase kinase (GSK)-3, first identified in mammals as an inhibitor of glycogen synthase [42], is now known as an ubiquitous, constitutively active, multisubstrate serine/threonine kinase, acting on diverse substrates, including transcription factors, regulatory enzymes, and structural proteins. GSK-3 plays a role in multiple cellular processes, including metabolism, proliferation, differentiation, development, and apoptosis [43,44] (Fig. 6). It is highly abundant in brain tissue and is regulated by inhibition through numerous signal transduction systems [8,45]. Overexpression of GSK-3 to levels 3.5 times that in control (in human neuroblastoma cells) potentiated staurosporine and heat-shockinduced apoptosis [46]. GSK-3 is directly inhibited by lithium at nearly therapeutically relevant concentrations (2:1 0:6 mM) in vitro [47]. Valproic acid, another antibipolar compound, also inhibits GSK-3 [48], strengthening the possibility that this enzyme represents the key site of antibipolar action.

Acute and chronic lithium effect on glutamate neurotransmission.


Figure 6

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GSK-3 is involved in so many different cascades that it is not possible to draw the usual diagram.

Lithium has a dramatic effect on morphogenesis in the early development of numerous organisms. Klein and Melton [49] presented evidence that inositol monophosphatase inhibition does not explain the teratogenic effect of lithium on development. Lithium teratogenesis in Xenopus embryos caused the same effects as activation of Wnt signaling [50,51]. It leads to accumulation of cytosolic -catenin, which plays a central role in developmental and apoptotic processes by regulation of gene expression [45]. Inhibition of GSK-3 by lithium could explain lithium’s ability to mimic Wnt signaling. Because of GSK-3’s central role in the cell, it could be an attractive candidate as lithium’s target. Apparently, inhibition of GSK-3 by lithium occurs at the top level of its therapeutic range [47], or even higher (H. Eldar, personal communication), suggesting that GSK-3 inhibition could be more relevant to lithium’s toxic side effects. However, Ryves and Harwood [52] have recently shown that lithium inhibits GSK-3 by competing with Mg2þ . Therefore, this inhibition is dependent on free Mg2þ concentration, and the latter is dependent on chelation by ATP. Consequently, given the cellular concentrations of Mg2þ and ATP, these authors calculated that lithium’s in vivo inhibitory effect on GSK-3 would have a Ki of 0.8 mM or less—well within the therapeutic range. A critical experiment would be to test whether chronic in vivo lithium treatment of rats causes downstream events due to GSK-3 inhibition, such as changes in -catenin levels.

VIII.

CONCLUSIONS

Lithium is a simple ion with numerous biochemical effects. Lithium’s clinical effects include prophylaxis of bipolar disorder, antimanic, antidepressant, and antiagressive action; action against migraine and cluster headaches; action in the syndrome of inappropriate secretion of antidiuretic hormone; and alleviation of chemotherapy-induced leukopenia. ‘‘Lumpers’’ tend to see all or almost all of these clinical effects, or at least the CNS effects, as deriving from a common CNS mechanism. ‘‘Occam’s razor’’ would urge that the multiplicity of lithium’s biochemical effects be reduced to one true mechanism of clinical action, with other effects being epiphenomena or related to side effects or toxicity. ‘‘Clinical splitters,’’ however, see the numerous clinical effects as independent properties of the lithium ion in biology. Biochemical ‘‘integrationists’’ suggest that the multitude of lithium effects together account for its clinical action, and that one biochemical mechanism could not account for even one of lithium’s clinical effects. Critical experiments must be devised to distinguish among these profoundly different and fascinating approaches. For instance, synthetic IMPase inhibitors exist that must be studied for behavioral effects; GSK3 inhibitors have also been developed [53], and it will be critical to know if they are behaviorally active or only teratogenic. PAP accumulates during lithium administration: it will be important to deliver PAP

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intracerebroventricularly (perhaps as a penetrable derivative or in liposomes) and to see whether its behavioral effects mimic those of lithium. Bcl-2 knockout mice are available [54]: do they show behavioral effects?

Shaldubina et al.

13.

14.

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51 Mechanisms of Action of Anticonvulsants and New Mood Stabilizers ROBERT M. POST National Institute of Mental Health, Bethesda, Maryland, U.S.A.

ELZBIETA CHALECKA-FRANASZEK AND CHRISTOPHER J. HOUGH Uniformed Services University of the Health Sciences, Bethesda, Maryland, U.S.A.

I.

INTRODUCTION

the illness has emerged among a long list of many candidates [7].

With the recognition of the inadequacy of lithium carbonate treatment for a substantial proportion of patients with bipolar illness [1], the anticonvulsants have come to play an increasingly important alternative or adjunctive role in bipolar illness and related affective syndromes [2,3] (Table 1). The early demonstration of the efficacy of lithium in bipolar illness gave hope that these results would rapidly translate into better understanding of the drug’s mechanisms of action and, secondarily, the neurobiological defects in the illness to which it was targeted. However, an expanding list of candidate mechanisms has been elucidated for lithium with no single mechanism being definitively linked to its mood-stabilizing effects [4]. These mechanisms can now be compared and contrasted with the putative mechanisms of the anticonvulsants involved in their psychotropic action. Electroconvulsive therapy (ECT) also exhibits potent anticonvulsant effects in many animal models as well as clinically [5,6]. As the seizures of ECT have stood the test of time for their excellent acute efficacy in both manic and depressive episodes, no single mechanism of action for their psychotropic effects in either phase of

A.

Anticonvulsant Versus Psychotropic Mechanisms

The use of anticonvulsants in bipolar illness has provided a surrogate marker for their mechanisms of action because one can readily investigate the mechanisms of their acute anticonvulsant effects [4,8] (Tables 2, 3). However, there are multiple caveats. The anticonvulsant mechanisms of action have not been clearly identified, and they may differ for the same drug as a function of seizure type. Moreover, there is considerable reason to believe that the anticonvulsant mechanisms (Fig. 1) may not be identical to the psychotropic ones as evidenced by dysjunctions in their time course of action and efficacy in different models. It is also clear from the effects of lithium, which is not a potent anticonvulsant in most models and tends to be pro-convulsant in many, that an anticonvulsant mechanism is not necessary for mood stabilization. The different temporal domains of carbamazepine’s actions, for exam767

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Post et al. Table 1

Spectrum of Psychotropic Efficacy of the Anticonvulsants Mania

Depression

Prophylaxis

Other

VPA GPN

þþþ —

þ (þ)

þþþ ?

Migraine, panic Pain; restless leg OCD; anxiety; social phobia; alcohol withdrawal

TIA PRI PHT CBZ

— () (þ) þþþ

? () (þ) þ

? () (þ) þþþ

OXC LTG ZNS TPM FBM LEV

þþþ þ? (þ) () ? ?

(þ) þþþ ? (þ) ? ?

(þ þ þ) þþþ ? (þþ) ? ?

Absence epilepsy Paroxysmal pain syndromes; alcohol withdrawal; ?PTSD Paraoxsymal pain syndromes Pain; ?PTSD ?PTSD

Abbreviations: VPA, valproate; GPN, gabapentin; TIA, tiagabine; PRI, primidone; PHT, phenytoin; CBZ, carbamazepine; OXC, oxcarbazepine; LTG, lamotrigine; ZNS, zonisamide; TPM, topiramate; FBM, felbamate; LEV, levetiracetam; OCD, obsessive-compulsive disorder; PTSD, posttraumatic stress disorder. Strength of evidence: þ þ þ, well recognized and documented; þþ, substantial; þ, weak to moderate evidence and efficacy; , equivocal; ?, unknown.

ple, illustrate a likely separation between its anticonvulsant and psychotropic effects [9]. The anticonvulsant effects of carbamazepine appear to be acute in most animal models, and clinical antiepileptic effects are readily achieved as adequate doses are administered (Fig. 2). The same appears to be the case for its antinociceptive effects in paroxysmal pain syndromes such as trigeminal neuralgia, in which the therapeutic effect occurs within 1 or 2 days. However, there is usually a delay of several days before carbamazepine exerts its initial efficacy in the treatment of acute mania, and often some weeks until maximum effect is achieved. Finally, as is typical in the time course of most antidepressants, although initial antidepressant effects of carbamazepine may be observed in the first several weeks, it is often 4–6 weeks before maximal effects are achieved [9]. Therefore, if one were examining mechanisms potentially related to antidepressant efficacy of carbamazepine, one would examine animal models and biochemical effects that required chronic administration and/or a considerable time period to develop [10]. Thus, the time required for a given biochemical action may be important in examining potentially relevant mechanisms of psychotropic action, in addition to critical pharmacokinetic variables necessary to a drug’s pharmacodynamic effects, i.e., the achievement of clinically relevant blood levels sufficient to induce the mechanism postulated to be involved clinically.

B.

Chronic Biochemical Effects as Candidates for Psychotropic Action

There is also a partial parallel between the acute to chronic temporal effects of the anticonvulsants and their presumed molecular targets. Mechanisms related to ion channel effects, neurotransmitter release, and receptor agonism/antagonism or modulation are likely to emerge acutely, whereas a variety of neuroadaptive effects may take place with an intermediate time course, and effects involving long-term changes in gene expression may evolve over longer time domains (in accordance with those changes more likely to be related to the antidepressant effects of these agents) (Fig. 3). An implied corollary of this postulate is that one might be able to find a more acutely active antidepressant if one were able to target the long-term adaptive changes more directly. For example, it is thought that the cascade of antidepressant effects beginning at the blockade of neurotransmitter reuptake leads to receptor adaptations, changes in adenylate cyclase, the phosphorylation of cyclic AMP response element-binding protein (CREB), and the induction of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) [11,12]. If BDNF were part of the final common pathway of antidepressant effects, one might suggest that direct application of BDNF to appropriate areas of brain could be clinically effective in a rapid fashion [11,13]. BDNF is

Anticonvulsants and New Mood Stabilizers Table 2

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Putative Mechanisms of Action of Anticonvulsants Pre-synaptic Effects

Naþ blockade

# Glutamate release

(PHT) Phenytoin (Li) Lithium (CBZ) Carbamazepine (PHT) Phenytoin (VPA) Valproate (LTG) Lamotrigine (TPM) Topiramate (LTG) Lamotrigine (ZNS) Zonisamide

Post-synaptic Effects # Ca2þ influx NMDAR

NMDAR block

(Li) Lithium (CBZ) Carbamazepine (VPA) Valproate

(FBM) Felbamate AMPAR block ðTPMÞ Topiramate

(CBZ) Carbamazepine (LTG) Lamotrigine

T-Type-Ca2þ (absence seizures) (VPA) Valproate (ETX) Ethosuximide (ZON) Zonisamide

GABA-benzodiazepine-Cl ionophore (VPA) Valproate (LOR) Lorazepam (GPN) Gabapentin (KLN) Clonazepam (TIA) Tiagabine (LEV) Levetiracetam

Dihydropyridine L-type Ca2þ (voltage sensitive) (NIM) Nimodipine (AML) Amlodipine Peripheral or Mitochondrial-type BenzodiazepineR (ISR) Isradipine

(CBZ) Carbamazepine (antagonist) (PK-11195) antagonist (RO5-4864) agonist

Modulatory via # Zn2þ and beta-carboline inhibition

Abbreviations: NMDAR , N-methyl-D-aspartate receptors; AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4propionate; GABA, gamma-amimobutryric acid; Na+, sodium channel; Ca2+, calcium channel; CI , chloride channel.

positive in a variety of animal models of depression [14], and attempts are being made to find ways of administering BDNF or its analogs to patients for direct tests of this hypothesis. Because there are not any well-established and convenient animal models of mania and depression [15], in contrast to the many available for the different types of epilepsies [16], one may have to wait until future developments in pharmacogenetics establish that a given mechanism is linked to a manifestation of affective illness, and this in turn is ameliorated by effective treatments and not by those that are ineffective. One can also use anatomy/anatomical biochemistry to establish a mechanism of action, by confirming that a general defect in metabolism or specific alteration in neurotransmitter receptor function is ameliorated by a given agent in association with its therapeutic effects. As more specific anatomical and biochemical alterations are uncovered using functional brain imaging [17], this approach will likely become increasingly important.

C.

Bimodal Effects from a Single Mechanism of Action

A final issue pertinent to considering mechanisms of action of mood stabilizers is their ability to stabilize both manic and depressive moods without exacerbating the other phase. This is in contrast to the unimodal antidepressants which, although effective in unipolar and bipolar depression, can precipitate a switch into mania or accelerate cycling [18,19]. Conversely, particularly with the older typical antipsychotics, although they have clear antimanic properties, some investigators have found that they could be associated with the induction of more severe, prolonged, or frequent depressions [20,21]. Thus, to the extent that one is seeking the mechanisms of mood stabilization as opposed to acute antimanic or acute antidepressant effects, it would appear that one should be looking for bidirectional or neuromodulatory effects on the one hand, or a single dampening mechanism of an overactive system in either an excitatory or an inhibitory part of the brain on the other.

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Post et al. Table 3 Mechanisms of Action of Anticonvulsants Ca2þ

VPAa

GABA GABAA -R p NMDA Ca2þ levels (indirect) # Naþ T N P p " þþ T #

GPN

"

TIA PRI PHT CBZ

"

OXC LTGa ZNSa TPM FBMa LEVa

p

p p p

( )

þþ þþ þþ

#

N? T

p p p

þþ

" AVP; " Sub P; # SRIF; # Da T.O., " K efflux " K efflux

# þ þ þAMPA

p N?

Other Multiple effects on GABA synthesis and catabolism, " K efflux # Strychnine-insensitive glycine receptors

p

þþ þþ þþ

p

Glutamate receptor block

þ þ þNMDA

"# DA, 5HT þþ (CA#) free radical scavenger Carbonic anhydrase þþ (CA #) inhibition # Zn2þ and beta-carboline-negative modulation of GABAA -R

a Broad-spectrum anticonvulsants. Abbreviations: VPA, valproate; GPN, gabapentin; TIA, tiagabine; PRI, primidone; PHT, phenytoin; CBZ, carbamazepine; OXC, oxcarbazepine; LTG, lamotrigine; ZNS, zonisamide; TPM, topiramate; FBM, felbamate; LEV, levetiracetam; GABA, gamma-amino butyric acid; NMDA, N-methyl-D-asparate; K, potassium; AVP, activator protein-1; Sub P, substance P; SRIF, somatostatin; Da T.O., dopamine turnover; Ca2+, calcium channel; Na+, sodium channel; 5HT, p serotonin; , voltage dependent.

The latter proposition is highly convergent with the idea that anticonvulsant mechanisms of these drugs are surrogate markers for psychotropic ones. Clearly, seizures represent increased excitability or hypersynchrony of a given brain area and its associated pathways that one would seek to dampen with the use of appropriate anticonvulsant interventions which either decrease excitation or enhance inhibition (Fig. 1) or both. One could readily envision the occurrence of increased neural excitability in systems either enhancing activity or arousal more closely associated with the occurrence of mania, whereas a similar overactive process in largely inhibitory structures or neurotransmitter systems (i.e., those mediating behavioral inhibition) could be associated with the occurrence of depression. Both of these overactive processes could be moderated by the same anticonvulsant effect that decreases paroxysmal neuronal firing. D.

Kindling as a Nonhomologous Model for Affective Disorders

It has been argued elsewhere that the kindling model is clearly a nonhomologous one for the affective disor-

ders in that there is not behavioral homology between seizures and affective episodes and, in fact, there are marked dysjunctions in their duration, inciting circumstances, likely neuroanatomy and chemistry, and clearly in their pharmacology [22]. There is no isomorphism between the agents that are effective in the different stages of kindled seizure evolution and those that are effective in the different stages of bipolar illness evolution. Nonetheless, it is clear that the kindling model reveals the principle that the neurochemistry and neuroanatomy of this pathological neurophysiological process changes as a function of time and stage of kindling evolution, and that drugs effective in one stage are not necessarily effective in another [23,24]. This model allows one to address the question of whether similar temporal distinctions are important in the different stages of affective illness, even though specific drugs that show differential efficacy as a function of stage of illness evolution may not be precisely or predictably parallel from kindled seizures to affective episodes. Given these clear distinctions between the kindling model and the pharmacology of affective disorders, one might then ask why there is partial overlap

Anticonvulsants and New Mood Stabilizers

771

Figure 1 Dual targets of mood stabilizing drugs. NMDA ¼ N-methyl-D-aspartate; GABA ¼ gamma-aminobutyric acid; GAD ¼ glutamate decarboxylase; BzR ¼ benzodiazepine receptor; AMPA ¼ alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; L.A.A: ¼ l-amino acid; KT, potassium channel; Na+, sodium channel; CI , chloride channel.

between many of the anticonvulsant medications and their ability to exert therapeutic actions in one or both phases of bipolar illness. In this regard, the authors would postulate that at one level of analysis, the principles of antiepileptogenesis and acute and prophylactic anticonvulsant effects that are relevant in the treatment of acute behavioral convulsions may nonetheless share some commonalities with those involved in longer phases of emotion dysregulation. Affective episodes do not involve a motor seizure as an end point, but more likely a more sustained process of regional increased or decreased excitability. It is perhaps this similar ability to dampen overactive circuits related to either the paroxysmal firing of a behavioral convulsion or a more sustained neuronal regional dysregulation pertinent to psychomotor and affective modulation that could relate to the large area of drug overlap with both inherent anticonvulsant and mood-stabilizing properties. It will also be useful to consider the exceptions to this postulate, i.e., the drugs that are potent anticon-

vulsant agents which do not have clear antimanic or mood stabilizing properties. These exceptions may also give important hints in a negative sense to mechanisms not likely to be critically involved in psychotropic actions. For example, both tiagabine and gabapentin increase brain gamma-aminobutyric acid (GABA) [25] (Fig. 1; Table 3), but are ineffective in mania (Table 1) [26,27]. Thus, whereas valproate also increases brain GABA, it is likely that some of its other mechanisms are critical to its antimanic efficacy based on the ineffectiveness of tiagabine and gabapentin in mania despite their potent GABA-ergic effects. The major focus of this chapter will be on the potential anticonvulsant and mood-stabilizing mechanisms of the commonly used medications valproate and carbamazepine, as well as on the most promising of the newer anticonvulsants such as lamotrigine and topiramate. We will also note the putative mechanisms of the newest anticonvulsants such as levetiracetam and zonisamide, even though they have not yet been systematically studied in affective illness. Potential molecular

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Figure 2 Time course of clinical and biochemical effects of carbamazepine. GABA ¼ gamma-aminobutyric acid; NE ¼ norepinephrine; l:c: ¼ locus ceruleus; CSF ¼ cerebrospinal fluid; HVA ¼ homovanillic acid; DA ¼ dopamine; NPY ¼ neuropeptide Y; Hippo ¼ hippocampus; Na+, sodium channel; Hippo, hippocampus.

mechanisms involved in loss of anticonvulsant efficacy to these agents by tolerance mechanisms will also be reviewed, as these may be important in the possible development of clinical tolerance to the anticonvulsant, antinociceptive, or psychotropic effects of these agents. Relatively pure GABA-ergic drugs such as gabapentin and tiagabine appear less promising.

II.

CARBAMAZEPINE AND OXCARBAZEPINE

There is a very substantial database supporting the psychotropic efficacy of carbamazepine [3,28] and a

more preliminary database for oxcarbazepine [29–31]. However, the two drugs differ by only one oxygen molecule on the midring of the tricyclic structure and appear to have similar anticonvulsant, antinociceptive, and antimanic properties (on the basis of the few preliminary studies available for the latter findings) [29,30,32]. Thus, until evidence emerges otherwise, we will assume that oxcarbazepine is a similar congener or sister drug to carbamazepine and that many of the principles of their actions will be in parallel. However, it is clear that oxcarbazepine is a much less potent hepatic P450 enzyme inducer and therefore yields fewer pharmacokinetic interactions, and is clinically easier to use with other agents [33]. It may emerge


773

Figure 3 Mechanisms of mood stabilization. Depicted schematically at the top of the figure is a synapse with various types of channels, neurotransmitters, and proteins associated with the mechanisms of action of the mood stabilizers listed in the table below. Arrows indicate increases or decreases in substance/activity. Row headings: Li, lithium; CBZ, carbamazepine; VPA, valproate; Ca, calcium; LTG, lamotrigine; GPN, gabapentin; TPM, topiranmate. Column headings: K, potassium efflux; Na, sodium influx; EAA, excitatory amino acids; GABA, GABA t.o., gamma-aminobutyric acid, GABA turnover; Tryp, tryptophan; 5HT, serotonin; NMDA Ca, N-methyl-D-aspartate calcium channel; L-type Ca, L-type calcium channel; G, G protein; c-AMP, cyclic adenosine monophosphatase; IPtase, inositol monophosphatase; AP-1, activator protein-1; Sub P, substance P; SRIF, somatostatin.

that there are also substantial differences in pharmacodynamic effects as well as these major differences in catabolism. Although carbamazepine, phenytoin, and lamotrigine show the ability to potently block batrachotoxin type-2 sodium channels [34,35] (Fig. 1) and therefore decrease release of excitatory amino acids and inhibit sustained rapid firing, there appear to be substantial differences in their clinical profiles. Carbamazepine is much more potent than phenytoin in inhibiting amygdala kindling compared with cortical kindling [36], a potential marker of clinical utility in complex partial seizures and other dysrhythmias of the limbic system.

In addition, whereas both phenytoin and carbamazepine can exacerbate petit mal or absence epilepsy, lamotrigine does not and may even be clinically useful in the syndrome as well [37]. Thus, some other mechanisms of action of these agents must account for these pharmacological and clinical differences. Carbamazepine and lamotrigine both likely modulate calcium influx through the NMDA receptor [38,39] and lamotrigine may also affect N- or P-type calcium channels [40,41]. Carbamazepine also blocks peripheral-type benzodiazepine receptors (also called the mitochondrial-type benzodiazepine receptor) [42– 44]. This receptor is thought to affect calcium influx

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not only at neural and glial membranes, but also at the mitochondrial permeability transition pore, modulating cholesterol transport [45–47] (Fig. 4). Although noradrenergic effects are important to carbamazepine’s anticonvulsant effects in some models, they do not appear to be directly related to its psychotropic effects. Carbamazepine’s blockade of norepinephrine reuptake is weak [48], although it does block stimulation-induced release of norepinephrine at clinically relevant concentrations (a sodium channel-mediated event) [49] and may decrease norepi-

Post et al.

nephrine turnover [50], as do many other antidepressant compounds. However, many of carbamazepine’s effects are not only uncharacteristic of, but even opposite to, those of traditional antidepressants. Instead of decreasing forebrain beta-adrenergic receptor expression, carbamazepine appears to increase it [51]. Most antidepressants decrease cortisol, presumably in part by downregulating corticotropin-releasing factor (CRF) receptors or upregulating glucocorticoid receptors, but carbamazepine appears to increase cortisol excretion as measured

Figure 4 Peripheral-type benzodiazepine ligands modulate multiple receptors and ion channels via neurosteroids. GABA, gamma-aminobutyric acid; BZ, benzodiazepine; TBPS, [35S]-tert-butylbicyclophosphorothionate; NMDA, N-methyl-D-aspartate; CI , chloride channel; Ca++, calcium channel.


by urinary free cortisol [52]. At the same time, carbamazepine appears to decrease release of CRF in some in vitro hypothalamic preparations [53,54]. These or other differences from traditional antidepressants may account for the fact that carbamazepine can exert acute and prophylactic antidepressant effects in some unipolar and bipolar depressed patients who have not responded to more traditional antidepressant modalities [55,56]. In addition to these acute effects, carbamazepine has a variety of effects on neuropeptide systems that are likely to be pertinent to its profile of either therapeutic efficacy or side effects in the affective disorders (Fig. 3). Chronic administration of carbamazepine in

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patients with both seizure and affective disorders is associated with a decrease in somatostatin in cerebrospinal fluid (CSF) [57]. Presumably, this reflects a decrease in brain somatostatin, although the regional neurochemistry of this effect has not yet been delineated. This decrement in CSF somatostatin contrasts with the increases in CSF somatostatin observed following chronic administration of the dihydropyridine L-type calcium channel blocker nimodipine [58]. Carbamazepine and nimodipine also block calcium influx through different mechanisms [59] (Fig. 5), and appear to have different predictors and correlates of clinical response observed in clinical neuroimaging with deoxyglucose [60]. Affectively ill patients with evi-

Figure 5 Differential targets of carbamazepine and nimodipine on intracellular calcium. AMPA, alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionate; B-D, brain derived; CaM, calmodulin; CaRE, calcium-response element; cGMP, cyclic guanosine monophosphate; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; CRE, cyclic adenosine monophosphate (cAMP)-response element; CREB, cAMP response element-binding protein; MAP, mitogen-activated protein; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NOS, nitric oxide synthase; NT, neurotrophin; R, receptor; SRE, serum response element; PO2, phosphorylated CREB; CBZ, carbamazepine; Ca++, calcium channel; Mg, magnesium.

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dence of hypermetabolism, particularly in the left insula at baseline, appear to respond better to carbamazepine in association with normalization of this hyperactivity. Nimodipine shows the opposite pattern with better responses in those with baseline hypoactivity, which tends to normalize in association with treatment response. Whether these differential effects are directly or indirectly related to the alterations in somatostatin remains to be clarified. There is a direct positive correlation with the degree of metabolism in the subgenual anterior cingulate gyrus and the concentration of somatostatin in CSF [61]. The subgenual area of the cingulate has been one of the brain regions most closely associated with alterations not only in metabolism, but also in neuroanatomy, with substantial deficits reported in the number of glial cells in this area of brain in those with familial unipolar and bipolar affective disorders [62–64]. Carbamazepine increases striatal substance P levels and substance P sensitivity upon chronic (but not acute) administration, which is interesting in relation to observations that chronic, but not acute, treatment with lithium also increases substance P levels in the striatum [65–67] (Table 4). These observations, and a variety of antidepressants increase substance P sensitivity [68], and that a substance P antagonist [69] exhibited antidepressant effects equal to that of the conventional SSRI paroxetine (both were more effective than placebo), all suggest a potential role for substance P alterations in antidepressant effectiveness [70]. Carbamazepine’s effects on vasopressinergic systems are more likely related to its side-effects profile than its therapeutic efficacy. Carbamazepine appears to indirectly enhance vasopressinergic function at or near the receptor, which may account for the fact that lithium’s inhibition of vasopressin actions (by

inhibiting transduction mechanisms at the level of adenylate cyclase inhibition, i.e., downstream of the receptor) is not able to be surmounted by carbamazepine [71]. Thus, carbamazepine will not reverse lithiuminduced diabetes insipidus. In some animal models, carbamazepine is able to enhance some measures of learning and memory [72], and whether its vasopressinergic profile or some other effect accounts for these observations also needs to be further delineated. However, carbamazepine’s ability to enhance antidiuretic effects at the vasopressin receptor is likely associated with its liability to induce hyponatremia [73–75]. Lithium is able to counter the effects of carbamazepine on hyponatremia, as is demeclocycline [76– 78]. It remains to be directly assessed whether either of these agents would also be effective in ameliorating the hyponatremia of oxcarbazepine, which may occur in 1–3% of patients.

III.

VALPROATE: SIMILARITIES AND DIFFERENCES FROM LITHIUM

Although valproate increases brain GABA through a variety of effects on GABA synthesis and degradation [32,79], there is considerable controversy as to whether this is directly related to its anticonvulsant or psychotropic efficacy [80]. Valproate also blocks sodium channel influx, and T-type calcium channels, and enhances potassium channel efflux [81–83]. It also shares a number of mechanisms of action with carbamazepine (Table 5), and with lithium carbonate, making these mechanisms candidate systems for its psychotropic efficacy, including the ability to inhibit protein kinase C (PKC) (Table 6) [84] and other downstream effects in this signal transduction cascade

Table 4 Effects of Lithium and Carbamazepine on Substance P

Acute Treatment " Substance P levels " Substance P sensitivity Chronic Treatment Substance P levels

" Substance P is haloperidol-reversible " Substance P sensitivity

Lithium

Carbamazepine

None None

None None

" Striatum " Substantia nigra " Nucleus accumbens " Frontal cortex Yes ?

" Striatum " Substantia nigra

Yes Yes


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Table 5 Comparative Effects of Two Anticonvulsant Mood Stabilizers in Bipolar Illness

GABA turnovera GABAB receptorsa (hippocampus) GABA levels prepulse inhibition [3 H]-picrotoxinin binding Dopamine turnovera Naþ influx Kþ efflux NMDA-mediated currents currents NMDA-mediated Ca2þ influx Release of aspartate Somatostatin levels Substantia nigra lesions block CBZ’s anticonvulsant effects on kindling Decrease AD in: Hippocampus Cortex

Carbamazepine

Valproate

# "

# "

(") 0 #

" " #

# # " (#)

# # " #

# # # þþ

# # 0

— #

# —

a

Effects shared by lithium. Abbreviations: GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; CBZ, carbamazepine; AD, afterdischarge; Na+, sodium channel; K+, potassium channel; Ca2+, calcium channel Symbols: ", increase; #, decrease; ( ), equivocal; 0, none; —, not relevant, no evidence.

[85], inhibit glycogen synthase kinase-3 (GSK-3) [86,87], increase activator protein-1 (AP-1) binding [88,89], activate Akt (also known as protein kinase B) [90], and induce the neuroprotective factor Bcl-2 [91]. Recent studies have shown that lithium exerts neurotrophic or neuroprotective effects [92–94]. Moreover, it has been demonstrated in cultured neurons that lithium increases activity of the serine/theronine protein kinase Akt (Fig. 6) [90]. Akt is known as a key regulator of cellular survival [95]. The identification of Akt as a target for lithium may have significant implications for an understanding of its neuroprotective mechanism. Several targets of Akt have been recently identified that may underlie the ability of this regulatory kinase to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD [96] and caspase-9 [97], transcription factors of the forkhead family [98], CREB [99], endothelial NOS [100], and a kinase, IKK, that regulates the NF-kB transcription factor [101]. Moreover, activated Akt is involved in the potentiation of L-type calcium channels [102], inhibition of the

cytochrome C release from the mitochondria [103], and inactivation of a critical regulator of cellular metabolism GSK-3 [104]. It has been recently determined that not only lithium but also valproate induces activation of Akt in cultured neurons (ChaleckaFranaszek, unpublished information). Lithium also

Table 6 Drug Effects on Protein Kinase C (PKC) Isozymes and Substrates

PKC activity PKC PKC MARCKS levels AP-1 binding activity Inositol responsive

Lithium

VPA

# # # # " þ

# # # # " —

MARCKS, myristoylated alanine-rich C kinase substrate; AP-1, activator protein 1; VPA, valproate; " increase; # decrease; þ, yes; —, unknown, no effect

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Figure 6 Drug effects on Akt: possible downstream consequences. PI 3-kinase. phosphatidylinositol 3-kinase; PDKs, phosphoinositide-dependent kinases; NF-eˆB, nuclear factor-kappaB; IKK, IkappaB kinase; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; GSK-3, glycogen synthase kinase-3; BDNF, brain-derived neurotrophic factor; CREB, cAMP response element-binding protein.

enhances neuroprotective factors such as brain-derived neurotrophic factor (BDNF) while inhibiting cell death factors such as Bax and p53 [92,105]. These and other neural intracellular mechanisms may account for lithium’s apparent neuroprotective effects in a variety of animal models including stroke [93], Huntington’s chorea [106], and in vitro protection for an AIDS-related neurodegenerative process [107]. Whether valproate and other putative mood-stabilizing anticonvulsants share lithium’s apparent neuroprotective effects via mechanisms listed above, remains to be further delineated (Fig. 7). In addition, lithium has recently been shown to increase neurogenesis [108], an effect shared by some antidepressants [109] and opposite that of some stressors [110]. Together, these data may explain why lithium has recently been observed to increase human brain gray matter volume in subjects treated for 4 weeks [111] and to increase brain N-acetyl-aspartate (NAA) [112], a putative marker of neuronal viability and function. Recently, lithium, carbamazepine, and valproate have all been shown to increase inositol transport, also raising the possibility that this could be a common mechanism involved in their mood-stabilizing properties [113].

IV.

LAMOTRIGINE

Lamotrigine has particular promise as an effective treatment for the depressive phase of bipolar illness with evidence of mood stabilization in rapid-cycling patients [27,114,115]. Aside from the occurrence of serious rash in approximately one of every 500 patients [116], its side-effects profile is benign and well targeted toward many of the symptoms more prominently evident in bipolar depression. In contrast to lithium and valproate, lamotrigine does not increase weight and appears to be somewhat activating and able to decrease the hypersomnia of bipolar depression, rather than sedating and setting a psychomotor baseline slightly below normal. As noted previously in Figure 1, lamotrigine is thought to block type 2 sodium channels [117], decrease release of glutamate [118], and inhibit calcium influx through the NMDA receptor (Hough et al., 1998, unpublished observations). However, it is likely to have other important mechanisms that could account for its additional effects in blocking absence seizures and a broader spectrum of both anticonvulsant and psychotropic actions than carbamazepine. Data suggest that lamotrigine may also be active at N- or P-type calcium channels [40,41], but


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Figure 7 Common and differential mechanisms of mood stabilizers. PI, phosphoinositol; AC, adenylate cyclase; IMPase, inositol monophosphatase; PLC, phospholipase C; cAMP, cyclic adenosine monophosphate; NPY, neuropeptide Y; Ach, acetylcholine; Gs, G protein alpha (s) subunit; DA, dopamine; Ne, norepinephrine; PKC, protein kinase C; A1R, adenosine A1 receptors; T4, thyroxine; Gap 43, growth-associated protein 43; CRE, cyclic response element; CBZ, carbamazepine; TRH, thyrotropin-releasing hormone; CREB, cyclic response element-binding protein; VPA, valproate; SRIF, somatostatin; t.o., turnover; GABA, gamma-aminobutyric acid; CSF, cerebrospinal fluid; MARCKS, myristoylated alanine-rich C kinase substrate; cGMP, cyclic guanosine 3 0 ; 5 0 -monophosphate; CBZ-E, carbamazepine epoxide; PO4, phosphorylation; 5HT, serotonin; sub P, substance P; cGMP, cyclic guanosine monophosphate; Na+, sodium channel; K+, potassium channel.

other differential mechanisms remain to be elucidated (Fig. 8).

V.

TOPIRAMATE

Consistent with its broad spectrum of anticonvulsant action, topiramate has multiple putative mechanisms of action. In addition to its ability to block sodium channels and thus presumptively decrease glutamate and other excitatory amino acid release [119], topiramate indirectly enhances GABA-ergic mechanisms through an unclear molecular effect [120,121]. It also directly inhibits binding at the AMPA/kainate subtype of glutamate receptors [120], which may account for some of its broader spectrum of anticonvulsant action because AMPA receptor activity is necessary for the expression (as opposed to development) of long-term

potentiation (LTP) [122]. This mechanism could account for topiramate’s proclivity to impair some aspects of cognition, particularly upon rapid dose escalation [123,124]. This latter effect tends to involve speech and word-finding difficulties in a small percentage of patients. It is also possible that topiramate’s ability to block AMPA receptors could account for other aspects of its psychotropic profile, including the preliminary report of its potential promise in the treatment of posttraumatic stress disorder (PTSD) [125]. To the extent that AMPA receptors are crucial to the maintenance of LTP, and PTSD involves an overactive replay of memory circuits, blockade of AMPA receptors could be of clinical importance. As a carbonic anhydrase inhibitor, topiramate possesses an approximately 1% risk of causing renal calculi [126]. These are reportedly less frequent in women than in men, and are likely to respond rapidly to litho-

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Figure 8 Calcium channel diversity and drug targets. CBZ, carbamazepine; 5-HT, serotonin; TRH, thyrotrophin-releasing hormone; Ach, acetylcholine; PKC, protein kinase C; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; MBR, mitochondrial (or peripheral-type) benzodiazepine receptor; NMDA, N-methyl-D-aspartate receptor; PIP2 , phosphatidylinositol-4,5biphosphate; Ca++, calcium channel; Na+, sodium channel; Mg++, magnesium channel.

tripsy treatment in an emergency room setting because the calculi are usually calcium based. It is noteworthy that in uncontrolled but long-term follow-up trials in clinical practice settings, more patients remained on topiramate than on gabapentin or lamotrigine [127], suggesting that for the sake of therapeutic efficacy, patients are willing to tolerate a modicum of side effects with this agent.

VI.

GABAPENTIN AND TIAGABINE: ENHANCERS OF BRAIN GABA

Both gabapentin and tiagabine increase brain GABA [128] (Table 3). Tiagabine is a highly selective inhibitor of GABA reuptake. The mechanism of increasing

GABA is somewhat obscure for gabapentin, although actions on the GABA transporter are thought to contribute. Gabapentin has other actions on calcium channels and on strychnine-insensitive glycine receptors [129]. Although it was originally synthesized as a GABA agonist, it possesses no direct effects at the GABAA receptor [129]. Whereas a series of open studies have suggested the efficacy of adjunctive gabapentin in bipolar disorders, two controlled studies do not support this conclusion for mania [27,130]. In the controlled trial of 6 weeks of monotherapy in patients with refractory mood disorders, the 28% response rate to gabapentin was not significantly (statistically) different from the 23% response rate achieved with placebo, and both were inferior to lamotrigine [27]. Moreover, in some patients, gabapentin appeared to exacerbate


manic components of the illness, including cycle acceleration or increasing the severity of manic presentations. These data parallel those of Pande et al. [130], who reported that in a randomized double-blind study in acute mania, gabapentin augmentation did not exceed that of placebo. Two studies suggest that tiagabine is not an effective antimanic or mood-stabilizing agent. Grunze and colleagues [26] treated 10 patients with tiagabine and none responded, and one patient who had not had a previous seizure disorder experienced a major motor seizure. Little evidence of efficacy was observed in an open add-on case series of 17 patients with bipolar illness (Suppes et al., 2000, unpublished observation). Again, there was one definitive occurrence of a seizure and another in which there was likely a seizure. The findings that these two agents, which enhance brain GABA levels via two different mechanisms and are not likely to possess antimanic properties, suggest that the ability of valproate to increase brain GABA is not sufficient to account for its antimanic efficacy, and other candidate mechanisms should be sought. These data are, to some extent, convergent with the findings of lower CSF GABA in depressed patients, and increasing or normalizing CSF GABA with a switch into mania [131,132]. Perhaps these agents should be further explored in controlled trials of the depressive phase of the illness, given this putative deficit in brain GABA in this phase of the illness. What might account for gabapentin’s widespread use in the affective disorders, given its unlikely utility as an antimanic or mood-stabilizing agent? It is possible that effects of gabapentin on other symptoms and syndromes that are often comorbid in patients with bipolar illness may account for this phenomenon. For example, gabapentin is reported to be effective in controlled trials in the treatment of social phobia [133] and holds promise in other anxiety disorders [134,135]. Forty percent of the patients in the Stanley Foundation Bipolar Network have a comorbid anxiety disorder diagnosis [136,137]. Similarly, gabapentin has been suggested to have a role in the treatment of obsessive-compulsive disorder [138]; a variety of pain syndromes, tremor, and restless leg syndromes [139–141]; and perhaps parkinsonism [142]. In the NIMH clinical trial [27], although gabapentin response was not statistically significantly different from placebo, a positive clinical response was correlated with younger age, shorter duration of illness, and a lower weight at baseline entry into the study [143]. It is possible that the high doses that were used (averaging 3000–4000 mg/day) were too high for older

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patients, and more systematic controlled trials of both lower doses and younger populations would appear indicated. VII.

LEVETIRACETAM

Although, to our knowledge, there have been no case reports or systematic studies of the potential psychotropic effects of levetiracetam, it nonetheless remains a drug of considerable interest for further investigation. It appears to have a unique mechanism of action unshared by most of the other anticonvulsants, because it has not been shown to act at any neurotransmitter, receptor reuptake site, or ion channel among the many traditional candidates that have been tested based on the action of other psychotropic agents and anticonvulsants [144–146]. Recent data suggest that levetiracetam may decrease intracellular Ca2þ , but the precise site of action for this effect remains uncertain. Levetiracetam inhibits the ability of zinc ions and beta-carboline to negatively modulate GABAA receptors, thus enhancing chloride influx. It also decreases both neuronal hyperexcitability and hypersynchronization [147,148]. Additional support for its potential unique actions are the findings that it is not active in the traditional models for major motor and absence seizures, i.e., maximal electroshock (MES) and pentylenetetrazol, respectively [149]. Moreover, in contrast to many other agents, such as carbamazepine, phenytoin, and lamotrigine, which are not active in preventing the development of amygdala kindling (epileptogenesis), levetiracetam is an effective agent in preventing both the development and the expression of amygdala-kindled seizures [150]. These findings, taken with its apparently benign side-effects profile, make it an ideal candidate for further exploration in the affective disorders with the hope that its anti-epileptogenic properties in the initial phases of kindling may parallel other preventive effects in the affective disorders. VIII.

ZONISAMIDE

This recently approved adjunctive agent for partial onset seizures has multiple putative mechanisms of action. These include blockade of voltage dependent sodium channels; blockade of T-type, but possible enhancement of N-type channels; biphasic modulation of serotonin function; and free radical scavaging [151– 155]. Kanba et al. [156] reported that open-label addition of zonisamide (100–600 mg/day) to other mood-

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stabilizing agents was associated with improvement in 80% of 15 acutely manic patients, but no controlled studies have been reported.

IX.

LOSS OF ANTICONVULSANT EFFICACY: THE CONTINGENT TOLERANCE MODEL

A loss of efficacy to the prophylactic effects of a wide range of psychotropic agents is becoming increasingly evident in a small subgroup of affectively ill patients in the course of long-term treatment and followup. This has been noted for antidepressants and monoamine oxidase inhibitors [157,158] and the SSRIs [159]. Some of the molecular mechanisms of tolerance to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures have been elucidated [160]. This type of tolerance is associative or ‘‘contingent’’ upon the drug’s being present at the time of the seizure and is not based solely on repeated or chronic drug administration per se, i.e., pharmacodynamic tolerance (Fig. 9). Kindled seizures normally elicit a

host of changes in gene expression leading to both pathological and adaptive (anticonvulsant) mechanisms, which lower and raise seizure threshold, respectively. During tolerance to the anticonvulsant effects of carbamazepine, some of the putative anticonvulsant mechanisms fail to be induced despite the occurrence of a full-blown seizure, because the presence of carbamazepine (Fig. 10). These include the failure of normal seizure-induced increases in the mRNA for TRH [161], the alpha-4 subunit of GABAA receptors (but not benzodiazepine receptors) [162], mineralocorticoid (but not glucocorticoid) receptors, and CRH and its binding protein CRH-BP [160]. Whereas CRH is usually thought to be proconvulsant, in the hippocampus, it is colocalized in GABA interneurons and thus could be part of an inhibitory pathway. In tolerant animals, if seizures are induced in the absence of drug (either if it is discontinued or if it is administered immediately after the kindled stimulation rather than before), anticonvulsant efficacy (and the associated increase in seizure threshold produced by carbamazepine in the medication-free situation) is

Figure 9 Schematic illustration of contingent tolerance to carbamazepine: development and reversal. In fully kindled animals (open circles), carbamazepine treatment (filled circles) inhibits kindled seizures. Repeated drug administration before (filled circles) but not after (filled squares), stimulation results in tolerance development. Tolerance induced in this manner can be reversed by a period of kindled seizures without drugs or with drug administration after each seizure (filled squares).


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Figure 10 Competing pathological and adaptive endogenous responses to kindled seizures. Tolerance is associated with loss of selective kindling-induced effects on gene expression. Schematic illustration of potential transcription factor, neurotransmitter, and peptidergic alterations that follow repeated kindled seizures. Putative mechanisms related to the lasting primary pathological drive (i.e., kindled seizure evolution) are illustrated on top, and those thought to be related to the more transient secondary compensatory responses (i.e., anticonvulsant effects) are shown on the bottom. The horizontal line represents time. Sequential transient increases (above line) or decreases (below the line) in second messengers, immediate early genes, and neurotrophic factors are followed by longer-lasting alterations in peptides, neurotransmitters, and receptors or their mRNAs. Given the unfolding of these competing mechanisms in the evolution of seizures and their remission, the question arises as to whether parallel opposing processes also occur in the course of affective illness or other psychiatric disorders. Such endogenous adaptive changes may be exploited in the design of the new treatment strategies. fras, fos-related antigens; NT3, neurotrophin-3; BDNF, brain-derived neurotrophic factor; NPY, neuropeptide Y; CRH, corticotropin-releasing hormone; TRH, thyrotrophin-releasing hormone; TBPS, [35S]-tert-butylbicyclophosphorothionate; GABA, gamma-aminobutyric acid; BENZO, benzodiazepine receptors; glu, glutamate; Ca++, calcium channel.

restored. This is presumably because some of the compensatory endogenous, seizure-induced anticonvulsant mechanisms have now been able to reemerge in the absence of carbamazepine and thus enable carbamazepine to again be more effective. It is apparent that carbamazepine requires these increases in compensatory adaptive mechanisms in order to be an effective anticonvulsant. The seizureinduced increases in TRH mRNA and protein last 4–5 days after a given seizure. If carbamazepine is administered after an interval of > 4 days from the last seizure, it is no longer effective [160]. These observations of the ‘‘time-off effect,’’ taken in conjunction

with those indicating that TRH administered directly into the hippocampus exerts anticonvulsant properties [163], suggest that this neuropeptide represents one of the factors that are transiently induced following a seizure that either are endogenously anticonvulsant in their own right or facilitate the actions of exogenous anticonvulsant drugs such as carbamazepine, diazepam, or lamotrigine achieving anticonvulsant efficacy. In the anticonvulsant model of carbamazepine tolerance, the development of tolerance can be slowed by a variety of manipulations, as summarized in Table 7. Whether these are pertinent to the development of tolerance to the psychotropic effects of carbamazepine in

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Post et al. Table 7 Clinical Predictions (Left) to Be Explored Based on Observations from a Preclinical Model of Amygdala-Kindled Seizures (Right) Preclinical studies

Future studies; is there predictive validity for clinical tolerance in affective illness?

Tolerance to anticonvulsant effects slowed by: Higher doses (except w/LTG) Not escalating doses More efficacious drugs (VPA > CBZ) Treatments initiated early in illness

Would tolerance be slowed by: Maximum tolerated doses Stable dosing Different rate of treatment resistance (CBZ > VPA)? Early institution of lithium treatment is more effective than late Combination > monotherapy? Treatment comorbidities

Combination treatment (CBZ þ VPAÞ Reducing illness drive Treatment response restored by: Period of drug discontinuation then re-exposure Agents with different mechanisms of action, i.e., no cross-tolerance (cross tolerance from lamotrigine to CBZ, not VPA)

Treatment response restored by: Randomized study of continuation treatment vs. discontinuation and reexposure needed VPA should be more effective in those tolerant to LTG than would be CBZ

VPA, valproic acid; CBZ, carbamazepine; LTG, lamotrigine.

the recurrent affective disorders remains to be directly tested. Nonetheless, there are case observations suggesting that after a period of gradual loss of efficacy to carbamazepine via an apparent tolerance mechanism, therapeutic effects can again be achieved when the drug is reinstituted after a period of time off that medication [164]. A clinically more useful approach in the face of tolerance would be to use a drug with a different mechanism of action that does not display crosstolerance. For example, carbamazepine shows crosstolerance with PK-11195, lamotrigine, and (surprisingly) valproate, but not to diazepam, phenytoin, or clonazepam [160,165,166]. Although no systematic evidence has yet been offered that tolerance develops to the clinical anticonvulsant or psychotropic effects of lamotrigine, a number of preliminary case reports support this possibility. In this regard, it is noteworthy that lamotrigine, like carbamazepine, shows the rapid development of tolerance to its anticonvulsant effects on amygdala-kindled seizures [165]. There is essentially complete cross-tolerance between carbamazepine and lamotrigine, and vice versa. In contrast to a number of other agents in which higher doses appear to slow the development of tolerance, the converse appears to occur for lamotrigine [167]. Not only does lamotrigine in higher doses appear to propel a more rapid loss of efficacy, but the breakthrough seizures that are manifest become more severe, including stage VI type, with violent convulsions and running fits in rodents. Most interestingly, we have

also observed that administration of either lamotrigine or carbamazepine in the initial stages of kindling development (when they are not effective in preventing the progression to full-blown seizures) rendered both of those drugs also ineffective on completed kindled seizures (when these drugs are ordinarily highly effective) [165]. We have begun to examine the possible dose and other drug administration parameters that would be most likely to slow tolerance development in this anticonvulsant model in the hope that they may provide paradigms that might also be effective in other clinical situations of tolerance development. Although both higher (20 mg/kg) and lower (5 mg/kg) doses of lamotrigine appear to be ineffective, alternating moderate and low doses on a daily basis (15 mg/kg on one day and 5 mg/kg on the next) appears to be the most effective in slowing tolerance to lamotrigine; however, the increased number of days until complete loss of efficacy was not very substantial. Therefore, we examined other potential interventions, including use of anticonvulsants such as gabapentin, which have very different putative mechanisms of action and physiological effects. Lamotrigine (like carbamazepine) increases the threshold for seizure generation, whereas gabapentin affects its spread [168,169]. Gabapentin, at doses that in themselves were ineffective, appeared to slow tolerance development to the anticonvulsant effects of lamotrigine and to more notably inhibit the development of stage VI


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Table 8 Differential Effects of Carbamazepine (CBZ) and Lamotrigine (LTG) on Anticonvulsant Tolerance Development CBZ (15 mg/kg)

LTG (16 mg/kg)

Rapid tolerance to anticonvulsant effects (amygdala kindling) Cross-tolerance ‘‘Time-off’’ effect (seizures enhance efficacy) Seizure threshold ~ with tolerance

þþþ

þþþ

þþþ þþþ (4–5 days) ###

High doses

Slow tolerance

Alternating high & low doses Chronic noncontingent drug dosing MK801 on tolerance development Cross tolerance to valproate Valproate combination Gabapentin augmentation (2 h pretreatment) (12 h pretreatment) Tolerance reversal

? Slows tolerance No effect Yes Slows tolerance ? No effect ?

þþ þþþ (4–5 days "" (possible residual drug effect) Speed tolerance and are proconvulsant Slows tolerance ? Slows (NMDA implicated) No ? Slows tolerance # VI seizures þþþ

NMDA, N-methyl-D-aspartate.

seizures manifest during lamotrigine treatment. A variety of other similarities and differences between carbamazepine and lamotrigine are summarized in Table 8. Whether any of these preclinical observations will generalize to the clinic remains to be directly studied and tested.

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3.

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CONCLUSIONS

A variety of anticonvulsants have come to play a widely accepted and experimental role in the treatment of bipolar illness. Much further work is needed, not only to better understand their spectrum of therapeutic and mechanism of psychotropic action, but also most importantly, to develop better clinical and biological markers of therapeutic responsivity to these agents.

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52 Mechanisms of Action of New Mood-Stabilizing Drugs JOSEPH LEVINE, YULY BERSUDSKY, CARMIT NADRI, YURI YAROSLAVSKY, ABED AZAB, ALEX MISHORI, GALILA AGAM, and ROBERT H. BELMAKER Ben-Gurion University of the Negev, Beer-Sheva, Israel

I.

trate this argument we will describe in detail the reported beneficial effects of phenytoin—a classical sodium channel blocker with relatively few other relevant pharmacological properties—in the manic phase of BP. We will attempt to demonstrate a relationship between clinical plasma therapeutic level of antibipolar AC and inhibition concentration 50% (IC50 ) on sodium channels. The preferential effect of phenytoin on the persistent sodium current allows for this AC to reduce late openings of sodium channels, while leaving early channel openings relatively intact. Speculatively, this could be the basis for an effect of phenytoin and other antibipolar ACs in diseases characterized by neuronal hyperexcitability (including manic states) while interfering minimally with normal function.

INTRODUCTION

Several anticonvulsant (AC) compounds are useful in the treatment of bipolar disorder (BP). Carbamazepine and valproate were found to be effective treatments for BP [1,2]. Other ACs such as lamotrigine, topiramate, and more recently phenytoin also show promise [3–5]. However, much of the data regarding the clinical efficacy of the new AC depends on open, uncontrolled studies. AC compounds have a multiplicity of pharmacological properties including GABA-agonistic effects, modulation of excitatory amino acids release, and blockade of sodium and calcium channels. A pharmacological dissection might be useful to identify the key mechanism for the mood-stabilizing effect of these drugs. In a pharmacological dissection, one first enumerates pharmacological properties at clinically relevant plasma concentrations. Second, one searches for common pharmacological properties. Third, one excludes properties not shared by all AC compounds or present in compounds showing no efficacy in BP. In the following pages we will describe the pharmacological properties of AC reported to have antibipolar effects. Based on these data, we will propose that the shared common mechanism for antibipolar AC involves sodium channel–blocking activity. To illus-

II.

PHARMACOLOGICAL PROPERTIES OF MOOD-STABILIZING ANTICONVULSANT DRUGS

A.

Carbamazepine

Carbamazepine has been demonstrated in open and double blind studies to have beneficial effects in bipolar illness [6,7] and is now routinely prescribed for this illness. Carbamazepine causes blockage of voltage793

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activated sodium channels, causing decreased electrical activity and, probably, a subsequent reduction in glutamate release [8]. This effect on sodium channels occurs at therapeutically relevant concentrations. This drug also inhibits benzodiazepine binding to peripheral type benzodiazepine receptors present on astrocytes [9]. Carbamazepine was also shown to bind to GABAA receptors, to potentiate chloride currents [10], and to prevent upregulation of cortical and hypothalamic GABAA receptors [11]. Another proposed mechanism of action of this drug involves an antagonistic activity at L-type cell membrane calcium channels; other findings suggest that it may also exert such an effect on N-type calcium channel [12]. Finally, there are reports that carbamazepine is an antagonist of A-type adenosine receptors [12]. B.

Oxcarbazepine

Oxcarbazepine, 10-keto analog of carbamazepine, is indicated for the treatment of partial seizures with and without secondary generalization. There are data on the use of oxcarbazepine in patients with bipolar, schizoaffective, and schizophrenia-related disorders [13]. Macdonald and Kelly [14] suggested that its similarity in structure and clinical efficacy to carbamazepine suggests that its mechanism of action is similar to that of carbamazepine. C.

Valproate

Valproate is a branched-chain fatty acid. It is commercially available as the corresponding free acid, the sodium salt, and as divalproex sodium. Valproate causes blockage of voltage-operated sodium channels at therapeutic plasma levels [15]. Valproate is also reported to elevate brain GABA-ergic activity [16]. This mode of action may involve inhibition of GABA transaminase, an enzyme responsible for GABA metabolism, and it has also been suggested that valproate may inhibit succinic semialdehyde dehydrogenase [17], an enzyme that follows GABA transaminase in the process of GABA metabolism. The inhibition of the latter leads to product inhibition of GABA transaminase. Valproate has also been demonstrated to enhance the activity of glutamic acid decarboxylase, a key enzyme for GABA synthesis [18]. Thus, valproate increases synthesis of GABA and reduces its metabolism. It has also been reported that sodium valproate acts on T-type Ca2þ channels, and Franceschetti et al. [19] showed that this drug can suppress spontaneous epileptic activity

in hippocampal slices by activating calcium and potassium conductance. An antagonistic action at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has also been reported by several authors [20,21]. D.

Topiramate

Topiramate is a sulfamate-substituted fructose derivative that is approved in several countries for the treatment of adult and pediatric epileptic disorders. Open studies suggest that topiramate may have moodstabilizing properties for the treatment of bipolar disorder [22,23]. Topiramate, similarly to carbamazepine and valproate, blocks voltage-gated sodium channels [24]. Topiramate also potentiates GABA neuroinhibition [25], and increases cerebral GABA concentrations in healthy subjects [26]. In addition it has been reported to antagonize glutamate effects at NMDA receptors (AMPA/kainate type of glutamate receptor) [27], as well as to inhibit types II and IV isoenzymes of carbonic anhydrase [28]. Finally, topiramate has been reported to negatively modulate L- and N-type calcium channels, whereas its effects on T-type channels are still uncertain [28]. E.

Lamotrigine

Lamotrigine is an antiepileptic drug of the phenyltriazine class. Recent studies suggest that lamotrigine may have beneficial effects in patients with BP [29,30]. Lamotrigine has been reported to stabilize type II sodium channels via selectively inhibiting sodium currents [31]. This drug interacts specifically with the slow inactivated state of the sodium channel. Davies [8] and Macdonald and Kelly [14] suggested that blockage of voltage-operated sodium channels by lamotrigine leads to decreased electrical activity and, probably, to a subsequent reduction in glutamate release. It has been also suggested that lamotrigine may modulate calcium and potassium channel currents [32]. Finally, this drug was reported to block the release of the excitatory amino acids glutamate and aspartate [33]. F.

Gabapentin

Gabapentin was synthesized as an analog of GABA. It is approved as an adjunctive therapy for partial seizures with or without secondary generalization. Some preliminary data suggest that it may be effective for the acute or prophylactic treatment of bipolar illness [34,35]. However, a larger study did not

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demonstrate efficacy in bipolar disorder [36]. Gabapentin was reported to induce release of GABA from neurons and glia cells. Another mechanism offered was reversal of GABA transporter action, leading to increased extracellular GABA levels [37]. Yet another possibility is that this drug leads to increased synthesis of GABA [38]. Gabapentin also binds with high affinity to a brain binding site associated with an auxiliary subunit of voltage-sensitive Ca2þ channels, and it may thus modulate certain types of calcium current [39]. One could speculate that its lack of antibipolar activity in a double-blind controlled study [36] may be related to its clear lack of effect on sodium channels.

preparations of presynaptic nerve terminals [14], and it was suggested that it can at high concentrations inhibit calcium-calmodulin-dependent protein phosphorylation and regulate some neurotransmitter release [46]. Phenytoin was also reported to have little or no effect on T-type calcium channels in thalamic nuclei [14]. The blockade of sodium channels seems to be the main mode of action of this drug, and studies aiming at exploring the involvement of sodium channels blockade in the mode action of AC mood stabilizers may use phenytoin as a prototype drug for such exploration.

G.

While numerous biochemical properties have been found for carbamazepine, valproate, lamotrigine, and topiramate, all seem to share with phenytoin, the classical anticonvulsant, powerful inhibition of voltageactivated sodium channels. It thus seemed of considerable theoretical importance to determine whether phenytoin is antibipolar. Early uncontrolled reports of improvement of mania with phenytoin exist [47], and its cognitive side effects have recently been reassessed favorably [48–50]. We therefore decided to conduct a trial of phenytoin in mania [5]. Based on our previous study of carbamazepine [51] and lithium [52] we used an add-on design to ongoing neuroleptic treatment. The study was approved by our Helsinki Committee, and all patients gave informed written consent. Patients could participate if they met DSM-IV criteria for mania or schizoaffective disorder, manic type, and had no serious physical illness. Only patients who had side effects or nonresponse to previous mood-stabilizing treatment were included. Patients admitted to the study were treated with haloperidol at doses of physicians’ discretion. Trihexyphenidyl was available as necessary for extrapyramidal symptoms and benzodiazepines for sleep. Phenytoin was begun at doses of 300 mg/day and increased to 400 mg after 4 days, with the first blood sample being drawn on the third day after that. Patients received phenytoin or identical capsules of placebo as assigned by the control psychiatrist according to random order; manic and schizoaffective manic patients were randomized separately. Weekly ratings by a psychiatrist blind to the study drug were conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMS), and the Clinical Global Impression (CGI). Blood was drawn weekly for phenytoin levels, and the results

Tiagabine and Vigabatrin

Tiagabine is a nipecotic acid analog. There are anecdotal data regarding tiagabine’s use for BP [40]. The drug enhances GABA-ergic activity by decreasing the uptake of GABA, leading to increased synaptic GABA content [41]. No affinity for a wide range of receptors was reported for this drug [42]. Vigabatrin increases synaptic concentration of GABA by inhibition of GABA aminotransferase [43]. Presumably, vigabatrin possesses only one mechanism of action, associated with this increased GABA-ergic activity [8]. There are still no reported studies of these drugs in BP at this time. We speculate that these two drugs, lacking an effect on sodium channels, will be devoid of beneficial activity in bipolar disorder. H.

Felbamate

Felbamate has been shown to block voltage-dependent sodium channels, to enhance GABA-mediated events, and to inhibit glutamatergic neurotransmission via action at the strychnine-insensitive glycine-binding site of the NMDA receptor [44,45]. There are as yet no reported studies of this drug in BP at this time. However, if sodium channel blockade is the primary mode of action of AC in BP, one would expect that this drug will show efficacy in BP. I.

Phenytoin

Phenytoin (5,5-diphenylhydantoin) mainly acts via blockade of voltage-dependent sodium channels, and it does not seem to modify GABA-ergic neural synaptic transmission [14]. Phenytoin at high concentrations, but not at therapeutically relevant concentrations, blocks depolarization-dependent calcium uptake in

1.

Phenytoin in Bipolar Illness

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were reported to the control psychiatrist who created dummy levels for placebo patients and reported results to the treating physician, who adjusted dose of phenytoin accordingly. Thirty-nine patients entered the study over 1 year and 30 completed at least 3 weeks. Patients completing at least 3 weeks were included in the data analysis on a last-value-carried-forward basis. Eighteen patients were schizoaffective manic and 12 were manic. Nine dropped out before 3 weeks: one with phenytoin toxicity (gait instability, blood level ¼ 26 mg/mL); three refused to continue (one on phenytoin and two on placebo); three with exacerbation after 2 weeks on phenytoin; one on phenytoin after his brother’s suicide; one on placebo violated the protocol with nonstudy medication. Analyses were three-way MANCOVA, covariance for baseline (Greenhouse-Geisser corrected) for diagnosis, treatment, and time. For BPRS: Diagnosis, treatment and time showed a significant three-way interaction (F ¼ 5:09, df2:3;60:6 , P ¼ :006), with a significant two-way interaction between treatment and time (F ¼ 3:83, df2:3;60:6 , P ¼ :02) and significant twoway interaction between treatment and diagnosis (F ¼ 4:42, df1;25 , P ¼ :046). Tukey HSD posthoc comparisons show significant differences for manic patients only from week 3 to week 5 (p3 ¼ :01, p4 ¼ :006 and p5 ¼ :001) between phenytoin and placebo. The effect size of phenytoin improvement in manic patients and schizoaffective manic patients compares with similar figures for carbamazepine [51] in a similar acute addon design. Several patients illustrate the possible clinical utility of phenytoin in mania. A 44-year-old male with treatment resistance in previous episodes to lithium, valproate, carbamazapine, or Li-carbamazepine combination responded to haloperidol 15 mg/ day plus phenytoin (blood level 19 g/mL) by the end of week 2. He reached full remission but exacerbated rapidly when he stopped phenytoin at the end of the trial. A 26-year-old bipolar female with very long hospitalizations in the past improved on lithium within 2 weeks on haloperidol 25 mg/day plus phenytoin (blood level 17 g/mL). She reached full remission within a month for the first time in her history. A 60-year-old male had never reached a stable remission, despite numerous hospitalizations on lithium, carbamazepine, or valproate with severe side effects. By the third week of haloperidol 10 mg plus phenytoin (blood level 15 mg/mL), he became completely euthymic and for the first time cooperative with treatment.

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III.

VOLTAGE-GATED SODIUM CHANNELS

We argued that voltage-gated sodium channels, playing a pivotal role in action potential generation in central neurons, may be the key target for AC mood stabilizers. In this section we will survey current knowledge on the nature of these channels. A.

Structure of Voltage-Sensitive Na+ Channels

1.

Protein Subunits

Sodium channels were the first ion channels whose structure has been characterized. Purified Naþ channels were found to contain all the functional components necessary for electrical excitability: ion conductance and voltage-dependent gating. A variety of biochemical techniques such as: photoreactive derivatives of toxins that attach covalently to Naþ channels in intact cell membrane, enabling identifying channel components without purification [53]; reversible binding of the toxins tetrodotoxin (TTX) and saxitoxin (STX) to their receptor to quantify the channel protein amount and functionality [56]; and solubilization of excitable membranes with nonionic detergents releasing the Naþ channels in a form that retains their ability to bind TTX and STX with high affinity were used to identify the characteristics of the electrical exitability of the channels. Toward understanding structure-function relationship of this channel, several groups identified a large glycoprotein (260 KDa) as the major subunit—the asubunit. It is a transmembrane polypeptide composed of 1800–2000 amino acids and contains four repeated domains (designated I–IV) having 50% amino acid sequence identity, resulting in similar secondary and tertiary structures [53]. Each domain contains six segments (designated 1–6) that form transmembrane ahelices and additional hydrophobic sequences that are thought to be membrane associated contributing to the formation of the outer pore. The four domains are connected by a relatively hydrophilic intracellular amino acid sequence. This structural motif of the voltage-gated sodium channel homologous domains is the building block of all the voltage-gated channels [54]. The a-subunit has sites for the attachment of carbohydrate chains and for the binding of neurotoxins on the external surface of the channel, as well as phosphorylation sites by cAMP-dependent protein kinase (PKA) on the intracellular surface [54]. In frog oocytes the asubunit is sufficient to form an active channel by itself,


emphasizing the importance of this subunit for the function of the channel [54]. In mammalian brain the a-subunit is associated with two additional polypeptides: the auxiliary b1-subunit (36 KDa) and b2-subunit (33 KDa). They are integral membrane proteins that interact with the phospholipid bilayer [53]. The b1-subunit consists of a large glycosylated, extracellular N-terminal segment, a single-transmembrane segment, and a short intracellular segment. The glycosylating groups are sialic acid, contributing to the strong net negative charge of the channel subunits. It consists of 218 amino acids and has a large extracellular domain with four potential sites of Nlinked glycosylation, a single a-helical membrane spanning segment, and a very small intracellular domain [55]. The b1- and b2-subunits of Naþ channels have similar overall structures but are not closely related in amino acid sequence. The b1-subunit is noncovalently attached to the a-subunit while the b2-subunit is covalently attached to the a-subunit via a disulfide bond. The b1- and b2-subunits reveal a probable structural relationship to the family of proteins that contain immunoglobulin-like folds [54]. This is a sandwich of two b-sheets held together by hydrophobic interactions, a unique structure among ion channels subunits. A reentrant loop dipped in the transmembrane region of the sodium channel protein between the transmembrane segments S5 and S6 forms the outer pore of the channel. Relatively large extracellular loops were predicted in each homologous domain, connecting either the S5 or the S6 transmembrane segments to the membrane-reentrant loop. Even larger intracellular loops were predicted to connect the four homologous domains, and large N-terminal and C-terminal domains were also predicted to be intracellular. 2.

Outer Pore and the Selectivity Filter

The movement of an ion across the membrane is a continual exchange of oxygen ligands as the ion passes through relatively free water molecules and polar groups that form the wall of the pore. This pore may interact with permeated ions as they approach and move through the channel. It is assumed that as the ion permeates polar and charged groups in the pore provide stabilization energy, compensating for water molecules that are left behind [54]. The pore is narrow enough to sense different ions and to distinguish among them. The channels also contain charged components that sense the electric field in the membrane and drive conformational changes that open and close ‘‘gates’’ controlling the permeability of the pore. A

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single channel handles up to 6 107 monovalent ions per second, implicating that the channel is indeed a pore [53]. Based on evidence from the blockade of the channels’ permeability by lowering the pH of the external medium below 5.5, and from site-directed mutagenesis of aspartate and glutamate residues in cloned channels [54], these negatively charged residues were postulated to form outer and inner rings that serve as the receptor sites for TTX and STX and a selectivity filter in the outer pore of sodium channels. Mutational analysis identified glutamate 387 in the membrane reentrant loop in domain I, and another pair of important amino acid residues, mostly glutamate and aspartate, in analogous positions in all four domains near the Cterminal of the short hydrophobic segment between transmembrane a-helices S5 and S6, as crucial residues for the binding of the pore blockers TTX and STX [4]. Mutation of only two of the residues that are not negatively charged to glutamate (in domains III and IV) replaces the selectivity of the Naþ channel into a Ca2þ selective channel [54]. 3.

The Voltage Sensor

A membrane protein responding to changes in membrane potential must have either charged or dipolar amino acid residues, or both, located within the membrane electric field, acting as a voltage sensor [53]. When the energy of the field-charge interactions is high, the protein may undergo a change to a new stable conformational state in which the net charge or the location of charge has been altered. Such movement of membrane-bound charges gives rise to a ‘‘gating’’ current [57]. The S4 segments of the homologous domains have been proposed as the voltage sensor of the Naþ channel [58]. These segments are highly conserved in all voltage-gated channels, and consist of repeated triplets of two hydrophobic amino acids followed by positively charged residues. In the a-helical configuration they form a spiral of positive charge across the membrane, well suited for transmembrane movement of gating charges. Each positive charge is neutralized by a negative charge in one of the surrounding transmembrane segments. It is suggested that the movement of the S4 helix in each domain initiates a more general conformational change in that domain. After taking place in all four domains, the transmembrane pore can open and conduct ions. Shortly after opening, the channel goes through inactivation.

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Unlike activation, fast inactivation of the open state of Naþ channels is not a strongly voltage-sensitive process. Apparently, regions of ion channels mediating inactivation are exposed to the intracellular surface of the membrane. Treatment of the intracellular surface of the channel with proteolytic enzymes prevents inactivation [54]. The segment of the Naþ channel between domains III and IV is proposed to serve as the inactivation gate by forming a hinged lid which folds over the intracellular pore after activation [54]. Antibodies against the intracellular segment connecting domains III and IV completely block inactivation [54]; expression of the Naþ channel as two separate fragments cut between domains III and IV greatly attenuates inactivation [54]; phosphorylation of a single serin residue in this segment by protein kinase C slows inactivation [54]. Mutation of a cluster of three hydrophobic residues that is required for fast Naþ channel inactivation, with three glutamine residues (hydrophilic amino acid), completely eliminates fast inactivation of Naþ channels. Another essential residue is phenylalanine at position 1489. Its mutation to glutamine nearly blocks fast inactivation of the channel. The cluster of hydrophobic residues including Phe 1489 is thought to enter the pore and bind as a latch to keep the channel inactivated [53]. B.

Gating Mechanism of the Na+ Channel

Voltage-gated sodium channels, responsible for the rising phase of the action potential in the membranes of neurons and electrically excitable cells exhibit three key features: voltage-dependent activation, rapid inactivation, and selective ion conductance [54]. Together with Kþ channels they account for almost all the currents in axonal membranes. Hodgkin and Huxley [57] suggested a kinetic model for the opening and closing steps of Naþ channels: depolarization of the membrane is sensed by the voltage sensor and causes conformational reactions towards opening and activation of the channel. Repolarization or hyperpolarization causes closure and inactivation. An action potential due to a depolarizing stimulus begins with a transient, voltage-gated opening that allows Naþ to enter the fiber and depolarize the membrane fully. This is followed by a transient voltage-gated opening of Kþ channels that allows Kþ to leave the cell and repolarize the membrane. In myelinated nerves, depolarization spreads from one excitable membrane patch to another by local circuit currents, but because of the insulating properties of the

coating myelin, the excitable patches of axonal membrane (nodes of Ranvier) may be > 1 mm apart, and thus the rate of progression of the impulse is faster. Nodes of Ranvier have Naþ channels similar to those of other axonal membranes, but nodal membranes have at least 10 times as many channels per area unit to depolarize the long, passive, intranodal myelin. The intranodal axonal membrane has Kþ channels but far fewer than Naþ channels. Although hidden underneath the myelin, these Kþ channels may contribute to maintain resting potentials. C.

Pharmacological Agents Acting on the Na+ Channels

The pharmacology of potent poisons targeted at the Naþ channels aids in the definition of functional regions of the channel. At the outer end of the channel there is a site where the puffer fish poison, tetrodotoxin (TTX), and its analog saxitoxin (STX), a small lipidinsoluble charged molecule bind (Ki ¼ 1–10 nM) and block Naþ permeability [54]. Another class of Naþ channel blockers is local anesthetics such as lidocaine and procaine and related antiarrhythmic agents. They are lipid-soluble amines with a hydrophobic end and a polar end; they bind to a hydrophobic site on the channel protein interacting with the inactivation gating machinery [54]. The relevant clinical actions of local anesthetics are fully explained by their mode of Naþ channel blocking. Two other classes of toxins that either open Naþ channels spontaneously or prevent them from closing normally once they have opened are lipid-soluble steroids, such as batrachotoxin (BTX), aconitine, and veratridine, all acting at a site within the membrane; and peptide toxins from scorpion and anemone venom, which act at two sites on the outer surface of the membrane, blocking specifically the inactivation gating step [54]. The affinity of the Naþ channels toward these agents is dependent on the gating conformation state of the channel. D.

Brain Voltage-Gated Sodium Channels

The physiological role and properties of ion channels may be expected to be similar in all tissues. However, brain, heart (cardiac), and skeletal muscles sodium channels differ, particularly in their selectivity. Studies using tetrodotoxin revealed that the difference in selectivity of different sodium channels is determined by a single amino acid residue located in domain I (the selectivity filter) [54].


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Phosphorylation of brain sodium channels by cAMP-dependent protein kinase (PKA) on four sites in the intracellular loop connecting domains I and II in the a-subunit [54,59] causes a reduction in the peak of sodium currents in brain neurons, but does not alter Naþ channel voltage dependence [54]. Membrane potential is a crucial determinant of the neuromodulation of hippocampal neurons sodium channels via PKA signal cascade. PKA is one of the signal cascades by which dopamine manifests its functions. Depolarization of the membrane, or activation of protein kinase-C (PKC) results in the amplification of D1 -dopaminergic effects and PKA activation. The localization of PKA near the sodium channel is essential to achieve phosphorylation of the a-subunit and to manifest dopaminergic-induced reduction in sodium currents. Dopamine is also involved in excitation and firing of neurons in the striatonigral pathway. In addition, sodium currents in the nucleus accumbens are reduced after treatment with cocaine, a drug that blocks dopamine reuptake, implicating potential behavioral consequences of neuromodulation of sodium channels [53]. Activation of muscarinic acetylcholine receptors in hippocampal pyramidal neuron reduces peak sodium currents and slows inactivation of the Naþ channels via activation of the PKC signal cascade [60]. Phosphorylation of specific sites in the intracellular loop between domains I and II reduces peak sodium currents, and phosphorylation of a site in the inactivation gate (intracellular loop connecting domains III and IV) slows Naþ channels inactivation [53,54]. Several neurotransmitters, including dopamine and acetylcholine, activate brain G-proteins. Activation of G-proteins activates neuronal Naþ channels. Thus, modulation of brain Naþ channels by neurotransmission is apparently mediated via G-protein activation. In conclusion, neuromodulatory processes of brain Naþ channels affect excitability, overall conductance of neurons, and hence, their synaptic activity.

Table 1

IV.

RELATIONSHIP BETWEEN ANTIBIPOLAR AC PLASMA LEVEL AND IC50 FOR SODIUM CHANNELS

Peroutka and Snyder [61] correlated the clinical potency of antipsychotic drugs and their in vitro dopamine receptor blockade activity, and demonstrated a high correlation between these two properties. Such a high correlation strongly supported the involvement of dopamine receptor blockade in the mode of action of antipsychotic drugs. We explored whether a correlation between antibipolar therapeutic plasma levels and their 50% inhibition concentration (IC50 ) of sodium channels could be found for antibipolar AC. The antibipolar potencies of the AC were taken as the median effective clinical dosage used in the treatment of BP and the recommended therapeutic plasma level (Table 1). The sodium channel blocking capacity of each drug was calculated by its IC50 of sodium channels. In case the sodium blocking capacity varied between different studies (i.e., PHT and CBZ), the median IC50 was taken as the representative value. Sodium channel blockade induced by CBZ and PHT was analyzed by Willow et al. [62] in mouse neuroblastoma cells using a patch voltage clamp procedure in a whole cell configuration. The IC50 observed in this study was 30 mM for each of these drugs. Another study—investigating the effect of CBZ, PHT, and LTG on voltage-activated sodium channels present in N4TG1 mouse neuroblastoma clonal cells—reported a tonic inhibition of sodium channels with IC50 values of 140, 58, and 91 mM, respectively [63]. Taken together, these data showed IC50 in the range of 30–58 mM (median ¼ 44 mM) for PHT, and 30–140 mM (median ¼ 85 mM) for CBZ, whereas the value for LTG was 91mM. A study exploring sodium channel blockade by VPA in cultured rat hippocampal neurons using a whole-cell voltage clamp under conditions appropriate for isolating sodium currents [64], found that sodium

Therapeutic Blood Levels and Sodium Channel Blockade

Compound Carbamazepine (CBZ) Sodium Valproate (VPA) Lamotrigine (LTG) Topiramate (TPM) Phenytoin (PHT)

IC50 ðmM) [ref.] 85 [62,63] 2400 [65] 91 [63] 48.9 [66] 44 [63,64]

Clinical dosage mg/day Plasma Level (median) (mg/mL) 400–1600 1500–3000 50–200 200–400 300–500

(1000) (2250) (125) (300) (400)

12 100 14 5 20

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currents were reduced in a voltage-dependent manner. Even a large concentration (1 mM) of VPA did not lead to 50% inhibition of sodium currents. This effect of VPA was also determined by voltage and current clamp experiments in nodal membrane of peripheral nerve fibers of Xenopus laevis. Valproate was found to reduce sodium currents with IC50 of 2:4 mM [65]. The half-maximal inhibition of sodium channels by TPM was examined in rat cerebellar granule cells, as measured by whole-cell current clamp recording. Topiramate was found to reduce the voltage-gated sodium channels with IC50 of 48:9 mM [66]. The effect of GBP on limiting the repetitive firing of sodium-dependent action potentials was examined in monolayer dissociated cell culture of mouse spinal cord and neocortical neurons [71]. These authors reported that GBP limited high-frequency action potential firing, but that this effect was not likely to be due to a blockade of sodium channels [71]. More than that, another study [72] showed that even a high concentration (200 mM) of GPB did not block voltagedependent sodium currents. The anticonvulsant phenobarbital given in therapeutic doses did not seem to have an antibipolar effect [73] and did not inhibit sodium channels [74].

V.

FUTURE DIRECTIONS

A.

Prophylactic Study of Phenytoin in BP

In order to support the role of sodium channel blocking as a primary mechanism underlying the AC action in BP, prophylactic efficacy for phenytoin should be shown. We are conducting a 1-year double-blind crossover prophylactic study of phenytoin in BP illness. The study was approved by our Helsinki Committee, and patients gave informed written consent. Patients can participate if they meet DSM-IV criteria for mania or schizoaffective disorder, manic type, and have no serious physical illness. Patients can enter the study if they have been out of hospital for at least 1 month and had inadequate prophylaxis in the past on lithium, carbamazepine, or valproate, and had at least one episode per year for the last 2 years. All patients are evaluated by the clinical treating physician at baseline, weekly during the first month, and monthly thereafter. Ongoing prophylactic treatment is not changed (lithium, carbamazepine, valproate, or neuroleptic). Phenytoin or placebo (as randomized) is added slowly (100 mg per week) to ongoing antibipolar treatment. Blood levels of all

antibipolar treatments are monitored weekly for the first month and adjusted as necessary. Ratings (BPRS, YMS, HDS, GAS) are done by the clinical treating psychiatrist at baseline and once monthly thereafter. After 6 months patients are crossed over during a month of weekly visits with one drug (phenytoin or placebo) being reduced by 100 mg weekly and the other increased by 100 mg weekly. This is done with individualized packets of capsules, such that the double-blind is maintained. Blood levels of all antibipolar drugs are monitored weekly during this adjustment phase, and doses adjusted as necessary. Blood levels are monitored monthly after the adjustment phase. The treating psychiatrist, who also performs the rating scales, is blind to whether the patient is on phenytoin or placebo. He receives from the control psychiatrist a bottle of tablets of phenytoin or placebo, according to prearranged random order. Blood levels of phenytoin are reported by the lab to the treating psychiatrist after ‘‘dummy’’ levels are assigned by the control psychiatrist to patients on placebo. The second phase also lasts for 6 months of monthly clinical ratings. Patients terminate from the study if hospitalization is necessary. Symptoms of sufficient severity to require addition of neuroleptic or antidepressant treatment are the major outcome variable, but will not terminate patients from the study. Special attention is given to instruction of patients in dental hygiene, and patients showing signs of gingival hyperplasia will be dropped. Studies in epilepsy show that this side effect is surprisingly uncommon, despite wide publicity [75]. No cases were seen in our previous short-term study [5]. Nonlinear pharmacokinetics, drug interactions, and the consequent danger of toxicity will be handled by careful blood levels monitoring. B.

Intravenous Fosphenytoin in Acute Mania

There is a strong need in the clinical arena for fastacting antimanic agents. Lithium loading has been reported [76]. Valproate loading has recently been reported to be promising [77]. Phenytoin is a drug with a long history of intravenous use in status epilepticus but has not yet been studied intravenously in mania. Several authors explored the rapidity and magnitude of response of manic symptomatology in the hours following an intravenous administration of agents such as physostigmine or naloxone [77,78].


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Figure 1 Relationship of IC50 for sodium channels with therapeutic plasma levels. Legend: * = valproate; ~ = carbamazepine; & = phenytoin; = lorazepam; = gabapentin; = felbamate; = lamotrigine; = topiramate.

Physostigmine given openly led to 30% improvement in Pettersen Mania Rating Scale in the hour following its administration, which returned toward baseline 2–3 h later. Naloxone showed a more modest improvement up to 2 h following its administration. While physostigmine and naloxone IV have very limited clinical use today, they demonstrated that rapid improvement of manic symptoms is theoretically possible. In the above pages we described beneficial effect of phenytoin in mania and have noted that sodium channel blockade is the primary mechanism of phenytoin. We are now performing a study of IV fosphenytoin in acute manic patients. We wish to explore whether such a strategy can induce rapid improvement in symptomatology of acute manic state without sedation. This may shed light on the possible role of sodium channel blockade as a primary therapeutic mechanism in mania.

Drugs used to treat status epilepticus must be tolerated when administered rapidly IV. Intravenous phenytoin is effective, and relatively free of sedation or respiratory suppression in the treatment of tonic-clonic status epilepticus [80]. However, intravenous phenytoin has a side-effect profile which compromises its tolerability. If administered IV too rapidly, it may lead to cardiac complications or skin necrosis at the injection site. Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was specifically developed for the replacement of parenteral phenytoin sodium. It has the same pharmacological properties as phenytoin, but has lower potential for local tissue irritation (e.g., burning and itching at the injection site) and cardiac toxicity than phenytoin. CNS effects are similar for the two drugs, but transient paresthesias are more common with fosphenytoin [81]. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions. Fosphenytoin is metabolized to phenytoin by endogen-

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ous phosphatases (conversion half-life is 15 min). Therapeutic unbound free and total plasma phenytoin concentrations are consistently demonstrated after IV administration of fosphenytoin loading doses. Fosphenytoin dosage is expressed as phenytoin sodium equivalents (PE). The standard loading dose for adults with status epilepticus is 15–20 mg PE/kg IV infused at 100–150 mg/min [82,83]. For nonemergency situations, a 10–20 mg PE/kg loading dose can be given IV [84], such as for anticonvulsant loading before a neurosurgical operation. For our double-blind placebo-controlled study of IV fosphenytoin in acute manic patients, consenting manic patients with a score of > 20 points in Young Rating Mania Scale, with no psychiatric comorbidity and physically healthy, are administered fosphenytoin 5 mg/kg (half to quarter of the dose recommended for status epilepticus at a rate of 100 mg/min (similar to that given in status epilepticus). EKG, heart rate, and respiration are monitored during the drug administration and for 60 min after. Pettersen Mania Scale and Minimental Rating Scale will be rated at baseline and at 30 and 60 min after the IV fosphenytoin injection. Rapid relief of manic symptoms through use of this nonsedative sodium channel blocker would have theoretical as well as practical clinical significance. C.

Sodium Channel Abnormalities in Bipolar Patients

Several mutations have been reported in subunits of the sodium channel which may serve as candidate mutations in the search for the genetic etiology of BP illness. The rare autosomal-dominant disorder ‘‘generalized epilepsy with febrile seizures plus’’ was found to be associated with mutation in beta-1-subunit of the voltage-sensitive sodium channel [85]. This mutation changes a conserved cysteine residue, leading to disruption of a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Based on their studies in Xenopus laevis oocytes these authors argue that this mutation interferes with the ability of the beta-1-subunit to modulate the channelgating kinetics. Another rare autosomal-dominant disorder, ‘‘benign familial infantile convulsions,’’ was not found to be associated with mutations encoded in intron 5 of the human sodium channel beta-1-subunit gene [86]. Makita et al. [87] reported the existence of an intragenic polymorphic (TTA)n repeat in the beta-1subunit positioned between two tandem Alu repetitive sequences exhibiting five distinct alleles. Finally, Haug et al. [88] reported genetic variations in the human

sodium channel beta-2-subunit gene which included for example a missense mutation in codon 209 (Asp 209 Pro) found in one of 92 patients with idiopathic generalized epilepsy but not found in an affected sibling of the index patient. These mutations, irrespective of their association with epileptic syndromes, may serve as candidate mutations for association studies of BP illness. D.

Relationship Between Antibipolar Potency and IC50 Values for Sodium Channel Blocking

Figure 1 illustrates the relationship between sodium channel blockade and antibipolar potency of AC. Clearly, there is a group of highly potent sodium channel blockers such as phenytoin, carbamazepine, and lamotrigine. However, their spread of clinical dosages and therapeutic plasma levels does not allow a dissection of whether the therapeutic dosages and sodium channel blockade are truly related. Valproate requires higher clinical dosages and is also a less potent blocker of sodium channels, supporting our hypothesis. Further points on the graph between phenytoin and valproate are necessary, however, to truly support this hypothesis. We predict that drugs like gabapentin, phenobarbital, and lorazepam, which are unlikely to be effective sodium channel blockers, will also turn out to be poor antibipolar drugs. Phenobarbital is clearly an anticonvulsant in epilepsy, but its sedative nature sets it apart from nonsedative anticonvulsants like carbamazepine and phenytoin. It is clearly not antimanic. Benzodiazepines like lorazepam are clearly useful in mania and in agitated depression, but most clinicians would argue that this effect is essentially different from the true mood-stabilizing effect of lithium and the antibipolar AC. Clonazepam is felt by many neurologists to be a uniquely anticonvulsant benzodiazepine, so its effects in BP would be critical information. Unfortunately, convincing clinical data are lacking. Clinical use skyrocketed a few years back but has more recently greatly declined. We predict that it will turn out to be merely adjunctive as will other benzodiazepines that do not block sodium channels. Felbamate, as well as lamotrigine and topiramate, are high-potency sodium channel blockers, and our theory predicts true antibipolar efficacy for them. It is important to note that not only clinical data are lacking in this field. Sodium channel blockade can vary across species, tissues, and experimental designs. The sodium channel, as discussed above, is a highly com-


plex structure. Inhibition could occur at different steps in its opening and closing, which have different physiological meanings. Recent data in vivo on clozapine binding suggest that even the relatively simple dopamine receptor can be bound with differing degrees of reversibility in a way that could account for the unexpected excess efficacy of clozapine. The sodium channel blockade hypothesis is heuristic and unifying, but clearly only a hypothesis. Manufacturers of new anticonvulsants have a clear interest in emphasizing the unique pharmacological properties of their new drugs, to encourage use in the many patients nonresponsive to existing drugs. This can be scientifically misleading, however, for an AC drug like topiramate with unique effects on carbonic anhydrase, for example, is also a very effective sodium channel blocker. We know that even AC, with very similar modes of action, such as phenytoin and carbamazepine, can synergize in a highly positive way in seizure disorders. Preconceptions can also have negative effects on science. For example, phenytoin was almost universally dismissed as ineffective in BP for half a century and was simply not studied until recently. Clearly one controlled study of phenytoin is not enough, but its powerful sodium channel blockade surely justifies considerable further effort. REFERENCES 1. Small JG, Klapper MH, Milstein V, Kellams JJ, Miller MJ, Marhenke JD, Small IF. Carbamazepine compared with lithium in the treatment of mania. Arch Gen Psychiatry 1991; 48(10):915–921. 2. Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992; 149(1):108–111. 3. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999; 60(2):79–88. 4. Marcotte D. Use of topiramate, a new anti-epileptic as a mood stabilizer. J Affect Disord 1998; 50(2-3):245– 251. 5. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH. Phenytoin as an antimanic anticonvulsant: a controlled study. Am J Psychiatry 2000; 157(3):463–465. 6. Post RM, Denicoff KD, Frye MA, Dunn RT, Leverich GS, Osuch E, Speer A. A history of the use of anticonvulsants as mood stabilizers in the last two decades

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53 Advances in Treatment and Perspectives for New Interventions in Mood and Anxiety Disorders SANDEEP PATIL, SAEEDUDDIN AHMED, and WILLIAM ZEIGLER POTTER Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

I.

BACKGROUND

II.

During the past four decades, pharmacological treatment of mood and anxiety disorders has progressed dramatically, and clinicians have a bewildering number of choices among agents. We will focus first on mood disorders. To help clinicians in making decision judgments, algorithms for unipolar [1–4] and bipolar [5–7] disorders have been developed. The availability of safe and efficacious agents has reduced the disease burden of patients with mood disorders, and the gap between suffering and its treatment is narrower. However, this gap has not been closed, and the work of drug development continues. During the upcoming decade, a variety of factors should influence the availability of newer pharmacological treatments for mood disorders. These include increases in knowledge of the pathophysiology of mood disorders and mechanisms of drug action, improvements in drug discovery and development technology, changes in the regulatory environment, and changes in reimbursement methods. New candidates for treatment of mood disorders face stiff market competition from many existing drugs, new chemical entities, and alternative therapies.

HOW DRUGS COME TO MARKET

‘‘Drug development’’ is frequently a misnomer when applied to psychotropic drugs, because almost all available agents are products of accidental discoveries [8,9]. Most currently available psychotropic drugs were found to work, or work better than their predecessors, strictly by chance. Only then was their mechanism of action determined. This pattern of discovery has been repeated over and over again. However, this pattern appears to be changing for two main reasons. Firstly, our greater general understanding of molecular mechanisms has allowed ‘‘reasonable guesses’’ for cellular targets of drug action. Secondly, technological advancements have facilitated the fast production and assessment of greater numbers of potential drug candidates than ever before. The progression of new chemical entities to marketed drugs is usually divided into two processes: drug discovery and drug development. Discovery yields ‘‘leads,’’ or molecules that have promise as drug candidates. In the past, the most common method of producing leads was to make subtle changes to the structure of existing drugs and look for subsequent changes in activity that would be expected to improve efficacy or safety compared to the parent. Drug discovery has been greatly enhanced by computer aided 807

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drug design [10] and combinatorial chemistry [11–13]. The key to combinatorial chemistry is the formation of large libraries containing information on the constituent and reactive properties of many molecules. Miniaturization, efficiencies in cost, and availability of powerful computing resources have allowed such libraries to be effectively produced, which in turn have allowed systematic mass production of candidate molecules [14–16]. The candidate molecules then undergo ‘‘high-throughput’’ screening with in vitro and in vivo assays that can serve as predictors of drug disposition and chemical activity [17–19]. A well-designed combinatorial chemistry and highthroughput screening system can generate and test compounds cheaper, and about a thousandfold faster, than was possible 10 years ago [20]. In concert with developments in chemistry and information technology, the rapidly advancing fields of genomics and proteomics are providing vast numbers of lead molecules for the ‘‘engine’’ of highthroughput screening. Genomics has evolved from genetics and may be defined as the cellular and molecular biology of gene action [21]. Proteomics is a newer science than genomics, and refers to the ascertainment and application of protein expression and subcellular organization [22,23]. Genomics and proteomics complement each other, and have wide-ranging possibilities. One application is ‘‘pharmacogenomics,’’ the study of variations in drug responses attributed to defined genomic changes [24]. Pharmacogenomics, which combines genomics techniques and molecular pharmacology, may be considered a progression of pharmacogenetics, which explored drug response differences at a macro level [25]. This new technology may eventually provide the ability to customize drug therapies to specific populations of patients. A second application of genomics and proteomics is the identification of specific drug targets. The process is straightforward in principle, and is enabled by microarray and bioinformatic technology [26]. One approach is to characterize and analyze native biological samples (either from patient populations or animal models) to identify disease specific proteins and therapeutic targets. This amalgamation of technological advancements in discovery research has made it feasible to identify novel targets of drug action in a way not possible even a few years ago. Another fruitful area has been the molecular cloning of receptor families [27], particularly G-proteincoupled receptors [28], and testing the action of various compounds of interest on these cloned receptors using both in vitro and in vivo systems.

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After candidate molecules are generated, they enter the drug development process. There are two phases of development—nonclinical (animal studies) and clinical (human studies). Nonclinical development includes determination of the compounds toxicological properties in two or more animal species, basic pharmacokinetic parameters from in vitro and in vivo models, pharmacodynamic effects in animal models, and chemical synthesis considerations. Current animal models for assaying mood disorders continue to evolve, but their predictive value remains modest [29]. Based on data generated during nonclinical development, many potential drug candidates are removed from further consideration. By the time candidate drugs are first tested in humans, a substantial investment of research effort and money has been made over a period of several years. Clinical development generally consists of three phases before a drug is ‘‘launched’’ (made available to the public in routine clinical settings), and a fourth postlaunch phase [30]. Phase I consists of clinical trials that are designed to test the safety of the compound within a specific dose range. The initial efficacy trials to determine the therapeutic effect of the drug are conducted in Phase II. Phase III trials are conducted after there is a high degree of certainty about dose and efficacy, and are designed to achieve regulatory approval and registration. A typical Phase III trial for major depression may involve up to 50 investigational sites in three to five countries, and cost many millions of dollars [29]. Many trials ‘‘fail’’, despite adequate sample size, owing to large placebo responses. In recent years, five or more Phase III trials have been required for successful drug launches [31]. Phase IV trials, conducted after registration, assess additional safety and efficacy issues, and are sometimes mandated by regulatory authorities. During Phase IV, other indications for the drug are often explored. Pharmaceutical companies differ somewhat in their definitions of Phases I–IV, and sometimes these are subdivided or combined depending on priorities, timelines, and knowledge about particular compounds and therapeutic areas. The processes and techniques of drug development have not progressed as quickly as those of drug discovery, but some positive trends are becoming more and more noticeable. Pharmaceutical companies are making a concerted effort to reduce the overall time and cost of drug development. Established paradigms, such as fairly rigid separation of the four phases of development, are now being challenged. New ‘‘bridging strategies’’ are being adopted that emphasize

New Interventions in Mood and Anxiety Disorders

testing drugs in patients as early as possible. Electronic data-capture methods are being used to speed the availability of information to help drive faster decisions. Methodological and statistical techniques are being refined, and biomarkers are being incorporated into clinical development plans to detect valid clinical ‘‘signals’’ in relatively small clinical trials. One example of a biomarker approach is the use of radiolabeled ligands for determining receptor occupancy as a means of establishing dose ranges for clinical efficacy studies [32]. In general, the starting dose ranges for initial Phase I clinical trials in humans are based on animal behavioral pharmacology and toxicology studies. Subsequently, dose ceilings for initial efficacy studies are determined by the observed tolerability of the drug in humans derived from phase I studies. This is not a mechanistic approach, and can lead to major errors in dosing [33]. The availability of radiolabeled ligands for various receptors of interest has allowed for more rational dosing, by providing the ability to determine percentage of receptor binding as a function of drug plasma level. However, the widespread use of this methodology has been seriously hampered by the limited number of appropriate ligands, and by the number of investigational centers that are able to carry out this kind of research. Serendipity continues to play a major role in drug development. However, greater knowledge and faster production and evaluation of new candidates have made it technically and economically feasible to evaluate chemical entities acting on novel targets. It could be argued that despite the risk of failure in linking these to efficacy, only compounds with novel mechanisms of action will provide ‘‘breakthrough’’ treatments with commensurate impact. Therefore, it is likely that the pharmaceutical industry will continue to shift its investments to such compounds. By attempting to treat disorders by targeting novel sites of drug action, it is hoped that better efficacy and safety profiles will be achieved.

III.

WHY THE HUNT FOR NEW DRUGS FOR MOOD DISORDERS CONTINUES

Despite advances in drug discovery and development, no proven ‘‘breakthrough’’ treatments have yet emerged. Novel drugs are needed, as solo or adjunctive agents, to address some of the limitations of current treatments.

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A.

Speed of Onset

The time required to achieve clinical response is an enduring problem, particularly with antidepressant therapy. It has been frequently demonstrated that available antidepressants cause biochemical changes within minutes, yet clinical responses are not seen for 2–4 weeks. Claims for faster response have been made [34–39], but no antidepressant medication has been convincingly shown in prospective well-controlled studies to have a faster onset of action than other available agents. It is theoretically possible, however, to have a faster onset of action. Some somatic therapies do seem to work more quickly. These include electroconvulsive therapy [40,41], sleep deprivation [42,43], and perhaps transcranial magnetic stimulation [44] and light therapy in some patients [45]. One possible explanation is that all available antidepressants work through a very similar mechanism—alteration of synaptic monoamine concentrations—but this mechanism is not the immediate proximal cause of clinical response. Something else must occur. Current hypotheses about what this process could be focus on postreceptor signaling pathways, alterations in gene expression, and involvement of neuronal plasticity [46–49], as discussed later in this chapter. It is possible that ideal modulators of monoamine synaptic activity have not yet been discovered, and efforts continue to find them. The more likely possibility is that other molecular targets must be engaged to achieve a faster clinical response. There is no guarantee, however, that drugs that cause a faster onset of action will also be better than (or as good as) current agents in maintaining clinical response. Quitkin and colleagues have highlighted the importance of differentiating ‘‘early onset’’ and ‘‘persistence’’ of clinical response [50]. Showing that an antidepressant has a fast onset of action is a complicated problem [51], and a successful demonstration of this phenomenon is likely to require a clinically significant and evident response in addition to a prospective statistically significant result. To make an impact, the drug should show convincing effects in hours and days, rather than in weeks. B.

Response

Of even greater importance than the speed of onset is the well-documented fact that a substantial percentage of patients with unipolar and bipolar mood disorders do not respond adequately to available pharmacologic agents. Estimates for major depressive disorders vary,

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but 30–45% of patients show partial or no response to available agents [52,53]. For bipolar disorders, historical response rates for an episode have been somewhat higher. There are indications, however, that these rates are declining, or are not sustained over repeated episodes, and more refractory patients are emerging [54]. Three important parameters relating to treatment effect are ‘‘response’’ (the fractional reduction in severity of symptoms), ‘‘remission’’ (sufficient reduction in symptoms to cross a predefined threshold for a period of time), and ‘‘recovery’’ (sustained remission). In clinical trials, response generally means a 50% or greater reduction in symptoms, as determined by standard rating scales. Remission and recovery have been given operational definitions as compiled by Frank and coworkers [55], who also proposed definitions for relapse (return during remission of symptoms sufficient to meet diagnostic criteria of disorder) and recurrence (return of symptoms during recovery sufficient to meet diagnostic criteria of disorder). Although response is the most often used endpoint in industrysponsored clinical trials, the clinical goal of therapy is to achieve recovery, and the ultimate goal is to ‘‘cure’’ mood disorders. C.

Safety and Tolerability

A desired corollary of achieving better efficacy is to do so without side effects. All available treatments for mood disorders have limitations in safety and tolerability as well as some potential for drug-drug interactions. For unipolar depressive disorders, the leading agents for the last several years have been the selective serotonin reuptake inhibitors (SSRIs). These agents are widely used because, in the types of patients typically enrolled in large trials, they have comparable efficacy to tricyclic antidepressants (TCAs), but are much safer and are generally better tolerated. Although an improvement on TCAs and monoamine oxidase inhibitors, SSRIs are not free of troublesome side effects. These include sexual dysfunction, gastrointestinal disturbances, discontinuation syndromes, and neurological reactions [11,56–58]. Newer agents like bupropion, venlafaxine, and mirtazapine have not superceded the SSRIs because they don’t offer obvious advantages for most patients; their safety profiles are no better than SSRIs [59]. Certain sideeffect and efficacy advantages, however, may be seen, as in the case of fewer sexual side effects with bupropion [60] or greater overall antidepressant effects with higher doses of venlafaxine [61,62].

For patients who are first diagnosed with depression, there is another safety issue. Antidepressants can induce mania [63,64] or rapid cycling [65] in susceptible patients, as there is no way to be certain that an apparent unipolar depression is not the initial manifestation of bipolar disorder. An antidepressant medication that did not have this liability would be quite valuable. One could argue that such an antidepressant could be used for almost all cases of newly diagnosed depression. Ironically, such a drug may be available. Lithium has been shown to be effective in unipolar and bipolar depressions, although its equivalency to other agents is not established [66], and it carries no known risk of inducing mania. However, lithium’s narrow therapeutic window, requirement for perpetual laboratory monitoring, and poor tolerability have precluded its use as a primary antidepressant. It may be that a drug that worked through the mechanisms of action of lithium relevant to antidepressant and mood-stabilizing effects, but without its liabilities, could be used in higher relative doses to achieve greater efficacy with wide benefit for the treatment of mood disorders. [67]. For the treatment of mania, there are no ideal choices. Clinicians generally choose between lithium and anticonvulsants, sometimes supplemented by benzodiazepines and antipsychotics, these treatment regimens are hampered by many troublesome side effects and safety concerns such as gastrointestinal disturbances, hepatotoxicity, hematotoxicity, neurological reactions, and many others [68,69]. Some of the novel molecular targets discussed later in this chapter could be explored in mania as well as depression. D.

Other Factors

Future drug candidates for mood disorders may be viable if they provide coverage for a wider spectrum of psychiatric and somatic conditions, show extraordinary efficacy for particular subsets of mood disorder patients, demonstrate improvements in quality of life, or have pharmacoeconomic benefits. Historically, expansion of drug indications has been beneficial for producers and consumers of pharmaceuticals. One major reason SSRIs were successful was their safety profile compared to previous agents. However, another reason is that they can treat conditions other than depression. Initially many conditions such as obsessive-compulsive disorder, posttraumatic stress disorder, late-luteal phase disorder, social phobia, and panic disorder were treated by SSRIs ‘‘off-label.’’ In the past few years pharmaceutical companies that market individual SSRIs have conducted a sufficient num-


ber of studies in these indications to obtain regulatory approval for many of them. An emphasis on the discovery and development of compounds with novel mechanisms of action is likely to lead to drugs that may have many possible therapeutic indications in clinical syndromes that may not seem obviously related. Drugs that have differential and/or greater efficacy in particular subsets of mood disorder syndromes may also have a role in the future. For drugs that are currently available, these differences have not been demonstrated compellingly. Regulatory authorities have been skeptical about superiority claims over competitor products. Nevertheless, in a market that has many similarly efficacious products, companies are likely to continue to invest in clinical studies that help promote superior efficacy claims. The effects of drugs on the quality of life (QOL) of patients, and their pharmacoeconomic impact are two additional factors that have become better appreciated as important in the last decade. QOL implies overall sense of well being and, in assessing it, the subjective experiences of patients are important. Many clinical rating scale instruments have now been developed to assess effects of treatments on QOL [70]. These instruments encompass aspects of physical, psychological, social, and economic status. Pharmacoeconomic analyses depend on two basic inputs—cost (direct and indirect) and outcome (defined by either traditional rating scales, by QOL instruments, or both). Two or more treatments may be compared using different types of pharmacoeconomic analyses [71]. These may include cost-benefit (converts of cost and outcome data to monetary values), cost-minimization (emphasizes cost determination and comparison, often outcome equivalence is assumed), cost-effectiveness (outcomes and costs are defined in their own units, then compared across treatments), and cost-utility measures (outcomes are defined by quality of life adjusted years, and outcomes and costs of different treatments are compared). These analytic methods have their individual strengths and weaknesses, and share difficulties in placing appropriate values on outcomes and costs. Patients, health care providers, payers, and even regulatory authorities [72] are becoming increasingly interested in obtaining and evaluating QOL and pharmacoeconomic data. Pharmaceutical companies are beginning to include suitable prospective studies into their clinical plans [73]. Such studies, however, are usually planned only after efficacy has been established using more traditional measures.

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IV.

MECHANISTIC APPROACHES TO BETTER ANTIDEPRESSANTS

The general application of molecular biology, cell biology, and combinatorial chemistry in new drug development has already been noted. These disciplines, coupled with improved brain imaging technologies, have increased our insight into the working of the human brain. The evolving knowledge of neurobiology and neurochemistry has now uncovered 50–100 neurotransmitters, compared to just acetylcholine and norepinephrine 50 years ago [74]. The neuroscience field has moved beyond just the serotonin and norepinephrine monoamine hypotheses to focus on more fundamental molecular and cellular processes that may reveal how current antidepressants work. The number of molecular sites identified as potential novel targets for antidepressant action already exceed our ability to evaluate them in a timely manner. The challenge is to select those candidates that are most likely to address the clinical needs, described above, for greater efficacy and tolerability. This will ultimately involve pharmacogenomics whereby individualized treatments are based on the genetic makeup of the patient. A brief overview of targets being explored to advance the treatment of depression follows. A search of the clinical literature on new treatments in depression was performed using a number of databases: Medline-preMedline, the compound-specific Investigational Drug database (IDdb), International Pharmaceutical abstracts, and Current Contents. This search was narrowed to specifically focus on the biochemical targets most likely to be clinically evaluated over the next few years. We chose to include serotonin receptor subtype agonists and antagonists, neurokinin1 (substance P) antagonists, corticotrophin-releasing factor antagonists, N-methyl-D-aspartate antagonists, and nicotine agonists. Although a large number of alternative compounds targeted to other sites have been identified, no clinical data either are, or are likely to be, available in sufficient depth in the near future to draw firm conclusions. A.

Serotonin Augmentation by Targeting 5HT Receptor Subtypes

The neuropharmacological basis for the delay in the onset of antidepressant response remains to be determined. It is well known, for instance, that SSRIs rapidly increase serotonin concentration by blocking the serotonin transporter on the presynaptic mem-

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brane and on the cell bodies in the raphe nuclei [75– 77]. Increased serotonin in the synaptic cleft stimulates the presynaptic serotonin autoreceptors (5HT1B=D ) and in the raphe stimulate the somatodendritic autoreceptor (5HT1A ). This inhibits serotonin release directly at the nerve ending and reduces firing of the cell bodies. This negative feedback mechanism prevents the optimal increase in serotonin concentration believed by many investigators to be necessary for ‘‘early’’ antidepressant effect. The time required to counter this effect, involving desensitization of the 5HT1A somatodendritic autoreceptor, is proposed to be the cause of the socalled lag period, which can last several weeks [78–81]. Inhibition of the 5HT1A serotonin autoreceptor is one approach proposed to eliminate the lag period. Pindolol, a widely studied beta-adrenoceptor antagonist and a partial 5HT1A antagonist, has been at the center of a heated debate as to the utility of this approach thanks to a number of positive and negative studies [78–88]. In studies that showed a negative effect, the potential cause for the pindolol failure has been proposed as follows: (1) Pindolol did not achieve sufficient concentration at the autoreceptor level to exert its effect (standard dose in most clinical trials was 2.5 mg TID); (2) partial agonism of pindolol at the autoreceptor level outweighed any antagonistic effect; (3) 5HT1A postsynaptic receptor blockade counteracted benefits of increased intersynaptic serotonin; and (4) serotonin augmentation may not be relevant to enhancing antidepressant effects. Consistent with the first possibility, a study that utilized positron emission tomography (PET) in a small number of healthy subjects and patients demonstrated that higher doses of pindolol than previously employed are needed to achieve a substantial occupancy of the 5HT1A autoreceptor [89]. A more recent study showed that estimates of 5HT1A receptor occupancy, although low in other brain regions, averaged 40% in the dorsal raphe nucleus after 1 week on 7.5 mg/day sustained-release pindolol [90]. A 30-mg dose increased mean occupancy to 64%. This may indicate a suboptimal dosing in the prior clinical trials. At higher dosages of pindolol, however, hypotension and dizziness may emerge. Unpublished data from an Eli Lilly trial utilizing doses of pindolol from 4 to 32 mg/day in combination with fluoxetine does not provide evidence of quicker onset and greater efficacy, nor of significant side effects at the higher doses of pindolol. More recently, however, pindolol was reported to augment responses to electroconvulsive therapy (ECT). In a randomized, double-blind, placebo-controlled pilot study, the administration of pindolol (2.5 mg TID) was asso-

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ciated with antidepressant response to ECT within six treatments in four out of eight patients, while no response was seen in the placebo group in the same amount of time [91]. Pindolol did not enhance the ultimate efficacy of ECT treatment (as determined by the number of responders at the end of the study). A clear answer to the role of the 5HT1A autoreceptor in the onset of antidepressant effects is still elusive, and may have to wait until a more potent and selective antagonist is tested in properly powered clinical trials. B.

Substance P/Neurokinin (NK) Receptor Antagonist

Substance P (SP) belongs to a family of structurally related peptides, called tachykinins, which are involved in the regulation of many biologic processes. Tachykinins share a conserved carboxyl terminal sequence of Phe-X-gly-Leu-Met-NH2, but the amino terminal sequences are distinctive for each peptide. Although the existence of neuropeptide SP has been known since the 1970s [92], the exploration of many of its putative diverse therapeutic roles really began in earnest when selective, potent, nonpeptide analoges became available [93–95]. Actions of SP antagonists that would predictably lead to antidepressant effects remains to be established. However, there is some evidence that SP antagonists may modulate serotonergic or adrenergic systems in the brain and thereby link into monoaminergic mechanisms [96,97]. The SP neuropeptide colocalizes with the classical neurotransmitters (serotonin and norepinephrine) and other neuropeptides in the brain. In a recent preclinical report it was observed that neurokinin-1 (NK-1) antagonism and genetic deletion of the NK-1 receptors both lead to an enhanced serotonergic neurotransmission in the forebrain, a region believed to be involved in major depression [98,99]. NK-1 antagonists have also been shown to inactivate alpha-2 autoreceptors on the cell body of norepinephrine (NE) neurons in the locus coeruleus [98]. Several antidepressants, given chronically, decrease SP content in the striatum, substantia nigra, and amygdala [99]. Thus, NK-1 receptor antagonists may modulate NE and/or 5HT systems in the human brain. SP antagonists have also been hypothesized to be useful in anxiety disorders, irritable-bowel syndrome, migraine, chronic pain, and asthma [100,101]. The preclinical/clinical studies conducted with the SP receptor antagonist MK-869 have contributed to postulating a role for SP in the treatment of major depression [102]. In preclinical studies MK-869 was


found to reduce or inhibit the vocalization of guinea pig pups observed following maternal separation [103]. In a double-blind placebo controlled Phase II study, MK-869 was found to be as effective as paroxetine in treating depressed patients [102]. The MK-869 compound was associated with an incidence of nausea and sexual dysfunction no different from placebo. The report that MK-869 is an effective antidepressant with a novel mechanism of action has generated considerable excitement. For the first time, it appeared that a new antidepressant had been discovered, the mechanism of which did not involve direct modulation of monoamines in the brain. Unfortunately, a much larger follow-up dose-finding study failed to show separation between active control, test drug, and placebo [102]. At issue with the new NK-1 antagonists is whether they can achieve a therapeutic concentration in the brain. Current on-going studies by at least two companies include NK-1 antagonist compounds, which are claimed to be more potent and/or achieve greater penetration into brain. C.

NMDA Receptor Antagonists

The N-methyl-D-aspartate (NMDA) receptors has long served as a tempting but challenging target for new antidepressant drug development. This ion channel receptor is stimulated by glutamate, the most widely distributed excitatory neurotransmitter in the brain. Activation of NMDA receptors requires glycine as a mandatory cofactor. In addition, NMDA receptors show a voltage-sensitive block by Mg2þ under resting conditions [104,105]. NMDA receptor antagonists have been proposed to be clinically useful in depression, epilepsy, motor neuron disease, traumatic brain injury, hyperalgesia, and anxiety. One of the main difficulties in targeting these receptors has been a constant threat of severe psychotomimetic effects as evidenced by the well-known actions of phencyclidine, an uncompetitive NMDA antagonist. NMDA receptor antagonists show efficacy in various animal models used to evaluate potential antidepressant drugs. In addition, NMDA receptor antagonists have also been shown to be neuroprotective and anxiolytic in various animal studies [96,106,107]. An exploratory study with the uncompetitive NMDA antagonist ketamine supports a role for NMDA receptor-modulating drugs in the treatment of depression [108]. This small study, which is the only one of its kind, demonstrated that ketamine, but not placebo, infusion reduced Hamilton Depression

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Rating Scale scores by 14 points. Although questions remain about the role of psychotomimetic effects in the antidepressant effect mediated by ketamine, future studies will clearly help in clarifying the role of glutamate in the neuropathology of depression. There is also some preliminary evidence suggesting NMDA receptor modulation is a key factor in the delayed response to antidepressants. The ability of glycine to inhibit the binding of [3 H]5,7-dichlorokynurenic acid to strychnine-insensitive glycine receptors decreases after chronic antidepressant treatment [109–113]. This fact is suggestive of a ‘‘dampening’’ of NMDA receptors with chronic antidepressant treatment, and it has been proposed as a final common pathway utilized by all different antidepressants.

D.

Nicotine Receptor Agonist in Depression

Nicotinic agonists have potential therapeutic uses in conditions such as depression, attention deficit hyperactivity disorder, eating disorder, Alzheimer’s disease, a variety of cognitive disorders, pain, Tourette’s, Parkinson’s disease, and schizophrenia. Nicotinergic receptors belong to a large family of ligand-gated cation channels which, when stimulated by agonists, augment the release of numerous neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine, gamma-aminobutyric acid, and glutamate. A strong link between smoking and depression has been reported in various epidemiological studies [103,104, 114–116]. In one study, the lifetime prevalence of depression in smokers was found to be twice that of nonsmokers [115]. Furthermore, depressed smokers had a harder time trying to stop smoking than nondepressed smokers. There is preclinical and neurochemical evidence to support the role of nicotine agonists in depression. SIB-1508Y, a novel subtype-selective ligand for nicotinic acetylcholine receptors, was able to attenuate the learned helplessness deficit in rats which serves as a preclinical model for depression [117]. This was comparable to the effect produced by established antidepressants such as fluoxetine and imipramine. The rewarding effects of smoking and the beneficial effects of nicotine replacement therapy for depressed smokers may partially depend on genetic factors involved in dopamine transmission [118]. Interplay between the cholinergic and various monoaminergic systems might be relevant to any role of nicotinic agonists in the treatment of depression.

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Data on nicotinic agonists from clinical trials for psychiatric or nonpsychiatric use is scarce. In one Phase II study, altinicline (a nicotinic receptor subtype ligand, SIBIA) was not superior to placebo in the treatment of Parkinson’s disease [119]. It is still not clear whether it has been evaluated in depression. In a small pilot study, a nicotine patch applied to depressed nonsmokers decreased their Hamilton Depression Rating Scale scores an average of 44% [120]. Further studies are clearly indicated to explore nicotinic agonists in depression. E.

Corticotrophin-Releasing Factor (CRF) Antagonist and Depression

Elevated plasma corticosteroid concentrations, increased 24-h urinary free cortisol concentrations, and elevated cortisol metabolite levels in depressed patients have been noted for more than three decades [121–123]. Dexamethasone nonsuppression in a substantial proportion of depressed individuals is now well established [124–126]. Adrenocortical hyperactivity with associated elevated CRF concentrations in depressed patients has led to extensive research into the role of CRF in depression. CRF plays a major role in the regulation of cortisol secretion by being a primary physiological mediator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary [127]. CRF concentrations are elevated in the cerebrospinal fluid of depressed individuals [123,128–131]. The elevation seen in CRF concentration in major depression may be transient, as its level returns to normal after successful treatment [132–134]. In fact, symptomatic improvement in major depression not accompanied by a decrease in the elevated CRF concentration may indicate a poor prognosis [135]. CRF receptors are present in the pituitary and other neural tissue, and CRF peptide is considered to be a neurotransmitter playing a critical role in stress regulation. Clinical trial evidence supporting the role of a nonpeptide CRF receptor antagonist in the treatment of major depression is minimal. An open-label clinical trial conducted at the Max Planck Institute in Psychiatry in Munich, Germany, of a novel CRF antagonist, NBI 30775, was interpreted as supporting its efficacy in major depression [88]. It showed a dose-dependent decrease in HAM-D with 50% of patients responding in the low-dose group while 80% of patients responded in the high-dose group. Subsequent trials with this compound were discontinued because of a transient increase in hepatic enzymes

observed in some patients studied in the United Kingdom. Studies are under way with other CRF-1 antagonists.

V.

CELLULAR AND MOLECULAR MECHANISM OF ANTIDEPRESSANT ACTION

Could a final common pathway exist for the action of different antidepressants? The search for a possible common pathway for the action of disparate antidepressants continues. A multistep signal transduction pathway leading ultimately to modification in genetic expression and protein synthesis has been hypothesized as a possible underlying mechanism [47,48,111]. Most conventional antidepressants are known to stimulate adenyl cyclase via a G-protein dependent mechanism. The resulting elevation in cyclic-adenosine monophosphate (cAMP) leads to a corresponding activation of cAMP-dependent protein kinase A. A potentially relevant target for this enzyme is the cyclic AMP response element binding protein (CREB). The phosphorylated CREB is then thought to increase the expression of a brain-derived neurotrophic factor (BDNF) by modulating specific gene expression. Increased neuronal BDNF has been observed in the brain after chronic antidepressant treatment [74,136,137]. BDNF is considered to be a key factor in the protection of vulnerable neurons during chronic stress. Furthermore, in vitro longterm (> 6 h) exposure of cerebellar granule cell neurons to BDNF reduced the mRNA for subunits of NMDA receptors [138]. A similar effect is seen with chronic imipramine treatment in mouse brain [139]. This temporal connection among BDNF, NMDA receptor function, and depression forms the basis of a cellular and molecular theory of major depression [47,48]. The most obvious potential therapeutic target in the above intracellular pathway is the prevailing CNS form of phosphodiesterase (PDE, type IV). Inhibition of PDE type IV increases cAMP levels [48,140]. There was some preliminary evidence that a type IV PDE inhibitor, rolipram, showed efficacy in depression [141], but gastrointestinal side effects apparently prevented further exploration of this compound. The recent preclinical findings that chronic ECS and imipramine increase PDE-IV mRNA [48,142] further implicate the cAMP pathway in the mechanism of action of antidepressant treatments. Currently, however, PDE-IV inhibitors under development are targeted only to


the treatment of asthma because of difficulties in identifying compounds with sufficient brain activity and acceptable side effects. Other possible intracellular sites of drug action that may be more feasible than previously imagined, emerge from studies on the mechanism of action of lithium. It has recently been proposed that lithium may actually have neuroprotective effects, achieved through lasting changes in cell-signaling pathways and gene expression. Chronic lithium administration produces a reduction in the expression of protein kinase C (PKC), as well as its major substrate, myristoylated alanine-rich c-kinase substrate (MARCKS). The MARCKS protein has been implicated in neuronal migration and development [67]. Other molecules affected by lithium include glycogen synthase kinase 3beta (GSK-3b) and cytoprotective protein, bcl-2. Both of these proteins may play a major role in the longterm neuroprotective/neurotrophic effects of lithium [143–152]. Recently, with the aid of quantitative proton magnetic resonance spectroscopy, a significant increase in total brain N-acetyl-aspartate (NAA) concentration was noted (P < :0217) following 4 weeks of lithium treatment in bipolar patients [151]. NAA is believed to be a potential marker for neuronal viability, and has been followed to chart the course of neurodegenerative disorders. These findings have provided added support to the contention that chronic lithium increases neuronal viability/function in the human brain. Given its antidepressant, antimanic, and mood-stabilizing properties, finding how to duplicate the critical biochemical effects of lithium, while hopefully avoiding those that produce side effects, could have broad therapeutic benefits in the treatment of mood disorders. Compounds targeted to specific PKC enzymes and to GSK-3b should allow for this possibility to be tested. Such compounds that reach the CNS are not yet available for clinical studies, but should emerge in the next few years.

VI.

BASIS OF NEW TREATMENTS FOR ANXIETY DISORDERS

There is substantial overlap of treatments for depression with treatments for anxiety since, as already noted, most ‘‘antidepressants’’ also show efficacy in anxiety disorders. However, anxiety disorders may be distinct from depression. ‘‘Anxiety’’ constitutes a range of psychiatric conditions characterized by irrational

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fears and behaviors that are expressed to avoid the associated distressing feelings. Normally, fear and anxiety function as warning signals to alert an individual to potential dangers. Pathological anxiety occurs when normal daily functioning is disrupted by apprehension of unknown threats (i.e., generalized anxiety disorder), or when an inappropriate fear response occurs out of context of the current environment (panic, posttraumatic stress disorder) [153]. The ideal anxiolytic drug would be pharmacologically selective for the causative mechanisms of anxiety, thus allowing the patient to lead a normal life with no drug-related CNS impairment. Benzodiazepines are one of the most widely used drugs for the treatment of anxiety disorders. While highly efficacious in some anxiety disorders, their utility is greatly hampered by side effects that include CNS depression, drug interactions, cognitive impairment, dependence, and withdrawal liabilities [154]. In fact, this may be the primary reason why the SSRI drugs have replaced benzodiazepine as a first line of therapy for this indication. Specific SSRIs have recently been approved for the treatment of panic disorder (paroxetine), generalized anxiety disorder (paroxetine), obsessive-compulsive disorder (fluoxetine and fluvoxamine), PTSD (sertraline), and social anxiety disorder (paroxetine). Clomipramine, a tricyclic antidepressant with potent serotonin reuptake inhibition, has been effectively used for nearly three decades for the treatment of obsessive-compulsive disorder. The FDA approved buspirone, a partial 5HT1A agonist for the treatment of generalized anxiety disorder (GAD) in 1986. Venlafaxine, a mixed 5HT and NE reuptake inhibitor, has also been recently approved for GAD. For reasons specific to each class of compounds and diagnostic category, such as limited efficacy, side effects, and/or abuse potential, available medications are far from ideal, and the search for more selective and more effective treatments continues. Given the lack of understanding of the psychopathological mechanisms underlying anxiety disorders and the lack of validated objective measures or biomarkers to assess the efficacy of novel interventions, progress has been slow. Nevertheless, the success of early stage preclinical research has bought forward several new platforms for testing in the anxiety disorders. What follows is a brief overview of classes of new compounds targeted to molecular sites with potential application to anxiety disorders. Wherever possible, relevant preclinical and early clinical information is included.

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Gamma-Aminobutyric Acid (GABA) Modulators

GABA, a ligand for GABAA receptors, is a major inhibitory neurotransmitter. Conversely, abnormal GABA receptor-mediated responses have been reported in anxiety patients who show reduced sensitivity to benzodiazepines (BZD). Benzodiazepine inverse agonists, such as beta-carbolines, can induce severe anxiety reactions in normal human subjects [155]. Benzodiazepine receptor density has also been reported to be low in the peripheral lymphocytes of anxious patients. Interestingly, this abnormality reverses after chronic diazepam treatment [156]. The synthesis rate of these receptors may also be decreased in anxious patients as evidenced by reduced levels of mRNA-encoding peripheral benzodiazepine receptors [157]. Interestingly, BZD receptor function has been shown to be affected by modulation of the serotonin and cholecystokinin (CCK) systems. 5HT1A knockout mice exhibit BZD-resistant anxiety [158]. This was accompanied by abnormal BZD receptor a-subunit expression in the amygdala and hippocampus. One pathophysiological hypothesis is therefore that a 5HT1 A receptor deficit may be linked to abnormal composition and levels of GABAA receptor subunits, resulting in BZD resistance and anxiety. In a different series of experiments, CCK antagonists have been shown to possess anxiolytic properties in the various animal models [159], as discussed later in greater detail. One can speculate that multiple pathways impacted by different molecular targets can modulate GABA levels and/or receptor function. GABAA receptors display extensive structural heterogeneity since their assembly is based on a selection of at least 18 subunits (alpha1-6, beta1-3, gamma1-3, delta, varepsilon, and theta, rho1–3). Benzodiazepines are the allosteric modulators of GABAA receptors, and their effect can be attributed to specific GABAA receptor subtypes. Using in vivo gene dissection, it has been shown in preclinical models that anxiolytic action is mediated by the alpha2 subtype, while the sedative and in part the anticonvulsant action are mediated by the alpha1 subtype GABAA receptors [160,161]. It is thus hoped that a specific allosteric modulator of the relevant GABA receptor subtype for anxiety may be synthesized that does not produce the undesirable side effects of sedation, motor impairment, or abuse potential. Currently there is only one compound fairly advanced in development that may have such proper-

ties. Pagoclone (IP 456, RP 62955), although classified as a nonspecific GABA partial agonist, is in Phase III development for panic disorder, and has reportedly shown efficacy with a superior tolerability profile to classical benzodiazepines (Interneuron Pharmaceutical Inc.). Pagoclone significantly reduced panic attack in a Phase II/III clinical trial (media release Aug. 17, 1998, 2 pp). Earlier, in a 277-patient double-blind, placebo-controlled, randomized study, pagoclone effectively reduced the frequency of panic attacks by 73% at a dose of 0.3 mg (P ¼ :021). B.

Serotonin Receptor Agonists

A role for serotonin in various anxiety disorders is now well accepted. Treatment with SSRIs, SNRIs, TCAs, and MAOIs has been shown to be effective. A role for norepinephrine in the anxiety disorders is not as clear. With the advent of selective norepinephrine reuptake inhibitors, such as reboxetine and tomoxetine, it should now be possible to assess the potential of NE as a target. Despite more than a decade of knowing that treatments which enhance intrasynaptic 5HT are efficacious, the role of specific 5HT receptor subtypes in anxiety has yet to be established. 5HT receptor subtypes such as 5-HT1A , 5-HT2A , and 5-HT3 have been associated with fear behavior in animal studies [162]. Decreased exploratory activity and increased fear of aversive environments is seen in mice bred without 5HT1A receptors, suggesting heightened anxiety [163]. Buspirone, marketed for the treatment of GAD, is believed to work as a partial 5HT1A agonist. Interestingly, no new partial or full agonists of the 5HT1A receptor have been approved during almost a decade and a half since the approval of buspirone, despite intense efforts. From a drug development perspective, pursuit of a ‘‘just right’’ agonist for 5HT1A has proved difficult. As many as 15 new chemical entities, in various stages of development, have failed to deliver [150]. Gepirone, a buspirone analog and a weak partial agonist at 5HT1A receptors, may still be in development despite negative clinical results. A large trial showed that any anxiolytic effects of gepirone were delayed and accompanied by a poorer adverseeffects profile than diazepam [164]. Bristol Myers Squibb, which makes buspirone, has recently submitted a patent that relates to 6-hydroxy buspirone. This buspirone metabolite is believed to be largely responsible for the onset of therapeutic relief. If the patent is approved, then further delay in the development of azaspirone anxiolytics (precursors of 6-hydro-


xybuspirone), such as gepirone, is likely. New drugs based on 6-hydroxybuspirone could emerge with potentially increased efficacy, but could be limited by problems related to a favorable therapeutic index. In other words, as reviewed elsewhere, any real efficacy with 5HT1A may come at the cost of unacceptable side effects [149]. Nevertheless, there is at least one other 5HT1A agonist, lesopitron, reported to be in Phase II trials for GAD and panic disorder [48,142,165]. According to the manufacturers, a double-blind study in patients with GAD and long-standing GAD showed anxiolytic effects similar to those observed with lorazepam and a potentially superior adverse effect profile (company communication, Esteve, March 1998). Therapeutic index may be less of a problem for repinotan hydrochloride (Bayer), a 5HT1A agonist, currently in Phase III development for the IV treatment of stroke and traumatic brain injury. It may also have potential in depression and anxiety (21st CINP, Glasgow, 1998, PM01007). It is expected to be launched in 2002 (company communication, May 1996). This drug has shown a good tolerability profile, with headache being the most common adverse effect. Sarizotan hydrochloride (EMD-128130), a dual 5HT1A agonist and dopamine D2 antagonist, is undergoing Phase II trial for treatment of dyskinesia in Parkinson’s disease (Analysts’ Conf, Merck KgaA, 2000). This compound is expected to be launched in 2005. Preclinical research suggests that this compound may have antianxiety effects and a low incidence of extrapyramidal effects (company communications, Feb 1995, Feb 1996). C.

Substance P Receptor Antagonists

The nonpeptide, substance P antagonists represent a potential new class of antidepressants and antianxiety agents with side-effects profiles superior to the current class of SSRIs and benzodiazepines. Two compounds from this class have come as far as Phase II for anxiety and/or depression—NKP 608 (Novartis) and MK 869 (Merck). The efficacy of MK 869 was evaluated in 213 patients with major depressive disorder and anxiety in a randomized, double-blind, placebo-controlled clinical trial. Patients received 6-week therapy with placebo, paroxetine (20 mg/day), or MK 869 (300 mg/ day). Subjects receiving MK 869, as opposed to those on paroxetine, showed a side-effects profile almost indistinguishable from placebo. For instance, 25% of paroxetine recipients complained of sexual dysfunction in comparison with 3% of MK 869 recipients and 4%

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of placebo recipients. Recipients of MK 869 and paroxetine also had significant improvements, compared with placebo recipients, according to the Hamilton Anxiety Rating Scale on weeks 4 and 6 [102,103,143]. Unfortunately, Phase III development on MK 869 was stopped, as this compound failed to separate from placebo at lower doses, which presumably were the only ones judged to be economically feasible. Results from NKP 608 trials in anxiety or depression are not yet available.

V.

METABOTROPIC GLUTAMATE RECEPTOR AGONISTS

Glutamate, the most abundant amino acid in the diet, is also a major excitatory neurotransmitter in the brain. Even though this has been known for about five decades, the putative role of glutamate in the neuropathology of various psychiatric illnesses is just beginning to be explored. The receptors for glutamate can be classified into a heterogeneous family of ionotropic and metabotropic receptors, the latter being localized to both pre- and postsynaptic sites. Metabotropic glutamate receptors (mGluR1, mGluR2, and mGluR3) belong to G-protein-coupled family of receptors and have been linked to presynaptic inhibition of excitatory and inhibitory amino acids, monoamines, and neuropeptides release [166]. Metabotropic glutamate (mGlu) may play important roles in the regulation of many physiological and pathological processes in the CNS. These include synaptic plasticity, learning and memory, motor coordination, pain transmission, and neurodegeneration [167]. Considerable excitement has been generated in the role of mGluR2 receptors in anxiety, schizophrenia, seizure disorder, and nicotine craving. LY-354740 is a conformationally constrained analog of glutamate that is a potent systemically active agonist of group II mGlu receptors. It prevented lactate-induced paniclike response in panic-prone rats similar to alprazolam, suggesting an antipanic effect [168]. In the fear-potentiated startle and elevated plus maze models of anxiety LY-354740 was as effective as diazepam without the adverse effect of motor impairment. Antianxiety effects of LY-354740 are specific, as it was ineffective in behavioral models of depression including despair a-test and a-tail suspension test [169]. Immunohistochemical studies have demonstrated significant presence of mGluR2 receptors in basal ganglia, hippocampus, thalamus, and cerebellar cortex in the human brain [170]. Hippocampus has

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been considered to be a possible neuroanatomical site for anxiolytic effects of mGluR2 agonists [170]. LY-354740 is undergoing Phase II trials for anxiety disorder.

VI.

OTHER POTENTIAL ANXIOLYTIC AGENTS

A.

Cholecystokinin Receptor Antagonists

Until now the neurobiology and pharmacological treatment of anxiety disorders, like depression, have been heavily focused on the noradrenergic and serotonergic systems in the brain. More recently, with the development of nonpeptide ligands for CCK and SP receptors (both are present in significant quantities inside and out of the brain), novel approaches for the treatment of this condition have become a possibility. Systemic injection of CCK-8S, an octapeptide, has been shown to produce dose-dependent regional specific changes on GABA levels in brain. Furthermore, a selective CCK(B) receptor antagonist, PD 135,158, prevented the action induced by CCK-8S [97]. There is also some evidence that CCK receptors in the brain may be involved in panic disorders. This hypothesis is supported by the results of animal electrophysiological studies, animal models of anxiety, and challenge test using CCK fragments in humans [159]. Interestingly, the octapeptide CCK-8 concentrations were found to be significantly lower in the peripherral lymphocytes of the patients with panic disorder than in healthy controls [171]. This level did not correlate with the severity of panic attacks and was unchanged by chronic treatment with alprazolam. Benzodiazepines have been shown to antagonize the satiety and hypothermic effect of CCK8 in mice by an hitherto unknown mechanism [148,172,173]. Findings from the preclinical models have not definitively translated into the clinic. In preclinical studies, CI-988 (Parke-Davis) was shown to be an extremely potent and selective cholecystokinin B antagonist, with potent anxiolytic effects and a favorable tolerability profile. But clinical trials conducted in patients with anxiety disorder or panic disorder have been disappointing [174,175]. Sixteen patients with a principal DSM-III-R diagnosis of generalized anxiety disorder were enrolled in a study that involved two challenge tests. In this double-blind, placebo-controlled study, patients received a single oral dose of CI-988 followed 30 min later by an IV infusion of 0.1 mg/kg mCPP (meta-chlorophenyl-peperazine). CI-988 (100 mg) did

not block the anxiety response to mCPP. Issues with brain penetration and poor pharmacokinetics make any interpretation from the data difficult. CI 1015 [PD 145942] is a second-generation molecule, developed by researchers at Parke-Davis (formerly a division of Warner-Lambert, now Pfizer) to improve on the low PO bioavailability. With an improved CI1015 pharmacokinetic profile, it will be a better test compound for any proof of concept trial [176,177] GW-150013 (GlaxoSmithKline) is another cholecystokinin-B receptor antagonist in Phase II development for the treatment of anxiety disorders. Similarly, LY288513, a novel selective cholecystokinin B (CCKB ) antagonist, may have potential as an anxiolytic. In the animal model of benzodiazepine withdrawal, acute pretreatment with both diazepam and LY288513 dose-dependently blocked withdrawal-induced increases in the auditory startle response [178]. B.

Corticotrophin-Releasing Factor (CRF)

CRF has been implicated in both depression and anxiety disorder [135]. It is found in most of the regions of brain, with highest concentration in the hypothalamus where it is secreted by neurons in the hypothalamic paraventricular nucleus. One of the principal functions of CRF is to regulate the basal and stress-induced release of adrenocorticotrophic, beta-endorphin, and other pro-opiomelanocortin-derived peptides. CRF is found in moderate to low levels in the extrahypothalamic tissue, which includes cortical and limbic structures. At this time, two types of G-protein-linked CRF receptors have been found. The CRF-1 receptor is mainly found in the neocortical, cerebellar, and limbic structures, where CRF-2 receptor is typically localized in subcortical structures and some hypothalamic areas. Animal data have implicated the role of CRF in anxiety disorder [127,179–181], and CRF antagonists are currently under investigation as anxiolytics. NBI30775 (Janssen) is the most researched and the first CRF antagonist to reach the clinic. This early study was argued to support its potential as an antidepressant and anxiolytic, but development was discontinued because of hepatic toxicity seen in two volunteers in an expanded safety study in the U.K.

CONCLUSION The multiple efforts to develop new antidepressants and anxiolytics testify to the perceived medical need. In the absence of known pathophysiology for anxiety


and depression, it is impossible to predict whether any of the novel mechanisms discussed above will result in improved therapeutic agents. Any relationships between improvement in efficacy and alternate mechanisms of action remain hypothetical. Would it be considered a significant improvement if a novel drug were successful in treating only 60% of a depressed population? Would it be worth investing hundreds of millions in developing such a drug? To what extent could a different mechanism of action ultimately be little more than a basis for marketing rather than a breakthrough in the treatment of depression? These questions are even more relevant today since generic forms of the major antidepressants will be widely available in the near future. Nevertheless, there remain many reasons to invest in novel compounds. The promise and potential for improvements in the treatment of psychiatric disorders has never been higher as a consequence of the exponentially expanding number of probes and targets. The ‘‘me-too’’ era of the drugs in psychiatry is all but over. There is clearly no major medical need or good scientific basis for a new SSRI or a tricyclic antidepressant.

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8. 9. 10.

11.

12.

13.

14.

15.

16.

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54 Perspectives for Pharmacological Interventions in Eating Disorders GUIDO K. FRANK Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

I.

INTRODUCTION

This chapter reviews past pharmacologic treatment approaches, reports on current treatment recommendations using drug treatment, and provides research perspectives for future drug trials based on current pilot studies and new neurobiological research findings.

Since their recognition as psychiatric disorders, eating disorders (EDs) have received a substantial amount of attention. Anorexia nervosa (AN) was found to have the highest mortality among all psychiatric disorders [1], and both AN and bulimia nervosa (BN) often have long and protracted courses [2]. Binge eating disorder (BED) has been identified more recently, and may be the most prevalent ED [3]. All three conditions are associated with high psychiatric or medical comorbidity, and cause significant impairment and distress for the affected individuals, as well as high treatment costs for the society [4]. The etiology of EDs is unknown. Sociocultural factors have been implicated in their development [5]; however, research over the past 20 years has shown that AN and BN are highly heritable disorders [6,7], and that neurotransmitters such as serotonin or dopamine are disturbed during the ill state and after recovery [8,9]. These findings suggest that a biological trait disturbance may predispose individuals to develop such illnesses. No specific medication for the treatment of EDs has been found. Most pharmacologic compounds used in the treatment of AN, BN, or BED were originally developed for other conditions, such as mood or anxiety disorders.

II.

ANOREXIA NERVOSA

The core symptoms of AN are (1) a refusal to maintain a minimally normal body weight; (2) an intense fear of gaining weight or becoming fat; (3) a body image disturbance, i.e., patients feel fat, even when being underweight; and (4) in postmenarcheal women, amenorrhea. A restricting type (AN-R), with food restriction and sometimes excessive exercising, has been distinguished from a binge-eating/purging type (AN-B/P), where episodes of binge eating and/or purging behavior such as self-induced vomiting or the use of laxatives, diuretics, or enemas, accompany fasting and overexercising [4]. AN patients typically have obsessive-compulsive features that are directly related to food and weight. However, obsessive-compulsive disorder (OCD) independent from AN-related content is also common. During the ill state and after recovery, individuals with AN frequently present with increased symptoms of depression and anxiety, and it has 827

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recently been recognized that anxiety disorders may be an antecedent in many patients with AN [10]. A.

Appetite Stimulants

Early pharmacologic interventions targeted the core symptom of food refusal and low weight, trying to induce appetite and thus weight gain. In an openlabel study [11], the antihistamine cyproheptadine (up to 32 mg/day) or placebo was given to 81 subjects with AN. In that study, cyproheptadine could induce weight gain only in a subgroup of more severe cases of AN. In a later double-blind, placebo-controlled study [12] in 72 subjects, where cyproheptadine (up to 32 mg/day, n ¼ 24), or amitryptiline (up to 160 mg/day, n ¼ 23) or placebo (n ¼ 25) was administered to patients with AN, it was found that cyproheptadine slightly reduced the number of days needed to reach normal weight. Two findings stood out in that study. First, cyproheptadine appeared to be beneficial for the AN-R subtype only, whereas for the AN-B/P subtype it seemed to hinder positive treatment effects. Second, higher doses of cyproheptadine (12–32 mg/dL) reduced depressive symptoms but without the significant side effects that were seen in the amitryptiline group. B.

Classic Antidopaminergic Neuroleptic Agents

Food consumption is regulated by a complex interplay of monoamine neurotransmitters such as serotonin (5HT), dopamine (DA), and norepinephrine (NA), but also endogenous opioids, as well as a multitude of central-acting neuropeptides [13]. In this feedback circuit of food craving and hunger on one side and food reward and satiety on the other, DA plays an important role in the food reward circuit [14]. Patients with AN do not appear to get pleasure out of food, and a disturbance, e.g., a hyperactivity or a disturbed feedback mechanism of brain dopamine activity in AN, was hypothesized [15]. Studies using the neuroleptic and dopamine-blocking agents pimozide (4–6 mg/day, n ¼ 18) and sulpiride (300 mg/day, n ¼ 13; 400 mg/day, n ¼ 5) in double-blind crossover designs, however, did not show a significant effect on eating behavior or weight gain in AN [16,17]. Recently, a study found reduced cerebrospinal fluid (CSF) levels of the DA metabolite homovanillin mandelic acid (HVA) in AN-R but not in AN-B/P [9], which suggests a DA disturbance in the restricting subtype of AN. Future studies are needed to investigate the involvement of the DA system in AN.

C.

Opiates and Cannabinoids

Endogenous opiates are involved in the modulation of feeding, and Marrazzi et al. [18] suggested an ‘‘autoaddiction’’ model, where increased endogenous opioids were hypothesized to reduce the desire to eat in AN. A few studies investigated opiate antagonists in AN with the rationale that a removal of a suggested self-reward through endogenous opioids would stimulate food reward and thus eating. Moore et al. [19] found that a continuous infusion of naloxone (3.2–6.4 mg/day) over 1–11 weeks improved weight gain compared to before or after the infusion. A more recent study using naltrexone 100 mg/day in a double-blind crossover design over 6 weeks showed reduced binge/purge episodes compared to placebo [20] in AN-B/P patients. However, no effect of the drug on body weight was observed. The use of opioid antagonists in AN is quite questionable since such substances reduce food intake in most studies [21]. Endogenous cannabinoids enhance appetite, and most interestingly, a link has been established to the appetite-regulating peptide leptin, which is derived from body fat stores [22]. An early trial [23] studied 9-tetrahydrocannabinol (active study drug, up to 30 mg/day) or diazepam (as an active placebo, up to 15 mg/day) in 11 AN in a 4-week double-blind crossover design. All subjects participated in a behavior modification program. However, no beneficial effect was observed from 9-tetrahydrocannabinol compared to placebo. In fact, AN on the active study drug reported side effects such as severe dysphoria and sleep disturbances. We are not aware of other studies in AN using cannabinoids. However, the recent report of a downregulation of endogenous cannabinoids by leptin [22,24] suggests that endogenous cannbinoids might be an interesting area of research for future pharmacologic interventions in AN, despite the disappointing results from Gross’s [23] study. D.

Antidepressant Medication

Several antidepressant medications have been studied in AN. One rationale for this intervention is the observation that AN is very frequently associated with depressive symptoms. Depressive disorders are frequently associated with disturbed eating behavior. It has even been proposed that AN may be a variant of mood disorders [25]. The effect of the tricyclic antidepressant clomipramine (50 mg/day) on time to reach target weight was studied double-blindly in 16 inpatients with AN during

Pharmacological Interventions in Eating Disorders

an intensive behavioral treatment program [26,27]. Clomipramine increased hunger, appetite, and energy intake; however, it reduced the rate of weight gain. At 1 year follow-up there was no significant difference between groups. In a double-blind placebo-controlled design, Biederman [28] studied 11 patients on up to 175 mg/day amitryptiline (mean dose 2.9 mg/kg/day) and 14 patients on placebo, all in addition to behavioral psychotherapeutic inpatient treatment, and compared them to 18 patients treated with psychotherapy alone. Overall, amitryptiline-treated patients did not do better than unmedicated subjects. In fact, subjects on amitryptiline complained of side effects from the medication. In addition, the treated group did not report a reduction of depressive symptoms compared to the placebo group. The monoamine serotonin most consistently has been shown to be disturbed in AN during the ill/underweight state as well as after refeeding and recovery [8]. Thus, with the advent of selective serotonin reuptake inhibitors (SSRIs), a promising new group of psychotropic medications for the treatment of AN seemed to be available. A pilot study in six subjects, using 20–60 mg/day fluoxetine, suggested reduced depressive symptoms and weight gain in the studied AN patients [29]. However, subsequent studies in underweight anorexic subjects could not replicate those initial findings. Attia et al. [30] conducted a double-blind, placebo-controlled study in 31 underweight inpatients over 7 weeks with a daily dose of 60 mg fluoxetine. They did not find statistically significant benefits regarding body weight, or general eating behavior from the medication over placebo. Similarly, Strober et al. [31] could not find a significant beneficial effect from fluoxetine administered over 6 weeks during inpatient treatment in underweight AN subjects compared to data from a matched historical control group. A recent open-label study using citalopram in AN [32] reported beneficial effects regarding binge eating and a reduction of ED-related psychological symptoms. However, no weight increase was demonstrated. Moreover, a case report on eight patients treated with 20 mg/day of citalopram in addition to a course of psychotherapy showed a mean weight loss of 5.4 kg (range 0:7 to 11 kg) compared to a control group that lost on average 0.2 kg (range 4:7 to þ2:4 kg) in the same treatment program but not on medication [33]. These findings suggest that citalopram should not be used during the underweight state in AN. Studies in underweight AN showed a reduction of the serotonin (5HT) metabolite 5-hydroxyindole acetic acid (5HIAA) in CSF [34], suggesting a reduction of

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5HT activity during the ill state. Brain 5HT is dependent on the brain uptake of the essential amino acid Ltryptophan (TRP), which is regulated by blood insulin levels as well as plasma concentrations of other large essential neutral amino acids (LNAAs) [35,36]. Anorexics severely restrict their food intake and supposedly reduce 5HT in the brain [37]. Since SSRIs act by increasing intrasynaptic 5HT via inhibiting 5HT presynaptic reuptake, this effect may not be functional in AN because of a low baseline brain 5HT availability. After recovery from AN however, increased levels of CSF 5HIAA were found [38]. AN patients show a substantial relapse rate, and medication trials after refeeding seemed to be a reasonable approach. An open trial of fluoxetine [39] in 31 AN patients after weight restoration and in outpatient treatment suggested a reduction of the usual relapse rate. By the time of follow-up (11 6 months) 29 out of the 31 subjects were still at or above 85% of average body weight (ABW). Strober et al. [40] performed a study in 33 patients on variable doses of fluoxetine (mean 34 mg/day), and followed this group over 24 months. Patients on the active drug did not do significantly better than a group of matched historical controls. However, it should be noted that the median survival time for staying on target weight was 15 weeks for the fluoxetine group vs. 7 weeks for the nonmedicated group, although this was not statistically significant. A recent double-blind study using flouxetine after weight restoration found an improved survival time with regard to healthy body weight in AN [41]. After inpatient weight restoration, 35 subjects were randomly assigned to fluoxetine (n ¼ 16) or placebo (n ¼ 19), and followed up over 1 year as outpatients. Ten subjects in the fluoxetine group (38 21 mg/day fluoxetine at study end at 352 5 total study days), whereas only three in the placebo group (368 2 total study days) were considered treatment responders. The nonresponders, six subjects in the fluoxetine group (43 15 mg/day fluoxetine at study end at 116 69 total study days), and 16 subjects in the placebo group (79 32 total study days), relapsed and dropped out of the study. In addition to a reduced relapse rate, fluoxetine administration was associated with a significant reduction in obsessions and compulsions and a trend toward a reduction of depressive feelings. The relatively small sample size in this study limits the power of the results. In addition, since subjects were in outpatient treatment, those conditions could not be entirely standardized. However, this is the first doubleblind controlled study that reports relapse prevention in AN. The approach of starting medication after

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weight restoration is appealing, and further studies seem to be warranted. A recent case report series from our group in bingeeating/purging type AN [42] suggested that sertraline may be useful in this subgroup of AN. Two of the five subjects reported had failed on previous partial hospital and outpatient psychotherapy treatment with or without different additional antidepressants. Sertraline (between 100 and 150 mg/day) was added to psychotherapy treatment. All five subjects gained weight to between 92% and 100% of age-adjusted ABW. Sertraline administration was also associated with a reduction in ED-related behaviors, as well as depression and obsessional thoughts. As noted above, underweight subjects often do not respond to SSRIs. Moreover, it is difficult to get underweight people with an ED to gain weight outside of a hospital setting [43]. These case reports raise the question of whether sertraline shows some advantage over other SSRI medications in terms of helping ED subjects gain weight. Although SSRI medications have similarities in terms of blocking serotonin reuptake, these compounds have different molecular structures and may have different central nervous system effects. For example, sertraline has effects on noradrenergic transmission [44–46]. E.

Mood Stabilizers

Lithium was among the first compounds studied [47]. In this 4-week double-blind study, Gross administered lithium carbonate (> 300 mg/day uptitrated to plasma levels of 0.9–1.4 mEq/L) to eight AN women and placebo to a matched AN group (all subjects were on an inpatient behavior modification program at the time of the study). The medicated group showed a limited weight gain. Considering the possibly severe side effects from this drug, the frequent repeated need for plasma level checkups, and the relatively small improvement found, lithium cannot be recommended for use in AN. F.

Atypical Neuroleptic Agents

With the discovery of the so-called atypical neuroleptic agents, a new and relatively safe group of medications was put on the market. An important side effect of several of those drugs is weight gain [48]. This effect may be related to alterations of central monoamine or histamine activity [49]. A few case reports have been published recently on olanzapine in AN. Hansen [50] first reported in 1999 on a patient with chronic AN who gained more than 20 kg over several months

and who improved on mood and cognitive performance after initiation of treatment with 10 mg/day and later 5 mg/day (reduced due to side effects such as tiredness and dizziness) of olanzapine. La Via et al. [51] found in two severe cases of AN with a 5- and 6year history of AN that administration of olanzapine in doses between 10 and 15 mg/day was associated with weight gain, and both patients were still at normal weight 4 and 6 months respectively after discharge from the hospital. Another case report, in three women with long-standing histories of AN treated with 5 mg olanzapine, indicated significant weight gain over several months and a normalization of EDrelated thoughts [52]. A critical comment on that report is the authors’ emphasis on psychotic experiences. AN is not recognized as a psychotic disorder. Also, there was no mention of other treatments those subjects may have received in addition to the olanzapine administration. We recently assessed a group of 18 subjects retrospectively on their experience with olanzapine [53]. Subjects reported reduced anxiety and less difficulty eating; however, there was no effect on weight gain attributable to the drug. Our clinical experience is that AN patients feel more relaxed and less anxious on olanzapine, but no clear reduction of days needed to regain to their target weight has been observed, nor were anxiety or depressive feelings reduced on standardized instruments compared to placebo. However, further investigation is warranted, in particular for assessing the specific behavioral effects olanzapine has in ED subjects. G.

Other Agents

In addition to psychoactive drugs, a few controlled trials investigated drugs that supposedly had peripheral effects. Women with AN very frequently complain about gastric fullness and abdominal discomfort after meals during the refeeding process. A double-blind study [54] using the gastrointestinal motility drug cisapride (30 mg/day, n ¼ 6) or placebo (n ¼ 6) over 6 weeks reported increased gastric emptying for both groups, but a tendency to more improvement in the medicated group. More recently, a study [55] using a total of 30 mg/day of oral cisapride over 8 weeks studied 29 inpatients in a double-blind, placebocontrolled design. In that study, gastric emptying normalized similarly in both groups, although subjectively, AN subjects rated themselves as hungrier and overall improved. In addition, weight gain was similar in the two groups. Thus, the addition of this gastro-


intestinal motility drug for the treatment of AN does not seem to be justified. Patients with AN show reduced zinc levels. This phenomenon is most likely a state related symptom that remits with normalization of food intake [56]. However, two double-blind and randomized studies found zinc supplementation beneficial for the treatment of AN. Katz et al. [57] found that zinc supplementation (50 mg/day) reduced symptoms of depression and anxiety AN patients, and Birmingham et al. [58] found in a double-blind, placebo-controlled study that 100 mg/day zinc supplementation doubled the rate of 10% BMI increase compared to the placebo group. However, in underweight women a 10% BMI increase is of very limited significance, and no further information exists about a beneficial effect beyond this early weight gain. Since AN patients often show increased central and peripheral cortisol levels, a dysregulation of the hypothalamus–pituitary axis during the ill state has been suggested. A recent pilot study [59] attempted to counteract endogenous glucocorticoid hyperactivity in AN by administration of dexamethasone to five AN women and 10 healthy control women. The AN subjects showed some reduced depressive feelings but increased feelings of anxiety while on dexamethasone. An important complication of AN is osteoporosis. Due to the reduced nutritional intake and impaired hormonal activity in AN, bone formation is significantly reduced but bone resorption is increased [60], leading to increased fracture risk [61]. Reduced bone density does not fully return to normal even after longterm recovery from AN [62]. In contrast to postmenopausal osteoporosis, hormone replacement therapy does not seem to be beneficial in AN [63]. The most accepted treatment for osteoporosis in AN beside weight restoration (resulting in a natural resumption of menses and improvement of bone density) is calcium supplementation [63]. The osteotrophic compound insulinlike growth factor I [64] administered in a controlled design at a dose of 100 g=kg, increased markers of bone formation and resorption compared to placebo or a lower dose of 30 g=kg. Future studies have to assess if long-term administration of such substances can improve bone mass in AN. H.

Recommendations

All medication trials performed were limited by relatively small sample sizes. No medication yet studied in controlled double-blind designs seemed to be able to specifically target core AN symptoms such as food

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refusal, body image distortion, or food- and weightrelated obsessions. Similarly, depression- or OCDrelated symptoms can often not effectively be treated during the underweight state. Studies with newer atypical neuroleptics appear to be encouraging despite the small groups and open-label application. Double-blind designs and control groups are needed for those agents in order to determine effects that are attributable to the medication. The supplementation of zinc and calcium during the underweight state might be an approach to complement other forms of treatment in an attempt, for example, to prevent associated conditions such as osteoporosis. Most promising at this point, appears to be the administration of fluoxetine—after weight restoration and at relatively normal food intake—for the reduction of relapse. Lastly, it might be necessary to study AN patients in pharmacological trials separated by their subtype and maybe even in relation to their comorbid conditions, since that may significantly determine the results.

III.

BULIMIA NERVOSA

BN is characterized by recurrent episodes of binge eating followed by behaviors to counteract weight gain— so-called purging behaviors—such as self-induced vomiting, or the use of diuretics or laxatives (purging-type BN). Excessive exercising and fasting occur frequently in BN and can be the only measures for prevention of weight gain (nonpurging-type BN). Patients with BN, usually at normal weight or slightly overweight, present with a fear of gaining weight, body image distortions, and food- and body weight–related preoccupations similar to AN. During the ill state and after recovery, BN is usually associated with increased depressive and anxious feelings [8]. Impulsive behaviors as well as cluster B personality disorders are frequent [4]. During the ill state several neurotransmitters are altered and binge-purge frequency has been shown to directly reduce 5HIAA as well as HVA in CSF [65]. After long-term recovery, and to a higher degree than in AN, CSF 5HIAA has been found to be increased in BN. No specific pharmacologic treatment has been established for BN. However, several compounds have been studied, targeting core behaviors such as bingeing and purging, and also depressive and anxious feelings. A major question was whether BN-specific pathology is related to mood alterations and major depressive disorder (MDD).

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Antidepressant Agents

As with AN, the compounds most investigated are antidepressant agents. This choice may have been driven by the frequency of depressive symptoms in BN. Among the first drugs studied were the monoamine oxidase inhibitors (MAOs). Walsh et al. reported on groups of 20 [66], 30 [67], and 50 [68] BN women in placebo-controlled double blind-study designs using the irreversible MAO phenelzine. The medication was administered at 60 mg/day, or alternatively at 90 mg/ day to patients who had previously not responded to the lower dose. Phenelzine was significantly more effective than placebo in reducing binge episodes. Those effects were not limited to subjects with comorbid depressive disorders. However, significant side effects occurred in 50% of study subjects, including sedation or severe blood pressure disturbances such as hypotension. Another MAO, isocarboxazid, was studied by Kennedy et al. [69] in a double-blind placebo-controlled crossover design in 18 BN women, at a dose that was gradually uptitrated from 10 mg/day to 60 mg/day. Similar to Walsh’s studies, this MAO significantly reduced binge and purge frequency, independent of depressive symptoms. In another double-blind, placebo-controlled study Kennedy et al. [70] investigated brofaromine, a selective reversible, and thus safer-to-use, MAO. Brofaromine administered over a period of 8 weeks at a dose of up 200 mg/day (n ¼ 19) compared to placebo (n ¼ 17) led to a body weight reduction in the active drug group. However, no differences in binge or purge frequency, or depression or anxiety ratings could be observed between groups. The reversible MAO moclobemide, studied in 52 BN women [71] in a double-blind placebo-controlled design at a dose of 600 mg/day, did not show to be superior to placebo in the reduction of BN pathology. Among the first placebo-controlled double-blind studies in BN was the tetracyclic antidepressant mianserin [72] studied in an inpatient setting. Twenty-eight subjects dropped out of the study; 14 subjects on active drug (titrated to 60 mg/day) and 30 subjects on placebo completed the full study over a period of 8 weeks. Both groups improved significantly on core BN symptoms as well as anxiety and depression. Mianserin was not superior to placebo. Although the authors do not report on psychological treatments, it can only be speculated about the treatment effect of the hospitalization alone. The TCA imipramine has been studied in a few placebo-controlled, double-blind studies. In a study

with 22 BN women Pope et al. [74] reported that imipramine up to 200 mg/day was associated with a reduction of binge eating. Agras et al. [74] found imipramine over 16 weeks and with a maximum of 300 mg/day in 10 patients to be superior compared to placebo in 12 controls in reducing binge eating and purging behavior. A larger study by Mitchell et al. [75] studied 172 patients with or without intensive group psychotherapy, with imipramine (titrated to 200 mg/ day) vs. placebo over a period of 12 weeks. All treatment groups were superior to placebo alone with respect to core ED behavior. Psychotherapy alone was superior to imipramine alone, but the combination of group therapy and imipramine resulted in greater improvement in symptoms of depression and anxiety. Several research studies used desipramine in BN. In a double-blind, placebo-controlled study with desipramine treatment in a dose of 200 mg/day Hughes et al. [76] reported a 87% reduction of binge frequency; 68% of patients were totally abstinent from binge eating and purging at the end of the study, and there was a greater reduction of depressive symptoms in the desipramine group. Another study in 47 BN patients using a double-blind crossover design for 6 weeks [77] showed a significant reduction of binge/purge episodes in response to 150 mg/day desipramine. Scores on the Eating Disorders Inventory (EDI) or Symptom Checklist (SCL-90), however, did not change, nor was the improvement of bingeing or purging related to a reduction of depressive symptoms. Blouin and colleagues [78] compared the effect of 150 mg/day desipramine or 60 mg/day fenfluramine (a central 5HT-releasing drug) with placebo in a double-blind design, and found both drugs beneficial in reducing binge eating and purging frequency. Interestingly, both drugs reduced the urge to binge as well as depressive feelings. Another study by Blouin et al. [79] in 24 BN women assessing the effect of 150 mg/ day desipramine in relation to depressive symptoms in a double-blind, controlled, crossover design, found that desipramine was significantly superior to placebo, and more importantly the antibulimic effect was independent of its antidepressive action. Furthermore, a placebo-controlled double-blind study in 33 nonpurging-type, in part obese, BN women (BMI 23–41) found a reduction of binge frequency [80] using 100– 300 mg/day of desipramine (mean 188 mg/day) over a period of 12 weeks. A reduction in hunger ratings and increased dietary restraint in the active treatment group in that study led to the hypothesis that desipramine acts by suppressing appetite. No effect on depression was noted.


Walsh et al. [81] studied desipramine (200 mg/day) in 80 patients in a double-blind and placebo-controlled design. After an 8-week initiation phase, patients who had responded well to the active drug were then again randomly assigned to placebo or desipramine in order to assess longer-term effects of the medication. Desipramine was superior to placebo in reducing binge frequency. However, prolonged medication treatment was also associated with frequent relapse, suggesting that longer-term treatment with desipramine had significant limitations. A comparison study of desipramine with cognitive behavioral therapy (CBT) [82] consisted of 71 BN patients randomly assigned to one of five groups, receiving either 15 sessions of CBT, desipramine alone over 16 or 24 weeks, or desipramine in addition to 15 sessions of CBT over 16 or 24 weeks. Desipramine was administered at doses of up to 350 mg/day, and the mean doses were 168 mg/day and 167 mg/day after 6 weeks and at the endpoint of the study respectively. After 16 weeks, both the CBT treatment group and the combined group (CBT plus 16 weeks of medication) were superior to medication alone. However, at week 32, only the combined treatment with desipramine over 24 weeks was superior to 16 week medication alone, and also reduced more effectively dietary preoccupation and hunger. A 1-year follow-up of that study [83] showed that the 16-week desipramine group did relatively poorly (18% in remission), and that the combined 24-week treatment regimen was the most beneficial, with 78% of that group being free of binge-purge episodes, and reduced emotional eating and dietary restraint. Leitenberg et al. [84] conducted a small study in groups of seven subjects per condition (CBT, desipramine, and CBT plus desipramine) over a study period of 20 weeks and reassessed on follow-up after 6 months. Desipramine alone reduced binge and purge frequency but was inferior to CBT alone, and no benefit from the addition of desipramine to CBT over CBT alone was noted. However, the results were confounded by high dropout rates (60% in the desipramine and 30% in the CBT plus desipramine group) and very variable plasma levels of desipramine (170–447 ng/mL). One study investigated amitryptiline in BN [85]. Thirty-two female outpatients were randomized in a double-blind design with 150 mg/day in the active treatment group. All subjects received a limited course of behavior therapy. Amitryptiline had a significant antidepressant effect, but was of no benefit over placebo regarding eating behavior.

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Another TCA, trazodone, showed in an open-label design [86] a reduction in binge-purge frequency, as well as in scores on the Hamilton Depression Inventory (HAM-D) and EDI. Pope et al. [87] studied 42 women with BN in a double-blind placebo-controlled design over a 6-week treatment course with trazodone 400 mg/day, and reassessed [88] subjects 9–19 months after the initial 6-week period. Trazodone was superior to placebo in reducing the frequency of binge episodes and self-induced vomiting. On follow-up, 36% of subjects were in remission, 72% were considered improved, and most subjects were on trazodone or another antidepressant. One double-blind and placebo-controlled study investigated the antidepressant bupropion in BN [89]. This medication has in general a low incidence of side effects and was shown to reduce hyperphagic episodes in depression in the past. Eighty-one subjects were enrolled, 55 of them on the active drug. Bupropion was superior to placebo in reducing binge-eating and purging episodes. However, four subjects (7%) in the bupropion group experienced grand mal seizures during the drug trial. The incidence of this side effect is much higher than in nonbulimic subjects, and might be attributable to electrolyte disturbances in BN due to bingeing and purging. Thus, the use of bupropion is contraindicated in both AN and BN. The best-studied drug in the treatment of BN is the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Early open-label data had suggested that fluoxetine could reduce binge and purge frequencies in BN [90]. The first double-blind placebo-controlled study [91] assessed 40 inpatients, randomized to 60 mg/day fluoxetine or placebo over 35 days. All subjects participated in an intensive CBT inpatient program. The addition of fluoxetine significantly reduced body weight; however, it was not superior to the psychotherapeutic inpatient program alone in reducing BN-related pathology. A large multicenter placebo-controlled study [92] in 387 BN women using fluoxetine either 20 or 60 mg/day over 8 weeks found that the drug significantly reduced episodes of binge eating and selfinduced vomiting, as well as depressive symptoms and pathologic eating attitudes. Most interestingly, higher dosage was associated with more improvement. Side effects included mostly insomnia, nausea, asthenia, and tremor. A reassessment of those data [93] found that more of the subjects on the active drug showed an attitudinal change toward their eating behaviors, and this was independent of depression or anxiety. A second large multicenter double-blind placebocontrolled study [94] using fluoxetine 60 mg/day over

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16 weeks in 398 subjects found results similar to the previous study. Fluoxetine administration is save in BN and is associated with a significant reduction of binge-eating and vomiting episodes. A drawback, as in other studies, was the high attrition rate of > 40%. Those two multicenter studies were assessed post hoc on the dependence of symptom improvement on depressive symptoms at the time of the study [95]. This reassessment showed that the improvement of ED-related symptoms was independent of either depressive ratings at baseline or a history of a diagnosis of depression. A recent study investigated medication benefits in BN in subjects that who had previously failed in psychotherapeutic treatment [96]. Twenty-two BN subjects, posttreatment failure or relapsed after psychotherapy, had been randomly and double-blindly assigned to fluoxetine or placebo. Most interestingly, binge eating and purging declined by > 80% in the active treatment group, whereas bingeing increased by 20% and purging by 150% in the placebo group. This suggests that fluoxetine may be a useful intervention in poor psychotherapy responders. However, the study was conducted over 8 weeks, and no long-term results exist. Another study [97] in 30 BN women using fluoxetine in a double-blind placebo-controlled design over 16 weeks also found a significantly reduced bingeing and purging frequency, together with a reduction of the cariogenic and thus tooth-eroding bacterium Streptococcus sobrinus. An additional aspect of disturbance in BN and its response to fluoxetine treatment was studied by Rissanen et al. [98], who found that BN women have increased cardiac vagal tone. Their study, a double-blind placebo-controlled design in 25 BN patients using fluoxetine 60 mg/day over 8 weeks, showed that drug treatment resulted in a normalization of cardiac vagal tone to the levels of healthy volunteer women. It was suggested that 5HT3 receptors may be involved in such disturbances in BN. Another SSRI studied in BN is fluvoxamine. A few studies have reported reduced BN-related pathology in open-label study designs after fluvoxamine [Gardiner, 1993 #771; Ayuso-Gutierrez, 1994 #770]. The first double-blind, placebo-controlled study published assessed this drug for relapse prevention in 72 patients after intensive psychotherapeutic inpatient treatment [99]. Fluvoxamine was given over 15 weeks in a dose of 100–300 mg/day. In that study fluvoxamine was superior to placebo in its ability to reduce urges to binge, the actual number of binges, and scores on psychological rating scales such as the Structured Interview for Anorexia and Bulimia Nervosa (SIAB)

Frank

or EDI. However, the study was limited by a high overall dropout rate (33%), that was particularly high in the fluvoxamine group (51%). Interestingly, fluvoxamine did not show a relapse-preventing effect in terms of depression or anxiety symptoms [100]. A recent study using the SSRI citalopram found, in an open label design in 12 BN patients, that the drug reduced bingeing in the treated group [32]. Another case report in 7 BN subjects [101] found that the noradrenegic antidepressant reboxetine (8 mg/day) administered over 12 weeks was beneficial in reducing bingeing by 73%, self-induced vomiting by 67%, and depressive symptoms by 50% in this group. However, three subjects (40%) dropped out prematurely, one after spontanoeus remission, and two after significant constipation and subsequent laxative use. B.

Mood Stabilizers

Mood instability and the frequent occurrence of impulsive behaviors warranted the trial of mood-stabilizing agents. An early report [102] on six BN women in a double-blind crossover design using carbamazepine (adjusted to plasma levels of 6–10 mg/mL) found a cessation of symptoms in one subject with a possible history of bipolar disorder. In another trial, in 91 BN patients [103], lithium administered in a double-blind randomized design over 8 weeks did not show the drug to be more effective than placebo for BN symptomatology. C.

Stimulants

Stimulants reduce appetite. Therefore it seemed reasonable to study such drugs for their effect on binge eating in BN. A small study using methylamphetamine supported this hypothesis [104]. This small doubleblind controlled study found that the administration of methylamphetamine in eight patients with BN reduced hunger ratings as well as the amount of food eaten. BN is frequently associated with cluster B personality traits and disorder. Another case report [105], using methylphenidate in doses of 20 mg/day and 15 mg/day, in two subjects with BN and cluster B personality disorder, respectively, who had previously failed on SSRIs, found that methylphenidate treatment was effective in reducing bingeing and purging episodes. D.

Opioids

As mentioned earlier, endogenous opioids play an important role in appetitive behavior and food inges-


tion in humans [106]. Since endogenous opioids stimulate feeding behaviors, opiate blockade was hypothesized to reduce episodes of binge eating and associated purging behaviors. In an open-label study, Jonas and Gold [107] showed that naltrexone reduced bulimic episodes and that 200–300 mg/day was more effective than 50–100 mg/day. In a double-blind placebo-controlled crossover trial by Mitchell et al. [108] in 16 BN women, the opioid antagonist naltrexone 50 mg/day did not show a beneficial effect over placebo; however, this could have been due to the relatively low dose administered. In another study [109], naltrexone 100– 150 mg/day reduced the duration of binge episodes in BN compared to placebo, but not the number of bulimic episodes. And naltrexone at 200 mg/day in a double-blind crossover design done by Marrazzi et al. [20] in 19 subjects showed a significant reduction of binge-and-purge episodes by the active drug over a 6-week period. An investigational, more basic research-oriented study using intravenous naloxone, another opiate antagonist, found that this drug reduced consumption of both sweet and high-fat foods in binge-eating subjects [110], suggesting that the endogenous opioid system might be involved in the etiology of BN or, alternatively, that targeting the opioid system using medication might be beneficial in the reduction of BN symptoms. However, the higher risk-benefit ratio of those compounds compared to other effective medications makes those drugs not a first-line treatment of choice for BN at this point. E.

Other Agents

Increased central 5HT reduces food intake, and so fenfluramine, a 5HT-releasing agent, was investigated in several studies with the rationale that it would decrease binge-eating episodes. Robinson et al. [111] found in a double-blind, placebo-controlled study that fenfluramine 60 mg/day significantly reduced food intake, and that the amount of food eaten was inversely correlated with plasma fenfluramine levels. Another controlled trial studied fenfluramine in 42 subjects over a 12-week period [112]. In that study, fenfluramine did not prove to be beneficial. Fahy et al. [113] studying fenfluramine (45 mg/day) or placebo in addition to psychotherapy, found that the added drug treatment was not superior to psychotherapy alone. Fenfluramine was found to lead to pulmonary hypertension, cardiac abnormalities, and central nervous system damage and therefore was taken off the market [114].

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Ondansetron is a 5HT3 receptor antagonist that is mainly used in the treatment of chemotherapy induced hyperemesis. Since in the past it was hypothesized that a vagal hyperactivity, possibly due to altered 5HT3 receptor activity, might contribute to the etiology of BN, ondansetron was studied in a double-blind placebo-controlled trial in 26 subjects after an initial placebo phase over 4 weeks [115]. A daily dose of 24 mg ondansetron was associated with a significantly reduced number of bingeing and purging episodes, and an increased number of normal meals. Ipsapirone, a partial 5HT1A receptor agonist, was studied in an open label design over 4 weeks in 17 subjects [116]. The authors reported that after only 1 week of treatment with flexible doses between 7.5 and 12.5 mg/day ipsapirone, five subjects were free from bingeing and purging, and after 4 weeks 14 subjects showed 50% reduced bingeing and purging. The average binge frequency after 4 weeks was still 2.6 times per week; however, EDI scores decreased significantly, and subjects were on no other treatment regimen. Myoinositol is involved in the second-messenger complex of brain 5HT receptors. It is possible that a modulation of this system could affect BN-related behaviors. Very recently, a report on inositol treatment in BN was published [117]. In this double-blind crossover study, 18 g/day inositol or placebo was administered over 6 weeks per condition to 24 nondepressed BN patients. Subjects on inositol scored significantly better on the EDI and on a visual analog scale of severity of binge eating. However, no information about the change of numbers of binge and purge episodes before and after inositol administration was presented. F.

Recommendations

Several antidepressant medications have been shown to be effective in the treatment of BN. Since SSRIs are of relatively low risk for side effects or intoxication toxicity compared to other medications such as tricyclic antidepressants, SSRIs are first-line drugs. Fluoxetine is the best-studied drug in BN. It has been shown that higher doses of fluoxetine (60 mg/ day) are more effective and well tolerated. Fluoxetine is to date the only drug FDA approved for BN. It should be noted that not all BN patients respond to an antidepressant, so it is desirable to switch to another substance or drug class if one medication has not proved to be effective [118–120]. In addition, there

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is evidence that the combination of psychotherapy and antidepressant medication is superior to psychotherapy alone. It has to be noted that medication may cause significant side effects, resulting in cessation of drug treatment. However, similar to studies in depression, tricyclics frequently lead to sedation, constipation, or dry mouth and may be lethal if consumed in overdose. SSRIs more frequently than placebo cause insomnia, nausea, and asthenia [121], but also sexual dysfunction [122]. At the beginning of pharmacologic interventions, patients should be carefully prepared for the possibility of occurrence and subsequent management of side effects. This may improve compliance. Long-term administration of medication is associated with significant dropout rates [123], and a reduction of efficacy over time may occur. Recently, Bacaltchuk and colleagues [124–126] reported on meta-analyses comparing drug treatment in BN with placebo or psychotherapeutic interventions. Consistent with single studies, antidepressant drug treatment was reported to be superior to placebo, with several drugs being effective. Psychotherapy is superior to drug treatment alone, but the difference between treatments may be small. Also, the efficacy of psychotherapy and medication combination treatment appears to be superior to single approaches. It has to be noted that the lengths of trials was between 5 and 24 weeks, and data on long-term results are very limited.

IV.

BINGE-EATING DISORDER

BED has officially been recognized as a proposed diagnostic category for further research [4]. However, research criteria have been tentatively established, and several pharmacological studies have been conducted using those criteria. BED is characterized by (1) recurrent episodes of binge eating at least 2 days per week without compensatory behaviors; (2) a sense of lack of control over eating during eating binges; (3) at least three of the following symptoms during the binge episodes: eating much more rapidly than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of being embarrassed at how much one is eating, or feeling disgusted with oneself, depressed, or very guilty after overeating; (4) the condition is associated with marked distress; (5) it lasts at least 6 months; and (6) it does not occur exclusively during the course of AN or BN. A relatively small

number of drug trials have been performed in BED, and these studies are thus described together. With the notion that BED might respond to 5HTspecific drugs because food intake is related to brain serotonin activity [127], SSRIs were studied for reducing binge eating episodes and reducing weight gain in BED. Fluoxetine was among the first studied [128]. In that double-blind, placebo-controlled study, fluoxetine at 60 mg/day was associated with weight loss compared to placebo in both obese binge-eaters and non-binge-eaters. No effect of fluoxetine on EDI or depression scores could be observed. Greeno et al. [129] studied fluoxetine in a double-blind, placebocontrolled short-term design over 6 days and found that the drug treatment reduced eating in obese BED subjects as well as in non-BED subjects. The 5HT-releasing and appetite suppressant drug fenfluramine (15–30 mg/day) administered over an 8week period (Stunkard et al. 1996) in a double-blind placebo-controlled design in 28 BED patients reduced binge-eating episodes, but at 4 months follow-up postfenfluramine, the medicated group was similar to the placebo group and thus similar to pretreatment severity, suggesting a very high relapse rate after discontinuation of the drug. An open trial [130] studied fluoxetine (up to 60 mg/ day) in combination with the appetite suppressant phentermine (up to 30 mg/day) over 20 weeks in addition to CBT treatment in 16 obese BED patients. Those subjects received monthly therapy sessions after this more intense treatment phase, and were followed up over 3 years. The dual-medication treatment was associated with reduction of binge eating. Between 3 and 23 months after medication discontinuation, patients’ weight had returned to baseline, and a few subjects were binge-free whereas a few had more binge-eating episodes compared to pretreatment status. The SSRI fluvoxamine (50–300 mg/day) was studied in a multicenter double-blind placebo-controlled investigation in 85 patients [131]. Fluvoxamine reduced binge-eating episodes, clinical global impression scores, and BMI. Interestingly, HAM-D scores were not affected by the active drug compared to placebo. However, significantly more subjects dropped out of the fluvoxamine group because of side effects. Another SSRI, sertraline, administered up to 200 mg/ day in 34 patients in a double-blind placebo-controlled design over 6 weeks [132], reduced binge-eating frequency as well as BMI and global severity scores. Marrazzi et al. [133] reported on the opioid antagonist naltrexone in one BED patient in a similar design


as previously reported in BN [20]. He suggested that the addition of the drug to psychotherapy might improve the outcome over psychotherapy alone. Neumeister et al. [1999] recently reported on a case where, after failure of fluoxetine and psychotherapy alone, naltrexone 100 mg/day was added to this treatment regimen. The patient improved from at least one binge per day to two binges per month within 2 weeks, lost weight, and was stable until a reduction of naltrexone to 50 mg/day after 1 year of treatment. The patient then showed increased binge frequency, but was free of binges after returning to a naltrexone dose of 100 mg/ day. No significant side effects were described in this report. Another class of medication was tested with the antiepileptic topiramate that had been shown to be associated with reduced appetite and weight loss in the past. A case series in 13 subjects reported reduced binge eating and a positive relationship of topiramate plasma levels with the amount of weight lost in the studied subjects [134]. Sibutramine has been shown to be useful for weight loss and weight maintenance in the treatment of obesity [135]. A multicenter trial in BED subjects has been carried out recently, and data are currently under review. Only very limited data exist on drug treatment in BED. The use of SSRIs seems to be a valid approach; however, relapse after medication discontinuation may have to be expected. The use of opiate receptor blockers appears to be a promising treatment possibility, but larger and controlled double-blind studies are needed to assess risks and benefits of such medications in BED. Sibutramine has been recognized in the treatment for obesity. However, results from the recent multicenter trial has to be reviewed before recommendation for the use in BED can be given.

V.

CLOSING REMARKS

The etiology of EDs is unknown, and no medication studied in AN, BN, or BED seems to specifically target the etiologic factor that leads to their development. Central neurotransmitter systems show a close interaction with each other [136], and it is possible that the nonspecific administration of antidepressant medication in BN may lead to a normalization of the disrupted equilibrium between neurotransmitter systems, and reduce symptoms. This may be supported by the fact that several medications used in BN are effective at the beginning of therapy, but lose efficacy over time

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when the primary disturbance possibly regains its disturbing influence. Substances such as opiate antagonists may reduce symptomatology, but it is not yet clear if this effect is simply a symptomatic treatment, or if a disturbance of those systems are involved in the etiology of EDs. Thus, future research studies, such as the use of brain-imaging techniques, need to target specific factors involved in the ill state, but even more important factors that could contribute to the etiology of EDs. In fact, 5HT1A and 5HT2A receptor alterations have been found after long-term recovery from AN and BN [137,138]. Such findings might open targets for future drug treatments. In addition, studies of other systems such a neuropeptides [139] or neuroactive steroids offer [140] promising areas for future research and possibly pharmacologic interventions. However, the absolute number of ED patients is relatively small, and to make trials comparable, uniform guidelines for pharmacologic trials in EDs should be developed [141]. This will also mean that since ED subtypes may have pathophysiologic traits that are distinct from each other, pharmacologic trials may have to be carried out in pure subgroups to be able to draw more meaningful conclusions.

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55 Perspectives for New Pharmacological Treatments of Alcoholism and Substance Dependence IHSAN M. SALLOUM, ANTOINE DOUAIHY, and SUBHAJIT CHAKRAVORTY Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

I.

limited, and only three (nicotine addiction, alcoholism, and opiate addiction) of the 13 substances of abuse classified in DSM-IV-TR have indicated pharmacotherapy. Pharmacotherapy for addictive disorders has recently received renewed fervor. The purpose of this chapter is to review recent advances in the psychopharmacology of nicotine dependence, alcoholism, and opioid and cocaine dependence.

INTRODUCTION

Alcoholism and other addictive disorders are chronic relapsing illnesses that are similar to other chronic medical conditions in terms of genetic transmission, treatment response, and presenting clinical challenges such as treatment compliance and treatment adherence [1]. The Diagnostic and Statistical Manual of Mental Disorders fourth Edition (DSM-IV-TR) presents 13 categories of substance-related disorders for each of the 11 classes of drugs of abuse. These categories are arranged into two broad groups: a Substance Use Disorders group, which compromises substance abuse and substance dependence, and a Substance-Induced Disorders group, which includes intoxication, withdrawal, cognitive dysfunction (e.g., delirium, persisting dementia, and persisting amnestic disorders); psychotic, mood, and anxiety disorders; sexual dysfunction; and substance-induced sleep disorders [2]. Substance dependence is defined by the DSM-IV-TR as a cluster of cognitive, behavioral, and physiological symptoms indicating maladaptive pattern of substance use leading to significant impairment or distress [2]. Although disulfiram is one of the oldest medications to treat a behavioral disorder, the number of approved medications to treat addictive disorders is still very

II.

PHARMACOTHERAPY OF NICOTINE DEPENDENCE

Tobacco use/nicotine dependence is a major public health problem in the United States. According to the latest Surgeon General’s report dedicated to the health hazards of smoking published in 2000, tobacco smoking is responsible for a staggering direct medical cost of $50 billion a year. Tobacco use causes > 400,000 deaths each year, which is more than alcohol, drug abuse, AIDS, car crashes, murders, suicides, and fire-related deaths combined. Tobacco use remains the leading preventable cause of deaths in the United States [3]. Nicotine dependence is characterized by a chronic course with remissions and frequent relapses. Most 843

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people who quit smoking eventually relapse. It is estimated that only a little more than 2% successfully quit each year. Treatment increases the cessation rate dramatically from a low of 10% a year reported for limited interventions such as physician advice to a 25% cessation rate per year for combined pharmacological and behavioral counseling. A salient feature of nicotine dependence, as noted by the DSM-IV-TR, is the continued use of nicotine products despite knowledge of medical problems related to smoking [2]. Nicotine is a highly rewarding substance. The rewarding effect of nicotine is believed to result from its action on dopaminergic and noradrenergic systems in the brain, particularly its action on the mesolimbic dopamine system. This system is believed to mediate the pleasure and reward circuits in the brain [4,5]. The action of nicotine or nicotinic cholinergic receptors in the brain enhances the release of a number of neurotransmitters [6], including dopamine, noradrenaline, acetylcholine, serotonin, vasopressin, b-endorphin, glutamate, and gamma-aminobutyric acid (GABA) [7]. Furthermore, nicotine exerts its effect on the locus ceruleus, which produces behavioral arousal [7]. Prolonged exposure to nicotine, however, produces a desensitization of nicotinic cholinergic receptors. This desensitization state may require the presence of nicotine to maintain normal functioning. Thus, smoking cessation may leave the individual in a state of subnormal neurotransmitter release, which produces the symptoms of withdrawal including inability to concentrate, irritability, restlessness, lethargy, and depression. A.

Pharmacotherapy of Nicotine Dependence

Although the focus of this section is on the pharmacotherapy of nicotine dependence, counseling strategies have been found to be helpful in smoking cessation. Particularly useful counseling strategies include those that focus on skill training and social support [8]. In spite of the availability of guidelines to smoking cessation, health care providers usually give advice to fewer than half the smokers they see. For example, a brief counseling session, even over the phone, may significantly enhance self-help interventions [8]. Several pharmacological approaches have been studied for the treatment of nicotine dependence and smoking cessation. These include nicotine replacement

therapies using different methods of nicotine delivery and non-nicotine-based medications with diverse mechanisms of action to enhance smoking cessation [9,10]. Medications with established efficacy and safety and which have the U.S. Food and Drug Administration (FDA) approval for smoking cessation are considered first-line therapies. These include the various nicotine replacement therapies and the antidepressant bupropion. Second-line treatments are not FDA approved because of concerns regarding side effects. These medications, however, may be used as an alternative to first-line treatments [8]. 1.

Nicotine Replacement Therapy

Nicotine replacement therapy (NRT) has been until recently the main pharmacological approach to smoking cessation. The goal of NRT is to aid in initiating abstinence from cigarette smoking so that effective relapse prevention strategies may be developed. NRT reduces nicotine withdrawal symptoms, decreases craving, and dampens the reinforcing effects of cigarettes. These compounds lack the toxic substances associated with smoking such as tar, and they also have low abuse potential [11]. Further benefit of nicotine replacement may include positive effects on mood and attention states [12]. NRT suppresses hunger and weight gain associated with smoking cessation [13,14]. Nicotine replacement is now available in four different forms of delivery system: nicotine gum products, transdermal nicotine patches, nicotine nasal spray, and nicotine inhaler [15]. Nicotine gum is available in 2- and 4-mg doses and is available over the counter as a replacement product. Heavier smokers may benefit more from the higher dose of the gum. Nicotine patches, on the other hand, provide a constant infusion of nicotine in the bloodstream, while the nicotine as a spray delivers 0.5 mg of nicotine with each spray. The nicotine inhaler is available as a prescription medication. Smokers puff on the inhaler as they would a cigarette [8]. Nicotine replacement therapy in its various forms has been shown to enhance smoking cessation about twice as much as placebo [16,17]. However, it is estimated that 70–90% of smokers using nicotine replacement therapy fail to quit. Factors contributing to poor response to NRT include depression, weight gain, the use of other substances such as alcohol, stressful life events, and cognitive impairment [7]. Women smokers appear to be less responsive to NRT than men [18].

New Pharmacological Treatments

2.

Non-Nicotine-Based Medications

A variety of non-nicotine-based medications have been tested for smoking cessation. These medications are based on different mechanisms of action to produce smoking cessation. These include medications that act on the neurotransmitter system to simulate the effects of nicotine, medications that block nicotine receptors, medications that influence the conditioned response associated with smoking, and medications that produce an aversive response to smoking. For example, medications that increase the brain levels of dopamine, noradrenaline, and serotonin may counteract the deficiency state produced by nicotine withdrawal. These drugs may also simulate the action of nicotine on the brain reward circuits. On the other hand, mecamylamine, a noncompetitive inhibitor of nicotine receptor [19,20], may block the reinforcing effects of nicotine. More recently, the use of vaccines to counteract the effects of nicotine has been proposed [9]. The use of sensory substitutes to target the significant conditioning to the smell, taste, and feel associated with cigarette smoking has also been tested. One sensory substitute, citric acid, has been shown to reduce withdrawal symptoms and cravings [21–23]. Also, dextrose has been proposed to reduce urges to smoking based on the theory that there is a mislabeling of a physiological desire for carbohydrates [24,25]. In one study, dextrose tablets produced significantly greater rates of abstinence than placebo whether taken alone or in combination with NRT [25]. Aversive therapy, on the other hand, aims at extinguishing the urge to smoking by pairing the pleasurable stimulus of smoking a cigarette with some unpleasant effect [26,27]. Rapid smoking and the use of silver acetate are examples of aversive therapy. The silver combination with tobacco produces a badtasting salt. These approaches, although they do not produce long-term benefit, are helpful when used in combination with NRT. Many non-nicotine-replacement medications have been tested alone and in combination with NRTs.

Clonidine Clonidine is a a2 -adrenergic receptor agonist used as an antihypertensive medication. Clonidine inhibits the release of noradrenaline and the firing of the locus ceruleus. These effects produce sedation and decrease in anxiety [7,28]. This medication has been found to be useful in reducing alcohol and opiate withdrawal syndromes.

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Clonidine reduces cravings and nicotine withdrawal symptoms such as anxiety, irritability, restlessness, and hunger in heavy cigarette smokers [28,29]. In a doubleblind placebo-controlled study, the clonidine-treated group had more than double the success rates in smoking cessation than those treated with placebo [30]. A review of the literature and a meta-analysis of nine trials of clonidine showed that the clonidine-treated patients were more likely to quit smoking than those treated with placebo [31]. The skin patch delivery system was found to be more effective than the oral administration; also, clonidine was more effective in combination with behavioral therapy [31]. Patients with more severe nicotine dependence and high blood concentration of clonidine showed the most favorable response [7]. Female smokers appear to have a better response than male smokers to clonidine therapy [32]. Studies have also reported higher frequency of adverse effects, especially with increased levels of drowsiness, dry mouth, and fatigue. Furthermore, the abrupt discontinuation of clonidine may cause agitation, headache, tremors, nervousness, and rapid increase in blood pressure. These disadvantages limit the usefulness of clonidine for smoking cessation. Antidepressants Several studies have observed a strong link between depression, past history of depression, and smoking. Depressed mood predicts smoking relapse in many patients. Smokers are more likely to be depressed, and depressed patients are more likely to be dependent on nicotine and also have lower success rate at quitting [33,34]. Antidepressant medications are the most common non-nicotine-based medications used to treat nicotine dependence. BUPROPION (AMFEBUTAMONE). The sustained-release bupropion, an antidepressant medication, is the first non-nicotine-based agent approved by the FDA (in 1997) for the treatment of nicotine dependence. The sustained-release formulation provides a slower absorption and allows for less frequent dose administration. It is hypothesized to aid in smoking cessation by blocking the reuptake of dopamine and noradrenaline and by decreasing the firing of the locus ceruleus [35,36]. Bupropion functions as a noncompetitive inhibitor of the nicotine receptor site producing a functioning blockade of the nicotine receptors [37]. Bupropion reduces the reinforcing effects of nicotine by its effects on the reward pathways through the dopaminergic system. It lessens nicotine withdrawal symptoms by its effects on the noradrenergic system.

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A series of placebo-controlled studies have shown that bupropion is effective in smoking cessation as compared to placebo both in smokers who have depression and those without depression [38]. Studies have also demonstrated a dose response relationship. The 300-mg and 100-mg doses of the sustained-release formulation were found significantly more efficacious than placebo [39,40]. Sustained-release bupropion was also found superior to placebo on abstinence rate when tested with and without combination of NRT [38,40]. The effectiveness of the nicotine patch alone in those studies was no different from placebo. Additional benefit of bupropion includes decrease in weight gain and improvement in the lethargy associated with nicotine withdrawal and smoking cessation [31,39]. Bupropion is well tolerated. Dry mouth and insomnia were the most commonly reported side effects, and there were no bupropion-induced seizures reported during those studies. NORTRIPTYLINE. Nortriptyline is a tricyclic antidepressant. It blocks the reuptake of noradrenaline and serotonin and decreases the firing of the locus ceruleus. In addition it has anticholinergic activities that are sedating. However, nortriptyline does not block dopamine reuptake. Two placebo-controlled studies have reported superiority of nortriptyline over placebo in smoking cessation with abstinence rates double that of placebo (24% vs. 12%) [41,42]. Additionally, nortriptyline improved depressive symptoms, although women with history of major depression had lower cessation rate than women without depression history. There were numerous side effects reported including dry mouth, tremors, blurred vision, and lightheadedness. Another disadvantage to nortriptyline is the serious risk of toxicity on overdose. MOCLOBEMIDE. Moclobemide is a monoamine oxidase A (MAOA) inhibitor antidepressant that enhances dopamine activity [43]. A double-blind placebo-controlled study reported significant difference of moclobemide over placebo on self-report of smoking cessation. This difference, however, was not significant when the more objective serum cotinine concentration was examined [44,45]. Studies of other antidepressant agents have been conducted with some promising but mostly inconclusive evidence. Doxepin was reported to be superior to placebo in a small double-blind study [46]. Fluoxetine has been found ineffective in nondepressed smokers, although there is some suggestion that it may be helpful in smokers with symptoms of depression [7]. Similarly,

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buspirone does not appear to be helpful as a smoking cessation aid; however, one study suggested that buspirone may be helpful in reducing smoking in the initial phases of treatment of anxious individuals [47]. Mecamylamine Mecamylamine is an antihypertensive medication that blocks the peripheral and central nervous system effects of nicotine. The nicotine antagonist properties of mecamylamine have been used to help with smoking cessation [48,49]. Studies have shown that mecamylamine was helpful in smoking cessation and also in reducing the withdrawal symptoms. Severe side effects were observed, however, such as constipation and urinary retention, resulting in high dropout rate [31]. Low doses of mecamylamine combined with nicotine patch, on the other hand, appear to be well tolerated and provide a significant advantage when compared to nicotine patch alone [50]. Mecamylamine combined with NRT blocks the reinforcing effect of nicotine, provides relief from withdrawal symptoms, and limits the increase in appetite associated with smoking cessation [50–52]. Opioid Antagonists Mostly negative findings for smoking cessation were reported for the opioid antagonists naltrexone and naloxone. One study reported some benefit for female smokers with a history of major depression. High dropout rates were reported on naltrexone due to side effects which included drowsiness, disorientation, spaciness, problems with concentration, nausea, and abdominal pain [31]. In conclusion, there is substantial evidence to support the efficacy of bupropion in smoking cessation. Other medications may be effective in a limited subgroup of smokers. Combining medication with NRT may improve the outcome. Rates of relapse are quite high after the acute phase of treatment. The majority resume smoking within 6 months to 1 year after cessation of treatment. Subgroups of smokers, such as those with psychiatric comorbidity of depression and anxiety, may require a more targeted treatment strategy.

III.

PHARMACOTHERAPY OF ALCOHOLISM

Alcohol use is highly prevalent, affecting 11–15% of adults throughout their lifetime [53,54], and is related


to criminal activity, violence, accidental injuries, and both psychiatric and medical comorbidities. Research has enhanced our knowledge of the specific areas of the brain and the neurotransmitters associated with alcohol consumption, reinforcement, craving, and relapse. For examples, stress-induced craving has been associated with the serotonin-related mechanisms, while positive reinforcement and craving have been associated with the dopaminergic system [55]. Dopaminergic pathways projecting from the ventral tegmental area to the nucleus accumbens are associated with the pleasurable and stimulant effects of alcohol [57–59]. This pathway may be sensitized by continued, excessive alcohol ingestion, leading to development of dependence [57,60,61]. Thus, drugs targeting this dopaminergic system may reduce alcohol consumption [57]. Alterations in several neurotransmitter systems may be seen as part of an adaptive process to prolonged alcohol use, including downregulation of inhibitory neuronal g-aminobutyric acid (GABA) receptors [57,64], upregulation of the excitatory glutamate receptors [56–68], and increased central norepinephrine (NE) activity [57,65]. Although there is no cure for alcohol dependence, both our understanding of this disorder and the drugs in our armamentarium have improved substantially. The treatment of alcohol dependence may be conceptualized into three phases [66]: 1. Acute stabilization phase focuses on engaging the patient in treatment, inpatient or outpatient detoxification as deemed necessary, and treatment of any associated comorbid disorders. During this phase the patient is also enrolled in psychotherapy, which may include individual and/or group counseling 2. Continuation phase, which begins after the patient has achieved stability and is targeted at maintaining sobriety through continued use of medication and psychotherapy. 3. Maintenance phase aims at preventing relapse to alcohol, and it may also involve the use of psychotherapy and possibly medications. Self-help programs and building a social support network are important objectives of treatment throughout these phases.

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1. Medications to reduce alcohol intake which include dopaminergic, serotonergic, and opioid antagonist agents. 2. Agents to induce aversion to alcohol. 3. Agents to treat acute alcohol withdrawal such as benzodiazepines and anticonvulsants. 4. Agents to treat protracted alcohol withdrawal. 5. Agents to decrease drinking by treating associated psychiatric pathology such as anxiolytics, antidepressants, and antipsychotics. 6. Agents to induce sobriety such as adenosine receptor antagonists. 1.

The two drugs that have been studied in this category are bromocriptine and tiapride. Studies involving bromocriptine, a dopaminergic agonist, have demonstrated varied results. Some studies have reported decreased craving, depression, and abstinence for > 6 months [53,67], while other studies reported no improvement in the incidence of relapse compared to placebo [53,68]. Tiapride, a D2 dopamine antagonist available in Europe since the 1970s, is an atypical neuroleptic and an anxiolytic drug. Tiapride reduces the symptoms of alcohol withdrawal [57,69], reduces the amount of alcohol consumed, increases the occurrence of abstinence, and decreases the reports of anxiety and depression [53,70,71]. This drug is approved in some European countries for the treatment of alcoholism. Apomorphine has been used as an aversive agent and also to treat withdrawal, but no controlled trials are yet available [68,72]. In a case report, haloperidol has been suggested to decrease the alcohol-induced cravings among alcoholdependent subjects [72,73]. Routine use of antipsychotic medications in the treatment of alcohol dependence, however, is not warranted other than to treat hallucinations associated with alcohol withdrawal, as these medications increase the risk of seizures and can produce severe hypotension. Despite these risks, patients currently taking antipsychotic medications for other indications should continue their use [53,74]. 2.

A.

Medications Used to Treat Alcoholism

Medications used in the treatment of alcoholism and associated conditions have been classified as follow [53]:

Dopaminergic Agents

Opioid Antagonists

Animal studies have shown alcohol consumption to be increased by m-opioid agonists and reduced by m-opioid antagonists [53,75,76]. These findings led to clinical trials of naltrexone, and subsequently nalmefene, in the treatment of alcohol dependence.

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Naltrexone hydrochloride, a pure, reversible opioid antagonist, is the first medication to have been approved by the FDA for alcohol dependence since the introduction of disulfiram over 50 years ago. This drug, as well as the other m-opioid antagonists, blocks the release of dopamine secondary to alcohol use from the nucleus accumbens [53,78,79]. Naltrexone appears to decrease drinking, improve abstinence rates, reduce craving, and therefore reduce the risk for relapse [53,79–82]. Naltrexone use in social drinkers has been associated with increased sedation and unpleasant effects and decreased reward effects of alcohol [57,83]. Patients with alcoholism who continued to drink during treatment reportedly experienced less alcohol ‘‘high’’ and had decreased likelihood of progression to heavy drinking [57,82]. Naltrexone has been shown to reduce the craving for alcohol in alcohol-dependent patients as well as in social drinkers [57,84,85]. A posttreatment survey concluded that naltrexone is more effective in patients with higher craving and lower cognitive functioning [53,86]. Naltrexone is a synthetic congener of oxymorphone and is structurally related to naloxone. A 50-mg dose of naltrexone can block the effect of 25 mg of IVinjected heroin for up to 24 h [87,88]. Naltrexone is well absorbed orally. The pharmacologic activity is due to the parent compound as well as the 6-b-naltrexol metabolite. The mean half-lives of naltrexone and 6-b-naltrexol are 4 and 13 h, respectively. Although extrahepatic sites are postulated to exist, the drug is primarily metabolized by the liver and is excreted in the urine. The most common side effects reported include nausea and headache [87,89]. Nausea may diminish on decreasing the dose. Hepatotoxicity has been seen at doses significantly higher than 50 mg [87,90] and is due to direct toxic effects on the liver rather than an idiosyncratic reaction [57]. Liver function tests (LFTs) should be performed prior to the onset of naltrexone and at regular intervals thereafter. An elevation of the liver enzymes (AST, ALT) greater than three times the normal limit and an elevated bilirubin level preclude the use of naltrexone. Other contraindications to the use of naltrexone include current use of opioids or opioid dependence, a failed naloxone challenge test, a positive urine screen for opioids, a history of sensitivity to naltrexone or related compounds, acute hepatitis, and hepatic failure [121]. Nalmephene is a m- and k-opioid antagonist; while chemically similar to naltrexone, nalmephene is less hepatotoxic. Nalmephene is approved by the FDA for reversal of opioid intoxication and overdose [57].

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In a 12-week randomized, placebo-controlled trial of nalmephene (10 and 40 mg/day), a lower relapse rate was achieved with the higher dose of nalmephene [55,57,91]. 3.

GABA Agonists

Acamprosate or calcium acetyl homotaurinate, has excitatory effects on the GABA receptors and inhibits the N-methyl-d-aspartate receptors [57,92]. The normalization of the glutamatergic excitation that occurs in withdrawal and early abstinence may lead to a reduction in the craving, distress, and need to consume alcohol [57,93–95]. Several European trials have shown that abstinence rate on acamprosate over 3 months to a year is two times that of placebo [57,97–101]. Acamprosate is primarily excreted by the kidney and it is not metabolized in the body. It should thus be used with caution in patients with renal failure. The main side effects are headache and diarrhea [57,87]. Acamprosate is not available in the United States. 4.

Serotonergic Agents

Sustained use of alcohol has been hypothesized to disrupt the serotonin system or cause a reduction in the neurotransmission of serotonin [53]. Therefore serotonergic compounds are potential treatments for alcoholism [53,102,103]. In recent years they have been used off-label for patients with comorbid depressive and anxiety disorders. The main drugs studied are ondansetron, buspirone, and selective serotonin reuptake inhibitors (SSRIs). In one study, ondansetron, a 5HT3 antagonist, decreased the pleasurable effects of alcohol as well as the desire for drinking alcohol in healthy adult volunteers [53,104]. Likewise, another trial reported decreased alcohol consumption [53,105]. Buspirone, a 5HT1A agonist, was shown in one clinical trial to be associated with the subjects staying in treatment longer and drinking less than subjects on placebo [57,106]. Other studies have shown buspirone to be associated with reduced craving and consumption [53,106–108]. A 12-week placebo-controlled trial of patients with comorbid anxiety and alcoholism treated with buspirone showed that subjects remained in treatment longer and drank less than subjects on placebo [57,106]. On the contrary, a double-blind study of alcoholism and anxiety showed buspirone to be no more effective than placebo [57,109]. A review of the buspirone studies showed the only positive change in drinking behavior to be an increased time to the first drink [55].


Fluoxetine, citalopram, and other 5HT agonists (SSRTs) have been tested. Although some short-term studies in heavy social drinkers reported a modest decrease in alcohol use [110–112], studies of alcoholdependent patients without comorbid major depression did not report an advantage of the SSRI fluoxetine over placebo [113–115]. However, in a randomized double-blind placebo-controlled study of fluoxetine in patients with comorbid major depression and alcohol dependence, fluoxetine decreased the depression as well as the total number of drinks consumed compared to placebo [57,116]. 5.

Aversive Agents

Aversive agents are compounds that when given alone produce no sensations but rather produce nausea and other unpleasant reactions if alcohol is consumed. The two common drugs in this group are disulfiram and calcium carbimide. Disulfiram Disulfiram, an antioxidant used in the rubber industry, was initially discovered by two Danish physicians to be a useful deterrent to drinking alcohol. Chemically bis(diethylthiocarbamoyl)disulfide, disulfiram is an irreversible inhibitor of the enzyme aldehyde dehydrogenase, which is responsible for the metabolism of acetaldehyde. The aversive effects of disulfiram is due to the disulfiram-ethanol reaction (DER) which develops as a consequence of the accumulation of acetaldehyde [87,117,137]. Disulfiram may also produce hypotension as a result of decreased norepinephrine synthesis, secondary to inhibition of the enzyme dopamine beta-hydroxylase [87]. DER develops within a few minutes after the ingestion of alcohol while on disulfiram maintenance. A mild DER may consist of increased heart rate and blood pressure, chills, nausea, vomiting, hypertension, and shortness of breath and may be treated with antihistamines. A moderate to severe DER may be associated with intense tachycardia and EKG changes. There may be ensuing vomiting, convulsions, congestive heart failure, and cardiovascular collapse. Other complications may include myocardial infarction, cerebrovascular accident, and cardiac arrest. Severe, delayed DERs have also been reported [87,118]. Management consists of supportive measures, anticholinergics, ascorbic acid, and 4-methylbyrazol, which blocks the acetaldehyde production by blocking the metabolism of alcohol. Other sources of alcohol, the

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so-called latent alcohols (e.g., cough syrups, facial lotions, wine vinegar, sauces, and some candies) may induce a similar reaction. Medications that may potentiate DER include amitriptyline, vasodilators, beta-adrenergic antagonists, MAO inhibitors, and antipsychotics [87,119,120]. Disulfiram is both slowly absorbed and slowly eliminated from the body and may be present about 2 weeks after the last dose is administered [121]. In the initial phase of treatment, a maximum of up to 500 mg/day may be given in a single dose for 1–2 weeks. While preferably taken in the morning, the medication may be taken at night for patients who experience a sedative effect. The maintenance dose is on average 250 mg/day with a range of 125–500 mg/day. Adverse effects from disulfiram include a number of potentially serious side effects, especially at higher dosages, warranting caution and frequent monitoring [87,119]. Careful monitoring may include liver function tests, patient education, and warnings pertaining to the potential side effects. Side effects include transient mild drowsiness, fatigability, headache, decreased sexual desire, erectile dysfunction, skin eruptions, nickel dermatitis [53,122], a metallic or garlic aftertaste, restlessness, cholestatic and fulminant hepatitis, hepatic failure, optic neuritis, peripheral neuritis, polyneuritis, and psychotic reactions or unmasking of underlying psychosis. Disulfiram inhibits the metabolism of several medications including anticoagulants, phenytoin, and isoniazid [57]. The drug is contraindicated in patients concurrently consuming alcohol or receiving alcohol-containing preparations, metronidazole, or paraldehyde. Disulfiram is also contraindicated in patients who experience a hypersensitivity reaction to disulfiram or other thiuram derivatives or in the presence of psychoses, suicidal and impulsive behaviors [87], coronary artery occlusion, severe myocardial disease, or pregnancy [57,121]. Disulfiram may be particularly beneficial for motivated, older, and more severely affected subjects [56,123], and when used in conjunction with effective compliance-enhancing techniques [124,125]. Disulfiram implant trials have not shown satisfactory results aside from a reduction in the number of days that subjects consume alcohol [55]. Calcium Carbimide Calcium carbimide was previously available in Canada and Australia but has been withdrawn from the market by the manufacturer. Although it has not

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been studied as well as disulfiram, calcium carbimide has shown no greater efficacy than placebo in clinical trials. 6.

Benzodiazepines

Benzodiazepines are still the agents of choice for acute alcohol withdrawal [53,126–129]. They are particularly well suited as they treat both the anxiety and the seizures often seen in alcohol withdrawal [130]. The long-acting compounds chlordiazepoxide and diazepam and the intermediate-acting compounds lorazepam, oxazepam, and temazepam are most frequently used [87,119]. The long-acting compounds are most favorable since their long-acting metabolites allow less frequent dosing and produce a natural tapering effect. Adverse effects to the benzodiazepines include sedation, drowsiness, ataxia, dizziness, poor coordination, diplopia, vertigo, and impairment in motor performance. The long-acting benzodiazepines tend to produce these side effects due to their accumulation. Intermediate- and short-acting benzodiazepines are more likely to produce side effects from high peak levels as well as fluctuating blood levels. Episodes of severe agitation, hostility, and memory impairment have been reported [87,117,123, 131,132]. 7.

Adrenergic Agents

The majority of the symptoms of alcohol withdrawal are related to heightened activity of the sympathetic nervous system, manifesting as hypertension, tremors, nausea, and anxiety. Mild to moderate withdrawal symptoms may be effectively managed with alphaagonists but are associated with the adverse effects of sedation and hypotension [53,133–137]. Propranolol and atenolol have been shown to cause abatement of signs and symptoms with an earlier return to baseline, a reduction in the amount of benzodiazepines used, and a reduction in the length of inpatient stay [53,138]. Other studies have shown that propranolol and atenolol decrease the desire for alcohol, give rise to longer compliance with treatment, and cause fewer side effects compared to the other agents in this class [53,139–141]. However, both propranolol and atenolol may mask the severity of withdrawal [53,125] and may increase the occurrence of confusion and hallucinations during withdrawal [53,142–143]. For these reasons and because of the rapid development of tolerance to the anxiolytic effects of beta-blockers, their use is limited [53,144].

8.

Calcium Channel Blockers

Calcium channel blockers of the dihydropyridine family (e.g., nimodipine and darodipine) decrease the severity of alcohol withdrawal in rodents [53,145–148]. Further research involving this class of compounds is warranted given that calcium channel blockers have potential benefits in the treatment of alcohol withdrawal. 9.

NMDA-Receptor Channel Blockers

Some experimental evidence suggests that NMDAreceptor channel blockers such as MK-801 (dizocilpine) or related compounds might hold some promise for alcohol withdrawal, as MK-801 has been shown to decrease the frequency and severity of alcohol withdrawal-induced seizures [53,149,150]. 10.

Anticonvulsants

Although benzodiazepines are the preferred drugs for the control of seizures during alcohol withdrawal, other drugs that may be used include carbamazepine and valproate. Although more testing is warranted, both carbamazepine and valproate may be useful in the treatment of alcohol withdrawal [53,151,152]. Gabapentin has been reportedly used with some success in the detoxification from alcohol, in the treatment of alcohol-related sleep disorders, and in the augmentation of chlormethiazole, thereby decreasing the amount of chlormethiazole required for detoxification [153–156]. One important avenue of future direction may be to identify the genes that contribute to the risk for alcoholism and associated therapeutic response using the process of human genome sequencing [157–161]. IV.

PHARMACOLOGICAL TREATMENT OF OPIOID DEPENDENCE

Opioid dependence has remained a costly and personally destructive national health problem. Epidemiological studies show that opioid addiction affects 810,000 people each year, touching all segments of American society, with annual costs around $21 billion [162]. Of the U.S. adult population, 0.4–0.7% will develop heroin dependence at some point in their lives [162]. About one-quarter of people who have ever used heroin develop dependence [162]. Dependent heroin users typically use heroin daily, become tolerant to its effects, and experience withdrawal manifestations on abrupt cessation of use. Heroin-dependent patients


are at increased risk of premature death from drug overdose, HIV and hepatitis spread by sharing contaminated injecting equipment, violence, criminal behavior, and alcohol-related causes [163,164]. With the exception of naltrexone hydrochloride, opioid maintenance therapy remains the primary pharmacological approach to the treatment of opioid dependence. Opioid agonists, opioid antagonists, and more recently partial agonists, are the three primary types of medications available for the treatment of opioid dependence, all acting directly on opioid receptors, particularly m-receptors. A.

Naltrexone Hydrochloride

Naltrexone hydrochloride is an opioid antagonist that blocks the subjective effects of opioids, thereby eliminating opioid-induced euphoria, diminishing the reinforcing effects of heroin [165], and potentially extinguishing the association between conditioned stimuli and opioid use [166]. Relative to other maintenance therapies, naltrexone has no abuse potential, has a benign side-effects profile, and can be prescribed without concerns about diversion (rarely traded in the illicit market) [167]. Moreover, approved by the FDA in 1984, naltrexone, available in tablet form for use in detoxified patients, is not subject to the restrictive regulatory requirements with methadone and levomethadyl acetate, and therefore can be prescribed in a wide range of settings. Naltrexone displaces bound agonist and blocks the effects of heroin administration [166]. Peak plasma concentrations are achieved within 1 h, and antagonist effects can last up to 72 h [166]. Because of its long duration of action, standard dosages of naltrexone are 50 mg/day or 100 mg on Monday and Wednesday and 150 mg on Friday [166]. Potential side effects of naltrexone are similar to those described in the treatment of alcohol dependence. However, in opioid dependence, reported side effects of naltrexone may have been related to precipitation of the opiate withdrawal syndrome [168]. The most common side effects are nausea and headaches. Others include epigatric pain, dizziness, nervousness, fatigue or insomnia. Large doses (up to 300 mg/day) might increase the risk of hepatotoxicity [169]. Naltrexone has, despite its appealing properties, remained underused compared to methadone maintenance [170]. Its clinical usefulness has been limited [165,171] owing to problems with attrition and noncompliance. Induction can be difficult and early dropout is common. In one treatment program, 40% of

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patients dropped out during the first month of treatment and 60% dropped out by 3 months [172]. Randomized trials have shown low retention rates (2%), and one study demonstrated no efficacy in reducing opioid use compared to placebo [173,174]. Research on naltrexone has mostly focused on evaluating its utility in the treatment of selected populations (health care professionals and individuals mandated to treatment) [175]. Naltrexone has shown some efficacy in combination with fluoxetine and weekly drug counseling [176]. Since naltrexone lacks the pharmacological reward activity, contingency management (CM) and significant other (SO) involvement could be used to reward and provide incentives for retention and thus enhance naltrexone compliance [177]. A recent study evaluating CM and SO as treatments for recently detoxified opioid addicts taking naltrexone as maintenance treatment showed promising results which emphasized the importance of behavioral therapies targeting specific techniques to enhance compliance with pharmacological interventions [178].

B.

Opioid Maintenance Therapy

Repeated exposure to opioids leads to major changes in the neurons in the locus ceruleus and mesolimbic areas of the brain producing the clinical phenomena of tolerance, dependence, craving, and supranormal stimulation of the reward circuitry [179]. These neurobiological changes explain the rationale for opioid agonist maintenance to stabilize these complex systems. Opioid agonist maintenance therapies offer many advantages including their slower onset of action which minimizes their euphoric effects, their competitive antagonism with heroin, and their ability to prevent withdrawal by cross-tolerance. Opioid agonist maintenance eliminates the risk for infections associated with intravenous drug injection [180]. 1.

Methadone Hydrochloride

Methadone hydrochloride is a synthetic long-acting opioid m-receptor agonist. It is available in tablets or as a solution for oral or parenteral use in detoxification, maintenance, and treatment of severe pain. Methadone is taken once a day because its long duration of action eliminates opiate withdrawal symptoms for 24–36 h. Given in high doses, it reduces craving for heroin and blocks many of the euphoric effects of exogenously administered opioids [181], thereby breaking the cycle of seeking out, buying, and abusing heroin.

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However, when injected, methadone has potential for abuse in persons who are less opioid dependent. Long-term administration of methadone does not result in any adverse biochemical or tissue changes [182] but leads to tolerance to its analgesic, sedative, and euphoric effects [183], with minimal toxicity. Side effects usually appearing during the stabilization phase include constipation, sweating, and a skin rash (which may be transient), weight gain, decreased libido, menstrual irregularities (resulting from hyperprolactinemia), ankle edema, sedation (specially at higher doses) [184], and rare cases of reversible thrombocytopenia in patients with chronic hepatitis. Since methadone undergoes extensive hepatic metabolism, it interacts with medications metabolized by the cytochrome P450 pathway: Levels of methadone can be increased by concomitant administration of such medications as erythromycine, ketoconazole, cimetidine, and fluvoxamine [185]. Induction of the CYP 450 enzyme activity leads to decreased plasma levels of methadone and withdrawal due to interactions with alcohol, phenytoin, barbiturates, carbamazepine, isoniazid, rifampin, ritonavir, nevirapine, and possibly efavirenz [185–188]. Methadone interferes with the metabolism of desipramine and other tricyclic antidepressants leading to elevated plasma levels of those agents and their active metabolites. Reduction in the dosages of those agents is warranted if patients are symptomatic, show signs of toxicity, or have elevated plasma levels. Methadone administration is considered to be the treatment of choice for pregnant women who are addicted to opiates. It is reportedly safe with mild effects on the offspring. Offspring may, however, develop neonatal abstinence syndrome after delivery [189]. The model of methadone maintenance treatment (MMT) originally proposed by Dole and Nyswander (high doses of methadone, long duration of treatment, intensive rehabilitative services) was modified during its popularization in the 1970s in the United States and Australia [190,191]. The goal of the programs moved from maintenance toward abstinence from all opioid drugs, including methadone [190]. The original study by Dole and Nyswander that demonstrated the efficacy of methadone in decreasing heroin use was conducted with daily doses ranging from 50 to 150 mg [192]. Some clinics use relatively low doses (< 30 mg), while others use 60 mg or more per day. Most studies have demonstrated that higher doses of methadone (>50 mg) are more effective than lower doses and are associated with better treatment retention and decreased illicit drug use [193,194]. A recent 40-week randomized double-blind

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trial comparing the relative clinical efficacy of moderate (30–50 mg) versus high-dose (80–100 mg) methadone maintenance in 192 outpatients noted a greater decrease in illicit opioid use in the high-dose group [194]. Because of some degree of negativity and misconceptions about the methadone dose (195), many programs are reluctant to prescribe the optimal doses. Adopting a flexible dosing policy results in patients’ feeling more positive about their treatment’ and produces better retention rates [196,197]. The efficacy of methadone has been clearly demonstrated empirically in several experimental and observational studies [198–201]. An overview of 1-year follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS) showed that in the 727 patients who started methadone treatment, weekly heroin use dropped from 89% before treatment to 28% at 1 year [196]. One recent study showed the advantages of methadone maintenance over a long detoxification program combined with enriched psychosocial treatment [202]. In addition to decreasing heroin use, methadone maintenance has also been shown to reduce risk behavior for HIV infection and seroconversion in injection drug users [203–206]. However, a series of studies from the Netherlands has documented the failure of ‘‘low-threshold’’ methadone programs to reduce HIV risk behavior and HIV transmission, which explains the importance of not just simply providing a suboptimal dose of methadone but also how treatment is delivered [207]. Parallel to the reduction in heroin use and risk of contracting HIV is a reduction in acquisitive crime that can be substantial [200,208]. Other benefits include a reduced risk of death and an improvement of well-being, and normalization of disruptions in immune and neuroendocrine functions caused by heroin use [209–211]. As documented in the Treatment Outcome Prospective Study, the major benefits of treatment (reductions in drug use and crime) are noted while patients continue to receive methadone [212]. Methadone has been almost exclusively provided through treatment programs since 1972, when the FDA created regulations that specified the types and amount of treatment services to be provided [200]. ‘‘Quality’’ of treatment is crucial. The quality of the staff-patient interactions and attitude of staff [200], good management of clinics, and quality of record keeping [213] are factors related to outcome of treatment. Abstinence from illicit drug use is monitored by urine toxicology screens in addition to patient’s selfreport. Continued illicit drug use is met with various strategies, including loss of privileges for take-home


medication, increased frequency of clinic visits, and changes in medication dosage to address withdrawal manifestations. 2.

L-Alpha-Acetylmethadol

L-alpha-acetylmethadol (LAAM) is a long-acting derivative of methadone that was approved by the FDA for maintenance treatment in 1993. It prevents the opiate withdrawal symptoms for up to 72 h [214,215] and reduces craving. It also increases tolerance to the opiate and thus blocks the ‘‘high’’ effects of abused opiates. It is available in oral and parenteral forms and is metabolized to more potent metabolites that have a prolonged duration of action. The main advantage of LAAM is its long-acting property (up to 92 h) which allows patients to receive doses every 2–3 days, instead of daily with methadone. Adverse effects of LAAM are similar to those of other m-receptor agonists. Therefore these may be adverse events related to the development of dependence, withdrawal, risks of overdose, and side effects related to the physiological effects of LAAM [216]. Precautions must be undertaken in prescribing LAAM because its full effect is not felt for several days. Overdose on LAAM usually results from its combined use with other drugs, although overdose has also resulted from LAAM alone because of toofrequent dosing [217]. Comparative studies demonstrated similar rates of retention in treatment and opioid positive results on urine tests in patients receiving methadone and LAAM [218,219]. A recent meta-analysis of 14 randomized controlled trials comparing LAAM with methadone maintenance noted slightly greater treatment retention for methadone but a trend toward a greater decrease in illicit drug use with LAAM [220]. Recent trials have demonstrated that patients who received higher doses, a dose-related decrease in heroin use occurred [221,222]. However, they had greater incidence of adverse effects and dropout [221,223]. A recommended starting dose is 30 mg LAAM thrice weekly, with a dose increase by 10 mg every other day until a target of 70 mg is reached [223]. Despite the multiple advantages of LAAM, including the convenient dosing, sustained agonist activity, and decreased likelihood for diversion due to lack of ‘‘take-home’’ dosing, only a small proportion of patients enrolled in the maintenance programs receive it. Local and state regulatory processes and the delay in insurance reimbursement seem to be responsible for its slow acceptance in treatment programs [224].

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3.

Buprenorphine Hydrochloride

Buprenorphine hydrochloride is still an experimental medication for the treatment of opioid dependence. It is already available in Europe and is being considered for approval by the FDA. If approved, buprenorphine, unlike methadone and LAAM, may be available outside of regulated narcotic treatment programs, and in less stigmatized locations, most important, in office-based practices [225]. Buprenorphine is a high-affinity partial m-agonist and a weak antagonist at the k-receptor with a long duration of action [226,227]; thus, it may cause fewer withdrawal symptoms and have less potential for abuse, respiratory depression, and overdose [228–230]. It also has some advantages over methadone. Most notably, buprenorphine has a ceiling level on agonist activity, limiting adverse reactions at doses as high as 100 times the analgesic dose [231,232]. Buprenorphine exists in tablet form for sublingual administration, in parenteral form, and a new, sublingual tablet that combines buprenorphine with naloxone. Since the risk of diversion is significantly reduced by the combined buprenorphine-naloxone preparation, it has a great potential for use in office practice. Buprenorphine’s lengthy half-life may allow it to be dispensed every 3 or even every 4 days [233]. It produces limited physical dependence of the opioid type. Because of its binding to the m-receptor, the onset of the withdrawal symptoms after maintenance treatment is generally delayed for 24 h or more, and low symptom intensity may not worsen for 5 or more days. The major disadvantage of buprenorphine is its poor oral bioavailability; however, sublingual administration results in plasma concentrations that are 60–70% those of parenteral doses [230]. Its abuse potential limits its dispensing to home [230]. Buprenorphine has a more favorable safety profile than methadone. Buprenorphine appears to have a ceiling on pharmacodynamic effects in the presence of dose-proportionate plasma levels and has a high safety margin when given IV in the absence of other drugs [234]. The most common side effects include sedation or drowsiness, nausea, dizziness, headache, hypotension, miosis, and diaphoresis [235]. Constipation was the only significant side effect noted in a recent dose-ranging study of buprenorphine [225]. Buprenorphine is metabolized by the cytochrome P450 system, and potential drug-drug interactions may emerge between buprenorphine and benzodiazepines, fluoxetine, fluvoxamine, and ritonavir [187,236,237].

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Early work and subsequent research have established buprenorphine’s ability to suppress self-administration of heroin [238] and its effectiveness in opioid detoxification [239]. Clinical trials have demonstrated the efficacy of buprenorphine over placebo in decreasing illicit opioid use [240], and have shown that dosages ranging from 6 to 16 mg/day are as safe and effective as 60 mg methadone in stemming the use of opiates [225,241,242]. In addition, it has been shown that daily and alternate-day dosing have equivalent effects on opioid withdrawal syndrome and illicit drug use [243,244]. A 12-week randomized trial comparing the effects of thrice-weekly buprenorphine in a primary care setting with those in a traditional treatment program noted higher retention and lower illicit opioid use in the primary care setting group [245]. Another study demonstrated that buprenorphine administered three times weekly was similar to LAAM in terms of study retention and was similar to high-dose (60–100 mg) methadone in terms of abstinence [246]. C.

Matching Pharmacological Approaches to Patients with Opioid Dependence

Federal requirements have evolved from fairly restrictive criteria to more flexible criteria. Initially, candidates for methadone maintenance were required to be 21–40 years of age, to have been addicted to heroin for at least 4 years, to have evidence of relapse with previous attempts at detoxification, and to have no major medical or psychiatric problems or polysubstance dependence. Current criteria for maintenance with methadone or LAAM specify that patients must be at least 18 years of age and have at least a 1-year history of opioid addiction and evidence of physiological dependence [256]. Comorbid psychiatric, substance abuse, and medical problems are not excluded, and pregnant women are eligible under modified criteria [256]. The decision to implement opioid agonist maintenance involves careful evaluation of the clinical characteristics including the risks and the benefits for every patient, within the regulations guidelines. For example, patients with a long history of severe dependence, previous failed attempts at detoxification, and substantial risk for infectious complications due to injection drug use would more likely benefit from an opioid agonist or partial agonist maintenance to reduce the harm associated with heroin and promote abstinence. Further research focusing on the roles and efficacy of maintenance therapies is warranted to iden-

tify the most appropriate strategies matching patients to treatment. V.

PHARMACOLOGICAL TREATMENT OF COCAINE DEPENDENCE

A number of drugs have been tried to treat cocainerelated problems, in part because of the postulated role of antecedent disorders in the genesis of chronic abuse, as well as the neurobiologic consequences of abuse and dependence. For example, since dysphoric mood is reported during and after the cessation of cocaine use, antidepressants were assessed for effectiveness in the treatment of cocaine dependence. The efficacy of medications is difficult to evaluate due to concurrent abuse of other drugs, and diversity of patterns of abuse and routes of administration. Many studies have examined pharmacological treatments for cocaine dependence, but no medication has been demonstrated to be clearly effective [247–254]. There has been a consideration of opioid agonists and antagonists, dopamine agonists, antidepressants, anticonvulsants, and the newer antipsychotics as antagonist agents [247,255,256]. Even though some agents showed early promising results, these results have not been replicated in subsequent studies [250,255,257–259]. Other agents, including gabapentine and mecamylamine, were reported to be reducing cocaine craving [260– 262]. Transdermal selegeline seems to be safe and may be useful in the treatment of cocaine dependence [263]. Available agonists for cocaine dependence include methylphenidate and amphetamine analogs. Studies with methylphenidate showed no impact on retention or decrease in cocaine use [253,255,264,265]. A recent double-blind randomized clinical trial using sustainedrelease dextroamphetamine reported positive results for improved retention and reduction in illicit drug use in cocaine-dependent patients [266]. The work of others suggested that dextroamphetamine may likewise be of some use in amphetamine-abusing patients [256]. Other strategies explored in animal models, such as vaccination and manipulation of dopamine receptor subsets, offer potential possibilities for treatment of cocaine dependence [267–269]. ACKNOWLEDGEMENTS This work was supported by USPHS Grants AA10523 and AA-11929 from the National Institute of Alcohol Abuse and Alcoholism, Rickville, MD.


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56 Perspectives on the Pharmacological Treatment of Dementia BRUNO P. IMBIMBO Chiesi Farmaceutici, Parma, Italy

NUNZIO POMARA New York University School of Medicine, New York, and Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, U.S.A.

I.

INTRODUCTION

develop AD by the year 2050 [Johnson 2000]. Although the available cholinesterase inhibitors represent a significant therapeutic achievement, there is still an urgent medical need of effective treatments able to interfere with the natural history of the disease. This is theoretically achievable, since typical histopathologic changes of AD begin to appear in the brain of patients many decades before the onset of clinica1 symptoms [Ohm 1997]. Thus, the present pharmacological research is directed to the identification of drugs able to slow or halt the progression of the disease during earlier, asymptomatic or minimally symptomatic stages. Progress has been limited by our incomplete understanding of the disease and the relatively slow and costly nature of new drug development. Nevertheless, a number of hypothetical mechanisms that are thought to be contributory to disease progression are being tested in the clinic. Clinical trials for AD have evolved from short-term trials (3–6 months) adequate to test drug effects on symptoms, to longer trials ( 1 year) designed to test the ability of treatments to slow the disease process. The hypothesis that early intervention might reduce the prevalence of the disease has recently motivated

Alzheimer’s disease (AD) is the most frequent cause of dementia in the elderly. Due to its high prevalence, AD is the type of dementia for which the most intensive efforts for the development of pharmacological treatments have been produced. Cholinergic deficits in AD, first demonstrated in 1976 by Davies and Maloney and subsequently replicated, provided the basis for the cholinergic hypothesis of memory dysfunction in AD and led to the marketing of the first effective drug therapy for the treatment of AD. Subsequent progress in the understanding of the pathophysiology of the disease was made in the 1990s and resulted in the so-called amyloid hypothesis and consequently a number of new therapeutic approaches have been developed. It is estimated that there are currently 4 million people suffering from AD in the United States with associated direct and indirect costs of $100 billion per year. In the next 25 years, the proportion of the elderly population in the United States is expected to increase by 50%. This will lead to a dramatic rise in the prevalence of AD. Without effective therapeutic interventions, 14 million people are expected to 865

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the launch of trials directed at preventing or delaying the onset of AD. Due to practicality and costs considerations, most current prevention trials are focused on individuals considered at high risk for development of AD over the next 2–6 years. Risk factors are considered missense mutations in amyloid precursor protein, presenilin-1 and presenilin-2 genes, the e4 allele of apolipoprotein E gene, advanced age, positive family history, gender, head trauma, memory complaints, or diminished memory performance on psychometric measures. These trials attempt to intervene while individuals are still asymptomatic or on1y minimally symptomatic, and are directed at preventing or delaying disease progression to clinically apparent AD. Treatment of dementia can be divided as symptomatic treatment of cognitive or noncognitive symptoms and the treatment of underlying pathology, including prophylaxis. It should be emphasized, however, that certain approaches may have several effects; they may affect cognitive as well as noncognitive symptoms and theoretically also the underlying disease process. Some of these approaches may be appropriate for more than one type of dementia. This chapter reviews the major treatment strategies that are being pursued in dementia, especially in AD, and include anti-b-amyloid treatments, antiinflammatory drugs, antioxidants, estrogens, and statins.

II.

TREATMENT OF ALZHEIMER’S DISEASE

In the AD brain there is selective loss of cholinergic neurons projecting from basal forebrain to cerebral cortex and hippocampus, the critical areas involved in cognition. In 1976, autopsy studies revealed that the activity of choline acetyltransferase, the biosynthetic enzyme for acetylcholine, was reduced in brains from patients with AD. The reduction in choline acetyltransferase activity correlated with the degree of cognitive impairment and senile plaque formation [Perry 1978]. These observations led to the hypothesis that it might be possible to improve memory and cognitive performance in patients with AD by augmenting cholinergic activity in the brain. A number of pharmacological strategies have been attempted to boost the central cholinergic activity of AD patients, the most successful being the development of acetylcholinesterase inhibitors. These agents increase cholinergic transmission by inhibiting the hydrolysis of acetylcholine at the synaptic cleft.

In addition to the dramatic decrease in the cholinergic innervation of cerebral cortex, a number of other neurotransmitters and neuropeptides are also reduced in the brain of patients with AD. These include noradrenaline, serotonin, glutamate, somatostatin, and corticotropin-releasing factor, among others. Although several drugs targeted at a correction of these deficits have been evaluated, only the glutamatergic transmission modulator memantine has been shown to improve symptoms of AD patients, specifically those severely impaired. A.

Acetylcholinesterase Inhibitors

Cholinesterase inhibitors are the only pharmacological agents repeatedly proved to be effective for the treatment of AD in large, double-blind placebo-controlled trials. 1.

Approved Cholinesterase Inhibitors

Four acetylcholinesterase inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for treatment of mild to moderate AD: tacrine, in 1993; donepezil, in 1996; and rivastigmine and galantamine, in 2000 (Table 1). Statistically significant effects compared to placebo in cognitive functions, behavioral symptoms, and activities of daily living have been repeatedly demonstrated for these drugs in studies of generally 6months’ duration. The effects of donepezil on cognitive and functional decline have been also evaluated in two placebo-controlled studies of 1-year duration [Mohs 2001; Winblad 2001]. Although cholinesterase inhibitors have demonstrated statistically significant effects versus placebo in different symptom domains, dramatic clinical response has been observed in only 3–5% of patients. There are no major differences in terms of efficacy among the different drugs. The mean difference between drug and placebo effects on standardized psychometric scales is about 2–4 points on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2–0.5 points on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBICPlus; a 7-point global scale), or 5–14% of the average value of the scales (Table 1). The beneficial effects of donepezil have also been recently demonstrated for more severe stages of AD. In a 24-week, placebo-controlled study in 290 AD patients with Mini-Mental State Examination score ranging between 5 and 17 at baseline, significant dif-

Pharmacological Treatment of Dementia

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Table 1 Cholinesterase Inhibitors Approved by FDA for Treatment of Mild to Moderate Alzheimer’s Disease

Drug Tacrine (Cognex)

Clinical Cognitive Effective dose Dose effect global effect (mg/day) frequency (ADAS-Coga ) (CIBIC-Plusa ) 80–160

QID

1.4–2.2

0.10–0.20

Donepezil (Aricept) Rivastigmine (Exelon)

5–10

QD

1.5–2.9

0.28–0.44

6–12

BID

1.6–3.7

0.29–0.47

Galantamine (Reminyl)

16–24

BID

3.1–3.9

0.20–0.34

Main adverse events

Dropout rateb

36–40% Elevated liver transaminases, nausea, vomiting, diarrhea, anorexia Nausea, vomiting, diarrhea, 2–12% myalgia, anorexia, asthenia 20% Nausea, vomiting, diarrhea, anorexia, weight loss, dizziness, abdominal pain, asthenia Nausea, vomiting, anorexia, 5–13% weight loss, dizziness

a Treatment differences from placebo based on intention-to-treat analysis; for tacrine a global scale without the caregiver input was used. b Dropout rate in excess to that seen with placebo.

ferences in favor of donepezil on cognitive, functional, and behavioral performance were found (Feldman 2001). Another 6-month, placebo-controlled study indicated that AD patients residing in nursing home facilities treated with donepezil showed cognitive and behavioral responses [Tariot 2001]. In addition, observational studies suggested that cholinesterase inhibitors decrease the risk of nursing home admission but not the risk of death [Lopez 2002]. Although the positive effects of donepezil on cognitive and behavioral symptoms are able to significantly decrease the caregiver burden [Fillit 2000], this does not translate to an improvement of the quality of life (QOL) of the patient [Birks 2000]. On the other hand, the validity of self-ratings of QOL has been questioned for AD patients. A number of preliminary studies have demonstrated that the use of cholinesterase inhibitors results in reductions in the overall costs of care [Foster 1999]. Most health economic studies have focused only on comparison of the costs associated with paying for administering a treatment and the savings produced by postponed institutionalization. However, there is a growing realization that some measures of the QOL or well-being of both patient and caregiver should also be incorporated [Winblad 1999]. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, asthenia, and anorexia, symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which

depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations [Imbimbo 2001]. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea [in excess of that seen with placebo] at cognitively effective doses ranges from 13–17% with donepezil [10 mg/day] to 37–40% with rivastigmine (6–12 mg/day) [Imbimbo 2001]. Rivastigmine has been associated with weight loss, so monitoring of patient weight is important when using this agent. Unpublished head-to-head comparative trials seem to confirm similar efficacy but better tolerability of donepezil versus rivastigmine and galantamine. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Indeed, while central acetylcholine levels are reduced up to 70% in AD patients [Tohgi 1994], maximal cognitive improvement in AD patients is associated to peripheral acetylcholinesterase inhibition ranging between 40% and 80% [Imbimbo 2001]. Other contributing pharmacodynamic factors are the rates of onset of and fluctuations in acetylcholinesterase inhibition at steady state. 2.

New Cholinesterase Inhibitors

A number of new cholinesterase inhibitors are in development. Phenserine, TAK-147, and ganstigmine have reached clinical testing in AD patients. Phenserine has been shown to protect rats against cognitive deficit induced by cholinergic lesions of basal

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forebrain. Interestingly, these studies have also evidenced that phenserine is able to inhibit the amyloidogenic pathway of the amyloid precursor protein [APP] processing in both lesioned and naive animals [Shaw 2001]. In particular, it seems that the compound reduces the bAPP protein expression with a posttranscriptional mechanism not associated with the anticholinesterase activity. A recent 12-week, placebocontrolled study in 72 AD patients showed a significant effect of phenserine 10 mg BID on cognitive performance of the patients, as measured by the Cambridge Neuropsychological Test Automated Battery [Kirby 2002]. TAK-147, another reversible inhibitor of acetylcholinesterase, has been described to possess partial antagonistic activity at the muscarinic M1 and M2 receptors [Hirai 1997]. Animal studies have shown that TAK147 ameliorates learning and memory impairment without producing peripheral side effects [Miyamoto 1996]. In vitro experiments have claimed a nerve growth factor-like neurotrophic activity for TAK-147 [Ishihara 2000]. Although TAK-147 is indicated in Phase III clinical development in Japan, no clinical studies have been published [Mucke 2001]. Ganstigmine [CHF2819] is a novel acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral administration in young and aged animals. Ganstigmine significantly attenuates scopolamine-induced amnesia in a passive avoidance task. Interestingly, in addition to acetylcholine, ganstigmine induces a significant elevation of extracellular concentrations of 5-hydroxytryptamine [Trabace 2000]. The stimulatory effect on central serotonergic functions might have a therapeutic potential for AD patients in whom the cognitive impairment is accompanied by a depressive syndrome [Trabace 2000]. Phase II studies with ganstigmine have shown dose-dependent inhibition of red blood cell cholinesterase activity after oral administration in AD patients. The pharmacodynamic half-life is 15 h, allowing a once-a-day dosing [Shiovitz 2002]. B.

Selective M1 Receptor Agonists

Muscarinic M1 cholinergic receptors are localized in brain regions associated with learning and memory, whereas other types of muscarinic receptors found in the periphery are thought to be responsible for such side effects as salivation, sweating, nausea, and vomiting. Several postsynaptic muscarinic receptor agonists have been developed aiming to counteract the cholinergic deficit associated with AD. Selective M1 agonists

might be expected to be therapeutic at doses lower than those producing peripheral cholinergic side effects. A number of selective Ml muscarinic agonists have recently undergone testing in clinical trials. These include xanomeline [Bodick 1997], sabcomeline (Memric), [Loudon 1997], LU 25-109 [Thal 2000], AF102B [Nitsch 2000] milameline [Schwarz 1999], and talsaclidine [Wienrich 2001]. Unfortunately, none of these compounds have yet demonstrated a sufficient efficacy/tolerability balance for regulatory approval. Xanomeline, for example, was evaluated in a randomized, double-blind placebo-controlled trial of mildly to moderately impaired subjects with AD. A significant treatment effect was reported in the highest dose of xanomeline on the ADAS-Cog and CIBICPlus. Unfortunately, treatment at the highest dose also was associated with syncope and gastrointestinal side effects, requiring discontinuation of treatment in 52% of patients. It is presently unclear whether drugs of this class will yet emerge as viable treatments for AD. Of the compounds first mentioned, only talsaclidine is still in clinical development. C.

Nicotinic Acetylcholine Receptor Agonists

Nicotinic acetylcholine receptors are decreased in the brains of AD patients. In vitro, nicotinic stimulation is associated with increased presynaptic acetylcholine release. Nicotine has been shown to reverse spatial memory decline in rats with lesion in the medial septal nucleus and to show recovery on memory in aged monkeys. Nicotine also has effects on other transmitters like serotonin, dopamine, or GABA. Although nicotine has been reported to improve cognition in patients with AD [Parks 1996], its serious adverse effects do not allow clinical use. ABT-418, an analog of nicotine with cognition-enhancing properties, was unsuccessful in the clinic and its development has been discontinued [Potter 1999]. Nicotinic agonists, such as GTS-21 [Kem 2000] and SIB-1553A [Terry 2002] and others, are in development. It remains to be seen how they will perform in clinical trials. D.

Other Cholinergic Strategies

There are a number of compounds in development based on the cholinergic enhancement approach. They include XR-543, an acetylcholine release-enhancing agent [Earl 1998]; MKC-231, a choline uptake enhancer [Murai 1994]; and T-588, which stimulates acetylcholine and noradrenaline release [Nakada


2001]. Although these compounds are in clinical development, it is unlikely that they will produce dramatic beneficial effects in AD patients. E.

Adrenergic Compounds

There is evidence suggesting a facilitating role of noradrenaline on acetylcholine effects in the brain. Animal studies have shown that, noradrenergic activation through presynaptic a2-adrenoceptor blockade potentiate the effects of cholinesterase inhibitors on passive avoidance learning in the rat [Camacho 1996]. On the contrary, the presynaptic a2 receptor stimulation with clonidine has been shown to impair choice reaction time performance in healthy volunteers [Jakala 1999b] and disrupts attention and memory in AD patients [Riekkinen 1999]. Besipirdine, a combined a-adrenergic and cholinergic agonist, demonstrated some cognitive efficacy in a 3-month, placebo-controlled trial in 275 AD patients, although it did not affect clinical global rating [Huff 1996]. These data indicate that indirect cholinergic potentiation through postsynaptic adrenergic stimulation produce minor benefits in AD patients. F.

Serotoninergic Compounds

The serotoninergic system plays a complex role in learning and memory by interacting with the cholinergic, glutamatergic, dopaminergic, or GABA-ergic system. Serotonin receptors are primarily located in the septohippocampal complex and the nucleus basalis magnocellularis–frontal cortex. A better understanding of the role played by different serotonin receptor subtypes in learning and memory has been achieved from the availability of highly specific ligands and gene knockout mice [Buhot 2000]. While antagonism of 5HT3 receptors with ondansetron revealed ineffective in AD patients [Dysken 1998], animal studies suggest that specific antagonism of 5HT1A receptors with WAY-100,635 may have a cognitive potential [Harder 2000]. Most importantly, recent in vitro studies have shown that activation of the human 5HT4 receptors stimulates the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein [sAPPa]. Given the neuroprotective and enhancing memory effects of sAPPa, this approach could have some potential for the treatment of AD [Robert 2001]. Indeed, SL65.0102, a selective 5HT4 receptor agonist, was shown to improve learning and memory in rodents and is in clinical development [Moser 1998].

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G.

Excitatory Amino Acid Agonists and Antagonists

Ampakines are substances that enhance the glutamate activity by stimulating AMPA type of glutamate receptors. An ampakine derivative, CX516 (Ampalex), has been shown to improve memory in different animal models. Initial human studies in young and elderly healthy volunteers demonstrated favorable effects on memory functions [Ingvar 1997; Lynch 1997]. CX516 is currently being tested in a 12-week, double-blind placebo-controlled study in AD patients. The N-methyl-D-aspartate (NMDA) receptor complex is a subtype of glutamate receptor with a complex function in different neurodegenerative diseases. The clinical development of several NMDA receptor antagonists in different clinical indications has been terminated mainly due to the severe psychomimetic adverse effects. Memantine is a non-competitive NMDA-receptor antagonist. It exerts a rapid, voltage-dependent blockade of NMDA receptors and is suggested to allow glutamatergic transmission under physiological conditions and inhibit the excitotoxicity when there is excessive glutamate release [Wenk 1994; Zajaczkowski 1997]. Memantine was found to protect from Ab-induced neurotoxicity in hippocampus and improve learning in rats [Miguel-Hidalgo 1998]. The initial trials with memantine were short-term and included patients with AD, vascular or mixed dementia. Thus, the apparent benefits described in these studies are difficult to interpret [Jain 2000]. In the past few years, larger placebo-controlled studies have been carried out in moderately severe to severe AD patients and led to the recent approval in Europe for this specific subgroup of AD patients. D-Cycloserine, a partial agonist at the glycine site of NMDA receptor, was found to facilitate activation of NMDA receptor-ionophore complex in the AD brain [Chessell 1991]. Clinical trials with D-cycloserine in AD produced mixed results with earlier studies at lower doses showing no beneficial effects [Fakouhi 1995] and more recent studies with higher doses, suggesting improvement in memory [Schwartz 1996] and cognition [Tsai 1999]. However, these observations involved a small number of patients and should be confirmed in large, long-term, controlled studies. H.

Antiamyloid Treatments

Neuritic plaques, the characteristic lesions found in the brain of AD patients, are composed mainly of aggregates of a protein with 39–43 amino acid residues

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known as b-amyloid (Ab). The Ab protein is the metabolic product of the processing of a complex transmembrane glycoprotein known as amyloid precursor protein (APP). APP may be processed according two metabolic pathways. In the so-called nonamyloidogenic pathway, the a-secretase enzyme cleaves APP within the Ab sequence and releases its transmembrane fragment, APPa, which appears to exert neuroprotective activity. In the amyloidogenic pathway, the bsecretase enzyme releases APPb plus a 12-kDa protein fragment (C99), which in turn is cleaved by the g-secretase enzyme, giving way to Ab. The correlation among Ab histopathologic lesions, brain cell death and cognitive deficiency in AD represents the so-called Ab hypothesis of the disease. A number of important observations support this hypothesis: 1. Autopsies performed on the brain of AD patients consistently reveal Ab deposits [McKhann 1984]. 2. All of the dominating autosomic mutations associated with the familial early onset forms of AD are characterized by an overproduction of Ab42 [Citron 1992; Scheuner 1996; Suzuki 1994; Citron 1997; Borchelt 1996]. 3. The formation of Ab plaques precedes the symptoms of the disease [Lippa 1998] and correlates with the cognitive deficit of AD patients [Naslund 2000]. 4. The clearance of Ab42 in the brain of patients appears to be reduced compared to controls [Motter 1995]. Several therapeutic approaches are being developed based on the amyloid hypothesis of AD. One of these includes selective b-secretase or g-secretase inhibitors that block the metabolic generation of the Ab peptide and thus the formation of Ab plaques. Another approach involves the inhibition of Ab aggregates with products that modify the secondary structure of the protein or that bind to specific regions of the protein itself. However, the most revolutionary approach is based on Ab immunization that leads to an increase in the Ab clearance from brain. 1.

b-Secretase Inhibitors

The b-secretase enzyme, termed BACE [b-site-APPcleaving enzyme], is a transmembrane aspartic protease. The enzyme was firstly characterized at Amgen in 1999 [Vassar 1999]. Later, the enzyme was found to be identical to that under investigation at GlaxoSmithKline (Asp 2) and Oklahoma Medical

Research Foundation (memapsin 2). b-Secretase is considered to be a good therapeutic target for the prevention and treatment of AD. The enzyme catalyzes the initial step in Ab production. The inhibition of bsecretase would shunt APP into the a-secretase pathway increasing the amount of aAPP that is considered to be neuroprotective [Mattson 1993] and to enhance memory and prevent learning deficits [Meziane 1998]. In addition, studies with BACE knockout mice revealed the absence of Ab production but normal phenotype, suggesting that blocking b-secretase pharmacologically should effectively lower Ab with minimal side effects [Luo 2001; Roberds 2001]. On the other hand, some concerns are raised by the discovery of a close b-secretase homolog, BACE2, strongly expressed in heart, kidney, and placenta [Bennett 2000]. Mice deficient in BACE2 should clarify the physiological role of this enzyme. In the case of important function of this enzyme, it might be critical to develop agents that selectively block BACE1 over BACE2. However, despite strong interest and efforts, few inhibitors of b-secretase activity have been described up to now [Wolfe 2001]. Elan reported substrate-based inhibitors that ultimately were used to affinity purify the enzyme [Sinha 1999]. Ghosh and colleagues [2001] have recently reported peptidomimetics (OM99-1 and OM99-2) based on the Swedish mutated sequence of human APP. However, the selectivity of these prototype inhibitors with respect of other human aspartyl protease was poor. Recently, smaller substrate-based b-secretase inhibitors have been described [Tung 2002]. However, peptidomimetic compounds are not orally absorbed and are not able to cross the blood-brain barrier. Still, significant hurdles remain before the development of useful therapies. The recently solved structure of the enzyme-inhibitor complex should facilitate the identification of b-secretase inhibitors in the near future by using rational drug design. 2.

g-Secretase Inhibitors

Despite intense efforts, the g-secretase enzyme has not yet been purified and cloned. This is mainly because gsecretase appears to be a multiprotein complex, making its identification through conventional strategies, such as expression cloning, unlikely to succeed. In addition, the enzyme has unusual properties, the most peculiar being its ability to cut in the middle of the transmembrane region of its substrate. How hydrolysis takes place in what is otherwise a water-excluded environment is unclear. However, it has been estab-


lished that g-secretase is an aspartyl protease and requires presenilin 1 and 2 for activity that might be the catalytic component of the enzyme complex [Esler 2001]. Whether g-secretase is a good target for treating AD remains an open question. The enzyme is known to play a role in the activation of an important receptor protein known as Notch. The Notch receptor is involved in cell-fate determinations during embryonic development and in hematopoiesis in adult age. Knockout mice for presenilin-1 do not show g-secretase activity but die shortly after birth due to interference with Notch signaling [Shen 1997]. Treatment of thymus with g-secretase inhibitors represses the development of CD8 T cells [Hadland 2001]. On the other hand, current evidence indicates that Notch processing can be blocked down to a certain threshold without affecting Notch signaling [Berezovska 2000]. If so, then Ab production may be reduced to a substantial degree without untoward effects on Notch. Another source of concern is the increase in the APP C-terminal metabolite C99 generated by g-secretase inhibition that could impair learning, as shown in transgenic mice overexpressing C99 [Nalbantoglu 1997]. However, the learning deficits in C99 transgenic mice may be due to resultant amyloid deposition [Nalbantoglu 1997]. The first g-secretase inhibitor described in the literature [MW167] was a substrate-based peptidomimetic [Wolfe 1998]. This compound served as a starting point to develop several other peptidomimetic g-secretase inhibitors [Esler 2000; Seiffert 2000]. One of these, L-685,458 was identified by screening compounds originally designed against HIV aspartyl protease and displayed a very potent in vitro activity (IC50 ¼ 0:3 nM) [Shearman 2000]. At the same time, a number of nonpeptidic g-secretase inhibitors were identified using high throughput screening on whole-cell assay. One of these compounds, DAPT, has been found to reduce Ab levels in the brains of transgenic mice [Dovey 2001]. Administration of 100 mg/kg DAPT subcutaneously to young transgenic mice expressing mutated human APP (PDAPP) led to 30–50% reduction in total Ab in several brain regions examined. Importantly, this level of efficacy was maintained after subchronic administration of a similar dose twice daily for 7 days. Another nonpeptidic g-secretase inhibitor with a sulfonamide scaffold has been described [May 2001]. Oral administration of this compound markedly decreases levels of total Ab and Ab42 in brain, cerebrospinal fluid, and plasma of young transgenic mice expressing mutated human APP (Tg2576).

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Interestingly, the compound does not seem to affect significantly Notch processing, the in vitro activity on Notch cleavage being 17 times lower than on g-secretase. Phase I studies in normal volunteers showed a pharmacokinetic profile compatible with a once-daily dosing. The safety and tolerability of the compound after multiple ascending doses for 4 weeks is being evaluated in AD patients [Felsenstein 2002]. 3.

a-Secretase Activators

The shifting of the APP metabolism to the nonamyloidogenic pathway represents an alternative way to decrease brain Ab burden in AD patients. Animal studies indicate that the product resulting from the asecretase cleavage of APP, sAPPa, has potent memory-enhancing effects and block learning deficits induced by scopolamine [Meziane 1998]. Thus, augmenting a-secretase processing of APP to release sAPPa might be beneficial in treating AD. Although cells contain a certain level of basal asecretase activity, proteolysis by this enzyme can be increased pharmacologically. M1 and M3 muscarinic agonists have been shown to decrease Ab levels in neocortex and hippocampus and to increase sAPPa in cerebrospinal fluid of normal and cholinergic denervated rats. The effects on APP processing correlated with cognitive performance of the animals [Lin 1999]. Talsaclidine, a selective M1 agonist, was recently shown in placebo-controlled study in 24 AD patients to decrease by 27% in 4 weeks the levels of total Ab in cerebrospinal fluid [Hock 2000]. Lowering effects on total Ab levels in cerebrospinal fluid were also described another selective M1 agonist, AF102B, in 19 AD patients [Nitsch 2000]. Unfortunately, M1selective agonists are associated with important side effects, the most serious being syncope, which limit their clinical use. Stimulation of a-secretase can be obtained by direct stimulation of protein kinase C with phorbol esters [Jacobsen 1994]. Activation of receptors that work through protein kinase C can augment a-secretase cleavage of APP as well. Agonists of the metabotropic glutamate receptors can lower Ab by shunting APP toward the a-secretase pathway [Lee 1995]. 4.

Inhibitors of b-Amyloid Aggregation

Another strategy to reduce brain amyloid deposition is the development of inhibitors of Ab aggregation. Ab aggregation is a complex phenomenon that implies a nucleation and a deposition phase. The block of the initial steps of the formation of Ab fibrils is an attrac-

872

tive objective, because the neuronal toxicity of Ab is more linked to the oligomeric and protofibrillar forms than to the amyloid plaques. Interestingly, the initial observation that monoclonal antibodies raised against Ab peptide inhibit its aggregation has prompted the later development of Ab immunization strategies [Solomon 1996]. Several small organic molecules, synthetic peptides, and natural proteins have been shown to inhibit Ab aggregation and neurotoxicity in vitro [Soto 1999]. These compounds include sulfonated dyes [Lorenzo 1994], anthracycline derivatives [Merlini 1995], rifampicin [Tomiyama 1996], porphyrins [Howlett 1997], benzofuran derivatives [Howlett 1999], tetracyclic and carbazole-type compounds [Howlett 1999], melatonin [Pappolla 2000], and a large variety of Ab-derived peptides [Findeis 2000]. However, the large majority of these compounds have been tested in vitro. Few compounds have been shown to interfere with Ab fibril formation in vivo and to possess pharmacokinetic characteristics compatible with their use in humans. The best-documented compound is a pentapeptide (iAb5) that mimics the 17-21 region of the Ab peptide. iAb5 was shown to prevent amyloid neurotoxicity in cell cultures and to reduce the formation of amyloid fibrils in a rat model of cerebral Ab deposition [Soto 1998]. An end-protected derivative of this pentapeptide (iAb5p) is able to cross the blood brain barrier and to reach pharmacological levels in the brain. The in vivo pharmacological activity of iAb5p has been evaluated in double transgenic mice (APP-V717F/PS1-A246E) developing amyloid plaques at 6 months of age. The chronic (8 weeks) intraperitoneal administration of iAb5p caused a 47% reduction of brain amyloid load and a 24% increase in neuronal survival. The astrocytosis and microglial activation associated with amyloid plaques was also reduced by the peptide treatment [Soto 2001]. Although iAb5p has shown a good toxicological profile in rodents, its short plasma half-life (37 min) has limited the clinical development of the compound. A metabolic stabilized derivative of iAb5p is being developed for treatment of AD [Soto 2002]. Histological studies have shown that proteoglycans and their constituent glycosaminoglycans are associated with Ab deposits. Glycosaminoglycans are not simply involved in the lateral aggregation of fibrils or in nonspecific adhesion to plaques but promote the earliest stage of fibril formation [McLaurin 1999]. A small sulfonated compound (NC-531, Alzhemed) that mimics the anionic properties of glycosaminoglycans has been reported to significantly inhibit Ab fibril

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formation and deposition in vitro. In transgenic mice expressing the human APP Swedish mutation (TgCRND8), chronic administration of NC-531 (100 mg/kg for 8 weeks) induced a 61% reduction in Ab plasma levels and a 30% reduction in number and size of brain Ab plaques [Gervais 2002]. A decrease of Ab-associated inflammatory response was also observed. Phase I studies in young and elderly healthy subjects have established that maximum tolerated dose of NC-531 after single oral administration is 200 mg, the main adverse events being nausea, vomiting, dizziness, and headache. Multiple dose Phase I studies are ongoing [Garceau 2002]. PPI-1019 (Apan) is a modified peptide mimicking a particular region of Ab peptide. It is a potent and selective inhibitor of Ab polymerization that blocks the formation of neurotoxic species of Ab. Studies in rats have shown that after intravenous administration, PPI-1019 reaches brain concentrations believed to be sufficient to block Ab aggregation [Derr 2001]. The in vivo effects of PPI-1019 were studied in a rat model of AD obtained after continuous infusion of Ab into the lateral ventricles. Compared to vehicle-treated animals, PPI-1019 reduced total Ab burden in the brain [HarrisWhite 2001]. Studies in transgenic mice have shown that PPI-1019 significantly increases Ab levels in the cerebrospinal fluid, suggesting a stimulatory effect of the compound on brain Ab clearance. The safety and tolerability of PPI-1019 are being tested in healthy volunteers. It is well known that zinc and copper ions are enriched in Ab deposits in AD brain and that these heavy-metal ions catalyze the formation of Ab fibrils in vitro. Clioquinol is a metal ion chelator with high affinity for these metal ions. This compound has been extensively used in the past as an oral antibiotic, but later withdrawn due to its association with subacute myelooptic neuropathy. These toxic effects are apparently due to brain depletion of vitamin B12 and believed to be preventable with B12 supplementation [Yassin 2000]. In a transgenic mice model of AD (Tg2576), clioquinol, given orally for 9 weeks, significantly decreased (by 49%) brain Ab deposition [Cherny 2001]. Doses up 80 mg/day for 3 weeks were well tolerated in 30 AD patients [Regland 2001]. Recently a double-blind, placebo-controlled study of 9 months’ duration was carried out in 36 AD patients. Clioquinol was administered at increasing oral doses with the concomitant administration of vitamin B12 . The study was completed by 32 patients and results indicated that clioquinol consistently decreased serum Ab levels over time. Compared to placebo, there was a


trend at the end of treatment in favor of clioquinol on cognitive performance (ADAS-Cog) that became significant in the 10 patients with severe disease at baseline [Masters 2002]. Although preliminary, this is the first study in AD patients reporting a biologic effect of an anti-b-amyloid agent. 5.

b-Amyloid Immunization Approaches

The most revolutionary of the anti-Ab approaches was proposed in 1999 by scientists at Elan Pharmaceuticals, which immunized against transgenic mice expressing human mutated APP (PDAPP) and spontaneously developing Ab pathology [Schenk 1999]. The immunization was obtained by subcutaneous injections of a preaggregated form of the synthetic human Ab42 emulsified with Freund’s adjuvant, an immune stimulant. The vaccination caused a near complete inhibition of Ab plaque formation in younger animals and a marked reduction of the Ab burden in older animals. The effects on Ab plaques were accompanied by the reduction of Ab associated astrogliosis and neuritic dystrophy. These results were later confirmed by other groups [Lemere 2000] with similar vaccination protocols, which also demonstrated that Ab immunization of transgenic animals normalizes or reduces the cognitive impairment associated to Ab pathology [Morgan 2000; Janus 2000]. Interestingly, effective removal of brain Ab plaques was also obtained administering peripherally Ab antibodies [Bard 2000]. The mechanism with which the vaccine increases Ab clearance is not fully understood. Centrally, the vaccine appears to activate Ab phagocytosis by microglial monocytes [Bacskai 2001]. Peripherally, serum Ab antibodies bind and sequester Ab, thus altering its equilibrium between CNS and plasma [DeMattos 2001]. A vaccine preparation for human use (AN-1792) composed of preaggregated human Ab42 peptide and a highly purified saponin derivative (QS-21) was developed by Elan Pharmaceuticals and Wyeth and tested in AD patients. Unfortunately, a Phase IIa study aimed at evaluating the safety and immunological activity of AN-1792 in 360 AD patients was discontinued because 15 subjects receiving the vaccine developed serious signs of CNS inflammation, including fever, headache, vomiting, altered consciousness, muscle weakness, and seizures [Schenk 2002]. Both central activation of cytotoxic T cells and autoimmune reactions were proposed as potential mechanisms of toxicity [Imbimbo 2002]. Other Ab immunization strategies are being pursued. These include new antigens constituted by

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conjugation of Ab fractions (epitopes) with immune carriers [Frenkel 2000; Sigurdsson 2001]. This approach employing nonendogenous proteins should induce a robust immune response without activating autoimmune reactions. Another, alternative strategy includes passive immunization with monoclonal antibodies [Bard 2000] or antibody fragments [Frenkel 2001]. This approach is based on the hypothesis that binding of antibodies to Ab in plasma creates a peripheral sink which favors efflux of Ab from the brain. This results in decreased levels of free Ab in the brain and thus alters the kinetics of deposition favoring the dissolution of preexisting fibrils. This peripheral sink hypothesis should avoid central inflammatory responses. Whether active or passive Ab immunization approaches will work in humans is unknown. AD patients could develop tolerance or insufficient or inappropriate antibodies to Ab antigen injection [Monsonego 2001]. Either active or passive Ab immunization could provoke an inflammatory response [Grubeck-Loebenstein 2000]. Importantly, Ab immunization might work effectively at preventing aggregation of amyloid in preasymptomatic patients, but not so well once the amyloid plaques are formed in frank AD patients. Finally, it remains possible that Ab is not central to neuronal dysfunction and death but is, rather, a byproduct of the disease process. Despite these limitations, the revolutionary development of the first anti-Alzheimer vaccine has raised unprecedented hopes for an affective treatment of this devastating disease. A better understanding of the mechanism whereby Ab immunization promotes Ab clearance is needed in order to optimize the initial approach and render it successful in AD patients. I.

Approaches Against q Hyperphosphorylation

Neurofibrillary tangles, the intracellular hallmark of the AD brain, consist mainly of abnormally phosphorylated t proteins organized in paired helical filaments. Hyperphosphorylation of t protein causes impaired neurite outgrowth, disturbed synaptic function, and reduced response to neurotrophic factors [Nuydens 1995]. There is a close correlation between the burden of t-rich neurofibrillary lesions in selected telencephalic regions of the brain and the dementia severity in AD patients [Lee 1996]. Theoretically, both the inhibition of the kinases responsible for t hyperphosphorylation and the stimulation of phosphatases able of dephosphorylating aberrant t may

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have therapeutic potential [Iqbal 1996]. However, because of the ubiquity and multiplicity of kinases, the inhibition of their activity may impair other cellular functions. Dephosphorylation of t by stimulation of phosphatases 2A and 2B may represent a better therapeutic option because these enzymes are overexpressed in the AD brain. Both phosphatases 2A and 2B were demonstrated to dephosphorylate protein t in AD brain [Wang 1996] and phosphatase 2B was also found to dephosphorylate t in rat brain cortex [Fleming 1995]. The muscarinic M1 agonist AF150(S) was shown to selectively dephosphorylate the hyperphosphorylated protein t [Genis 1999]. This effect was associated to a reversal of the cognitive and cholinergic deficits in ApoE-deficient transgenic mice [Fisher 1998], suggesting that muscarinic agonists may offer some therapeutic potential in this regard. It has recently been shown that chronic (4–6 weeks) administration of testosterone is able to prevent the heat shock-induced hyperphosphorylation of t in female rats [Papasozomenos 2002]. This observation opens perspectives for the use of androgens for prevention or delay of AD.

J.

ApoE-Based Approaches

Apolipoprotein E (apoE), a plasma apolipoprotein that plays a central role in lipoprotein metabolism, is localized in the senile plaques, congophilic angiopathy, and neurofibrillary tangles of AD. ApoE e4 genotype has been found to be associated with a higher risk of AD whereas ApoE e2 allele may provide protection or delay the onset of the disease. It is not clear the mechanism by which the different ApoE alleles contribute toward accelerating or retarding the disease process. Recent findings suggest that ApoE e2 and e3 have greater avidity than ApoE e4 for the t protein. Thus, the presence of ApoE e2 and e3 proteins may help prevent abnormal phosphorylation of t [Huang 1994]. In addition, it has been demonstrated that ApoE e4 allele binds to amyloid plaques and may accelerate Ab deposition [Strittmatter 1993]. Finally, ApoE e4 protein does not neutralize efficiently free radicals or ApoE e2 and e3 proteins [Miyata 1996]. Taken together, this evidence implies that drugs that alter the production of ApoE e4 or the clearance of ApoE/Ab complexes may be useful. Alternatively, therapeutic administration of ApoE e2 or e3 alleles through gene therapy or development of ApoE e2 analogues can be pursued [Strittmatter 1994; Kaplitt 1996].

K.

Neurotrophic Agents

Neurotrophic agents represent another potential treatment modality for AD. Neurotrophic factors are proteins that promote the growth and differentiation of neurons in the developing nervous system and promote survival of neurons in the adult. 1.

Nerve Growth Factor

Nerve growth factor (NGF) has been considered in the past a very promising neurotrophic treatment for AD. NGF protects the cholinergic neurons from axotomyinduced degeneration [Gage 1988]. Intraventricular NGF infusion reverses the disappearance of axotomized cholinergic neurons in medial septum of adult rats [Hagg 1989] and improves retention of a spatial memory task in aged [Fischer 1987; Markowska 1994] and in lesioned rats [Dekker 1994]. Unfortunately, being a protein, NGF is inactive after oral administration and does not cross the blood brain barrier after intravenous administration. Nasal administration of NGF is not well tolerated. Thus, NGF has been administrated intraventricularly in few AD patients. Although some improvement in verbal episodic memory has been observed, the NGF infusions were associated with reversible back pain and weight loss [Eriksdotter Jonhagen 1998]. The results of these studies suggest that the intraventricular route of administration of NGF is associated with negative side effects that outweigh any potential benefit. An alternative approach is the use of autologous transplants of skin fibroblasts genetically modified to express NGF. Similar techniques were shown to reverse atrophy of cholinergic neurons in the basal forebrain of aged monkeys [Smith 1999]. A Phase I study of this procedure in eight AD patients is ongoing. Cells are administered by stereotactic injection into the nucleus basalis of Meynert. Patients will be closely monitored for a year and then evaluated annually for an indefinite period. In April 2001, it was announced that the implantation was well tolerated by the first patient, but no efficacy data have been released. 2.

AIT-082

AIT-082 (Neotrofin) is a neurotrophic agent under development as a potential treatment for AD. It is a metabolically stable derivative of the purine hypoxanthine and is able to cross the blood brain barrier [Taylor 2000]. In cell cultures, AIT-082 enhances NGF-mediated neurite outgrowth [Middlemiss 1995]


and increases levels of synaptophysin, a marker of synaptic numbers and density [Lahiri 2000]. In mice, AIT-082 counteracts age-induced deficits in working memory, although the effect is not significant in animals with severe memory impairment [Glasky 1995]. In rats, AIT-082 decreases mortality and loss of hippocampal neurons induced by kainate administration [Di Iorio 2001]. Animals treated with AIT-082 demonstrate increased neurotrophin messenger RNA for NGF, basic fibroblast growth factor, and neurotrophin-3 in their cortex and hippocampus. The capacity of AIT-082 to selectively stimulate the production of a number of neurotrophins may be the basis of its ability to restore working memory deficits in aged animals. Phase I studies in healthy volunteers indicated that AIT-082 is well tolerated [Grundman 2000]. However, Phase II double-blind placebo-controlled studies in AD patients employing doses up to 150 mg/day failed to demonstrate significant effects on cognitive performance. Additional trials with higher doses (500–1000 mg/day) are under way. L.

Antioxidants

Abnormal oxidative metabolism appears to be a fundamental process contributing to the neuronal death in AD. Oxidative stress generates free-radical species that damage cell membrane lipids, proteins, and DNA within the brain. A number of specific factors may promote oxidative damage in AD including Ab deposition, microglia inflammation, abnormal t hyperphosphorylation, and altered iron metabolism [Butterfield 2001]. The use of antioxidant agents to treat AD is based on their hypothesized neuroprotective properties. Although this is an area with encouraging promises, more controlled clinical trials need to be performed. It is not clear which agents may be effective and in what doses, or whether they may be more effective in combination with other treatments. Importantly, it not known whether antioxidant agents are effective in preventing AD or how many years before disease onset they need to be started to exert a protective effect. 1.

Vitamin E

Epidemiologic studies suggest that antioxidant vitamin intake is associated with a lower incidence of cognitive impairment [Perrig 1997] or AD [Morris 1998]. Vitamin E protects neurons against the oxidative cell death caused by Ab, hydrogen peroxide, and the exci-

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tatory amino acid glutamate [Behl 2000]. Vitamin E may provide neuroprotection in vivo through suppression of signaling events necessary for microglial activation [Li 2001]. Long-term (12 months) administration of vitamin E to aged apolipoprotein E-deficient mice significantly improves behavioural performance in the Morris water maze (Veinbergs 2000). In AD patients, supplementation with vitamin E significantly increases the concentrations of this vitamin in plasma and CSF [Kontush 2001]. The potential of vitamin E in AD was evaluated in a double-blind, placebo-controlled clinical trial of 2 years’ duration involving 341 patients. Patients received either vitamin E (2000 IU/day), selegiline (10 mg/day), a combination of vitamin E and selegiline, or placebo. An analysis adjusted for baseline cognitive performance of the patients indicated that both vitamin E and selegiline delay progression to a more advanced disease state and subsequent institutionalization [Sano 1997]. The benefit found for vitamin E remains to be confirmed in additional studies. A clinical trial in people with mild cognitive impairment is under way to determine if vitamin E can prevent or delay a diagnosis of AD [Grundman 2000b]. Finally, the role of vitamin E together with vitamins A and C in the prevention of dementia and cognitive decline is also being evaluated within a large double-blind randomized controlled trial (the Heart Protection Study) in 20,500 cognitive normal subjects [Collins 2002]. 2.

Ginkgo Biloba

Ginkgo biloba extract is approved in Germany for the treatment of dementia and is available in many countries, including the United States, as a dietary supplement. Flavonoids and terpenoids that are present in ginkgo extracts are believed to have antioxidant and free radical–scavenging properties. Ginkgo extracts also contain ginkgolide B, a platelet aggregation inhibitor. In preclinical studies, a plethora of pharmacological effects have been attributed to ginkgo biloba, including reversal of agerelated loss of muscarinic receptors, protection against ischemic neuronal death, increase of hippocampal high-affinity choline uptake, inhibition of the downregulation of hippocampal glucocorticoid receptors, enhancement of neuronal plasticity, and counteraction of the cognitive deficits induced by stress or traumatic brain injury [DeFeudis 2000]. In a 52-week, placebo-controlled trial in 309 AD patients, a modest benefit was reported for a particular extract of ginkgo biloba [EGb 761] at the dose of 40

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mg TID [Le Bars 1997]. Fewer than half of the patients completed the trial. The modest cognitive improvement produced by the ginkgo biloba extract (1.4 points on the ADAS-Cog) was detected by the caregiver but not by the clinician. The incidence of adverse events with ginkgo was similar to placebo. In a post hoc analysis, the beneficial effects of ginkgo biloba seemed to be greater in patients with very mild to mild cognitive impairment at baseline [Le Bars 2002]. In another, 26-week, placebo-controlled study in 214 patients with either AD or vascular dementia or age-associated memory impairment, neither standard (120 mg/day) or high (240 mg/day) doses of EGb 761 showed significant effect on all the outcome measure of efficacy [Van Dongen 2000]. A dementia prevention trial in 3000 elderly individuals is being performed. This double-blind, placebo-controlled trial will follow subjects every 6 months for 5 years and determine whether ginkgo, at a dose of 240 mg/day, can reduce the incidence of dementia compared to placebo-treated subjects. 3.

Idebenone

Idebenone is a benzoquinone derivative, structurally similar to coenzyme Q, with antioxidant and free radical scavenging properties. In vitro, idebenone protects cell membranes from lipid peroxidation [Bruno 1994; Wieland 1995] and neuronal cells against glutamateand Ab-induced neurotoxicity [Hirai 1996]. In vivo, idebenone stimulates synthesis of nerve growth factor and improves behavior in aged and basal forebraindamaged rats [Nitta 1994]. Clinical trials with idebenone in AD patients produced conflicting results. Studies carried out in Germany reported beneficial effects on cognitive, noncognitive, and overall measures [Weyer 1997; Gutzmann 1998, 2002]. On the other hand, 1-year studies in the United States were suspended because of lack of sufficient efficacy [Grundman 2000]. Indeed, a number of methodological flaws (inadequate control groups, high dropout rates, lack of effects on global measures) characterize the studies carried out in Europe. M.

Anti-Inflammatory Agents

The brain in AD shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines, complement factors, and acute-phase proteins surrounding amyloid deposits [McGeer 2001]. Inflammatory cytokines appear to directly interfere with APP processing and deposition

of Ab fibrils [Blasko 2000]. Anti-inflammatory approaches to AD are based on the idea that suppression of these mechanisms will lessen the rate of disease progression [Aisen 1994]. 1.

Glucocorticoids

Glucocorticoids suppress the acute-phase response and complement activation. A 1-year, double-blind, placebo-controlled trial of low doses of prednisone (10 mg daily) in 138 AD patients did not show any significant difference in cognitive decline between the prednisone and placebo treatment groups [Aisen 2000]. Patients treated with prednisone displayed a greater behavioral decline than those in the placebo group. These negative effects may be due ascribed to the dose of prednisone insufficient to suppress brain inflammatory activity or to potential hippocampal toxicity, previously described for glucocorticoids. Whatever the reasons, safety issues do not permit to test the hypothesis that higher doses of glucocorticoids may be effective in AD patients. 2.

Nonsteroidal Anti-Inflammatory Drugs

Epidemiological studies have documented a reduced prevalence of AD among users of nonsteroidal antiinflammatory drugs (NSAIDs), although not all studies are consistent. A recent population-based cohort study of 6989 subjects found a relative risk of AD of 0.95 in subjects with short-term use of NSAIDs, 0.83 in those with intermediate use, and 0.20 in those with long-term use. The use of NSAIDs was not found to be associated with a reduction in the risk of vascular dementia [in t’ Veld 2001]. Thus, it seems that the long-term use of NSAIDs may protect against AD. Recent studies indicate that the protective effects of NSAIDs may be independent from their anti-inflammatory activity but are linked to their ability to interfere with APP metabolism [Weggen 2001]. Specifically, ibuprofen, indomethacin, and sulindac were shown to inhibit the secretion of Ab42 peptide in a variety of cultured cells. This effect was not seen in other NSAIDs and seems to be mediated by inhibition of g-secretase. These observation were confirmed in vivo, where short-term administration of ibuprofen to transgenic mice expressing mutant human APP (Tg2576) lowered their brain levels of Ab42 [Weggen 2001]. Other studies in transgenic animal models of AD (Tg2576) confirmed that chronic oral ibuprofen administration decreases the number and total area of Ab deposits [Lim 2000] and ameliorates associated


behavioral deficits [Lim 2001]. Finally, a nitric oxide– releasing derivative of flurbiprofen (NCX-2216), dramatically reduces both Ab loads in doubly transgenic APP plus presenilin-1 mice [Jantzen 2002]. In AD patients, indomethacin (100–150 mg/day) was reported to slow cognitive decline in a 6-month, double-blind, placebo-controlled study [Rogers 1983]. However, the study involved only 44 patients, and many patients dropped out due to adverse events. Nonsignificant trends in favor of diclofenac (50 mg/ day), coadministered with the gastroprotective misoprostol, were reported in a 6-month, double-blind, placebo-controlled study in 41 AD patients [Scharf 1999]. Again, the withdrawal rate was high in the active treatment group (12 of 24 patients), indicating that AD patients poorly tolerate standard prescription doses of NSAIDs. The ability of the hydroxychloroquine to delay progression of AD was recently evaluated in an 18-month, double-blind, placebo-controlled study [Van Gool 2001]. Hydroxychloroquine is a potent anti-inflammatory drug widely used in the treatment of rheumatoid arthritis and able to cross the blood brain barrier [O’Dell 1998]. The study involved 168 patients and was completed by 92% of participants. Unfortunately, at the end of the 18-month treatment period there were no significant differences in the outcome measures of efficacy (activities of daily living, cognitive function, and behavioral abnormalities). These results suggest that different NSAIDs may have different efficacy in AD patients depending to their specific chemical structure and ability to interfere with APP metabolism. However, it may be possible that anti-inflammatory treatment does not prevent further deterioration after a diagnosis of AD has been established. 3.

Cyclo-oxygenase-2 Inhibitors

In brain, cyclo-oxygenase-2 (COX-2), the inducible isoform of cyclo-oxygenase, is selectively expressed in neurons of the cerebral cortex, hippocampus, and amygdala [McGeer 2000]. COX-2 is upregulated in the AD brain, and its expression in the hippocampal formation increases as the disease progresses [Ho 2001]. Transgenic mice overexpressing COX-2 show memory dysfunction, neuronal apoptosis, and astrocytic activation in an age-dependent manner [Andreasson 2001]. These studies suggest that COX-2 may contribute to the neurodegeneration occurring in AD brains and that inhibition of COX-2 may be a useful therapeutic target. COX-2 inhibitors would appear to be

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preferred agents over classic NSAIDs, given their better tolerability at full anti-inflammatory doses. Unfortunately, a 1-year, double-blind placebocontrolled study with the COX-2 inhibitor celecoxib (Celebrex) failed to demonstrate efficacy in slowing cognitive decline of AD patients [Sainati 2000]. Another 1-year, double-blind placebo-controlled study is ongoing in 300 AD patients to compare the ability of rofecoxib (Vioxx), another COX-2 inhibitor, and naproxen in slowing cognitive deterioration [Grundman 2000]. N.

Estrogens

A number of epidemiological studies suggest a protective effect of estrogen on development of AD. A metaanalysis of most of these observational studies indicated a 29% decreased risk of developing dementia among estrogen users [Yaffe 1998]. Several mechanisms have been suggested to explain how estrogens may affect neuropsychologic function [Yaffe 2001]. One mechanism is the modulation of neurotransmitters, particularly acetylcholine. Another possible mechanism is by promoting neuronal growth. In addition, estrogens may protect neurons by inducing vasodilatation, reducing platelet aggregation, or limiting oxidative stress-related injury induced by excitotoxins and Ab. Finally, estrogen could reduce the risk of AD in humans via apolipoprotein E alterations. Several open-label clinical trials and one placebocontrolled study [Asthana 1999] reported cognitive improvement in women with dementia who were receiving estrogen replacement therapy. These studies were all of brief duration and with relatively few subjects. Three larger controlled trials produced negative results. A 12-month, double-blind placebo-controlled study with two doses (0.625 and 1.25 mg/day) of conjugated equine estrogens (Premarin) was conducted in 120 hysterectomized women with AD [Mulnard 2000]. No differences were observed between the treatment groups in clinical global measure of efficacy. Deepvein thrombosis was observed in four of the women assigned to estrogen ( 5% incidence). A smaller, 16-week, placebo-controlled study of conjugated equine estrogens (1.25 mg/day) involving 42 women with AD similarly failed to find a beneficial effect for estrogen therapy [Henderson 2000]. Another, 12-week, placebo-controlled study in 50 female AD patients of conjugated estrogen (1.25 mg/day) did not show meaningful differences on all the outcome measures of efficacy between treatment groups. However, a recent 8-week, placebo-controlled study

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employing high doses (0.10 mg/day) of 17 b-estradiol in 20 postmenopausal women with AD showed significant effects of estrogen treatment on attention and on verbal and visual memory scales. Although the results of this small study must be extended to larger trials, it may be possible that high doses of estrogens are needed to produce significant benefits in AD patients. Two prevention trials are under way to determine whether estrogen can prevent the onset of dementia in cognitively normal postmenopausal women. The first is an ancillary study, the Women’s Health Initiative Memory Study [WHIMS] of the Women’s Health Initiative Randomized Trial [Shumaker 1998]. This ancillary study will determine the effect of hormone replacement therapy on cognitive function and risk of developing dementia in 8000 postmenopausal women treated for 10 years. The other prevention trial, Preventing Postmenopausal Memory Loss and AD with Replacement Estrogen (PREPARE), is enrolling 1000 older women with a family history of AD. This study will determine whether women who are randomized to receive estrogen for 3 years have less risk of developing AD than those receiving placebo [Yaffe 2001].

O.

Cholesterol-Lowering Agents

Statins are inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A (HMG Co-A) reductase and are used to lower elevated low-density lipoprotein (LDL) cholesterol levels. Three epidemiological studies have recently found an association between statin therapy and a reduction in the occurrence of AD by as much as 70% [Wolozin 2000; Jick 2000; Rockwood 2002]. In addition, an observational study of 1037 postmenopausal women with coronary heart disease has shown that high LDL and total cholesterol levels are associated with cognitive impairment and that statin users have a trend for a lower likelihood of cognitive impairment [Yaffe 2002]. Although the association between statins and AD is still controversial [Muldoon 2001; Lesser 2001], these observations suggest that lipids may play an important role in the development of AD. Indeed, a known risk factor for AD, the e4 allele of apolipoprotein E, also plays a role in cholesterol processing. In addition, many preclinical and some preliminary clinical studies indicate that statins may lower levels of Ab through a stimulation of the nonamyloidogenic a-secretase cleaved of APP [Kojro 2001].

1.

Lovastatin

Lovastatin reduces Ab secretion in cell cultures of hippocampal and cortical neurons [Simons 1998; Fassbender 2001] and in APP-transfected human embryonic kidney cells [Frears 1999]. Lovastatin decreases brain cholesterol in normal mice but not in ApoE-deficient animals [Eckert 2001], suggesting that the effects of lovastatin are mediated by interaction with apolipoprotein E. In a 3-month, placebo-controlled study, human subjects with elevated LDL cholesterol received 10, 20, 40, or 60 mg once-daily doses of a controlled-release formulation of lovastatin (ADX-159, Altocor). Lovastatin dose-dependently reduced serum concentrations of Ab [Friedhoff 2001]. The study did not measure cognitive impact, but these results support the need for further studies in AD patients. 2.

Simvastatin

Simvastatin has been shown to reduce intracellular and extracellular levels of Ab42 and Ab40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons [Fassbender 2001]. Guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Ab42 and Ab40 levels in the cerebrospinal fluid and brain homogenate [Fassbender 2001]. A recent study in hypercholesterolemic patients demonstrated that chronic administration of simvastatin (80 mg/day) is able to lower by 53% circulating levels of brain-derived 24S-hydroxycholesterol [Locatelli 2002]. This study suggests that the simvastatin may reduce cholesterol turnover in the brain. The ability of simvastatin to prevent dementia and cognitive decline is being tested in a large study (the Heart Protection Study) in which 20,500 subjects will receive for > 5 years 40 mg/day of the statin [Collins 2002]. 3.

Atorvastatin

A placebo-controlled study is ongoing to evaluate the role of atorvastatin in AD. The trial will enroll 120 patients with mild to moderate AD who will receive either 80 mg/day atorvastatin or placebo for 1 year. Results are expected in 2003 [Sparks 2002]. 4.

Other Approaches

Other approaches interfering with cholesterol metabolism are being explored as potential treatments of AD. Inhibition of 7-dehydrocholesterol delta-7 reductase,


the enzyme catalyzing the last step of cholesterol biosynthesis, with BM15.766 produced a strong reduction of brain Ab peptides and Ab load in APP transgenic mice [Refolo 2001]. Inhibitors of acyl-coenzyme A:cholesterol acyltransferase, the enzyme that catalyzes the formation of cholesteryl esters, have been shown to inhibit the generation of Ab through the control of the equilibrium between free cholesterol and cholesteryl esters [Puglielli 2001].

III.

TREATMENT OF BEHAVIORAL SYMPTOMS

In addition to cognitive and functional decline, behavioral disturbances such as agitation, apathy, anxiety, aggression, disinhibition, and psychoses are frequently evident in AD patients. Such neuropsychiatric symptoms are the source of considerable patient and caregiver distress, and represent a major factor in the decision to transfer the care of patients into nursing homes. Effectiveness of psychotropic medications in treating psychosis and behavioral symptoms in patients with AD has not been properly evaluated so far, and is being examined in conjunction with a federally funded project [Schneider 2001]. The existing literature consists mainly of clinical series and case reports, making interpretations of the efficacy of individual medications difficult. The few placebo-controlled studies have a small number of patients, showing at best very modest efficacy for study medication. Only in the last few years have a number of well-designed studies with large sample size been carried out. The principal treatable behavioral disturbances in AD are agitation, psychosis, depression, anxiety, and insomnia. A variety of psychotropic medications can be used to treat these disturbances (Table 2). However, some of these medications, such as the benzodiazepines, can worsen the cognitive symptoms and lead to postural instability and gait disturbances which can result in falls and other serious adverse events [Pomara 1989, 1998]. In the past few years it appears evident that cholinesterase inhibitors, in addition to treating the cognitive deficits, possess favorable effects on behavioral symptoms of AD patients. They reduce particularly apathy and visual hallucinations, and in some cases a variety of other neuropsychiatric symptoms. The beneficial response is most likely mediated through limbic cholinergic structures [Cummings 2000].

879 Table 2 Psychotropic Medications Commonly Used for the Treatment of Neuropsychiatric Symptoms in Alzheimer’s Disease Class of symptom Delusions

Medication

Risperidone Olanzapine Quetiapine Ziprasidone Haloperidol Agitation/aggression Risperidone Olanzapine Quetiapine Ziprasidone Haloperidol Carbamazepine Divalproex Trazodone Propranolol Buspirone Depression Citalopram Sertraline Fluoxetine Nortriptyline Venlafaxine Mirtazapine Anxiety Oxazepam Lorazepam Buspirone Propranolol Insomnia Trazodone Zolpidem Temazepam Zaleplon

A.

Usual daily dose (range) 1 mg (0.5–1.5 mg) 5 mg (5–20 mg) 200 mg (100–300 mg) 40 mg (20–80 mg) 1 mg (0.5–3 mg) 1 mg (0.5–1.5 mg) 5 mg (5–10 mg) 200 mg (100–300 mg) 40 mg (20–80 mg) 1 mg (0.5–3 mg) 400 mg (200–1200 mg) 500 mg (250–3000 mg) 100 mg (100–400 mg) 120 mg (80–240 mg) 15 mg (15–30 mg) 20 mg (10–30 mg) 50 mg (50–200 mg) 40 mg (20–80 mg) 50 mg (50–100 mg) 100 mg (50–300 mg) 15 mg (7.5–30 mg) 30 mg (20–60 mg) 1 mg (0.5–6 mg) 30 mg (15–45 mg) 120 mg (80–240 mg) 100 mg (50–200 mg) 10 mg (5–10 mg) 20 mg (15–30 mg) 10 mg (5–20 mg)

Antipsychotics

Agitation and psychosis are common in AD. Psychosis has a cumulative incidence of 50% and is manifested by delusions and less frequently by hallucinations. Benzodiazepines were frequently used in the past. Now the use of these drugs has declined since it was recognized that these medications often exacerbate behavioral disturbances and can produce marked cognitive toxicity. Sedating medications are frequently used in institutional environments to ease patient management by hospital staff. However, these medications have negative effects on patient movements, increasing the risk of falls and subsequent medical complications. Conventional neuroleptics such as haloperidol reduce psychotic symptoms but have a greater risk of inducing extrapyramidal side effects including parkinsonism

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and tardive dyskinesia. Atypical antipsychotics such as risperidone and olanzapine have been specifically evaluated in AD patients with controlled studies. They are the treatment of choice for patients manifesting psychotic symptoms because they cause less severe adverse events, especially extrapyramidal symptoms. 1.

Haloperidol

Haloperidol is the most commonly used antipsychotic in AD. Since 1986, several small trials of haloperidol in AD patients have been published. The first relatively large double-blind, placebo-controlled study that evaluated the antipsychotic effects of haloperidol was published in 1998 [Devanand 1998]. This was a 12-week, placebo-controlled, crossover study comparing haloperidol at standard (2–3 mg/day) and low (0.50–0.75 mg/day) doses in 71 outpatients with AD. Standarddose haloperidol was efficacious and superior to both low-dose haloperidol and placebo for scores on the Brief Psychiatric Rating Scale psychosis factor and on psychomotor agitation. However, moderate to severe extrapyramidal signs were observed more frequently with the haloperidol standard dose than with other treatments. Another 16-week, double-blind placebo-controlled study compared the effects of haloperidol, trazodone, and behavior management techniques on agitation in 149 AD outpatients [Teri 2000]. Although there was a trend in favor of haloperidol compared to placebo in improving agitation, no significant differences were detected in all outcome measures of efficacy between treatment groups. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the behavior management techniques arm. These studies indicate the modest behavioral effects of haloperidol in AD patients and point out its narrow therapeutic window. 2.

Risperidone

Risperidone is an atypical antipsychotic that has been specifically evaluated in AD patients. A 12-week, double-blind placebo-controlled study was conducted in 625 institutionalized AD patients to evaluate the effects of different doses of risperidone on psychotic and behavioral symptoms [Katz 1999]. The higher doses of risperidone (1 and 2 mg/day) were superior to placebo in reducing total scores of behavioral symptoms on the BEHAVE-AD scale. The dose of 0.5 mg/ kg significantly reduced aggression score. Adverse events were dose related and included extrapyramidal symptoms, somnolence, and mild peripheral edema.

The frequency of extrapyramidal symptoms in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients. The effects of flexible dose of risperidone (0.5–4 mg/ day) on behavioral symptoms of dementia were compared with that of haloperidol in a 13-week doubleblind placebo-controlled study involving 344 patients [De Deyn 1999]. Both risperidone and haloperidol significantly reduced (compared to placebo) behavioral symptoms, particularly aggression. Frequency of extrapyramidal symptoms with risperidone did not differ significantly from that of placebo and was less than that of haloperidol. Thus, risperidone appears effective in controlling agitation in patients with dementia and has a relatively benign adverse-effect profile, but more clinical trials are needed to elucidate its role for this indication [Falsetti 2000]. 3.

Olanzapine

Olanzapine is another atypical antipsychotic. The effects of olanzapine on psychosis and behavioral symptoms of AD were assessed in a 6-week, doubleblind placebo-controlled study in 206 nursing home patients [Street 2000]. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/day of olanzapine. Low-dose olanzapine (5 and 10 mg/day) produced a significant improvement compared with placebo on agitation, aggression, hallucinations, and delusions as assessed by the Neuropsychiatric Inventory Nursing Home Scale. The low dose of olanzapine [5 mg/day] positively affected (compared with placebo) the behavioral disturbance–associated distress of caregivers. Somnolence and gait disturbance were the most frequent adverse events of olanzapine. No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. Another double-blind, placebo-controlled study evaluated the efficacy of rapid-acting intramuscular olanzapine in treating acute agitation associated with AD and/or vascular dementia [Meehan 2002]. Both olanzapine (5 mg) and lorazepam (1 mg) showed superiority to placebo on the Cohen-Mansfield Agitation Inventory, but the effect of olanzapine appeared longlasting. Drug treatments were well tolerated. These studies indicate that that olanzapine (5 and 10 mg/day) is effective and relatively well tolerated in AD patients with agitation/aggression and psychosis. However, controlled studies of longer duration such as the ongoing NIMH CATIE trial [Schneider 2001]


will provide data on the long-term efficacy and safety of olanzapine and other atypicals in the treatment of psychosis and behavioral disturbances associated with AD. B.

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associated with greater behavioral improvement by trazodone-treated patients. However, the hypothesis that trazodone corrects behavioral and affective disturbance induced by serotonin depletion in AD requires confirmation in double-blind placebo-controlled trials.

Antidepressants 3.

Several studies have demonstrated marked atrophy of serotonin-containing neurites and serotonin uptake sites in AD brain. Depressive symptoms are frequent in AD, occurring in as many as 50% of individuals. Major depression is more unusual, occurring in 6–10% of patients with AD. Depression exacerbates functional disability in patients with dementia. Treatment of depressive symptoms in AD commonly utilizes selective serotonin reuptake inhibitors such as sertraline, citalopram, or fluoxetine. Alternatively, tricyclic antidepressants with few anticholinergic side effects such as nortriptyline or combined noradrenergic and serotonergic reuptake inhibitors such as venlafaxine have been utilized. Few double-blind, placebocontrolled trials have established the efficacy of antidepressants in the treatment of mood symptoms in AD. 1.

Paroxetine

Paroxetine is the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) in AD patients. Paroxetine and nortriptyline were compared in a 12week, double-blind study of 116 elderly psychiatric patients who presented with a major depressive episode or melancholic depression [Mulsant 2001]. There were no significant differences between the rates of response of the paroxetine and nortriptyline groups (55% vs. 57%), but the discontinuation rate due to side effects was significantly lower with paroxetine than with nortriptyline (16% vs. 33%). Thus, although paroxetine shows efficacy similar to that of tricyclic antidepressants, it appears to be better tolerated. 2.

Trazodone

Trazodone is commonly used when sedation is needed to aid in sleep or manage agitation. A 9-week, doubleblind study compared the trazodone and haloperidol in 28 patients with dementia and agitated or aggressive behaviors [Sultzer 2001]. Cohen-Mansfield Agitation Inventory scores improved in each treatment group. In the trazodone treatment group, improvement in agitation was higher in patients with higher depressive symptoms at baseline. Mild depressive symptoms in patients with dementia and agitated behavior were

Citalopram

There are many trials evaluating the antidepressant effects of citalopram in demented patients, but most of them are open label studies. Unfortunately, the controlled studies involved heterogeneous patient populations and employed short-term observation periods. In a 4-week, double-blind placebo-controlled study, the efficacy of citalopram was investigated in 98 patients with AD or vascular dementia [Nyth 1990]. AD patients treated with citalopram showed a significant improvement, compared to placebo, in emotional bluntness, confusion, irritability, anxiety, fear/panic, depressed mood, and restlessness. There were no significant improvements in patients with vascular dementia. Citalopram was associated with few and mild side effects. Another double-blind, placebo-controlled study of 6-weeks’ duration involved 149 depressed elderly patients with or without dementia [Nyth 1992]. Patients treated with citalopram improved more than those on placebo on both depression and clinical global scales. A 12-week, double-blind study compared citalopram (20–40 mg/day) and mianserin (30-60 mg/day) in 336 elderly depressed patients with or without dementia [Karlsson 2000]. Demented patients treated with the two drugs showed similar improvements on the Montgomery-Asberg Depression Rating Scale. Fatigue and somnolence were more frequent with mianserin, while insomnia was more frequent with citalopram. In a doubleblind, placebo-controlled study involving 85 nondepressed patients undergoing short-term hospitalization, the acute effects of citalopram on psychotic symptoms and behavioral disturbances were compared to those of the neuroleptic perphenazine [Pollock 2002]. Patients treated with citalopram showed significantly greater improvement in the total Neurobehavioral Rating Scale score and in agitation/aggression scores. 4.

Sertraline

Initial studies with sertraline in dementia involved patients with advanced stage of disease. An open study in 10 severely impaired AD patients found encouraging effects of sertraline on food refusal [Volicer 1994]. However, an 8-week, double-blind placebo-controlled study in 31 female nursing home

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patients with late-stage AD failed to show significant effects of sertraline on objective scales of depression, although differences on the ‘‘knit-brow’’ facial measure approached statistical significance [Magai 2000]. Another 12-week, double-blind placebo-controlled study in 22 AD patients evaluated the efficacy and safety of sertraline in the treatment of major depression [Lyketsos 2000]. Patients given sertraline had significantly greater mean declines from baseline in the Cornell Scale for Depression in Dementia scores. 5.

Fluoxetine

Again, for fluoxetine there are few and small controlled studies in patients with dementia. A recent doubleblind, placebo-controlled study in 41 AD patients with major or minor depression, failed to show a significant effect of fluoxetine (40 mg/day) on Hamilton Depression Scale scores [Petracca 2001]. Complete remission of depression was found in 47% of patients treated with fluoxetine and in 33% of subjects treated with placebo, the difference not being significant. Another, 6-week, double-blind study comparing the effects of fluoxetine and amitriptyline on major depression in 37 AD patients did not show significant differences between the two drugs [Taragano 1997]. However, more patients on amitriptyline than on fluoxetine failed to complete the study (58% vs. 22%). Finally, a small double-blind placebo-controlled study comparing fluoxetine and haloperidol on reduction of agitation in 15 AD patients did not show significant differences compared to placebo [Auchus 1997]. C.

Anxiolytics

Anxiety is a common symptom in AD, present in 40– 50% of individuals at some point in the course of the illness. Most patients do not require pharmacologic treatment of anxiety. For those requiring pharmacologic management, benzodiazepines are best avoided, given their potential adverse effects on cognition. Nonbenzodiazepine anxiolytics such as buspirone are preferred. Although the efficacy of buspirone has been well documented in generalized anxiety disorder, no placebo-controlled trials have been conducted with this agent in demented patients [Apter 1999]. D.

Hypnotics

Insomnia occurs at some point in the course of the illness in many patients with AD. Patient insomnia

may disturb the sleep of caregivers, thus increasing the family burden. Although few well-designed studies have been conducted, specific management strategies are recommended mainly based on clinical experience and case reports from the literature [Boeve 2002]. Anticholinergic hypnotics should be avoided in patients with AD, given the presence of an underlying cholinergic deficiency. Sedating antidepressants such as trazodone or low doses of atypical antipsychotics, such as Seroquel, may be useful in managing insomnia. Sleep hygiene measures, such as limiting daytime napping, morning exposure to sunlight, adequate treatment of pain, and limiting nighttime fluids, should be implemented.

IV.

TREATMENT OF VASCULAR DEMENTIA

Vascular dementia (VaD) is the second most common cause of dementia after AD. In VaD cognitive decline is caused by a single localized stroke or a series of strokes. VaD is directly correlated with risk factors for stroke, including high blood pressure, diabetes, elevated cholesterol levels, and smoking. VaD differs from AD in that there is no specific neurotransmitter deficiency. In contrast to patients with AD who often experience a gradual, progressive decline, patients with VaD typically experience a stepwise decline in function. However, some of the treatment approaches developed for AD have also been evaluated for VaD including antioxidants and neurotrophic and neuroprotective agents. Several other compounds have been recently tested in clinical studies. However, specific drugs have not been approved. Although many trials have been published, few of them were carried out according to a randomized, double-blind, placebo-controlled design. Most of these studies had major limitations regarding the definition of the patient population, the limited sample size, the short treatment duration, the unclear definition of outcome measures of efficacy, the incomplete description of patient accountability, and the lack of intention-to-treat analysis. Finally, the positive results observed in some studies were not replicated in further trials. Recently large, well-designed studies with cholinesterase inhibitors have been reported with positive results, supporting the existence of some degree of overlap between pathology AD and VaD [Kalaria 1999].


A.

Calcium Channel Blockers

The role played by calcium in regulating brain functions is well known. The calcium ion links membrane excitation to subsequent intracellular response. Change in calcium homeostasis is one important effect of aging with consequences on higher cortical functions. The primary action of calcium channel blockers is to reduce the number of open channels, thus restricting influx of calcium ions into the cell. Initial open studies with nimodipine, a calcium channel blocker able to cross the blood brain barrier, suggested beneficial effects of nimodipine in VaD [Parnetti 1993; Pantoni 1996]. A later, 26-week, doubleblind placebo-controlled study of nimodipine in 259 patients with multiinfarct dementia (DSM-III-R criteria) failed to show a significant effect of nimodipine on cognitive or global assessments although some trend favored the calcium channel blocker [Pantoni 2000]. A recent review reported that there is no convincing evidence that nimodipine is a useful treatment for the symptoms of either VaD or AD [Lopez-Arrieta 2001]. Nicardipine, another calcium antagonist, was also evaluated in VaD. In a pilot study, nicardipine was compared with placebo over a 6-month period in 40 patients who had a previous transient ischemic attack. Although no significant differences were found, patients on nicardipine tended to perform better in certain tests [Molto 1995]. A larger double-blind, placebo-controlled study in 156 patients with VaD adopted as primary efficacy variable the loss of > 10 % of the basal score on the Mini-Mental State Examination after 1 year [Anonymous 1999]. At the end of the study, 35% of patients with placebo and 21% with nicardipine reached the endpoint, the difference not reaching statistical significance. These studies suggest a modest benefit, if any, of nicardipine in VaD. B.

Xanthine Derivatives

Methylxanthine derivatives are phosphodiesterase inhibitors with vasodilating properties. They also inhibit platelet aggregation and thromboxane A2 synthesis, decrease the release of free radicals, and may be neuroprotective. Methylxanthine derivatives have been evaluated mainly in peripheral vascular diseases, but a number of studies have been carried out in VaD and even in AD. Positive results with pentoxifylline have been reported in a double-blind placebo-controlled study in 80 patients with symptoms of VaD [Blume 1992].

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A well-designed placebo-controlled study in 64 patients meeting the DSM-III criteria for multi-infarct dementia showed borderline significance in favor of pentoxifylline on the rate of cognitive deterioration over a 36-week period [Black 1992]. There were no significant effects on global function of patients. Similarly, another 9-month, placebo-controlled study on pentoxifylline in 289 patients with multi-infarct dementia (DSM-III-R criteria) approached statistical significance on the primary outcome measure of efficacy [Gottfries-Brane-Steen scale] in the intent-to-treat analysis [Anonymous 1996]. Propentofylline, another xanthine derivative, was reported to increase regional cerebral glucose metabolism in the motor cortex of patients with VaD in a 3month, placebo-controlled study [Mielke 1996]. These effects were coupled to positive trends on cognitive performance of the patients. Another placebo-controlled trial in 190 patients with unspecified mild dementia also showed beneficial effects of propentofylline on the Gottfries-Brane-Steen scale [Saletu 1990]. In a further, 12-month, placebo-controlled study in 260 patients with VaD and AD, treatment differences in favor of propentofylline for both clinical global measures and cognitive scales were also reported [Marcusson 1997]. A review of clinical trials of propentofylline in VaD concluded that, although propentofylline appear to affect positively cognitive and global function, no benefits could be demonstrated for activities of daily living [Kittner 1999].

C.

Nootropics

So far, no generally accepted mechanism of action has emerged for piracetam-like nootropics [piracetam, oxiracetam, pramiracetam, and aniracetam]. Some indications seem to suggest cholinergic mechanisms [Gouliaev 1994]. A 12-week, placebo-controlled study of oxiracetam in 289 patients suffering from VaD or AD reported significant effects in favor of oxiracetam on Blessed Dementia Scale [Maina 1989]. Positive results were also described in a double-blind placebocontrolled study of oxiracetam in a mixed group of 65 demented patients treated for 12 weeks [Bottini 1992]. In another 3-month study in 60 patients with VaD and AD, significant improvements in patients treated with oxiracetam compared to placebo were observed on a number of cognitive tests [Villardita 1992]. However, a recent meta-analysis of all available studies of another nootropic, piracetam, concluded that there is no evidence supporting the use of piracetam in the treatment

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of people with dementia or cognitive impairment [Flicker 2001]. Nicergoline, an ergoloid derivative, is an a-adrenergic blocker claimed to possess activities on cell energy metabolism and platelet aggregation. In a 6-month, placebo-controlled study, nicergoline was found to improve cognitive and overall functions in 252 patients with VaD [Herrmann 1997]. A previous study of shorter duration (8 weeks) in 112 patients with VaD and AD also reported positive results [Saletu 1995]. A meta-analysis of controlled clinical trials of nicergoline in VaD and AD was recently published [Fioravanti 2001]. The analysis provides some evidence of positive effects of nicergoline on cognition and behavior in patients with VaD. In particular, the analysis found a difference in favor of nicergoline in reducing the behavioral symptoms as assessed by the Sandoz Clinical Assessment Geriatric Scale, but the effect size was minimal (4% of the scale range). Other outcome measures including functional scales failed to demonstrate statistically significant effects of nicergoline.

were observed with the 5-mg dose in Study 308 (CIBIC-Plus) and with the 10-mg dose in Study 307 (CDR-SB), indicating different sensitivities of the two scales to drug dose. The donepezil safety profile did not differ from that of previous AD trials. These studies are probably the best-designed and best-conducted clinical trials in VaD published so far. Positive effects in VaD were also recently shown with galantamine but in a less homogeneous population [Erkinjuntti 2002]. Five hundred ninety-two patients with a diagnosis of probable VaD or AD combined with cerebrovascular disease participated at this 6month, double-blind placebo-controlled study. Galantamine (24 mg/day) showed greater efficacy than placebo on cognitive (ADAS-Cog), clinical global (CIBIC-Plus), activities of daily living (Disability Assessment in Dementia), and behavioral [Neuropsychiatric Inventory] measures of efficacy. Galantamine was well tolerated. This study confirms the therapeutic role of cholinesterase inhibitors in VaD.

D.

V.

Cholinesterase Inhibitors

Studies in rats with tandem occlusion of left middle cerebral and common carotid arteries have shown that central cholinesterase inhibition improves cerebral blood flow in the ischemic brain [Scremin 1997]. The stimulating effects of cholinesterase inhibitors of regional cerebral blood flow and glucose metabolism have been confirmed in AD patients receiving long-term treatment with tacrine [Nordberg 1998] and donepezil [Nakano 2001]. These observations have opened the possibility to test cholinesterase inhibitors in VaD. A post hoc analysis of studies with rivastigmine in AD, revealed a larger effect size on cognitive measures in patients with concurrent vascular risk factors at baseline (Modified Hachinski Ischemic Score > 0) [Kumar 2000]. Preliminary clinical experience with donepezil in VaD showed encouraging results [Mendez 2000]. Recently two large double-blind, placebo-controlled trials of donepezil in VaD found statistically significant effects of the drug on both cognitive and clinical global scales [Pratt 2002]. In both studies diagnosis of probable or possible VaD was made according to NINDS-AIREN criteria. The two studies involved 616 and 603 patients, respectively, randomized to receive placebo or donepezil 5 mg or 10 mg daily for 24 weeks. In both studies, both doses of donepezil produced significant effects on cognitive measures of efficacy (ADAS-Cog and MMSE). On the clinical global measure of efficacy significant effects

TREATMENT OF DEMENTIA WITH LEWY BODIES

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly, characterized clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Many deficits in cholinergic neurotransmission are seen in the brains of patients with DLB. Thus, drugs enhancing central cholinergic function represent a rationally based therapeutic approach to this disorder. The effects of the cholinesterase inhibitor rivastigmine in DLB were initially evaluated in a preliminary open-label study [McKeith 2000] and later in a doubleblind, placebo-controlled study in 120 patients [McKeith 2000]. Subjects were given up to 12 mg rivastigmine or placebo daily for 20 weeks. Patients on rivastigmine had significant improvement with regard to apathy, anxiety, delusions, and hallucinations. About twice as many patients on rivastigmine (38%) as on placebo (18%), showed at least a 30% improvement from baseline. Cognitive effects of rivastigmine were detected with a computerized assessment system and with neuropsychological tests. Nausea, vomiting, and anorexia were seen more frequently with rivastigmine than with placebo. Recently, a post hoc analysis was carried out in a subgroup of patients with DLB included in a placebocontrolled trial of olanzapine for the treatment of psy-


chosis in AD patients [Cummings 2001]. Patients meeting the clinical criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Patients treated with 5 mg olanzapine showed significant reductions in delusions and hallucinations, while patients treated with 10 mg showed a significant improvement in the Neuropsychiatric Inventory/Nursing Home delusion subscale score. This post hoc analysis suggests that olanzapine reduces psychosis in patients with DLB without worsening parkinsonism. VI.

TREATMENT OF FRONTOTEMPORAL DEMENTIA

Patients with frontotemporal dementia [FTD] include those who suffer from Pick’s disease or corticobasal degeneration, as well as the infrequent families with FTD and parkinsonism associated with chromosome 17. This type of dementia is clinically characterized by behavior and personality disorders, more than cognitive alterations. Behavioral symptoms (disinhibition, aggression, hyperorality, and speech disturbance) may trouble caregivers and present a safety risk to the individual suffering from the disease. Treatment approaches to FTD are still in their infancy. Many of the therapies developed for AD may not work for FTD because the two disorders have different behavioral, cognitive, neurochemical, and molecular features. The recent discovery of mutations in the t gene and the development of mouse models for FTD should eventually lead to more rational therapies. However, the treatment of frontotemporal dementia is currently directed toward the psychiatric alterations that characterize this disorder [Perry 2001]. Atypical antipsychotics have improved ‘‘positive symptoms’’ such as logorrhea, wandering, agitation, and aggression, without impairing cognitive function. There is some evidence from open trials that SSRIs improve depressive symptoms, compulsions, food craving, and disinhibition [Swartz 1997]. VII.

TREATMENT OF MILD COGNITIVE IMPAIRMENT

Mild cognitive impairment (MCI) is the term used to describe a condition with isolated memory deficits in individuals who do not have significant impairment of other cognitive domains (beyond that expected for their age and level of education) and have normal

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basic activities of daily living. MCI represents the transitional zone between normal aging and AD. As many as 60–80% of patients with MCI may progress to AD over a 5-year period. Specific memory deficit, apolipoprotein E status, and hippocampus atrophy on magnetic resonance imaging are predictors of a more rapid progression [Petersen 2001]. It has been estimated that there are from 2.5 million to 4 million people in the United States with MCI, and probably an equivalent number in Western Europe. In March 2001, the U.S. Food and Drug Administration recognized MCI as an indication that could be defined and that was separate from AD. At present, no treatments are recommended for MCI. The only published controlled clinical trial in MCI regards piribedil, a dopamine receptor agonist [Nagaraja 2001]. This study was based on the hypothesis that cognitive decline in healthy elderly individuals is associated with age-related decrease in dopamine receptors [Wang 1998]. The 3-month, double-blind placebo-controlled study was carried out in 60 patients with clinically diagnosed MCI and a MMSE score of 21–25 at baseline. At 3 months, 19 patients (63%) of those taking piribedil and 8 (27%) of those treated with placebo had increases in MMSE scores to 26 or more, the difference being significant. Current major efforts are aimed to find drugs able to impede the progression of MCI to AD. A number of clinical trials on potential therapies are under way. These refer mainly to drugs developed for AD, specifically cholinesterase inhibitors and COX-2 inhibitors [Sramek 2001]. One of these studies is assessing the ability of donepezil, compared to vitamin E and placebo, in reducing the conversion of amnestic MCI to AD [Doody 2002]. In another study, rofecoxib is being studied in individuals with MCI to see if it can delay the onset of AD in this population [Grundman 2000]. Finally, in a large prevention study, the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT), cognitively normal individuals at risk for AD (age > 70 years and first-degree relative with dementia) are being randomized to receive a traditional NSAID or a COX-2 inhibitor or placebo [Sparks 2002]. They will be assessed yearly for 7 years. The major endpoint is conversion to dementia. In the Ancillary Study on Cholesterol and Statin parameters, yearly cholesterol levels will be determined in subjects where statin use is known at entry. Conversion to dementia and changes in yearly cognitive indices will be correlated to changes in cholesterol levels and use of statins.

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CONCLUSIONS

Because of its high prevalence, AD is the type of dementia for which the most intensive efforts for the development of pharmacological treatments have been directed. These efforts have resulted in the introduction of cholinesterase inhibitors which have been shown to produce a temporary amelioration of cognitive symptoms and delay of functional decline of the patients. The pharmacological treatments of the behavioral and psychotic disturbances of AD patients have been less systematically addressed. However, a number of clinical trials using atypical antipsychotics have recently been conducted or are in progress. The development of pharmacological treatments for other types of dementia is at earlier stages, with encouraging results in VaD and LBD, again with cholinesterase inhibitors. Neurotransmitter substitution therapy of AD will probably soon reach its limits and is not likely to provide additional efficacy with the novel compounds that are being developed. The major breakthrough in terms of therapeutic success is expected from approaches directed toward the interference with the so-called b-amyloid cascade. The testing of the b-amyloid hypothesis in clinical trials is likely to be achieved within the next 5 years. The most exciting products include b-amyloid immunization, although a putative b-amyloid vaccine has recently discontinued owing to central inflammation adverse events. Therapeutic efforts are also being concentrated on prevention of dementia. The large ongoing studies with estrogens (WHIMS) and NSAIDs (Alzheimer’s Disease Anti-Inflammatory Prevention Trial) will probably determine their prophylactic potential in the next few years. Randomized, placebo-controlled prospective studies with certain statins are also expected to provide definitive results on their potential. Finally the 20,500-patient Heart Protection Study of simvastatin and vitamins A, C, and E will assess the role of lipid reduction and antioxidants in the prevention of dementia and cognitive decline. Other promising approaches for the treatment and prevention of Alzheimer’s disease may involve the use of antiglucocorticoid agents such as Mifepristone [Pomara et al. 2002]. REFERENCES Aisen PS, Davis KL. Inflammatory mechanisms in Alzheimer’s disease. Implications for therapy. Am J Psychiatr 1994; 151:1105–1113.

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Imbimbo and Pomara Whitehouse P, Tariot P, Mellow AM, Auchus AP, Grundman M, Thomas RG, Schafer K, Thal LJ. Alzheimer’s Disease Cooperative Study. Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology 2000; 55:1271–1278. Terry AV Jr, Risbrough VB, Buccafusco JJ, Menzaghi F. Effects of (þ=)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl] thio}phenol hydrochloride (SIB-1553A), a selective ligand for nicotinic acetylcholine receptors, in tests of visual attention and distractibility in rats and monkeys. J Pharmacol Exp Ther 2002; 301:284–292. Thal LJ, Forrest M, Loft H, Mengel H. Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer’s disease. Lu25-109 Study Group. Neurology 2000; 54:421–426. Tohgi H, Abe T, Hashiguchi K, Saheki M, Takahashi S. Remarkable reduction in acetylcholine concentration in the cerebrospinal fluid from patients with Alzheimer type dementia. Neurosci Lett 1994; 177:139–142. Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H, Endo N. Inhibition of amyloid b protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J Biol Chem 1996; 271:6839–6844. Trabace L, Cassano T, Steardo L, Pietra C, Villetti G, Kendrick KM, Cuomo V. Biochemical and neurobehavioral profile of CHF2819, a novel, orally active acetylcholinesterase inhibitor for Alzheimer’s disease. J Pharmacol Exp Ther 2000; 294:187–194. Tsai GE, Falk WE, Gunther J, Coyle JT. Improved cognition in Alzheimer’s disease with short-term D-cycloserine treatment. Am J Psychiatry 1999; 156:467–469. Tung JS, Davis DL, Anderson JP, Walker DE, Mamo S, Jewett N, Hom RK, Sinha S, Thorsett ED, John V. Design of substrate-based inhibitors of human b-secretase. J Med Chem 2002; 45:259–262. Van Dongen MC, van Rossum E, Kessels AG, Sielhorst HJ, Knipschild PG. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 2000; 48:1183–1194. Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ, Scheltens PK. Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18month randomised, double-blind, placebo-controlled study. Lancet 2001; 358:455–460. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. b-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286:735–741. Veinbergs I, Mallory M, Sagara Y, Masliah E. Vitamin E supplementation prevents spatial learning deficits and

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57 Pharmacological Interventions in Psychiatric Disorders Due to Medical Conditions E. SHERWOOD BROWN and DANA C. PERANTIE University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

I.

The third category consists of psychiatric disturbances associated with medications used to treat general medical conditions. These are classified as substance-induced disorders in DSM-IV-TR [2]. The treatment of each of these categories of illnesses will be discussed. Several general principles useful in the treatment of psychiatric disorders in general medical conditions are outlined in Table 1. The first is to consider possible drug interactions between the psychotropic agent and medications used to treat the general medical condition. The second is to consider possible side effects of the psychotropic agent which might exacerbate symptoms of the general medical condition. Third, titration or dosage of psychotropic medications may need to be adjusted in those patients with illnesses affecting drug metabolism, such as liver or kidney disease. Also, some medications used to treat medical conditions may induce or exacerbate psychiatric symptoms. An additional consideration is that an improvement in psychiatric symptoms may result in an improvement or perceived improvement in the medical condition. These principles will be discussed as individual disorders and agents are reviewed.

INTRODUCTION

Psychiatric illnesses, particularly mood and anxiety disorders, are clearly more common in patients with general medical conditions than in the general population [1]. However, the nature, course, and treatment of psychiatric disorders in general medical conditions have been the subject of relatively little research. In this chapter, the relationship between psychiatric disorders and general medical conditions is divided into three categories. The first category is psychiatric illnesses, primarily mood and anxiety disorders, associated with but not necessarily secondary to a general medical condition. In the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM-IV-TR) [2], these are classified as major depressive disorder, dysthymic disorder, and panic disorder, as are similar symptoms with persons without a general medical condition. The second category of psychiatric illnesses includes not only depression and anxiety disorders, but also mania and psychosis—those thought to be etiologically linked to the general medical condition. These are classified as mood disorders or psychotic disorders due to a general medical condition in the DSM-IV-TR [2]. 899

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Table 1 General Principles in Treating Psychiatric Disorders in General Medical Conditions Interactions may exist between psychotropic medications and those being used to treat the medical condition. Psychiatric medications may affect the general medical condition (positively or negatively). Certain medical conditions (e.g., hepatic and renal disease) affect the metabolism of psychotropic medications, so dosage and/or titration may need to be adjusted. Some medications used to treat general medical conditions can induce or exacerbate psychiatric symptoms. Improvement in psychiatric symptoms may positively influence the outcome of the medical illness.

II.

PHARMACOTHERAPY OF PSYCHIATRIC DISORDERS ASSOCIATED WITH MEDICAL CONDITIONS

Most research related to the pharmacotherapy of psychiatric illnesses associated with general medical conditions involves the treatment of depression, although a few studies have examined the treatment of anxiety disorders. A summary of controlled antidepressant Table 2

trials in general medical conditions is provided in Table 2. A summary of findings in individual medical illnesses is given below. A.

Cardiovascular Diseases

Several investigations have shown a strong though complex relationship between cardiovascular disease and depression. Depression following a myocardial infarction appears to be a risk factor for death, and depressive symptoms appear to also predict future development of cardiovascular disease [3–5]. Therefore, the use of antidepressants in patients with coronary artery disease or at risk for coronary artery disease is an area of great interest. However, thus far only two controlled trials of an antidepressant have been published in the peer-reviewed literature. Veith et al. [6] examined the use of imipramine versus doxepin versus placebo in a group of 24 depressed patients with heart disease. Antidepressant therapy was more effective than placebo for depressive symptoms; however, the use of antidepressants had no effect on ejection fraction although imipramine appeared to reduce premature contractions. More recently, Roose et al.

Controlled Trials of Antidepressant Medications in Medical Conditions

Medical condition

Medication(s) investigated

Psychiatric benefits

SSRIs

ðþÞ (6,7) ðþÞ (7) ðþÞ (12) ðÞ (11,13) n/a (14) ðÞ (17,18) n/a (19–24) ðþÞ (25,26) ðÞ (18,27) ðþÞ (28) ðþÞ (29) ðþÞ (34,37,41) n/a (39,40) ðþÞ (35,36,41)

Cancer Renal disease COPD

Mianserin (tetracyclic) Fluoxetine nortriptyline

ðþÞ (52,53) ðþÞ (54) ðþÞ (55)

Asthma

tianeptine (atypical TCA)

n/a (57)

Heart disease Arthritis

TCAs SSRI TCAs

Fibromyalgia

TCAs SSRIs

Diabetes HIV/AIDS

nortriptyline fluoxetine TCAs

Benefits to Medical condition [Ref] ðþÞ [6] (þ=) [7] ðþÞ [11–13] ðÞ [14] ðþÞ [17–20,22–24] ðÞ [21] ðþÞ [18,26] ðÞ [25,27] ðÞ [28] ðþÞ [29] ðÞ [34,39–41] n/a [37] ðÞ [35,41] n/a [36] n/a [52,53] n/a [54] subjective measures: ðþÞ [55] objective measures: ðÞ [55] ðþÞ [57]

n/a=Not assessed. ðþÞ = Benefit reported. ðÞ = Absence of benefit, which is not meant to imply the treatment was harmful.

Pharmacological Interventions

compared paroxetine to nortriptyline in 81 depressed patients with ischemic heart disease [7]. Both antidepressants appeared effective for treatment of depressive symptoms. However, nortriptyline was associated with an 11% increase in heart rate, a decrease in orthostatic blood pressure, and suppression of ventricular arrhythmia, while paroxetine had no clinically significant effects on these variables. The rate of cardiac events that required intervention by a cardiologist and discontinuation of the medication was 17% in nortriptyline-treated patients, but only 2% in the paroxetine-treated patients. Although the data in this area are relatively limited, the lack of cardiovascular effects of the selective serotonin reuptake inhibitors (SSRIs) has led some experts in the field to recommend these as first-line treatment of depression in patients with heart disease [8,9]. However, there are significant drug interactions between several SSRIs and also nefazodone, with digoxin (10). In addition, citalopram appears to potentiate the effects of beta-blockers [10]. B.

Collagen Vascular Diseases

1.

Rheumatoid Arthritis

Four placebo-controlled trials have examined the use of a tricyclic antidepressant (TCA) in patients with rheumatoid arthritis. In one study, Ash et al. examined the use of dothiepin versus placebo in a group of 48 female outpatients with rheumatoid arthritis and depression [11]. The study found a significant reduction in disability scores, duration of early morning stiffness, and pain in the dothiepin group. The reductions in pain were significantly correlated with reduction in depression and anxiety scores, but no significant difference was found at 12 weeks in depression scores between dothiepin- and placebo-treated groups. However, in a 4-week study of dothiepin and ibuprofen versus placebo and ibuprofen in 60 rheumatoid arthritis patients, Sarzi Puttini et al. found that the patients receiving dothiepin who were classified as depressed at baseline had a significant reduction in depression scores, in addition to a reduction in daytime pain [12]. In another placebo-controlled study, Macfarlane et al. examined the use of low-dose trimipramine in 36 patients with arthritis who were depressed according to a self-rated depression scale [13]. Joint pain and tenderness were found to be significantly reduced, while depression scores did not change. These studies are among only a few that demonstrate an improvement in symptoms of the gen-

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eral medical condition with antidepressant treatment. Amitriptyline has also been examined by Grace et al. in a controlled study in 36 arthritis patients, but no differences were found between amitriptyline and placebo in joint pain or tenderness [14]. The above data suggest TCAs are useful in depressed patients with arthritis. However, Bird et al. recently reported in a placebocontrolled trial (n ¼ 76) that both paroxetine and amitriptyline were effective for both depressive and arthritic symptoms, but side effects were much more common in the amitriptyline group [15]. Thus, as with cardiovascular disease patients, improved tolerability over TCAs suggest SSRIs may be appropriate first line treatment for arthritis patients. 2.

Fibromyalgia

Numerous controlled trials of antidepressants have been conducted in patients with fibromyalgia as recently reviewed by Arnold et al. [16]. In fact, more controlled antidepressant trials may have been conducted in fibromyalgia patients than in all other general medical conditions combined. In general, the trials have shown some improvement in symptoms of fibromyalgia including pain, stiffness, tenderness, fatigue, and sleep quality with the use of antidepressants [17– 24]. The use of second-generation antidepressants (e.g., SSRIs) has generally shown either negative results or very modest improvement in symptoms of the disease [18,25–27]. Therefore, despite their side effect burden, TCAs appear at present to remain first line agents in fibromyalgia patients. C.

Diabetes

Two controlled studies have examined the use of antidepressants in depressed patients with diabetes. Lustman et al. examined nortriptyline versus placebo in 68 depressed patients with diabetes, finding significantly greater reduction in depressive symptoms in the nortriptyline-treated group [28]. However, nortriptyline was not superior to placebo in reducing glycosylated hemoglobin levels (a measure of diabetic control). The lack of improvement in glycemic control with nortriptyline was attributed to a direct effect of nortriptyline to worsen glycemic control even though improvement in depression appeared to have a beneficial effect on glycosylated hemoglobins in the subjects studied. More recently, Lustman et al. examined fluoxetine versus placebo in depressed patients (n ¼ 60) with diabetes [29]. The fluoxetine-treated group had a significant improvement in depression compared to

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placebo, and a trend toward a reduction in glycosylated hemoglobin levels (p ¼ :13). Thus, in the limited diabetes literature available, both TCAs and SSRIs appear to be effective for depressive symptoms. However, only SSRIs appear to be associated with improvement in glycosylated hemoglobin levels.

D.

HIV and AIDS

The psychiatric disorders associated with human immunodeficiency virus (HIV) infection are highly variable in presentation and include depressive or anxiety symptoms possibly related to the disability and life-threatening nature of the illness. Psychiatric symptoms may also be related to direct effects of the virus on the central nervous system or side effects of antiviral medications [30]. The medications used to treat HIV infections can be associated with psychiatric symptoms [31,32]. Thus, HIV infection includes all three categories of psychiatric illnesses in general medical conditions contained in the introduction to this chapter. The treatment of psychiatric disorders in patients with HIV has been the subject of several investigations. Recently the American Psychiatric Association released practice guidelines for the treatment of patients with HIV and acquired immunodeficiency syndrome (AIDS) [33]. These guidelines emphasize starting with low doses and slow upward titration of medications when possible, avoiding medications with unfavorable side-effects profiles, and an awareness of the many potential drug interactions of antiviral drug regimens used in HIVaffected persons. Several placebo-controlled trials have examined the use of antidepressants in HIV-positive patients with depression. In general, these studies suggest that antidepressant therapy including TCAs and SSRIs is effective for depressive symptoms in HIV [34–41]. However, the SSRIs appear to be better tolerated than TCAs in this population [41]. The studies that examined variables of immune functioning such as CD4 cell count found that immunity was not affected by the psychotropic medications [34,35,41,42]. Although the studies suggest that antidepressants are useful for depressive symptoms, no controlled trials to date have shown improvement in measures of severity of HIV illness or disease progression. However, finding a significant improvement in somatic symptoms on an HIV Symptom Scale in an open-label trial of SSRIs in 33 depressed, HIV-positive patients, Ferrando et al. suggest that depression

significantly affects the perception of symptom severity, even in late stage HIV illness [43]. Although no controlled studies are available for the treatment of other psychiatric disorders in HIVpositive patients, anecdotal reports and small open studies suggest that valproic acid, clonazapam, phenytoin, and carbamazepine may be useful in some patients with mania [44,45]. Buspirone and fluoxetine may be useful for anxiety disorders [46,47], and low doses of antipsychotics may be useful for psychotic symptoms [48–51]. E.

Cancer

As with HIV-positive patients, appreciation of the numerous drug interactions and side effects of the many chemotherapeutic agents available is important in treating patients with cancer and depression. Surprisingly few data are available in the form of controlled studies on the treatment of depression in patients with cancer. Costa et al. examined mianserin versus placebo in 73 women with cancer and depression, finding that antidepressant therapy was superior to placebo [52]. Van Heeringen and Zivkov found that mianserin was superior to placebo for depressive symptoms in 57 women with breast cancer and depression [53]. No controlled trials using SSRIs were found in our literature search. F.

Renal Diseases

One small placebo-controlled trial of an antidepressant in depressed patients (n ¼ 14) on dialysis has been reported. Blumenfield et al. found a significant reduction in depression with fluoxetine compared to placebo at 4 weeks but not at 8 weeks [54]. In treating patients with renal disease, caution is required particularly with medications metabolized by the kidneys (e.g., lithium, gabapentin). Slow dose titration and careful monitoring of blood levels may be necessary when prescribing medications metabolized by the renal system in this population. G.

Pulmonary Diseases

One double-blind, placebo-controlled study examined the use of antidepressants in depressed patients with lung disease. Borson et al. examined the use of 12 weeks of nortriptyline versus placebo in 30 patients with chronic obstructive pulmonary disease, finding an improvement in mood and subjective but not objective symptoms of airway obstruction [55]. Although

Pharmacological Interventions

numerous studies suggest that depressive symptoms are common and may be associated with medication noncompliance and even sudden death from asthma, no placebo-controlled trials of antidepressants in depressed asthma patients have been published [56]. However, one study using tianeptine, a serotonin reuptake enhancer, in children with asthma found a substantial improvement in asthma symptoms [57]. Given the at least partially reversible nature of the airway obstruction in asthma patients, controlled trials of antidepressants in depressed asthma patients are needed, examining both changes in mood and asthma symptoms.

III.

PSYCHIATRIC DISORDERS ETIOLOGICALLY RELATED TO GENERAL MEDICAL CONDITIONS

Some medical conditions in which psychiatric disturbance appear to frequently occur include porphyria, thyroid abnormalities, and hypothalamic-pituitaryadrenal axis disorders. The treatment of psychiatric disturbances secondary to general medical conditions should begin with the appropriate treatment of the general medical condition. However, this is not always sufficient to ameliorate the psychiatric disturbance, necessitating the use of psychotropic medications. The literature on the use of psychotropic medications for psychiatric illnesses secondary to general medical conditions consists of case reports and small open studies. Two of these medical conditions have had an influence on psychopharmacology of idiopathic mood disorders. For many years, physicians have noted that persons with hypothyroidism and Cushing’s disease often have affective symptomatology which resolves with successful treatment of the endocrine abnormality [58–60]. In addition, a subset of patients with mood disorders have subtle abnormalities of the neuroendocrine system including a blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) [61] and nonsuppression on the dexamethasone suppression test (DST) [62], leading to the use of thyroid supplementation and antiglucocorticoid medications (i.e., ketoconazole, metyrapone) in patients with mood disorders [63–66]. However, the treatment of psychiatric disturbance associated with these endocrine disorders has not been a topic of systematic investigation, although the symptoms appear to frequently resolve with successful treatment of the general medical condition [58–60].

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IV.

PSYCHIATRIC DISTURBANCES SECONDARY TO MEDICATIONS USED TO TREAT MEDICAL CONDITIONS

A wide variety of medications has been implicated in psychiatric disturbances including digoxin, antihypertensives, antibiotics, corticosteroids, interferon alpha, and thyroid supplements. The treatment of psychiatric disturbances secondary to a medication begins with dose reduction or discontinuation of the medication or a switch to a different medication when possible. Minimal data are available on the pharmacotherapy of medication-induced psychiatric disturbances. Almost all reports consist of anecdotal evidence or small open case series. Medication-induced psychiatric disturbances are of historical interest in that reports of depressive symptomatology with reserpine in the 1950s were consistent with norepinephrine theories of depression which were put forward at that time [67,68]. This section will focus on data on the treatment of two medications that appear to be frequently associated with psychiatric disturbances: interferon alpha and oral corticosteroids. In recent years, it has become clear that interferon alpha, used to treat hepatitis C and other disorders, is frequently associated with the development of depressive symptoms. A report by Miyaoka et al. found that 37% of patients free of mood disturbance developed a major depressive episode during interferon alpha therapy [69]. Case reports of the successful use of fluoxetine 20 mg/day or lowdose nortriptyline (25–50 mg/day) for interferon alpha–induced depression have been published [70,71]. Gleason and Yates presented five cases of interferon alpha–induced depression which were successfully treated with SSRIs or a TCA [72]. In perhaps the only placebo-controlled study on the treatment of a medication-induced psychiatric disorder to date, Miller et al. reported the successful use of paroxetine as a prophylactic agent to prevent depression during alpha interferon [73]. Corticosteroids are frequently prescribed medications given for a variety of diseases mediated by the immune system. Despite their use for > 50 years, no controlled trials have examined the treatment of psychiatric disorders associated with their use [74,75]. Anecdotal reports suggest that lithium [76–81], neuroleptics [82–84], atypical antipsychotics [85,86], valproic acid [87], and lamotrigine [88] may be useful for psychiatric symptoms associated with corticosteroids. Falk et al. pretreated 27 patients in an open design with lithium carbonate and found none of these patients developed severe psychiatric disturbances,

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but 6/44 patients (14%) not receiving lithium developed mania or depression with psychotic features [76]. Anecdotal data suggest that TCAs may in some cases lead to a worsening of mood symptoms in patients with steroid-induced depressions [83,89]. In contrast, a single case report found that fluoxetine may improve depressive symptoms in patients on steroids [90]. In general, the evidence seems to support treating corticosteroid-induced psychiatric symptoms with agents effective for bipolar disorder (i.e., mood stabilizers).

7.

8.

9.

10.

V.

CONCLUSION

Some psychiatric symptoms and disorders appear to be more common in general medical settings than in the general population. However, the treatment of these disorders has been the topic of relatively little attention. The SSRIs appear to be the agents of first choice for depression in some, but not all, general medical conditions. Almost no data are available on the treatment of anxiety in medical settings. Future studies are needed to examine the efficacy, tolerability, and acceptability of standard psychotropic agents in these medical settings. Of particular interest is whether treatment of psychiatric symptoms leads to improvement in the general medical condition or, conversely, treatment of the medical symptoms improves the psychiatric disorder.

11.

12.

13.

14.

15.

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Pharmacological Interventions 21. S Carette, G Oakson, C Guimont, M Steriade. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis Rheum 38:1211–1217, 1995. 22. LG Quimby, GM Gratwick, CD Whitney, SR Block. A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. J Rheumatol 19(suppl):140–143, 1989. 23. L Caruso, PC Sarzi Puttini, L Boccassini, S Santandrea, M Locati, R Volpato, F Montrone, C Benvenuti, A Beretta. Double-blind study of dothiepin versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res 15:154–159, 1987. 24. RM Bennett, RA Gatter, SM Campbell, RP Andrews, SR Clark, JA Scarola. A comparison of cyclobenzaprine and placebo in the management of fibrositis. A double-blind controlled study. Arthritis Rheum 31:1535–1542, 1988. 25. F Wolfe, MA Cathey, DJ Hawley. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol 23:255–259, 1994. 26. UM Anderberg, I Marteinsdottir, L von Knorring. Citalopram in patients with fibromyalgia—a randomized, double-blind, placebo-controlled study. Eur J Pain 4:27–35, 2000. 27. J Norregaard, H Volkmann, B Danneskiold-Samsoe. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain 61:445–449, 1995. 28. PJ Lustman, LS Griffith, RE Clouse, KE Freedland, SA Eisen, EH Rubin, RM Carney, JB McGill. Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med 59:241–250, 1997. 29. PJ Lustman, KE Freedland, LS Griffith, RE Clouse. Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial. Diabetes Care 23:618–623, 2000. 30. RS el-Mallakh. Mania in AIDS: clinical significance and theoretical considerations. Int J Psychiatry Med 21:383–391, 1991. 31. MJ Brouilette, G Chouinard, R Lalonde. Didanosineinduced mania in HIV infection. Am J Psychiatry 151:1839–1340, 1994. 32. JM Wright, PS Sachdev, RJ Perkins, P Rodriguez. Zidovudine-related mania. Med J Aust 150:339–341, 1989. 33. American Psychiatric Association. Practice guideline for the treatment of patients with HIV/AIDS. Am J Psychiatry 157(suppl 11):1–62, 2000. 34. JG Rabkin, R Rabkin, W Harrison, G Wagner. Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry 151:516–523, 1994. 35. JG Rabkin, GJ Wagner, R Rabkin. Fluoxetine treatment for depression in patients with HIV and AIDS: a randomized, placebo-controlled trial. Am J Psychiatry 156:101–107, 1999.

905 36. S Zisook, J Peterkin, KJ Goggin, P Sledge, JH Atkinson, I Grant. Treatment of major depression in HIV-seropositive men. HIV Neurobehavioral Research Center Group. J Clin Psychiatry 59:217– 224, 1998. 37. JC Markowitz, JH Kocsis, B Fishman, LA Spielman, LB Jacobsberg, AJ Frances, GL Klerman, SW Perry. Treatment of depressive symptoms in human immunodeficiency virus-positive patients. Arch Gen Psychiatry 55:452–457, 1998. 38. EF Targ, DH Karasic, PN Diefenbach, DA Anderson, A Bystritsky, FI Fawzy. Structured group therapy and fluoxetine to treat depression in HIV-positive persons. Psychosomatics 35:132–137, 1994. 39. K Kieburtz, D Simpson, C Yiannoutsos, MB Max, CD Hall, RJ Ellis, CM Marra R McKendall, E Singer, GJ Dal Pan, DB Clifford, T Tucker, B Cohen. A randomized trial of amitrityline and mexiletine for painful neuropathy in HIV infection. Neurology 51:1682– 1688, 1998. 40. JC Shlay, K Chaloner, MB Max, B Flaws, P Reichelderfer, D Wentworth, S Hillman, B Brizz, DL Cohn. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. JAMA 280:1590–1595, 1998. 41. AJ Elliott, KK Uldall, K Bergam, J Russo, K Claypoole, PP Roy-Byrne. Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am J Psychiatry 155:367–372, 1998. 42. JG Rabkin, R Rabkin, Wagner G. Effects of fluoxetine on mood and immune status in depressed patients with HIV illness. J Clin Psychiatry 55:92–97, 1994. 43. SJ Ferrando, JD Goldman, WE Charness. Selective serotonin reuptake inhibitor treatment of depression in symptomatic HIV infection and AIDS. Improvements in affective and somatic symptoms. Gen Hosp Psychiatry 19:89–97, 1997. 44. MH Halman, JL Worth, DM Sanders, PR Renshaw, GB Murray. Anticonvulsant use in the treatment of manic syndromes in patients with HIV-1 infection. J Neuropsychiatry Clin Neurosci 5:430–434, 1993. 45. JA RachBeisel, E Weintraub. Valproic acid treatment of AIDS-related mania. J Clin Psychiatry 58:406–407, 1997. 46. SL Batki. Buspirone in drug users with AIDS or AIDSrelated complex. J Clin Psychopharmacol 10 (suppl): 111S–115S, 1990. 47. J McDaniel, K Johnson. Obsessive-compulsive disorder in HIV disease: response to lfuoxetine. Psychosomatics 36:417–418, 1995. 48. W Breitbart, RF Marotta, P Call. AIDS and neuroleptic malignant syndrome. Lancet 2:1488–1489, 1988. 49. M Maccario, DW Sharre. HIV and acute onset of psychosis. Lancet 2:342, 1987.

906 50. LR Belzie. Risperidone for AIDS-associated dementia—a case series. AIDS Patient Care and STDs 10:246–249, 1996. 51. F Fernandez, L Joel. The use of molidone in the treatment of psychotic and delirious patients infected with the human immunodeficiency virus: case reports. Gen Hosp Psychiatry 15:31–35, 1993. 52. D Costa, I Mogos, T Toma. Efficacy and safety of mianserin in the treatment of depression of women with cancer. Acta Psychiatr Scand 320(suppl):85–92, 1985. 53. K van Heeringen, M Zivkov. Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br J Psychiatry 169:440–443, 1996. 54. M Blumenfield, NB Levy, B Spinowitz, C Charytan, CM Beasley, AK Dubey, RJ Solomon, R Todd, A Goodman, RF Bergstrom. Fluoxetine in depressed patients on dialysis. Int J Psychiatry Med 27:71–80, 1997. 55. S Borson, J Gwendolyn, RN McDonald, MD TerenceGayle, M Deffebach, S Lakshminarayan, MD VanTuinen. Improvement in mood, physical symptoms and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease. Psychosomatics 33:190–201, 1992. 56. TA Zielinski, ES Brown, VA Nejtek, DA Khan, JJ Moore, AJ Rush. Depression in asthma: prevalence and clinical implications. Primary Care Companion J Clin Psychiatry 2:153–158, 2000. 57. F Lechin, B van der Dijs, B Orozco, H Jara, I Rada, ME Lechin, AE Lechin. Neuropharmacologic treatment of bronchial asthma with the antidepressant tianeptine: a double-blind, crossover placebo-controlled study. Clin Pharmacol Ther 64:223–232, 1998. 58. VK Jain. A psychiatric study of hypothyroidism. Psychiatr Clin 5:121–130, 1972. 59. J McGaffee, MA Barnes, S Lippmann. Psychiatric presentations of hypothyroidism. Am Fam Physician 23:129–133, 1981. 60. MN Starkman, DE Schteingart, MA Schork. Cushing’s syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome. Psychiatry Res 19:177–188, 1986. 61. PT Loosen, AJ Prange. Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review. Am J Psychiatry 139:405–416, 1982. 62. GW Arana, D Mossman. The dexamethasone suppression test and depression. Endocrinol Metabol Clin North Amer 17:21–39, 1988. 63. ES Brown, L Bobadilla, AJ Rush. Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review. Bipolar Disord (in press). 64. OM Wolkowitz, VI Reus. Treatment of depression with antiglucocorticoid drugs. Psychosom Med 61:698–711, 1999.

Brown and Perantie 65. BEP Murphy. Antiglucocorticoid therapies in major depression: a review. Psychoneuroendocrinology 22(suppl):S125–S132, 1997. 66. OM Wolkowitz, VI Reus, T Chan, F Manfrdi, W Raum, R Johnson, J Canick. Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry 45:1070–1074, 1999. 67. JJ Schildkraut. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122:509–522, 1965. 68. WE Bunney Jr, JM Davis. Norepinephrine in depressive reactions: review. Arch Gen Psychiatry 13:483–494, 1965. 69. H Miyaoka, T Otsubo, K Kamijima, M Ishii, M Onuki, K Mitamura. Depression from interferon therapy in patients with hepatitis C. Am J Psychiatry 156:1120, 1999. 70. JL Levenson, HJ Fallon. Fluoxetine treatment of depression caused by interferon-alpha. Am J Gastroenterol 88:760–761, 1993. 71. LS Goldman. Successful treatment of interferon alpha-induced mood disorder with nortriptyline. Psychosomatics 35:412–413, 1994. 72. OC Gleason, WR Yates. Five cases of interferon-alphainduced depression treated with antidepressant therapy. Psychosomatics 40:510-512, 1999. 73. AH Miller, DL Musselman, BD Pearce, S Penna, CB Nemeroff. Pretreatment with the antidepressant, paroxetine, attenuates development of sickness behavior during high dose interferon alpha therapy (abstr). Presented at XXXth Congress of International Society of Psychoneuroendocrinology, Orlando, FL, 1999. 74. ES Brown, T Suppes. Mood symptoms during corticosteroid therapy: a review. Harv Rev Psychiatry 5:239– 246, 1998. 75. ES Brown, DA Khan, VA Nejtek. The psychiatric side effects of corticosteroids. Ann Allergy Asthma Immunol 83:495–504, 1999. 76. WE Falk, MW Mahnke, DC Poskanzer. Lithium prophylaxis of corticotropin-induced psychosis. JAMA 241:1011–1012, 1979. 77. VI Reus, K Dark, HVS Puke, R Johnson, O Wolkowitz. Lithium prophylaxis of steroid-induced changes in behavior and biochemistry. Biol Psychiatry 29(suppl):162A, 1991 78. DG Blazer, WM Petrie, WP Wilson. Affective psychosis following renal transplant. Dis Nerv Syst 37:663– 667, 1976. 79. K Kemp, JR Lion, G Magram. Lithium in the treatment of a manic patient with multiple sclerosis: a case report. Dis Nerv Syst 38:210–211, 1977. 80. T Terao, T Mizuki, T Ohji, K Abe. Antidepressant effect of lithium in patients with systemic lupus erythematosus and cerebral infarction, treated with corticosteroid. Br J Psychiatry 164:109–111, 1994.

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907 86. TM Kramer, EM Cottingham. Risperidone in the treatment of steroid-induced psychosis. J Child Adolesc Psychopharmacol 9:315–316, 1999. 87. A Abbas, R Styra. Valproate prophylaxis against steroid induced psychosis. Can J Psychiatry 39:188–189, 1994. 88. A Preda, A Fazeli, BG McKay, MB Bowers Jr, CM Mazure. Lamotrigine as prophylaxis against steroidinduced mania. J Clin Psychiatry 60:708–709, 1999. 89. RC Hall, MK Popkin, B Kirkpatrick. Tricyclic exacerbation of steroid psychosis. J Nerv Ment Dis 166:738– 742, 1978. 90. AA Wyszynski, B Wyszynski. Treatment of depression with fluoxetine in cortico-steroid-dependent central nervous system Sjogren’s syndrome. Psychosomatics 34:173–177, 1993.

58 Perspectives on Treatment Interventions in Paraphilias FLORENCE THIBAUT Rouen University Hospital, Rouen, France

I.

INTRODUCTION

very specific and unchanging. Furthermore, there is considerable comorbidity among the paraphilias (one-third of pedophiles are also exhibitionists) [3]. The actual incidence and prevalence of the paraphilias remain unknown. Most sex offenders are male, but studies have estimated that up to 20% of abusers of boys and 5% of abusers of girls are women. In some of these cases, but not all, the abuse is carried out with, or under the influence of, a male partner [4]. The onset of paraphilic sexual interest usually occurs prior to age 18, and primary prevention in adolescence for paraphilias might be suggested. In spite of years of research, not much is known about the etiology of paraphilias. Nevertheless, paraphilias seem to be of multifactorial origin. Paraphilic subjects rarely seek treatment unless an arrest or discovery by a family member traps them into it. Paraphilia treatment studies are difficult to conduct and much of the research has been done on male paraphilias. For ethical reasons, double-blind placebo-controlled studies are not conducted in violent or recidivist sex offenders. Usual treatment approaches have included traditional psychoanalysis and behavior therapy techniques, but often they have not been very successful. Pharmacological treatment had historically been based on studies that involved the surgical castration of sex offenders. Traditionally, the pharmacological treatment of sexually deviant behavior was based

A variety of interventions have been attempted to reduce sexual violence. These include strengthening sanctions for punishment, establishing laws and a registry of offenders, and of course, treatment of offenders. Soothill and Gibbens [1], in a study on sex offenders with a 22-year follow-up, found that the recidivism rate rose by 3% per year and that at the end of the follow-up period, 48% of the sample had recidivated. The strongest predictor of sexual reoffence was sexual interest in children as measured by plethysmography. Indeed, homosexual pedophiles are more likely to recidivate (53.4%) as compared with a rate of 33% in heterosexual pedophiles [2]. Some sexually deviant acts are classified as paraphilias. Others arise in the context of neurological or psychiatric diseases, alcohol, or drug abuse. The term paraphilia involves the sexual fixation on an unusual object (e.g., animals, underwear), a child or other nonconsenting person, or an act that leads to the suffering or humiliation of oneself or one’s partner. The most common paraphilias are pedophilia, exhibitionism, voyeurism, sadomasochism, fetishism, or transvestism. Rape is not included in this classification. However, a small number of rapists may meet the criteria for having a paraphilia as well (often exhibitionism or pedophilia). The focus of a paraphilia is usually 909

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on the assumption that suppression of the sexual drive would decrease paraphilic sexual behavior. Ideally, successful treatment would mean that deviant sexual behaviors were suppressed, while conventional sexual fantasies and urges would be maintained or enhanced. Antiandrogen treatments, which either drastically lower testosterone levels or antagonize the action of testosterone at the receptor level, have been used alone or in conjunction with other treatment modalities. Psychotropic drugs and, more recently, serotoninergic antidepressants have also been used in the treatment of paraphilias. In the first part of this review we will evoke the efficacy of psychotropic drugs in some types of paraphilias; in a second part, we will focus on hormonal therapies.

II.

BACKGROUND

A.

Testosterone

Approximately 95% of the testosterone is produced in the testes, the other 5% by the adrenal glands. The secretion of testosterone is regulated by a feedback mechanism in the hypothalamus-pituitary-testis axis. The hypothalamus produces gonadotrophin hormone-releasing hormone (GnRH), which stimulates the pituitary gland to produce luteinizing hormone (LH). LH stimulates the release of testosterone from the testes. Testosterone has an inhibiting effect on the hypothalamus and the pituitary. The physiological effects of testosterone (and of its reduced metabolite 5a-dihydrotestosterone) are mediated through their actions on the intracellular androgen receptor. In humans, testosterone plays a major role not only in the development and maintenance of male sexual characteristics but also in sexuality and aggression [for review, see 5]. Testosterone has been shown to restore nocturnal penile tumescence responses in hypogonadal men with impaired nocturnal penile tumescence. A certain level of testosterone is necessary for sexual desire in males, above which testosterone levels does not seem to be correlated with levels of sexual drive. However, the threshold remains questionable. Although rigidity and detumescence seem to be androgen dependent to a certain degree, erections in response to visual erotic stimuli are not dependent on androgens, but erections in response to auditory stimuli possibly are [6]. Whether, or to what extent, erections as a result of

fantasies and tactile stimulation are androgen dependent remains controversial. The role of testosterone and its influence on general aggression remains unclear. In animals, testosterone plays a significant role in facilitating aggression among males [7]. In humans, more aggressive acts are often associated with high testosterone levels, but these levels remain in the normal range [5]. Although androgen-depleting agents are useful in controlling paraphilia, there is neither evidence that sex offenders have higher testosterone levels nor data indicating an increased androgen receptor activity. The expected benefit of decreasing testosterone activity (by lowering testosterone levels or by competing with testosterone at the receptor level) is probably derived from decreasing nonspecifically sexual arousal and behavior. However, Gaffney and Berlin [8] reported a marked hypersecretion of LH in response to GnRH in pedophiles, as compared to controls and other paraphilias, whereas baseline LH and testosterone values were in the normal range. B.

Estrogens and Progesterone

Most studies suggest that estrogens have little direct influence on sexual desire in either males or females. In men, relatively high levels of exogenous estrogens have been effective in inhibiting sexual desire among sex offenders [9]. Few studies have examined the effects of progesterone on male sexuality; some authors have used progesterone treatment to reduce excessive sexual desire in men [10]. C.

Serotonin

In humans, selective serotonin reuptake inhibitors (SSRIs) are associated with sexual side effects such as decreased libido and impaired ejaculation. It is not known why SSRIs produce sexual side effects, but some authors suggest that activation of the 5HT2 receptors impairs sexual functioning and stimulation of the 5HT1A receptors facilitates sexual functioning [for review see 11]. D.

Brain Regions Involved in Sexual Behavior

Animal studies indicate that lesions to the medial preoptic area, which is connected to the limbic system and brainstem, significantly impairs male copulatory behavior by impairing the animal’s ability to recognize a

Treatment Interventions in Paraphilias

sexual partner. Electrical stimulation of the paraventricular nucleus elicits penile erections [11]. Recently, positron emission tomography (PET) was used to study the brain areas activated in eight healthy males during visually evoked sexual arousal [12]. They reported the following pattern of activation: (1) a bilateral activation of the inferior temporal cortex (a visual association area); (2) an activation of the right insula and right inferior frontal cortex (two paralimbic areas relating highly processed sensory information with motivational states); and (3) the activation of the left anterior cingulate cortex (another paralimbic area known to control autonomic and endocrine functions). Activation of some of these areas was positively correlated with plasma testosterone levels. III.

BEHAVIOR THERAPY

Sex offenders employ distorted patterns of thinking which allow them to rationalize their behavior. These attitudes include, for example, the belief that children can consent to sex with an adult and that victims are responsible for being sexually assaulted. Behavior therapy programs for sex offenders seek to tackle and change these distorted attitudes as well as other major factors which can contribute to sexual offending, including inability to control anger (anger serves as the primary motivation for many sex crimes, especially for rapists), inability to express feelings and communicate effectively, problems in managing stress, alcohol and drug abuse, or deviant sexual arousal. The offenders who have the most distorted thoughts and attitudes toward children are fixated pedophiles. The aims of such programmes are to (1) counter the offender’s distorted beliefs; (2) increase their awareness of the effects of their crimes on victims; (3) get offenders to accept responsibility for the results of their actions; and (4) assist offenders to develop ways of controlling their deviant behavior, preventing relapse and avoiding high-risk situations. Research studies in the United States into these treatment programs in prisons and in the community have identified substantial reductions in reoffending rates [for review see 13]. IV.

PSYCHOTROPIC DRUGS

A.

SSRIs

Several authors have conceptualized hypersexuality and some paraphilias as related to obsessive-compulsive disorders (OCD), or even impulsive control

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disorders [14]. In addition, there is a very high comorbidity of depression in the paraphilic patients. Since 1990, numerous uncontrolled single-case studies have reported the efficacy of SSRIs or clomipramine in the treatment of paraphilias, as well as hypersexuality without paraphilia [for review see 15–17]. One of the first reports on the efficacy of an antidepressant in a male exhibitionist was accidental. This man was suffering from dysphoria which was treated and the paraphilic behavior concomitantly decreased. The starting doses of SSRIs are low and may be progressively increased to the dosages usually prescribed in OCD. The maximal reduction of the symptoms occurs after 1–3 months. In most studies that have reported on the duration of treatment, the treatment period varied between 3 to 12 months. Coleman et al. [18], Kafka [19], and Greenberg et al. [20] conducted several open clinical trials reporting the efficacy of SSRIs in paraphilia. In Kafka’s study [19], paraphilic and hypersexual male nonresponders to sertraline for at least 4 weeks (100 mg/ day) were offered fluoxetine (50 mg/day), and twothirds (six of nine subjects) showed clinical improvement. No pedophiles were included in this study. Most subjects had comorbid mood disorders. Greenberg et al. [20] have found fluvoxamine, fluoxetine, and sertraline equally effective in a retrospective study of 58 paraphilic male subjects for 12 weeks. However, Stein et al. [14] reported that fluvoxamine (200–300 mg/day) or fluoxetine (60–80 mg/ day) did not improve five paraphilic subjects after 2–10 months of treatment. However, comorbid nonsexual OCD symptoms improved in these patients. With the exception of Stein’s study, SSRIs had improved paraphilic patients. Kafka and Prentsky [21] reported that fluoxetine (40 mg/day for 12 weeks) reduced the frequency of paraphilic behaviors preferentially, and they hypothesized that SSRIs may even facilitate normal sexual arousal. In the same way, Bradford [3] reported that the physiologic measures of sexual arousal (penile plethysmography) showed a decrease in pedophilic arousal (by 53%) and an improved or maintained normophilic arousal after 12 weeks of sertraline treatment (130 mg/ day). Interestingly, Kruesi et al. [22], in a double-blind crossover study, have observed that clomipramine (25–250 mg/day) and desipramine (25–250 mg/day) reduced equally paraphilic behavior in 8 subjects (7 of 15 dropped out). These results indicate that there was no preferential response to the more specific serotoninergic antidepressant.

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In many studies, heterogeneous groups of paraphilic subjects were included. Exhibitionism, compulsive masturbation, and pedophilia were the most frequent paraphilias in which SSRIs have shown improvement. In most cases, other psychiatric diagnoses were associated to paraphilias (mostly affective disorders or OCD). These studies draw attention to a new option for treating paraphilias that are accompanied by OCD, impulse control disorders, or depressive disorders. However, despite the increasing clinical use of SSRIs for paraphilia and hypersexuality, double-blind placebo-controlled trials with these agents are lacking and, in addition, the use of SSRI in adolescents deserves investigations.

B.

Other Psychotropic Drugs

Various phenothiazines such as thioridazine, fluphenazine, or butyrophenones such as benperidol, have been used in sex offenders [23,24]. Their incomplete efficacy and the risk of tardive dyskinesia have limited their prescription in the treatment of paraphilia. However, antipsychotic agents may benefit sex offenders with comorbid psychotic disorders; indeed, in these patients hormonal therapy may even exacerbate psychosis. Anecdotal reports have reported the quick response observed with lithium in different types of paraphilia (within 1–10 days). Most of these subjects had paraphilia comorbid with mood disorders [18].

V.

SURGICAL TREATMENTS

A.

Surgical Castration

Castration has been practiced on human beings in all cultures for thousands of years. In ancient China and Oriental sagas, eunuchs served as chamberlains or guards of women’s quarters. In Europe, castration was done on modern psychiatric indication for the first time in Switzerland in 1892, as an ‘‘imbecile’’ was cured from his neuralgic pains from the testes and his hypersexuality. Heim and Hursch [25], in their review of European literature, reported that populations of surgically castrated sex offenders (follow-up max 20 years) showed recidivism rates of 2.5– 7.5% (1200 sex offenders), as opposed to recidivism rate of 60–84% before castration, and of 39% in 685 sex offenders who were not castrated. Reoffence rates

were usually based on rearrest or conviction. The decline of the nonsexual crimes after castration was less obvious. In castrated subjects, there was no change in the object of the offender’s sexual desire or sexual orientation. Unfortunately, these studies were not controlled. Forty percent to 50% of subjects were content with the outcome of castration, whereas 30% of patients complained of undesirable side effects. Twenty percent to 40% of castrates felt calmer after castration, whereas 20–30% complained that they were often depressed since castration. A substantial percentage of surgical castrates retain sexual functioning (sex drive and potency) (35% of young subjects). Moreover, Eibl [26] reported that 19 of 38 castrated sex offenders whose penile erections were measured while viewing a sex movie, exhibited full erections. In the United States (in several states) and in Europe (in Germany and Czechoslovakia), surgical castration is allowed in place of chemical castration. In some countries (e.g., Germany) the Law on Voluntary Castration provided that voluntary castration be available in men aged at least 25 years. This would be available in the case of seriously disturbed and dangerous sexual offenders. A board of experts is required to review the request in order to establish that castration is necessary for the prevention of further sexual offences. The incidence of surgical castration in Germany is small (five cases per year). California passed a law in 1996 that mandated chemical castration for repeat child molesters. Several other states have considered passing such laws (Colorado, Florida, Louisiana, Massachusetts, Michigan, Texas, and Washington). Castration has increasingly been seen as ethically problematic. However, Bailey and Greenberg [27] argued that offering castration as an option to sex offenders in exchange for sentence reduction is not unethical. The results obtained using surgical castration have motivated further research in antiandrogenic treatment.

B.

Neurosurgery

Stereotactic neurosurgery has previously been attempted in sex offenders. Because of the level of invasiveness of this technique, it has not been practical to any extent.


VI.

HORMONAL THERAPIES

A.

Estrogens

Historically, estrogens were the first hormonal agents used for the treatment of sex offenders. Despite their clinical efficacy, their adverse effects (gynecomastia, increased occurrence of thrombosis, testes atrophy, carcinoma of breast) rapidly limited their use [28]. B.

Medroxyprogesterone Acetate (DepoProvera) and Cyproterone Acetate (Androcur)

Medroxyprogesterone acetate (MPA) is a progesterone derivative. MPA is already used as a contraceptive, and as a treatment for endometriosis or breast cancer. The first report of its efficacy in reducing sexual drive was published in 1958 in healthy males [29]. MPA may be prescribed as a depot preparation (300–500 mg/ week) or PO [50–100 mg/day) (oral administration may sometimes be used even if its absorption is less erratic) [30]. MPA reduces testosterone by inhibiting its production through reducing LH. MPA induces the testosterone reductase which accelerates testosterone metabolism, and reduces plasma testosterone by enhancing its clearance. In addition, MPA also has an effect in increasing testosterone binding to testosterone hormone-binding globulin (TeBG), which reduces the availability of free testosterone, and finally, MPA may also bind to androgen receptors [31]. The drug was first noted for its efficacy in the treatment of one case of paraphilia by Money in 1968 [32]. Cyproterone acetate (CPA) is already used as a treatment for precocious puberty and as a treatment for carcinoma of the prostate. CPA is a synthetic steroid, similar to progesterone, which acts directly on all androgen receptors (including brain receptors), where it blocks intracellular testosterone uptake and the intracellular metabolism of the androgen. Indeed, CPA is a competitive inhibitor of testosterone and dihydrotestosterone at androgen receptor sites. In addition, it has a strong progestational action which causes an inhibition of GnRH secretion. CPA may be given either by injection (depot form: 200–400 mg once weekly or every 2 weeks) or by tablets (100–200 mg/ day). The first clinical use of CPA in sex offenders (predominantly exhibitionists) occurred in Germany [33], which reported efficacy of CPA in 80% of the cases in an open study. Moreover, in 80% of the cases, 100 mg/

913

day oral CPA was sufficient. Depending on dosage, the authors suggested that CPA could be used as a chemical castration agent or as a reductor of sexual drive, allowing erecting ability in nondeviant sexual behavior. MPA is available in the United States; CPA is used predominantly in Canada, the Middle East, and Europe. Numerous uncontrolled case studies involving several hundreds of patients and some controlled studies (alternating antiandrogens with placebo and using each subject as his own control) have repeatedly reported the efficacy of MPA and CPA in the treatment of paraphilias [10,34–36; for review see 15,16,37]. Both CPA and MPA, along with reduction of active testosterone levels, significantly decreased self-reported deviant sexual behavior or fantasies and frequency of masturbation within 2–4 weeks in 80% of patients. Morning erections, ejaculations, and spermatogenesis were decreased. The efficacy was maintained while on treatment for up to 8 years. Meyer and Cole [38] have examined the reoffence rates for 127 individuals taking CPA and have found a mean rate of 6% at the end of the follow-up period, as compared with 85% before treatment from seven studies; the duration of followup varied from 2 months to 4.5 years. Many of the reoffences were committed by individuals who did not comply with therapy. In addition, a significant number of patients reoffend after stopping therapy. The reoffence rate for 334 individuals taking depot MPA was greater than with CPA with a mean rate of 27% at the end of the follow-up period, as compared with 50% before treatment (follow-up 6 months to 13 years) [38]. Five studies reported increased recidivism after MPA was stopped. Money et al. [39], using MPA, reported no reduction in nonsexual crimes in sex offenders with antisocial behavior. However, some studies have reported reduced anxiety and irritability with CPA or MPA in their patients [10,36]. The results of the evaluation of penile responses to a variety of erotic stimuli, using plethysmography, for CPA and MPA, have been less impressive than when subjective measures of improvement have been used. Using visual erotic stimuli, Bancroft et al. [9], Langevin et al. [40], and Cooper et al. [10] found that CPA or MPA had no significant or more variable effects on the erectile responses of sex offenders. These results are in accordance with the view that erections in response to visual stimuli are less androgen dependent. By contrast, Bradford and Pawlak [36], using CPA, have reported a consistent trend toward preferential sup-

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Thibaut

pression of deviant arousal during phallometric measures in a group of pedophiles with high levels of testosterone (within the normal range). The adverse effects of CPA, in addition to those related to hypoandrogenism (such as bone mineral loss), include gynecomastia (20% of cases, reversible), depression, fatigue, weight gain, leg cramps, decreased glucose tolerance, increased level of prolactin, and hepatocellular damage (which may be rarely fatal). Adrenal suppression has been described primarily in adolescents with CPA [41]. The adverse effects of MPA include weight gain, hypertension, gynecomastia, lethargy, leg cramps, bone mineral loss, hot and cold flashes, diabetes mellitus, gallstones, adrenal suppression, and thromboembolic phenomena. Pulmonary embolism is the most severe side effect reported. CPA and MPA treatment have to be carefully managed medically, via physical examination, especially for the effects of feminization. Biochemical monitoring of liver function is required when CPA is used. The treatment effects of CPA or MPA were completely reversible, 1 or 2 months after medication withdrawal. CPA treatment has been compared with estrogens, MPA, and GnRHa treatments in sex offenders. Brancroft et al. [9] compared the effects of 100 mg/ day CPA and of 0.01 mg ethinylestradiol twice a day. The two treatments equally decreased sexual interest, sexual activity, and objective measurement of sexual arousal with no major side effects. Cooper et al. [10] reported the first double-blind comparison of MPA (100–200 mg/day) and CPA (100–200 mg/day) and concluded that MPA and CPA performed equally in seven sex offenders with no side effects except for those related to hypoandrogenism. Cooper and Cernovsky [42] described a significantly greater decrease in self-report and objective measure of sexual arousal with leuprolide (7.5 mg IM per month), as compared with previous CPA treatment (after a 10-week washout period), in one case of pedophilia. Although there is no consensus on the optimal duration of CPA or MPA treatment, many authors have written that 3–5 years of treatment are necessary [for review, see 15]. Unfortunately, MPA and CPA have rarely been used in women with paraphilia [43]. C.

GnRH Analogs or GnRH Agonists (GnRHa) [Triptorelin (Decapeptyl-CR), Leuprolide (Lupron), and Gosereline (Zoladex)]

After an initial stimulation, these long-acting GnRH analogs cause rapid desensitization of GnRH recep-

tors, resulting in reduction of LH (and to a lesser extent of FSH) and testosterone to castration levels. They do not interfere with the action of androgens of adrenal origin. Somehow, only 40% of normal controls reported reduction in normal sexual desire with GnRH treatment [44]. In addition, GnRH-containing neurons project into pituitary and extrapituitary sites, such as the olfactory bulb or the amygdala. At these latter sites, GnRH is believed to act as a neuromodulator and, through this action, may be involved in sexual behavior [45,46]. Moreover, the intracerebroventricular administration of GnRH suppresses aggression in male rats [47]. Leuprolide (Lupron) and gosereline (Zoladex) are already approved by the U.S. Food and Drug Administration for prostate cancer, central precocious puberty, and endometriosis. Rousseau et al. [48] reported the first case of a male severe exhibitionist who has been successfully treated for 26 weeks with the combination of a short-acting GnRHa and the antiandrogen flutamide. The assessment of the patient’s sexual fantasies and activities was achieved through self-reports. Concurrently with the decrease of testosterone, a sharp decline in the patient’s deviant sexual activities and fantasies was observed. The patient’s deviant activities completely ended after 2–4 weeks. Two months after discontinuation of the treatment, the patient relapsed. Dickey [49] reported the case of a male patient with multiple paraphilias, successfully treated for 6 months with a long-acting GnRH agonist (leuprolide acetate), and observed that suppression of androgen of testicular origin alone was sufficient for treatment. Thibaut et al. [50] reported the first open study describing the efficacy of triptorelin (3.75 mg IM monthly) in five out of six cases of severe male paraphilia (four cases of pedophilia, one case of severe exhibitionism, one case of sexual sadism). In all patients, CPA treatment had been initiated 1 week before GnRHa and concurrently prescribed for at least 10 days with GnRHa in order to control the early and transient increase in plasma testosterone level, and possibly in sexual drive, due to an initial stimulation effect of GnRHa. In five cases, concurrent with the decrease of plasma testosterone, LH, and estradiol levels within the first month, we observed a parallel drop of deviant sexual interest and activities (using self-reports), and the deviant behavior ended. The TeBG remained unchanged, which leads to a decrease in free testosterone level. The beneficial effect of the treatment was maintained during follow-up periods varying from 7 months to 3 years. Apparently,


the remaining secretion of androgens of adrenal origin did not interfere with the efficacy of GnRHa, and the addition of a pure antiandrogen did not seem useful. However, the remaining low levels of testosterone of adrenal origin might have played a role in the failure of GnRHa in one patient. In this case, the combination of CPA and GnRHa might have been effective. Ro¨sler and Witztum [51], using a similar methodology, reported the efficacy of GnRHa (triptorelin, 3.75 mg IM monthly) in 30 men (25 pedophiles) with severe, long-standing paraphilia, in an open study, with a duration of follow-up of 12–42 months. They did not use CPA to counter the possible initial increase in deviant sexual behavior during the first weeks of GnRHa treatment. In five cases of paraphilia, a diagnosis of paranoid schizophrenia was reported. The maximal reduction in sexual desire and activity occurred after 3–10 months according to patients. The authors reported a decrease of 50% of baseline testicular volume after 36 months of treatment. The duration of antiandrogen treatment necessary to achieve a definite disappearance of deviant sexual behavior and the conditions of treatment interruption remain unanswered. In most studies, the duration of antiandrogenic treatment is < 1 year, except for the study by Davies [52], which reported no recidivism during 3 years of follow-up after cessation of 5 years’ CPA treatment in different types of paraphilias. In Rousseau’s study [48], they reported recidivism when successful GnRHa treatment was abruptly stopped at the 26th week. In Thibaut’s study [53], the authors described recidivism of deviant sexual behavior within 8–10 weeks in two cases, when successful GnRHa treatment was abruptly interrupted after 12 and 34 months, respectively. In one case, GnRHa treatment was reintroduced and the deviant behavior disappeared. In Ro¨sler’s study [51], in eight cases, treatment was interrupted after 8–10 months (owing to unspecified intolerable side effects in three cases). In five cases, in whom follow-up was possible, paraphilia resumed. In men who interrupted treatment, serum testosterone returned to baseline level within 2 months. In these three studies, the patients’ recidivism might have been encouraged by the abrupt withdrawal of GnRHa and might have resulted from a release of testosterone interacting with hypersensitive androgen receptors. By contrast, in Thibaut’s study [53], in a third case, after 4.5 years of effective GnRHa treatment, testosterone was gradually added to GnRHa in order to avoid the ‘‘rebound effect’’ in sexual behavior, which could be observed 4–6 weeks

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after abrupt antiandrogen treatment withdrawal, when a transient increase in testosterone levels to above baseline levels appeared [48,53,54]. In our case, the deviant sexual behavior did not return when GnRHa and testosterone were interrupted, after 10 months of concurrent prescription, as soon as testosterone level was back in the normal range. Maintenance of the beneficial effect of antiandrogen treatment after interruption could be the result of a conditioned behavioral response, or it could result from changes in androgen-receptor sensitivity. In summary, concurrent with the decrease in testosterone levels, GnRHa treatment was effective in 37 out of 38 cases of severe paraphilia with a maximal followup duration of 6 years [55]. Twenty-one patients out of 38 were convicted for sexual offences prior to treatment. GnRHa treatment was more potent than CPA or MPA: 13 patients out of 38 were previously unsuccessfully treated with CPA (150–300 mg/day for up to 10 years) or MPA, and seven patients were previously unsuccessfully treated with SSRIs. The use of longacting GnRHa excluded the uncontrolled breaks in the therapy often observed with oral CPA treatment (depot CPA is not available in France). In addition, GnRHa treatment can lead to reversible castration without further side effects than those related to hypoandrogenism (i.e., hot flashes, asthenia, depression, decrease in normal sexual behavior, and decrease in bone mineral density, which needs to be closely monitored, especially after a duration of 2 years of antiandrogen treatment, and treated if necessary). These studies do not support the specificity of GnRHa treatment in reducing sex drive for deviant versus normal stimuli. However, while treated, 14 patients out of 37 maintained lower erectile capacity and were able to maintain some masturbation and coital activities; this was proportional to age. The direction of the sexual drive was not affected. Some people may argue that sex offenders may try to revive their libidos by obtaining exogenous testosterone. We can answer that many paraphilic men feel their paraphilia as unwanted and experience the diminution of their deviant behavior as relief. In addition, these patients could be subject to random blood tests which could detect excess testosterone. However, none of these studies utilized placebo, because of the potential for the men to continue to offend without active medication. Moreover, none of these studies used objective measurements of sexual activity. The need for controlled studies, using large samples of well-defined paraphilic patients, to confirm these promising results is urgent.

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VII.

Thibaut

CONCLUSION

Most people recognize that incarceration alone will not solve sexual violence. Treating the offenders is critical in an approach to preventing sexual violence and reducing victimization. A recent meta-analysis of factors predicting recidivism, based on 61 follow-up studies, including 23,400 sex offenders, found that failure to complete treatment was associated with higher risk of recidivism of sex offences [56]. However, it is not possible at this time to identify those individuals who will not have any recurrence compared with those who may. Sex offenders with intellectual disabilities or sequella of head injury are particularly susceptible to reoffend after stopping therapy. Alcohol and drug abuse have also been reported as risk factors of reoffences. By contrast, self-referred or highly motivated subjects are best responders to chemical treatment. Paraphilic men may be ordered by the judge to undergo psychiatric treatment as part of the rehabilitative aspect of sentencing, but these situations should leave treatment options up to the professionals. In case of antiandrogen treatment, it may include freely given informed consent. Indeed, these treatments must remain a choice for the patient to make on the basis of medical advice. Somehow, in some cases, failure of the offender to participate in treatment could lead to sanctions by the court. Prior to treatment, each individual should be carefully examined by at least one mental health professional, in order to identify and evaluate sex offenders and, if necessary, protect offenders who are suffering from a major mental illness or mental retardation. However, little is known about which treatments are most effective, for which offenders, over what duration, or in what combination. Because of ethical issues, the great majority of pharmacological studies are uncontrolled studies with methodological problems. One major difficulty is the identification of standardized and reliable measures of sexual behavior. Sex offenders’ self-reports of their sexual activity and arrest records reports are usually used, but they do not constitute reliable indices of deviant or nondeviant sexual behavior. In addition, the definition of recidivism is often different from one study to another. In the same way, the validity and reliability of the evaluation of sexual response via penile plethysmography, which measures penile erectile responses to various visual erotic stimuli in a laboratory, are still a subject of debate. In any case, plethysmography should be used to predict further sex offences or to make a diagnosis.

Moreover, various types of sex offenders are included in the same studies and makes it difficult to draw definite conclusions owing to the great heterogeneity of the samples of patients. Duration of follow-up periods is another source of variability among studies. Large international controlled studies including big samples of well-defined paraphilic patients are clearly needed to confirm these preliminary data, reporting the efficacy of pharmacological treatments in paraphilias. In accordance with Gijs and Gooren [15], we may propose the following guidelines: 1. Not every sex offender is a candidate for antiandrogen treatment, even if it has the benefit of being reversible once discontinued. For paraphilias characterized by intense and frequent deviant sexual desire and arousal, which highly predispose the patient to severe paraphilic behaviors (such as pedophilia or rape), a hormonal intervention may be needed. Antiandrogens have to be prescribed by a physician after appropriate medical assessment and after informed consent is given. These medications should be used after other alternatives are ruled out or when there is a high risk of sexual violence. However, hormonal agents cannot be easily used in the treatment of sexually deviant adolescents owing to possible interference with the development or course of puberty. 2. Antiandrogens significantly reduce the intensity and frequency of sexual arousal but do not change the content of paraphilias. However, MPA and CPA treatments are associated with high dropout rates [16]. In spite of their efficacy, there are associated with a high percentage of side effects which have considerably limited their use, especially for MPA, in Europe. In addition, uncontrolled breaks in the therapy are often observed with oral CPA treatment. Long-acting GnRHa is more potent than CPA or MPA. Moreover, it induces fewer side effects, except for those related to hypoandrogenism. Long-acting GnRHa may be administered parentally once every 1–3 months. GnRHa treatment probably constitutes the most promising treatment for sex offenders at high risk of sexual violence, such as pedophiles or rapists. In spite of these new treatments, which induce chemical reversible castration, in the United States (in several states) and in Europe (in Germany and Czechoslovakia), surgical castration is still allowed in place of chemical castration for repeat child molesters. 3. SSRIs are useful in paraphilias associated with obsessive-compulsive disorders, impulse control disorders, or depressive disorders. Some paraphilic subjects clearly suffer from an inability to resist their sexual urges, which has a strong compulsive element and


often causes considerable subjective distress. SSRIs can be effective in these cases, which are usually not associated with dangerous sex offending. 4. Pharmacological interventions should always be part of a more comprehensive treatment plan including psychotherapy and, in most cases, behavior therapy. It would be informative for future research to include a focus on all sex offenders including women and adolescents.

REFERENCES 1. KL Soothill, TCN Gibbens. Recidivism of sexual offenders: reappraisal. Br J Criminol 18:267–275, 1978. 2. PH Gebhard, JH Gagnon, WB Pomeroy, CV Christeason. Sex Offenders: An Analysis of Types. New York: Harper and Row, 1965, pp 811–812. 3. JMW Bradford. The paraphilias, obsessive compulsive spectrum disorder, and the treatment of sexually deviant behaviour. Psychiatr Q 70(3):209–219, 1999. 4. M Elliott. Female sexual abusers: the ultimate taboo. In: M Elliott, ed. Female Sexual Abusers: The Ultimate Taboo. London: J. Wiley and Sons, 1993. 5. DR Rubinow, PJ Schmidt. Androgens, brain and behavior. Am J Psychiatry 153:974–984, 1996. 6. C Carani, J Bancroft, A Granata, G Del Rio, P Marrama. Testosterone and erectile function, nocturnal penile tumescence and rigidity, and erectile response to visual erotic stimuli in hypogonadal and eugonadal men. Psychoneuroendocrinology 17(6): 647–654, 1992. 7. RM Rose, JW Holaday, IS Bernstein. Plasma testosterone, dominance rank and aggressive behaviour in male rhesus monkeys. Nature 231:366–368, 1972. 8. GR Gaffney, FS Berlin. Is there hypothalamic-pituitary-gonadal dysfunction in paedophilia? Br J Psychiatry 145:657–660, 1984. 9. J Bancroft, G Tennent, K Loucas, J Cass. The control of deviant sexual behavior by drugs. I. Behavioral changes following estrogens and antiandrogens. Br J Psychiatry 125:310–315, 1974. 10. AJ Cooper, S Sandhu, S Losztyn, ZZ Cernovsky. A double-blind placebo controlled trial of medroxyprogesterone acetate and cyproterone acetate with seven pedophiles. Can J Psychiatry 37:687–693, 1992. 11. CM Meston, PF Frohlich. The neurobiology of sexual function. Arch Gen Psychiatry 57:1012–1030, 2000. 12. S Stole´ru, MC Gre´goire, D Ge´rard, J Decety, E Lafarge, L Cinotti, F Lavenne, D Le Bars, E VernetMaury, H Rada, C Collet, B Mazoyer, MG Forest, F Magnin, A Spira, D Comar. Neuroanatomical correlates of visually evoked sexual arousal in human males. Arch Sex Behav 28(1):1–21, 1999.

917 13. LS Grossman, B Martis, CG Fichter. Are sex offenders treatable? A research overview. Psychiatr Serv 50:349– 391, 1999. 14. DJ Stein, E Hollander, DT Anthony, FR Schneier, B Fallon, MR Liebowitz, DF Klein. Serotonergic medication of sexual obsessions, sexual addictions, and paraphilias. J Clin Psychiatry 53:267–271, 1992. 15. L Gijs, L Gooren. Hormonal and psychopharmacological interventions in the treatment of paraphilias: an update. J Sex Res 33(4):273–290, 1996. 16. JMW Bradford, DM Greenberg. Pharmacological treatment of deviant sexual behaviour. Annu Rev Sex Behav 7:283–306, 1996. 17. R Balon. Pharmacological treatment of paraphilias with a focus on antidepressants. J Sex Marital Ther 24:241–254, 1998. 18. E. Coleman, J Cesnik, AM Moore, SM Dwyer. An exploratory study of the role of psychotropic medications in treatment of sexual offenders. J Off Rehab 18:75–88, 1992. 19. MP Kafka. Sertraline pharmacotherapy for paraphilias and paraphilia-related disorders: an open trial. Ann Clin Psychiatry 6:189–195, 1994. 20. DM Greenberg, JMW Bradford, S Curry, A O’Rourke. A comparison of treatment of paraphilias with three serotonin reuptake inhibitors: a retrospective study. Bull Am Acad Psychiatry Law 24:525–532, 1996. 21. MP Kafka, R. Prentsky. A comparative study of nonparaphilic sexual addictions and paraphilias in men. J Clin Psychiatry 53: 345–350, 1992. 22. MP Kruesi, S Fine, L Valladares, RA Phillips, J Rapoport. Paraphilias : a double bind cross-over comparison of clomipramine versus desipramine. Arch Sex Behav 21:587–593, 1992. 23. P Sterkman, F Geerts. Is benperidol (RF 504) the specific drug for the treatment of excessive and disinhibited sexual behaviour? Acta Neurol Psychiatr 66:1030– 1040, 1966. 24. AA Bartholomew. A long-acting phenothiazine as a possible agent to control deviant sexual behavior. Am J Psychiatr 124:917–923, 1968. 25. N Heim, CJ Hursch. Castration for sex offenders: treatment or punishment? A review and critique of recent European literature. Arch Sex Behav 8(3):281– 304, 1979. 26. E Eibl. Treatment and after-care of 300 sex offenders, especially with regard to penile plethysmography. Justizministerium Baden-Wu¨rttemberg. Proceedings of the German Conference on Treatment Possibilities for Sex Offenders in Eppingen, Stuttgart, 1978. 27. JM Bailey, AS Greenberg. The science and ethics of castration: lessons from the Morse case. Northwestern Law Rev 92: 266–277, 1998. 28. LH Whittaker. Estrogens and psychosexual disorders. Med J Aust 2:547–549, 1959.

918 29. CG Heller, M Laidlaw, HT Harvey, DL Nelson. The effects of the progestational compounds on the reproductive processes of the human male. Ann NY Acad Sci 71:649–655, 1958. 30. HG Gottesman, DS Schubert. Low-dose oral medroxyprogesterone acetate in the management of the paraphilias. J Clin Psychiatry 54(5):182–188, 1993. 31. AL Southren, GG Gordon, J Vittek, K Altman. Effect of progestagens on androgen metabolism. In: L Martini, M Motta, eds. Androgens and antiandrogens. New York: Raven Press, 1977, pp 263–279. 32. J Money. Discussion on hormonal inhibition of libido in male sex offenders. In: RP Michael, ed. Endocrinology and Human Behavior. London: Oxford University Press, 1968, p 169. 33. U Laschet, L Laschet. Psychopharmacotherapy of sex offenders with cyproterone acetate. Pharmacopsychiatr Neuropsychopharmacol Adv Clin Res 4:99–110, 1971. 34. AJ Cooper A placebo controlled trial of the antiandrogen cyproterone acetate in deviant hypersexuality. Compr Psychiatry 22:458–465, 1981. 35. TA Kiersch. Treatment of sex offenders with DepoProvera. Bull Am Acad Psychiatry Law 18:179–187, 1990. 36. JMW Bradford, A Pawlak. Double-blind placebo cross-over study of cyproterone acetate in the treatment of paraphilias. Arch Sex Behav 22:383–402, 1993. 37. A Ro¨sler, E Witztum. Pharmacotherapy of paraphilias in the next millennium. Behav Sci Law 18:43–56, 2000. 38. WJ Meyer, CM Cole. Physical and chemical castration of sex offenders: a review. J Off Rehab 25(3/4):1–18, 1997. 39. J Money, C Wiedeking, P Walker, C Migeon, W Meyer, D Borgaonkar. 47,XYY and 46,XY males with antisocial and/or sex-offending behavior: antiandrogen therapy plus counselling. Psychoneuroendocrinology 1:165–178, 1975. 40. R Langevin, D Paitich, S Hucker, S Newman, G Ramsey, S Pope, G Geller, C Anderson. The effect of assertiveness training, Provera, and sex of therapist in the treatment of genital exhibitionism. J Behav Ther Exp Psychiatry 10:275–282, 1979. 41. F Neumann. Pharmacology and potential use of cyproterone acetate. Horm Metab Res 9:1–13, 1977. 42. AJ Cooper, ZZ Cernovski. Comparison of cyproterone acetate and leuprolide acetate (LHRH agonist) in a chronic pedophile: a clinical case study. Biol Psychiatry 36(4):269–271, 1994.

Thibaut 43. AJ Cooper, S Swaminath, D Baxter, C Poulin. A female sex offender with multiple paraphilias: a psychological, physiologic (laboratory sexual arousal) and endocrine case study. Can J Psychiatry 35:334– 337, 1990. 44. PT Loosen, SE Purdon, SN Pavlou. Effects on behavior of modulation of gonadal function in men with gonadotrophin releasing hormone antagonists. Am J Psychiatry 151:271–273, 1994. 45. KM Kendrick, AF Dixson. Luteinizing hormone releasing hormone enhances proceptivity in a primate. Neuroendocrinology 41:449–453, 1985. 46. RL Moss, CA Dudley. Luteinizing hormone–releasing hormone (LHRH): peptidergic signals in the neural integration of female reproductive behavior. In: JM Lakoski, JR Perez-Polo, DK Rassin, eds. Neural Control of Reproductive Function. New York: Liss, 1989, pp 485–499. 47. T Kadar G Telegdy, AV Schally. Behavioral effects of centrally administered LH-RH agonist in rats. Physiol Behav 50:601–605, 1992. 48. L Rousseau, M Couture, A Dupont, F Labrie, N Couture. Effect of combined androgen blockade with an LHRH agonist and flutamide in one severe case of male exhibitionism. Can J Psychiatry 35:338–341, 1990. 49. R Dickey. The management of a case of treatmentresistant paraphilia with a long-acting LHRH agonist. Can J Psychiatry 37:567–569, 1992. 50. F Thibaut, B Cordier, JM Kuhn. Effect of a longlasting gonadotrophin hormone–releasing hormone agonist in six cases of severe male paraphilia. Acta Psychiatr Scand 87:445–450, 1993. 51. A Ro¨sler, E Witztum. Treatment of men with paraphilia with a long-acting analogue of gonadotropinreleasing hormone. N Engl J Med 338:416–422, 1998. 52. TS Davies. Cyproterone acetate for male hypersexuality. J Int Med Res 2:159–163, 1974. 53. F Thibaut, B Cordier, JM Kuhn. Gonadotrophin hormone releasing hormone agonist in cases of severe paraphilia: a lifetime treatment? Psychoneuroendocrinology 21(4):411–419, 1996. 54. JM Bradford. Organic treatment for the male sexual offender. Ann NY Acad Sci 528:193–202, 1998. 55. F Thibaut, JM Kuhn, B Cordier, M Petit. Les traitements hormonaux de la de´linquance sexuelle. Ence´phale XXIV:132–137, 1998. 56. RK Hanson, MT Bussiere. Predicting relapse: a metaanalysis of sexual offender recidivism studies. J Consult Clin Psychol 66:348–362, 1998.

59 Potential of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric Conditions THOMAS E. SCHLAEPFER University of Bern, Bern, Switzerland, and Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

MARKUS KOSEL University of Bern, Bern, Switzerland

I.

INTRODUCTION

by the FDA in 1997 for the management of medically refractory partial-onset epileptic seizures. Stimulation electrodes are attached to the left vagus nerve at the cervical level and linked to an implanted nerve stimulator—in function and size similar to a cardiac pacemaker—which is inserted in a pouch in the left chest wall. Applications in psychiatry are currently being investigated, and first multicenter studies for the treatment of depression have been completed [2]. DBS is a method of treating motor symptoms, mainly in Parkinson’s disease, where stimulatory electrodes are placed in appropriate structures of the brain and linked to a nerve stimulator similar to those used for VNS. Studies of its potential efficacy in patients suffering from depressive disorder and obsessive-compulsive disorder (OCD) are being conducted at the moment. TMS refers to the delivery of a magnetic pulse to the cortex of a subject trough a handheld stimulating coil, which is directly applied to the head (Figs. 1, 2). The magnetic pulses pass unimpeded through scalp and skull and induce an electrical current in the underlying tissue, which in turn is able to depolarize neurons. The main advantages of this stimulation

Transcranial magnetic stimulation (TMS) is a noninvasive technique to stimulate the human brain in vivo using very strong, pulsed magnetic fields. Owing to recent technical advances, the needed equipment is comparatively affordable and no surgery and/or anesthesia is needed in contrast to other new methods of direct brain stimulation, like magnetic seizure therapy (MST), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). These techniques have received considerable research and clinical interest in recent years because there are indications that they might have effects in neuropsychiatric disorders, especially affective disorders. MST is a novel approach in which a focal magnetic stimulus applied to the cortex is used to elicit generalized convulsions in patients under general anesthesia and muscle relaxation, similar to electroconvulsive therapy (ECT). At the present moment, it is clearly an experimental procedure, since no results from trials assessing its clinical efficacy are available. However, the general feasibility in human patients has been established [1]. VNS is a method approved 919

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Figure 1 Transcranial magnetic stimulation: principle of action. A transient current in a magnetic stimulating coil over the scalp induces a small current in the brain, which is able to activate neural elements in the motor cortex.

method are its relative noninvasiveness and the possibility to stimulate very focused. With recent technology, single or paired pulse technique which are used to assess brain physiology and pathophysiology [3], as well as repetitive transcranial magnetic stimulation (rTMS) (high- frequency rTMS: stimulation faster than 1 Hz; low-frequency rTMS: stimulation at 1 or less Hz) up to 80 Hz can be delivered. At the moment, clinical interest in the rTMS technique originates mainly from 15 placebo-controlled clinical studies involving up to 70 subjects [4] where rTMS was delivered to patients suffering from treatment refractory depression. However, results are not yet conclusive with respect to clinical efficacy. It has been demonstrated that rTMS has effects on the brain, but whether its properties are clinically useful and constitute meaningful alternatives to already available treatment modalities remains to be investigated. Today rTMS seems to be a very interesting and potentially promising technique in search of useful applications in neuropsychiatry. We focus this review on practical details concerning the delivery of rTMS and on the current state of knowledge concerning its clinical applications in neuropsychiatric disorders. We will give an overview of TMS to the clinical psychiatrist. After a brief historical overview, results of application of rTMS in patients suffering mainly from mood disorders are discussed. Then we will discuss practical issues of rTMS application in volunteers and patients, its side effects and safety issues, and data on putative mechanisms of action. We will finish with a brief outlook on future developments.

Figure 2 Practical use of repetitive transcranial magnetic stimulation. This is a usual setting for nonconvulsive rTMS studies. Patients are awake, sitting relaxed in a chair while stimulation (here to the left dorsolateral prefrontal cortex) is applied. A typical stimulator, here with four booster modules affording high-frequency stimulation, is used. Note the oxygen tank nearby, which would be used as most important therapy in the event of a seizure developing.

II.

HISTORICAL OVERVIEW

With the observation of Faraday in 1831 that a timevarying magnetic field can induce a current in a nearby conductor, the theoretical basis of inducing depolarizing currents by electromagnetic coils was established. The French scientist d’Arsonval reported on the first human application of TMS in 1896. He was able to induce phosphenes (flickering-light sensation, not elicited by visual perception), vertigo, and syncope in subjects whose head was placed in a large electromagnetic coil [5]. In 1959, Kolin demonstrated for the first

rTMS in Treatment of Neuropsychiatric Conditions

time that an alternating magnetic field is able to stimulate a sciatic frog nerve and could induce contractions of the gastrocnemic muscle [5]. In 1965, Bickford was able to induce muscle twitching in humans by applying a pulsed magnetic field with a maximum field strength of 20,000–30,000 Gauss to ulnar, peroneal, and sciatic nerves [5]. The induction of muscle potentials by magnetic stimulation of the central nervous system was first demonstrated by Barker in 1985 [6]. He induced muscle twitching with a coil of 10 cm diameter placed on the scalp over the motor cortex. A brief pulse of 110 ms with a peak current of 4000 amps was applied and pulses at a maximal rate of 0.33 Hz were delivered. With the possibility of stimulating the motor cortex noninvasively (Fig. 2), TMS replaced high-voltage transcutaneous electrical stimulation used in clinical studies, mainly to measure central motor conduction time. This variable may be altered by a variety of neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, cervical myelopathy, and degenerative ataxic disorders. It seems that TMS has great potential in the intraoperative monitoring of the integrity of motor tracts during surgery of the brain and spinal tract [7]. TMS has subsequently found diagnostic use in neurology for disorders such as demyelinating diseases involving the excitability and the connections of the motor cortex with other parts of the nervous system involved in motor pathways [8]. In 1987 Bickford made an observation that changed the whole field of neuropsychiatric TMS research: He described transient mood elevation in several normal volunteers receiving single-pulse stimulations to the motor cortex [9]. This was the starting point of the scientific investigation of effects of depolarizing magnetic fields on a variety of neuropsychiatric disorders. Subsequently, unblinded pilot studies of TMS with depressed patients were done using single pulse stimulations at frequencies < 0:3 Hz [10–12]. In these studies relatively large areas under the vertex were stimulated bilaterally, and all involved only few subjects. More recent work has suggested that rTMS at 1 Hz with a round coil may have some value in depression [4]. After studies on mood alteration in healthy volunteers and open studies involving only very few subjects, the first subject-blinded rTMS study involving 17 patients suffering from treatment-resistant major depression, psychotic subtype, was published by Pascual-Leone [13]. More recently, larger studies were conducted and researchers attempted to establish meaningful sham conditions. These include stimulations at different cortical sites (e.g., right prefrontal

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vs. left prefrontal cortex in depression), and holding of the stimulation coil not tangentially to the head but tilted at 45 or 90 . With technical advances in the past 2 years, it has been possible to develop stimulators that were able to deliver strong pulses at high frequency. Therapeutic effects were investigated not only in mood disorders, but also in other psychiatric disorders, such as anxiety, schizophrenia, and tic disorders. Other studies investigated the basic neurobiology of TMS effects at different levels. TMS techniques also allowed investigations of neuronal connectivity and functionality of neural circuits [8,14]. An important recent development is the combination of TMS with functional imaging; this approach affords testing of important novel hypotheses on TMS effects.

III.

PUTATIVE CLINICAL APPLICATIONS OF RTMS

Today, rTMS is not indicated as a clinical treatment approach to any of the neuropsychiatric conditions. The only disorder for which a substantial body of information about clinical efficacy is available is major depression. For other disorders, only preliminary results are available, or only small, nonconclusive studies have been conducted. rTMS has mainly been delivered to adult subjects, older than 20 and younger than 60 years old. For instance, in a study with adolescent depressive patients, a group that would particularly benefit from a treatment with a favorable sideeffects profile, only very preliminary data on the application of rTMS to seven adolescents suffering from bipolar disorder (1 subject), major depression (3 subjects), or schizophrenia (3 subjects), between 16 and 18 years old, were found. All subjects showed improvement except for the patient suffering from bipolar disorder and one subject suffering from major depression [15]. A.

Affective Disorders

rTMS as a putative treatment in neuropsychiatry has been researched thoroughly in affective disorders and especially in major depressive disorders. There are studies about the use of single-pulse TMS, slow rTMS, and fast rTMS. Different locations of TMS application have been studied as well. At the present time, there is still controversy about the effectiveness of TMS as a potential treatment. This is not astonishing, since only a small part of the full parameter space of possible

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stimulation conditions has been explored, and the total number of patients studied falls far short of the numbers in registration trials for new drug treatments. Many technical details as where to stimulate, at which frequency, the total number of stimuli, the duration of the treatment, etc., have yet to be resolved. Double-blind, thoroughly controlled multicenter studies involving large numbers of patients are lacking. This is the reason why rTMS cannot be considered as a treatment option in depressive disorder and even less as an alternative to already established treatments at the present time. The dorsolateral prefrontal cortex (DLPFC) has been the most important target for stimulation in depression. Converging evidence from different areas of research supports the hypothesis that mood is regulated by a interconnected network of brain regions encompassing prefrontal, cingulate, parietal, and temporal cortical regions an well as parts of the striatum, thalamus, and hypothalamus. Lesions of this network from tumor, infarction, or transient disruption may result in mood changes. In addition, alterations of cerebral blood flow and metabolism in the dorsolateral, ventrolateral, orbitofrontal, and mediofrontal regions, as well as the subgenual prefrontal and anterior cingulate cortex, have been demonstrated in patients suffering from major depression [16,17]. Studies of rTMS in mood in healthy subjects [18] and treatment-refractory major depression selected the DLPFC as a region that is both a key part of the network discussed above and at the same time accessible to focally limited effects of TMS. George reported the first open study of the antidepressant effects of rTMS in six treatment-resistant depressed patients treated with five daily rTMS sessions to the left DLPFC [19]. He demonstrated that two patients in this study experienced substantial improvement as assessed by a drop of 26% in Hamilton Rating Scale for Depression (HRSD) scores. Open and blinded studies of rTMS to the left DLPFC followed with varying results. Figiel showed in a comparatively large open study that 42% of 56 patients responded to five daily rTMS sessions with a considerably lower response rate in the elderly [20]. Triggs demonstrated in a study of 2 weeks’ treatment a 41% drop in HRSD in another open trial [21]. It is important to note that there have been open studies that have failed to find any antidepressant activity of rTMS [22]. Effect sizes have varied considerably in controlled single blinded studies of rTMS in treatment resistant depression. George found only modest antidepressant


efficacy of rTMS in a within-subject crossover sham-controlled study of 12 depressed patients whom he treated for 2 weeks with stimulation to the left DLPFC [23]. Berman found an antidepressant response in 20 subjects that was statistically different from sham stimulation using similar stimulation parameters in a parallel design, but still only of modest clinical impact [24]. Both George and Berman used a low stimulation intensity of 80% of motor threshold. Generally, it seems that higher intensity may be more effective; however, Loo found no differences between active and sham rTMS using 110% of motor threshold [25]. In a study looking at low-frequency rTMS Klein demonstrated in a sham-controlled trial of 71 patients that 1 Hz stimulation to the right DLPFC was significantly more effective than sham [4]. It is unclear whether stimulation of the left hemisphere at these parameters would have had the same effect. More recent work on rTMS treatment of acute mania suggests that right-hemisphere treatment may be more effective in that condition [26]. In a study looking at the effect of frequency, Padberg randomized 18 patients to single-pulse TMS, 10 Hz rTMS, and sham rTMS delivered to the left DLPFC, and demonstrated a mild antidepressant effect with single-pulse TMS [27]. George recently reported a sham-controlled trial in which 20 patients were randomly assigned to receive an equivalent number of pulses at 5 Hz or 20 Hz over 2 weeks. Both active groups had a 45% response, and no patients responded to sham stimulation [28]. This suggests that lower frequencies may have therapeutic efficacy as well, which is important because slow rTMS is associated with a lower risk of seizure. An analysis of treatment response and cerebral metabolism suggests that patients with hypometabolism at baseline may respond better to high-frequency stimulation (20 Hz), whereas those with baseline hypermetabolism respond better to 1 Hz stimulation [29]; however, the effects of rTMS on mood examined in this study were not statistically significant. Contrary to depression, in which disorder several studies about the efficacy of TMS have been performed, there is only one study on mania in which right prefrontal cortex stimulation was compared with left prefrontal cortex stimulation in manic patients [26]. The results suggest that rTMS of right prefrontal cortex might have some therapeutic effect in mania. In one case report a treatment-resistant patient was treated with right prefrontal rTMS, and she responded well to the treatment [30]. These results have to be considered as very preliminary.


There is some indication that TMS stimulation at higher amplitudes might be more efficacious. This observation, together with the established fact that therapeutic seizures have a strong and reliable effect in depression, leads to another which uses rTMS at convulsive levels as a more targeted form of ECT. Efficacy and side effects of ECT seem to depend on the path of the current passed through the brain [31,32]; this is why targeting seizures to focal cortical areas, such as regions of the prefrontal cortex, may reduce some side effects of convulsive treatment. Magnetic seizure therapy (MST) has now been tested in proof-of-concept studies both in nonhuman primates and patients [1,33], and preliminary results on cognitive side effects of the treatment compared to those of ECT have been obtained [34]. Much additional research is needed to evaluate the putative clinical efficacy of this approach and to determine if it has significant advantages over ECT. In conclusion, the key findings in depression have not been systematically replicated, and effect sizes have often been small and variable. Sources of variability across studies include differences in stimulation parameter settings, concomitant medications, and patient sample characteristics. In addition, simple and economical methods for precise and reliable coil placement are needed, as this factor is likely important for effectiveness [35]. In much of this work, the magnitude of antidepressant effects, while often statistically significant, has been below the threshold of clinical usefulness [24] and has not lived up to expectations raised by encouraging results in animal studies. The disparity between the human and animal studies on depression may relate to the differences in amount and site of stimulation between humans and rodents (see section on animal studies above). Furthermore, the persistence of antidepressant effects beyond the 1- to 2-week treatment period has rarely been examined. Initial evidence suggests that the beneficial effects may be transitory, making the development of maintenance strategies important if rTMS is to move to the clinic Establishing whether nonconvulsive rTMS has antidepressant properties aside from their clinical usefulness is of theoretical importance, since positive data support the notion that focally targeted manipulations of cortical function can result in mood improvement. Nonetheless, as a clinical antidepressant intervention, the future of rTMS is far from certain. More work and larger studies are needed to establish its efficacy, the optimal treatment paradigm, and the appropriate patient population. The main problems that need to be dealt with in order to gain more conclusive data are:

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1. The establishment of true double blind conditions of delivering TMS, implying that no one getting in contact with the subjects knows whether real or sham TMS is applied. In addition, subject’s sensations during the application of TMS may not significantly differ between real and sham conditions. 2. Large multicenter studies assessing the therapeutic efficacy of TMS for instance in major depression disorder are in urgent need. To date, effects on mood improvement of TMS have not been compared in blinded studies against established treatments, such as pharmacotherapy and ECT. B.

Anxiety Disorders

Preliminary results of the application of rTMS in anxiety disorders are available for obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) only. The results from two case reports and an open study in patients suffering from PTSD are somewhat encouraging. Concerning OCD, an open study showed improving when rapid rTMS was applied to the right prefrontal cortex; however, in a double-blinded, placebo-controlled study no differences could be found between the sham and the real condition. 1.

Obsessive Compulsive Disorder

In a study involving 12 patients suffering from OCD effects of rTMS at the right and left prefrontal cortex were compared. rTMS at 80% motor threshold was applied at 20 Hz. Compulsive urges decreased significantly for 8 h after right lateral prefrontal repetitive transcranial magnetic stimulation [36]. In a doubleblind, sham-controlled study, slow rTMS was applied at 110% of motor threshold for 6 weeks to 10 subjects. Sham rTMS (circular coil held perpendicular to the head) was given to eight subjects at 20% of motor threshold. Assessments were carried out at baseline, every week during the treatment, and 4 weeks after the treatment as assessed with the Yale-Brown obsessive-compulsive scale. No difference in the outcome was found between the two groups [37]. 2.

Posttraumatic Stress Disorder

In an open study, slow rTMS was applied first to one side of the vertex (motor cortex) and after 5 min to the other side. Compared to baseline assessment (prior to the treatment), avoidance, anxiety and somatization symptoms improved transiently and were at baseline level after 7 days of treatment [38]. Application of slow

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rTMS to the right frontal cortex of to two patients was also encouraging: symptoms improved during 1 month but returned to the level at baseline 1 month after end of treatment [39].

C.

In summary, these studies show that TMS at the chosen parameters clearly has an effect on the brain and consecutively psychotic symptoms, but a general therapeutic effect has not been established. This is encouraging and should provide impetus for further studies in this area.

Schizophrenia

Compared to depression, only a few studies are available for schizophrenia. A very important finding which was established in a double-blinded cross-over design study of rTMS to the dorsolateral cortex in 12 schizophrenic patients was a decrease in the brief psychiatric rating scale score [40]. In another study six righthanded patients suffering from chronic schizophrenia negative symptoms showed a general decrease for all patients that could be documented in the Positive and Negative Symptom Scale negative-symptoms subscale [41]. Ten schizophrenic patients were given 15 stimuli over the frontal area on each side at 100% stimulus intensity, at 1 Hz. Measured with the Brief Psychiatric Rating Scale scale, an improvement of symptoms could be documented 1, 7, and 28 days after rTMS [42]. However, these encouraging findings could not be confirmed in another randomized placebo controlled study in which 15 patients received sham and 16 real treatment. Stimulation occurred at the right prefrontal cortex, at 10% above motor threshold, at 1 Hz. No statistical significant differences in Clinical Global Impression Scale, Positive and Negative Symptom Scale, or Brief Psychiatric Rating Scale could be found by comparing the placebo group with the real treatment group at the end of the treatment and after 1 week [43]. In this study positive findings reported earlier by the same group could not be replicated [44]. Probably more relevant than the up-to-date controversial and still very preliminary findings about therapeutic efficacy are the strong results on influencing the key symptom in schizophrenia of hallucinations: 12 right-handed schizophrenic patients, all receiving antipsychotic medication, with hallucinations were treated in a double-blind crossover study with 1 Hz stimulation at 80% motor threshold over the left temporoparietal area. There was a significant decrease in hallucination score 12 and 16 min after active stimulation, and not after sham stimulation. In the follow-up assessment, the effect of rTMS on hallucinations lasted maximally for 2 months in one patient. Other positive and negative symptoms did not vary much [45]. This study confirmed preliminary findings reported earlier in three patients [46].

IV.

PRACTICAL APPROACH, SIDE EFFECTS, AND SAFETY CONSIDERATIONS

A.

Delivery of TMS

The equipment necessary for delivering TMS consists basically of two parts: (1) a stimulator, which generates brief pulses of strong electrical currents (frequency and intensity of the current pulses, train duration, and intertrain interval can be varied); and (2) stimulation coil connected to the stimulator. The TMS stimulus interfering with the brain consists of very strong pulsating magnetic fields changing amplitude from 0 to 1.5 Tesla in a few milliseconds. The shape of the magnetic field depends on the design of the coil. There are circular coils with a cylinder-shaped field, figure-8 coils with a more focal field (maximum strength at the intersection of the two circles), and iron core coils that also generate focal fields with a maximum strength in the center of the coil. The magnetic field generated by the coil is perpendicular to its surface and passes unimpeded through the skin and the skull. Since the strength of magnetic fields declines exponentially with distance from the inducing conductor, depolarization of neurons occurs only to a distance of 2–3 cm from the surface of the coil. This is why only superficial structures of the brain can be directly interfered with. However, distant effects of the application of TMS, for example, on regional cerebral blood flow, can be measured and might be important for biologic effects. Older coil models that use water or air-cooling have to be connected to water circulation or a ventilating system. The costs of a device capable of delivering fast rTMS amount to $10,000– 40,000. Subjects and patients undergoing rTMS treatment should first be carefully evaluated and informed about side effects as outlined below (Sec. IV.2; safety considerations). During stimulation, which should always be done in the presence of a person trained to manage eventual emergency situations (mainly epileptic seizure), subjects should be seated comfortably so as to


eliminate the risk of accidental falling or hurting oneself even by ample movements. To endure a stimulation session, which may last for up to 30 min, a head holder should support the head, which should not be moved during the application. The rTMS coil is directly held to the head of the subject and placed over the brain region, which is intended to be stimulated (Fig. 2). This can be done by an administrator or by a specially designed coil holder. The exact site of stimulation can be determined using either anatomical or functional landmarks. In clinical studies on mood disorder, the preferred site of stimulation is the prefrontal cortex. In practice, this place is found by first identifying the spot of inducing movements of contralateral finger muscles, the abductor pollicis brevis, or extensor digiti minimi. The stimulation occurs 5 cm anterior to the spot of maximum response in a line parallel to the midsagittal line. The intensity of stimulation is expressed as percentage of the motor threshold, which can be defined in different ways, for example, as the intensity to elicit evoked motor potentials in the above-mentioned contralateral finger muscles of 50 V in 50% of the applied pulses, e.g., in 5 out of 10. The practical value of determining the motor threshold is to establish safe stimulation amplitudes, which are much below the seizure threshold.

B.

Side Effects and Safety Considerations

Compared to ECT, MST, DBS, and VNS, rTMS can be considered as relatively safe since (1) it is noninvasive, and (2) the induction of convulsions is not required for a treatment. Therefore, side effects linked to anesthesia and convulsion do not occur. However, there are side effects directly linked to the application of rTMS or occurring a few hours later. Of major concern are involuntarily induced epileptic seizure, local pain during application, changes in the auditory performance due to the noise generated in the coil by the passing electrical current, and headache as well as the concern of alterations of cognitive functions. Until now, in research applications, mainly short-term problems (application of TMS, follow-up of a few weeks) were addressed. Long-term concerns have also to be addressed. These might include longlasting cognitive impairment which includes the most frequent unwanted long-term side effect of ECT, sleep problems, or, potentially, problems linked to effects of the influence of the strong magnetic fields on the brain.

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1.

Immediate and Short-Term Risks Seizures

The risk of causing a seizure is the primary safety concern with TMS. Even if this risk is primarily associated with rTMS, single-pulse stimulation also has been reported to produce seizures in patients with large cerebral infarcts, contusions, or other structural brain lesions. According to Wassermann [47], in patients with completely subcortical lesions, no seizures are reported. According to the same author, there are a few articles reporting the induction of seizures in epilepsy patients without gross lesions. In at least six normal volunteers, and at least two patients with depression, inadvertent seizure occurred during rTMS stimulation [47]. None of the subjects who experienced rTMS-induced seizures suffered lasting sequelae. EEG recordings became normal after at least 2 days. Recorded effects were mild recall deficits, which returned to normal after 24 h in two individuals, and significant anxiety in one subject concerning the possibility of a recurrent seizure. Until today, several thousand individuals have been subjected to rTMS treatments. It seems reasonable to assume that under observation of the safety guidelines as discussed below, a development of seizure activity is extremely unlikely. Cognitive Impairment Mainly short-term observations concerning cognitive function after TMS administration are available. rTMS can produce transient disruption of various cerebral functions, depending on the site of stimulation. Observations reported include a significant decrease in a memory subtest within an hour after stimulation with 150 trains of rTMS at 15 Hz and 120% motor threshold delivered at four different positions [48]. Commenting on these results, Lorberbaum concludes that these cognitive effects were due to subconvulsive epileptic activity or that the threshold for adverse effects on memory might be near that of seizure [49]. Loo reported results from a study in wich 12 subjects suffering from major depression received rTMS during 4 weeks. No significant changes in neuropsychologic functioning after 4 weeks were observed [50]. Cardiovascular Effects No significant changes in blood pressure or heart rate have been reported during and after the administration of rTMS [51].

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Hearing No significant changes in auditory threshold were observed in a study involving 12 depressed subjects undergoing rTMS over 4 weeks when assessed for 4 weeks after the end of the study [50]. Headache The application of TMS may cause local pain resulting from direct stimulation of muscles underlying the coil and from stimulation of facial and scalp nerves. It is generally more painful at higher intensities and frequencies. About 5–20% of subjects subsequently experience tension headache [52]. Special Conditions ‘‘Special conditions’’ refers to subjects who have risk factors which are investigated by the proposed questionnaire (pregnancy, medical implants in the head, implanted medical devices such as pacemakers, or drug delivery pumps). We would advise care in administering rTMS to such subjects, since until now, rTMS cannot be considered as treatment of choice in a medical condition. There are no systematic studies about the application of rTMS to subjects presenting with special conditions. However, there are some isolated reports which might indicate that TMS might be administered to pregnant subjects [53], or to subjects with some implanted medical devices [54,55]. 2.

Potential Long-Term Effects

There is, of course, legitimate concern that the application of rTMS might cause brain damage in the widest sense. Mechanisms discussed are heating of neuronal tissue, excitotoxicity, and any influences of magnetic fields. As with other side effects, besides the occurrence of seizure, there are very few data and no thorough investigations available which address these questions. There are, however, after the administration of TMS and rTMS to many thousand subjects, no indications that their application might cause brain damage. The kind of low-frequency, high-strength magnetic fields delivered to the human brain during rTMS are not known from other applications. Considerable evidence has accumulated about constant, strong static magnetic fields with the introduction of MRI techniques in medicine. These fields have about the same strength as those produced by rTMS. Since the introduction of MRI, more than 150,000,000 examinations

have been performed and only seven deaths occurred due to these procedures [56]. One involved a ferromagnetic cerebral aneurysm clip, and five examinations involved patients with cardiac pacemakers. High-frequency ( 1000 MHz) electromagnetic fields as generated by cellphones raised concern in the public about adverse health effects. They are known to induce changes in sleep EEG patterns 20– 50 min after electromagnetic fields were applied to awake subjects [57]. In rTMS, very different energies and frequencies of electromagnetic fields are applied to the human brain. In a safety study, rTMS at therapeutic parameters has been demonstrated to have no significant effects on sleep EEG [58]. 3.

Safety Guidelines and Assessment of Subjects Undergoing rTMS

The widely accepted safety guidelines on rTMS application are based on the report of the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation,1996 [59]. Absolute contraindications retained are metal in cranium, intracardial lines, and increased intracranial pressure. Relative contraindications are pregnancy, heart disease, cardiac pacemaker, medication pump, ongoing medication with tricyclic antidepressants or neuroleptics, and family history of epilepsy. Since inadvertent seizures may develop during rTMS and even TMS, one has to prepare for their management on site. Seizures in nonepileptic patients are always self-limiting. The risk of permanent damage to the brain is minimal and can be reduced considerably by prompt administration of oxygen. Diazepam 10 mg might be administered to end a seizure lasting > 2 min. Keel [60] proposed a transcranial magnetic stimulation adult safety screen (TASS) which consists of the following 14 yes-or-no questions: Have you ever: 1. 2. 3. 4. 5. 6.

7.

8.

Had an adverse reaction to TMS? Had a seizure? Had an EEG? Had a stroke? Had a head injury (including neurosurgery)? Do you have any metal in your head (outside of the mouth), such as shrapnel, surgical clips, or fragments from welding or metalwork? Do you have any implanted devices, such as cardiac pacemakers, medical pumps, or intracardiac lines? Do you suffer from frequent or severe headaches?


9. 10. 11. 12.

13. 14.

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Have you ever had any other brain-related condition? Have you ever had any illness that caused brain injury? Are you taking any medications? If you are a woman of childbearing age, are you sexually active, and if so, are you not using a reliable mode of birth control? Does anyone in your family have epilepsy? Do you need further explanation of TMS and its associated risks?

A positive screen is any ‘‘yes’’ answer, indicating further investigation by the clinician (but not indicating exclusion from TMS). Subjects assessed with this questionnaire and subjected to rTMS within the proposed safe limits of the stimulation parameters are very unlikely to experience a seizure. Maximum recommended train durations are displayed in Table 1. According to Chen et al. [61], the following intertrain intervals are proposed as reasonably safe: in rTMS below 20 Hz, 5 sec intertrain interval seems to be safe below a stimulation intensity of 110% of motor threshold. Above, no data were available. Intertrain intervals of 0.25 and 1 sec were not considered to be safe. They advised intertrain intervals of 1 min at an intensity of < 120% of motor threshold. V.

BASIC EFFECTS INDUCED BY TMS

The generated magnetic fields are interacting with an extremely complex biological system where essential interactions between brain and mind take place [62,63]. It seems obvious that the impact of these magnetic fields on the underlying brain structures is difficult to evaluate, since monitoring the functions of the living human brain is only possible by assessing sum-

Table 1

mation responses which are determined by the action of many thousand or more cells. The actual psychopathological models of psychiatric disorders are integrating so-called functional systems at molecular, cellular, neurotransmitter, organ, systemic, or individual and social levels that are not known in detail. Presenting the mechanisms of action of TMS as a research or treatment tool challenges old hypotheses of aspects of the function of the brain and, hopefully, allows the construction of new ones. Several acute and chronic alterations at different levels, ranging from changes in gene expression of cells in the central nervous system to alterations in mood and behavior, have been documented during and after the application of TMS. Among the many interesting approaches, where valuable studies are available, only a few examples are cited. Ji recently reported that one single train of rTMS applied to rats in vivo induced c-fos and c-jun expression in different brain regions and among them in key regions controlling circadian biological rhythms [64]. Similar stimulation parameters have earlier been shown to have efficacy in an animal model of depression [65]. These findings might point to a possible antidepressant mode of action of TMS effects via circadian rhythms. The finding that immediate to early gene expression is modified by TMS has been replicated and further examined recently by other authors, in vivo as well as in vitro [66,67]. Keck measured modulatory effects of frontal rTMS in rat brain in vivo using intracerebral microdialysis [68]. There was a continuous reduction in arginine vasopressin release of up to 50% within the hypothalamic paraventricular nucleus in response to rTMS. In contrast, the release of taurine, aspartate, and serine was selectively stimulated within this nucleus by rTMS. Furthermore, in the dorsal hippocampus the extracel-

Maximum Safe Duration (sec) for Single Trains of rTMS Intensity (% of stimulator output at motor threshold

Frequency (Hz) 1 5 10 20 25

100

110

120

130

140

150

160

170

180

190

>1800 >1800 360 >50 >50 >50 >50 27 11 11 >10 >10 >10 >10 7.6 5.2 3.6 2.6 2.4 1.6 >5 >5 4.2 2.9 1.3 0.8 0.9 0.8 0.5 0.6 2.05 1.6 1.0 0.55 0.35 0.25 0.25 0.15 0.2 0.25 1.28 0.84 0.4 0.24 0.2 0.24 0.2 0.12 0.08 0.12

200 210 220 8 1.4 0.4 0.2 0.12

7 1.6 0.3 0.1 0.08

6 1.2 0.3 0.1 0.08

Indicated are durations of single rTMS trains, after which no after discharge or spread of excitation has been encountered at the specified conditions (frequency, intensity). Numbers preceded by > are the longest durations tested. Source: Ref. 59.

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lular concentration of dopamine was elevated in response to rTMS. By using PET scanning, a diminished 11C raclopride binding to dopamine receptors in the left dorsal caudate nucleus could be measured in eight volunteers after left dorsolateral prefrontal cortex rTMS. This implies that rTMS can trigger dopamine release in these brain structures [69]. Several studies documented the effect of rTMS on human blood hormone levels. They include effects on cortisol, prolactin, and TSH. Actual results cannot be considered as conclusive. They indicate, however, that TMS might significantly influence endocrine functions of the brain [70–72]. TMS can transiently disrupt or induce activity in focal brain regions, depending on the region stimulated. Applied to the visual cortex, for example, strong TMS can produce phosphenes, and a stimulus of lower intensity can induce transient scotomas [73]. Other functions, such as linguistic processing, can also be investigated with rTMS [48]. Peinemann reported a neuromodulatory effect of subthreshold high frequency rTMS in 10 subjects. After 1250 stimulations at 90% motor threshold, an intracortical inhibition could be measured which lasted at least 10 min after the rTMS stimulation [74]. The combination of noninvasive stimulation of the brain coupled with functional neuroimaging techniques offers new opportunities to investigate functions of the human brain. It also allows visualization of effects of TMS which are documented to occur at distant sites from the stimulation [75]. In another study, 10 medication-free subjects suffering form major depression (eight unipolar, two bipolar) received rTMS in a crossover, randomized study at the left prefrontal cortex, at 100% motor threshold at 20 Hz or 1 Hz. With 20 Hz, an increase in rCBF in the prefrontal cortex left > right, cingulated gyrus left right, left amygdala, bilaterally insula, basal ganglia, uncus hippocampus, parahippocampus, thalamus, cerebellum was observed, with a 1 Hz only decreases in rCBF: right prefrontal cortex, left medial cortex, left basal ganglia, left amygdala. Individuals who improved in one frequency concerning their depressive symptoms worsened in the other [76]. All these approaches from different areas of neuroscience convergingly show that TMS has prominent and reproducible effects on the brain, which is certainly encouraging and puts TMS apart from some other putative approaches to treat neuropsychiatric disorders [73]. The problem is that the connection from cellular levels to complex behavioral changes—


such as those observed in depression—is difficult to do. The field has suffered somewhat from a ‘‘top-down’’ approach in which early promising results in depression have led to enthusiasm for clinical studies without sufficient neuroscientific foundations. Approaches integrating findings from all levels of biologic systems are extremely important and should be undertaken in order to support the ongoing clinical research.

VI.

DISCUSSION AND OUTLOOK

rTMS is a relatively affordable and—if the safety precautions are followed—safe method to apply magnetic fields noninvasively to the human brain. As has been discussed in this chapter, research into different clinical applications for rTMS in neuropsychiatric disorders remains active and has the potential to provide useful data, but as of yet there is no consensus among the blinded controlled trials that rTMS has beneficial effects that replace or even match the effectiveness of conventional treatments in any disorder. From the viewpoint of the clinician, the following comments can be made: 1. Today data on clinical efficacy of rTMS in mood disorders are not unequivocal, and results on other psychiatric disorders, such as schizophrenia and anxiety disorders, have to be considered as very preliminary but nevertheless interesting and encouraging. 2. For the therapeutic application in mood disorders rigorously controlled and double-blinded multicenter trials are needed to address the question of the clinical efficacy of TMS. Even before that, technical problems in the application of TMS have to be solved; e.g., more satisfactory sham conditions have to be developed. Today, using analogies to pharmacological drug development, valid Phase II trials have still to be conducted. Crucial open questions remain regarding medium- and long-term efficacy of TMS, prevention of relapse, and medium- and long-term side effects. There are virtually no data on these issues since most trials assessed only treatment response after 2 weeks. rTMS has not been demonstrated to be clinically superior or even equal to pharmacological treatment or to ECT. Double-blinded Phase III trials, comparing established drug treatments and ECT with TMS, have still to be conducted. 3. There is no consensus at all about possible mechanisms of action of antidepressant effects of TMS. However, this is also the case for many other treatments in psychiatry. rTMS research is basically


empirical. Many variables play a role in rTMS, and a large parameter space has therefore to be carefully explored in order to find the most efficacious treatment. This complicated process will likely be very slow, since there is not a large amount of funding for such studies. Nevertheless, rTMS has clearly effects on the brain—which is certainly remarkable—and it might be that rTMS is a treatment modality in search of a suitable application in psychiatry. Therefore it is of utmost importance to continue on the long and difficult path of research on clinical rTMS applications. 4. Today, different TMS methodologies have a place as diagnostic tools in neurological disorders, where neural conductivity is assessed in different, mainly demyelinating disorders. From the viewpoint of the neuroscientist, TMS is a methodology with great potential as a research tool [14,73]. This technique, by itself and combined with other methods such as EEG and neuroimaging, may be useful to test functional connectivity, neuroplasticity, information processing (for example in the visual system), indirect and direct motor control, and aspects of mood control. It affords testing of both general hypotheses of the function of the brain at different levels and hypotheses of the underlying pathology of neuropsychiatric disorders. Even if the early enthusiasm, which prevailed after early studies of clinical effects in the treatment of mood disorders settled down somewhat, rTMS will be even more useful as an investigational tool of basic and clinical research.

929 6.

7. 8.

9.

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60 Pharmacokinetic Principles and Drug Interactions AHSAN Y. KHAN and SHELDON H. PRESKORN University of Kansas School of Medicine, Wichita, Kansas, U.S.A.

I.

tation and combination drug strategies are planned DDIs with the goal of increasing efficacy and/or tolerability. Conversely, adverse DDIs can result in patient morbidity, patient mortality, and reduced efficacy. All of the above in turn increases health care costs.

INTRODUCTION

This chapter is dedicated to explaining the basic concepts of clinical pharmacokinetics to aid the prescriber in avoiding adverse drug-drug interactions (DDIs) and practice rationale therapeutics (i.e., prescribing drugs to maximize the chances of efficacy and to minimize drug-induced illness). These concepts are important for patients in general and in particular in those on antidepressants because of their high likelihood of being on other medications. That is true regardless of the type of medical setting in which they are being seen (Table 1). In this era of medicine, polypharmacy is common. This frequency is a natural consequence of the increase in drug discovery. The Food and Drug Administration currently approves an average of 25 new chemical entities per year. Physicians typically learn about new drugs from pharmaceutical company–sponsored lunches and/or dinners, colleagues, and other sources. These may all lack scientific details. The general focus is on the pharmacology alone. However, most patients on an antidepressant are also on other medications. This issue is important because the more drugs a patient is taking, the greater the risk that they will experience a DDI. Such interactions can be intended or unintended, beneficial, or adverse. In fact, augmen-

II.

WHAT IS A DRUG-DRUG INTERACTION?

A DDI is a measurable change in magnitude, nature, or duration of the action of one drug as a result of prior or concomitant administration of another drug. DDIs are not limited to any specific therapeutic class, and drugs from different therapeutic classes can nevertheless interact. Knowledge about pharmacokinetic drug interactions (i.e., the effects of one drug on the absorption, distribution, metabolism, or elimination of another, coadministered drug) is critical for the safe and effective use of drug combinations. A point central to this chapter is understanding that a patient’s response to any drug treatment is determined by the relationship of three variables: the drug’s pharmacodynamics (Pd), the drug’s pharmacokinetics (Pk), and the biological variance between patients as shown in Eq. (1). 933

934

Khan and Preskorn Table 1 Percentage of Patients on Antidepressants Having the Potential to Experience a Drug-Drug Interaction as a Function of Treatment Setting Clinical

Number of patients

Prescribed only an antidepressant

Prescribed at least one other medication

Prescribed three or more other medications

2045 224 1076 66

28% 29% 7% 2%

72% 71% 93% 98%

34% 30% 68% 77%

Primary-care setting Psychiatry clinic VA medical clinics HIV clinic

Other medications include a systemically taken, prescription drug from any therapeutic class. Does not include over-the-counter medications, topicals, or herbs. Source: Ref. 46.

III. clinical reponse

¼

Affinity for site action

Drug

Underlying

concentration at site of action

biology of patient

absorption distribution

diagonsis genetics

metabolism elimination

age organ function

ð1Þ

internal environment

Pd is what the drug does to the body, i.e., the drug’s affinity for its sites of action, whereas Pk is what the body does to the drug, i.e., the factors that determine the drug concentration at the site of action. The third variable in Eq. (1) is critical to understanding why different patients respond differently to the same dose of the same medicine. The prescriber usually cannot change the diagnosis, genetics, or age or organ function of a patient; however, the prescriber can change the internal environment of the patient by the drugs they prescribe. These drugs become part of the biology of the patient and can alter their response, either quantitatively or qualitatively, to another drug. That is the essence of what is meant by a drugdrug interaction. DDIs can be grouped into two major classes: pharmacodynamics or pharmacokinetics. Both types are important, but this chapter will focus only on pharmacokinetically mediated DDIs and will explain how one drug can affect the absorption, distribution, metabolism, and elimination of another drug and how that in turn can change the effect observed in the patient [Eq. (1)]. This chapter will first review general pharmacokinetic principles to set the stage and will then discuss the relevance of the specific principles to specific types of DDIs.

RELATIONSHIP BETWEEN DOSE AND CONCENTRATION

Following systemic administration, a drug achieves a certain concentration in plasma. That concentration ultimately determines and is in equilibrium with the concentration of drug at its site of action. The latter in combination with the binding affinity of the drug for different targets, determines which sites of action of the drug (variable 1) in Eq. (1) are engaged and to what degree. That in turn determines the nature and the magnitude of the drug’s effect (i.e., whether beneficial or adverse). Drug concentration is directly proportional to the dosing rate and inversely related to the clearance, as expressed in Eq. (2): Drug concentration ¼

Dosing rate Clearance

ð2Þ

The relationship between dose of the drug and its concentration in plasma is the second variable in Eq. (1), and is determined by the pharmacokinetics of drug in that specific patients in relationship to the dose of the drug ingested by the patient as a function of time (e.g., usually the daily dosing rate). As mentioned before, pharmacokinetics of a drug is what the body does to the drug. Pharmacokinetics can be divided into four phases: absorption, distribution, metabolism, and elimination. Each of these phases will be described beginning with a case vignette that illustrate the relevance of that phase in understanding and thus avoiding the risk of an intended and unintended DDI. A.

Absorption Case Example. A 47-year old schizoaffective patient was treated with thioridazine (100 mg

Pharmacokinetic Principles and Drug Interactions

orally QID), phenytoin (100 mg orally QID), and amitriptyline (50 mg orally q.i.d.). The patient had been stabilized on this regimen for several weeks, but then complained of daytime sedation. The treating physician therefore combined all three into a single bedtime regimen. The patient expired the first night of the new schedule from acute cardiac arrest. In this case, each of the drugs the patient was taking was individually capable of slowing the intracardiac conduction in a concentration-dependent manner. The patient died as a result of their additive effects. Those individual effects were in turn amplified by the decision to give each drug as a single nighttime dose, and all at the same time. As a result of that decision, the peak concentration of each drug was substantially increased. That in turn resulted in a fatal arrhythmia. Absorption of the drugs depends upon route of administration, the state of the patient, and factors related to drug itself. Common routes of administration include oral, intramuscular, and intravenous. While many drugs can be administered using any one of these routes, different routes can result in somewhat different concentrations of the drug. Most drugs, including psychiatric medications, are taken orally, with absorption generally occurring in the small bowel. Drugs then pass into the portal circulation and enter the liver. Most psychiatric medications are highly lipophilic, and hence readily cross the blood brain barrier to enter the central nervous system. When a drug is given by intravenous (IV) route it completely and immediately enters the systemic circulation (i.e., 100% bioavailability). Thus, bioavailability usually refers to the percentage of total orally administered dose which reaches systemic circulation. Factors that can influence bioavailability include: 1. 2. 3.

4.

5. 6.

Formulation of the product. Physiochemical characteristics of the drug. Disease states that affect gastrointestinal function (e.g., slower transit time in small intestine delays drug absorption and peak levels; lowers peak blood concentration). Lower acidic environment (which can increase absorption of weak bases (e.g., TCAs, BZDs, some antipsychotics). Precipitation of a drug at the injection site. Ingestion of drugs with food which generally increases their bioavailability through transient increase in hepatic blood flow and transient inhibition of drug metabolism associated with

935

eating (e.g., food-drug interaction while using monoamine oxidase inhibitors). 7. Coadministration with a drug capable of enhancing or retarding the entrance of the drug from the gastrointestinal tract into the central compartment. When drugs are given by any route other than IV, the extent of absorption and bioavailability may be incomplete and must be understood to prescribe the drug rationally and to make adequate adjustments if the route of administration is changed. For example, a patient whose pain is under control on demerol 75 mg IV every 4 h might need an oral dose of 300 mg because of the change in route of administration which affects bioavailability. The state of the patient is also important in determining absorption of the drug. Patients in shock have decreased blood flow to subcutaneous tissues and variable rate of flow through skeletal muscles. Therefore, intramuscular and subcutaneous routes should not be used in case of emergencies. For orally administered drugs, rate of absorption can be manipulated by altering the physicochemical properties of the tablets or capsules. With rapid-release formulations there is a higher peak concentration (Cmax ) and a shorter time (Tmax ) i.e., as a general rule, Cmax is inversely related to Tmax . Sustainedrelease formulations typically produce a lower peak (Cmax ) that is reached later (Tmax ). This information about the drug can help the physician to avoid DDIs related to the peak concentration, especially when the drug has narrow therapeutic index, or if the patient is on two rapid-release formulations. Fast absorption may not always be desirable, because adverse effects may be a function of Cmax . In the case example at the beginning of this section on absorption, failure to appreciate the effect of rate of absorption on the magnitude of the effect resulted in the death of the patient. Cardiotoxicity, due to stabilization of excitable membranes, is as much a function of the peak plasma concentration as it is of steady-state tissue concentration. Case Example. A 22-year-old woman was admitted to the emergency room with palpitations and dizziness. Her past medical and psychiatric history was negative. She had been taking terfenadine (Seldane) 120 mg/day for 5 days and ketoconazole (Nizoral) 200 mg/day also for 5 days, for allergic rhinitis and a fungal infection of the skin. She claimed to have taken

936

Khan and Preskorn

no other medications. The 12-lead resting electrocardiogram recorded on admission showed sinus rhythm with prolonged QT (0.58 sec) and QTc (0.52 sec) intervals. Multiple premature ventricular complexes with a long coupling interval (> 500 msec) were observed. Slight exercise during the physical examination provoked palpitation with syncope, and torsades de pointes were identified on the electrocardiogram. The patient was transferred to ICU and all medications were withdrawn. During the next 5 days QT and QTc intervals slowly returned to normal values (0.44 sec for QT and 0.42 sec for QTc) [1]. ‘‘First-pass’’ refers to the metabolism of a drug before it reaches the systemic circulation. During the absorption stage of an orally administered drug, firstpass metabolism may occur either in the bowel wall or in the liver. Gut wall metabolism of many drugs is extensively accomplished by cytochrome P450 (CYP) enzymes in the luminal epithilium of the small intestine, particularly CYP3A3/4. Drugs that pass to the liver may be taken up by hepatocytes and then biotransformed by CYP enzymes. The parent drug and any metabolites (which may have similar or substantially different Pk or Pd in relation to the parent drug) that survive these two processes, then enter the systemic circulation [2,3]. A large number of commonly prescribed drugs are subject to significant first-pass metabolism either via the gut wall or the liver and thus have low oral bioavailability (e.g., propranolol, amitriptyline, imipramine, morphine) [4,5]. These drugs have a high extraction ratio and high intrinsic gut wall and/or hepatic clearance [5]. For such drugs oral bioavailability can be altered by: 1.

2. 3.

4. 5.

Decrease liver blood flow as seen in cirrhosis, persistent hepatitis, and portacaval shunting [6,7]. Congestive heart failure. Drugs inhibiting or inducing cytochrome P-450 (CYP) enzymes (e.g., alcohol, ketoconazole) [1,4,8,9]. Antacids like magnesium hydroxide or aluminium hydroxide can also decrease the bioavailability of some drugs such as gabapentin (an anticonvulsant) by 20% [10]. Ingestion of drugs with food. Even the dose (i.e., the concentration) of the drug itself can alter the extent of its first-pass metabolism (e.g., nefazodone in a dose-dependent fashion inhibits its own first-pass metabolism) [4,11].

Once first-pass metabolism has occurred, metabolites may be excreted back into the small bowel. Metabolites that are sufficiently lipid soluble can then be reabsorbed into the portal circulation, eventually entering the systemic circulation. First-pass metabolism is extensive with the TCAs [4,5,12]. Acute ingestion of alcohol can impair hepatic extraction of TCAs, increasing the amount reaching the target tissue, and thus cause concentration- (or dose-) dependent toxicity [8,13]. This information about drug-alcohol interactions can help physicians avoid adverse events from concomitant use of alcohol or other drugs. In fact, it is part of the basis for commonly advising patients to not combine their drugs with alcohol. As mentioned previously, CYP3A is an enzyme responsible for a substantial amount of first pass metabolism of a number of drugs [4,6]. Substantial inhibition of this enzyme by drugs such as the antifungal ketoconazole or the antidepressant nefazodone can substantially elevate the amount of a coprescribed drug reaching the systemic circulation [4,11,14]. That in turn can substantially increase the effect of that coprescribed drug. It can also alter the ratio of the parent drug to its metabolite. In the case example which began this section, that was the problem. Terfenadine (Seldane), the parent drug, was relatively inactive as an antihistamine but more active at slowing intracardiac conduction [1,15,16]. The reverse was true of its active metabolite, fexofenadine (Allegra). When terfenadine was given alone, it was essentially completely biotransformed by CYP3A in the bowel wall and liver during its absorption (i.e., first-pass metabolism) to the active and safe fexofenadine [1,15]. When given concomitantly with ketoconazole or comparable CYP3A inhibitor, terfenadine was not biotransformed during absorption and thus directly enter the systemic circulation from where it could reach the heart and could slow intracardiac conduction sufficiently to cause sudden death [1,15]. B.

Distribution Case Example. A 44-year-old healthy, physically active, white man developed major depressive disorder. He was started on an oral dose of 20 mg/day fluoxetine. On 23rd day of treatment, the patient developed hives believed to be due to fluoxetine, which was discontinued. The patient was given an oral dose of 25 mg of diphenhydramine as needed. The hives persisted for 11 days after fluoxetine discontinuation [17].


The treatment plan was to wait for at least 48 h after the disappearance of all hives and then to start a structurally dissimilar serotonin selective reuptake inhibitor (SSRI) such as sertraline. However, 36 h into the hive-free period, the patient took an oral dose of two tablets of (650 mg) of acetylsalicylic acid for an unrelated painful joint condition, and the hives reappeared. Despite the recurrence of hives, he continued to take two tablets of ASA every 6 h. The hives eventually resolved. At that point, sertraline was started after a 48-hour hives-free period without subsequent problems [17]. In this case, the authors attributed the initial occurrence of hives to an allergic reaction to fluoxetine. The persistence of the hives for 11 days after the fluoxetine discontinuation is consistent with the long half-life of fluoxetine (3–5 days) and its active metabolite, norfluoxetine (7–15 days). The authors invoked displacement of the highly bound fluoxetine and norfluoxetine by ASA and its metabolite, salicylic acid, as the mechanism explaining the recurrence of hives when the patient took ASA 36 h after resolution of the hives. Their hypothesis was that this displacement produced sufficiently elevated free levels of fluoxetine and/or norfluoxetine to cause the recurrence of the allergic reaction [17]. This case thus illustrates the issue of DDIs mediated by changes in drug distribution. The authors proposed that there was an increase in the free level of drug (i.e., the concentration ‘‘seen’’ by the site of action) rather than the total concentration (i.e., free þ bound). Drug distribution begins as soon as the drug reaches the systemic circulation. Many factors affect how a drug distributes within the body. Factors that favor a high ratio of drug in plasma versus tissue include low lipid solubility, low tissue protein binding, and increased plasma protein binding. Factors that encourage greater tissue accumulation include high lipid solubility, high tissue protein binding, and decreased plasma protein binding either due to decreased circulating plasma proteins (e.g., malnutrition) or due to displacement as a result of DDIs. Most psychotropic drugs are tightly bound to plasma proteins [18,19]. Such bound drugs often account for > 90% of the total plasma concentration. Although the free fraction is small, that concentration determines the concentration of the drug at the site of action and hence is important [18,19]. For this reason, a small change in the percent bound, from 95% to 90%, doubles the effective concentration at the site

937

of action from 5% to 10% [19,20]. Drugs that are highly bound in plasma therefore have the potential for a displacement DDI from this carrier protein by another drug with higher affinity for the same protein, resulting in an increase in the free concentration of the displaced drug. There are also populations at increased risk for such a phenomenon. For example, protein binding is lower in women than in men [20–22]. Also, exogenous hormone and pregnancy can alter protein binding and are reduced in the elderly and in patients with chronic hepatic and renal diseases, as well as due to displacement DDIs [14,19]. An example of the latter is the fact that valproate free concentration can be increased upto fourfold in the presence of aspirin compared to valproate alone [23]. In addition to increasing the free concentration of drug, changes in plasma protein binding can cause large apparent changes in volume of distribution (Vd), and clearance (Cl) based on total drug concentration [18–20]. Vd refers to the apparent volume into which the drug must have been distributed to reach a specific concentration. Many psychotropic drugs have much larger apparent volumes of distribution than would be expected based on physical size of the body, because the drugs dissolve disproportionately more in lipid and protein compartments (i.e. tissue) than in the body’s water compartment. The Vd can be calculated as shown in Eq. (3). Volume of distribution (Vd) ¼ Dose/Plasma concentration C.

ð3Þ

Metabolism Case Example. A 52-year-old male was being seen by four different prescribers and was on eight medications: acetaminophen, cimetidine, codeine, erythromycin, ibuprofen, metoprolol, paroxetine, and thiothixene. As a result of the interaction among these medications, this patient could present with a worsening of his depressive syndrome [29].

For simplicity, the discussion of this case will focus only on the following four drugs codeine, erythromycin, metoprolol, and paroxetine (Table 2). The DDIs among these drugs can be seen in Figure 1. Codeine is an inactive prodrug that must be converted by CYP2D6 to morphine to produce analgesia [24–26]. On the other hand, metoprolol is a beta blocker

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Khan and Preskorn

Table 2 Medication Regimen of a Patient Seeing Four Physiciansa Drug Codeine Erythromycin Metoprolol Paroxetine

Indication

Prescriber

Pain Infection Hypertension Depression

Primary care physician Infectious disease specialist Cardiologist Psychiatrist

a These medications could have been prescribed by a single physician in any one of these specialities, but in this case, the patient happened to be seeing four different prescribers Source: Ref. 29.

whose clearance is dependent on CYP2D6-mediated biotransformation [26,27]. Paroxetine produces substantial inhibition of CYP2D6 under usual dosing conditions [3,4,6]. While paroxetine is metabolized by CYP2D6 at low concentrations, but at higher concentrations is most likely dependent on CYP3A-mediated biotransformation for its elimination [4,6,28], CYP3A is substantially inhibited by erythromycin under usual dosing conditions [4,28]. The inhibition of CYP3A by erythromycin should produce an increase accumulation of paroxetine, which in turn would lead to less conversion of codeine to morphine and more accumulation of metoprolol [27,29]. Due to inhibition of the conversion of codeine to morphine, the patient should have less than optimal pain control. A sufficient accumulation of metoprolol can lead to profound hypotension as a result of reduced cardiac output [27,29]. More modest increases

in metoprolol levels might simply present as fatigue. Elevated levels of paroxetine can cause sexual dysfunction including decreased libido, and can interfere with sleep, causing insomnia and daytime tiredness. As a result of all these effects, the patient might clinically appear ironically to be more depressed. This case makes the point that DDIs can be complex, can cross therapeutic classes, can occur across prescribers, and can present in masked ways. As a result of the patient’s looking more depressed, the prescriber might conclude that the patient was in need of more paroxetine or a switch to a different antidepressant or the addition of an augmentation or combination treatment. Thus, DDIs ironically can result in more rather than less polypharmacy as prescribers add drugs to treat the symptoms caused by the DDI. The metabolism of most drugs occurs principally in the liver and involves the conversion of an active, lipophilic drug into inactive polar metabolites through the process of oxidative biotransformation [2–4]. The resultant polar metabolites are then cleared by the kidneys. The necessary biotransformation steps may involve one or several of the following steps: hydroxylation, demethylation, oxidation, and/or sulfoxide formation [3,4,6]. Many drugs undergo extensive biotransformation (phase 1 reaction), and are susceptible to factors that can alter the rate of drug metabolism, as phase 1 oxidation reactions occur through a large group of cytochrome P450 enzymes [3,30]. For example, in the case that began this section, an important fact was that codeine itself is not a potent analgesic. To be effective,

Figure 1 Cytochrome P450 (CYP)-mediated drug-drug interactions among codeine, erythromycin, metoprolol, and paroxetine. Source: Ref. 29.


codeine needs to be converted to morphine [24,31]. This transformation requires the action of CYP2D6 [24,29]. The addition of paroxetine, a substantial inhibitor of CYP2D6 [3,4,6,28] could cause codeine to become ineffective as an analgesic, and the patient could be interpreted to be drug seeking. Another example is the coadministration of lorazepam with probenecid resulting in increased plasma concentration of lorazepam by impairing the glucuronidation and in turn clearance of lorazepam [23]. Oxidative biotransformation results in the formation of metabolites whose pharmacologic profile may be same as or different from the parent compound and may themselves be toxic [3,4]. For example, trazodone is converted to its active metabolite, metacholorophenylpiperazine (mCPP), through CYP3A4 [3,4,14]. mCPP has a different pharmacologic profile from the parent compound [11,28]. It is highly anxiogenic through its 5HT2C agonism [6,11,32]. Elimination of mCPP is dependent on CYP2D6 [11,14]. Coadministration of trazodone with fluoxetine can result in a DDI where fluoxetine-induced CYP2D6 inhibition can increase levels of mCPP by blocking its excretion from the body. As norfluoxetine has essentially the same activity as fluoxetine in terms of both serotonin uptake blockade and inhibition of CYP enzymes [4,28,33,34], this inhibition will continue as long as norfluoxetine is in the body because fluoxetine-induced inhibition of CYP enzymes is competitive and concentration dependent. This DDI between trazodone and fluoxetine can result in increased concentration of mCPP which in turn produces more 5HT2C stimulation and worsening of anxiety. The long half-

939

life of fluoxetine and norfluoxetine in combination with their inhibition of multiple CYP enzymes makes this antidepressant particularly prone to causing DDIs. For that reason, fluoxetine has fallen out of favor as a first-line antidepressant and should generally be avoided, particularly in patients on other medications. Knowledge of phase 1 metabolism has expanded substantially over the past decade as a result of improved understanding of cytochrome P450 (CYP) enzymes (Table 2). These advances came as a result of molecular biology, which permitted identification and cloning of the genes that encode specific CYP enzymes. Studies are now directed at identifying which CYP enzymes are involved in the biotransformation of specific drugs and also determining whether specific drugs can induce or inhibit specific CYP enzymes (Table 3). In addition to such in vitro studies, the metabolism of the drug can be assessed in individuals who are genetically deficient in a specific enzyme, but this approach is limited to those CYP enzymes that have a genetic polymorphism, such as CYP2D6 and CYP2C19 [2,4,6,28]. 1.

CYP Enzyme Induction

This phenomenon refers to an increase in the clearance as a result of increase in the drug-metabolizing capacity of the individual generally by increasing the production of the enzyme mediating the metabolism of the drug. As a result, the plasma concentration of the affected drug will fall unless there is a compensatory increase in the dosing rate. Induction refers to inducing the expression of the gene that makes the enzyme. This

Table 3 Inhibitory Effect of Newer Antidepressants at Their Usually Effective Minimum Dose on Specific CYP Enzymes No or minimal effect (< 20%) Citalopram Fluoxetine Fluvoxamine Nefazodone Paraxetine Sertraline Venlafaxine

1A2, 2C9/10, 2C19,3A3/4 1A2 2D6 1A2, 2C9/10, 2C19, 2D6 1A2, 2C9/10, 2C19, 3A3/4 1A2, 2C9/10, 2C19, 3A3/4 1A2, 2C9/10, 2C19, 3A3/4

Mild (20–50%) 2D6 3A3/4 — — — 2D6 2D6

Moderate (50–150%)

Substantial (> 150%)

— 2C19 3A3/4 — — — —

— 2D6, 2C9/10 1A2. 2C19 3A3/4 2D6 — —

Mirtazapine based on in vitro modeling is unlikely to produce clinically detectable inhibition of these five cytochrome P450 (CYP) enzymes. However, no in vivo studies have been done to confirm that prediction Source: Ref. 4.

940

Figure 2 Ref. 4.)

Khan and Preskorn

How knowledge of drug-metabolizing enzymes will simplify understanding of pharmacokinetic interactions. (From

process takes time as the enzyme concentration reaches a new steady-state level as a result of the increased production. As the concentration of the enzyme increases, the clearance of drugs metabolized by that enzyme increases and the levels of those drugs decrease. The achievement of the new steady-state level of the enzyme and the new clearance takes 2 weeks. When the inducer is stopped, the levels of the enzyme fall back to baseline as does the clearance of drugs metabolized by that enzyme. That process also takes 2 weeks as the basal (or noninduced) steadystate level of the enzyme is achieved. Thus, there is a delay in onset and offset of the induction phenomenon [6,35]. This delay must be taken into account by the prescriber when starting or stopping an inducer. The starting of an inducer is like stopping an inhibitor in terms of change in the clearance of the affected drug, and stopping an inducer is like starting an inhibitor in terms of change of clearance. The prescriber must keep those facts in mind as well. The time course of induction is considerably longer than inhibition, which occurs immediately. However, the magnitude of the inhibition is a function of reaching the steady state of the inhibitor. In the case of fluoxetine and its active metabolite, norfluoxetine, that can take weeks to months during which time the magnitude of the effect on the clearance of the drugs and hence their levels is increasing. Induction is often the equivalent of dropping the dose which can lead to a loss of efficacy. For example, certain anticonvulsants (e.g., CBZ, phenobarbital) potently induce psychotropics resulting in a fall in their levels because of an acceleration in their metabolism [14,30]. Thus, the addition of carbamazepine to control mood swings in a psychotic patient previously stabilized on an antipsychotic may precipitate a psychotic exacerbation or relapse unless the dose is adjusted to compensate. For example, quetiapine (Seroquel) is principally metabolized by CYP3A [35– 37]. The addition of an inducer like carbamazepine could decrease the levels of quetiapine below its minimum threshold for efficacy [30,35]. Another example

of enzyme induction is concomitant use of carbamazepine with sertraline which resulted in a lack of efficacy of sertraline as an antidepressant at doses two to four times higher than its usually effective minimum dose (i.e., 50 mg/day). This lack of sertraline efficacy was the result of a DDI with carbamazepine but might simply have been interpreted as the patient being ‘‘resistant’’ to the antidepressant effects of sertraline [38,39]. DDIs are not restricted to prescription drugs but can involve drugs such as alcohol, illicit drugs, herbs, and dietary substances. Acute alcohol ingestion has complex effects on the metabolism of drugs. Acute alcohol ingestion can reduce first-pass metabolism and thus increase the plasma concentration of some drugs with usually high first-pass metabolism [8,40]. Subchronic alcohol use on a regular basis for several weeks to months can induce CYP enzymes, resulting in lower plasma levels of drugs that undergo oxidative biotransformation as a necessary step in their elimination [3,6]. Chronic alcohol use can result in cirrhosis, reducing hepatic CYP enzyme concentration and liver mass and cause portacaval shunting [3,6,28]. Cirrohosis can also decrease circulating protein binding, resulting in an increase in the free drug fraction particularly for psychiatric drugs which as a group are usually highly protein bound (venlafaxine being an exception to this general rule). The amount and activity of biotransformation are dependent on the rate of delivery of the drugs to the liver which in turn are dependent on hepatic arterial flow. Drugs like cimetidine and propranolol decrease arterial flow, slowing the clearance of various drugs that undergo extensive oxidative biotransformation [3,39,40]. The effect of these drugs is comparable to the effect of a metabolic inhibition even though the mechanism is different. 2.

CYP Enzyme Inhibition

As mentioned previously, inhibition is usually a competitive process, so the magnitude of the inhibitors is a direct and immediate function of the concentration of the drug and its potency for inhibiting the enzyme. As


mentioned earlier, the terfenadine story is the tragic example of CYP enzyme inhibition and had by 1996 resulted in the death of > 125 otherwise healthy individuals and eventually resulted in the removal of the drug from the market [41]. Terfenadine is a pro-drug whose conversion to an active antihistamine required metabolism by CYP3A4 [15]. The principal effect of potent 3A4 inhibitors (e.g., ketoconazole, nefazodone) was to massively increase the levels of the parent drug, terfenadine, reaching the systemic circulation by blocking its first-pass metabolism [1,11,28,32]. However, these inhibitors also slowed the clearance of terfenadine following absorption and thus prolonged the period that the patient was at risk for a potentially fatal arrhythmia. Recall, as mentioned earlier, that the half life of the inhibitor drug is important because it determines that how long the inhibitor must be administered before its full effect on the clearance of other drugs is achieved and how long after its effects on their clearance will persist after its discontinuation. Individuals receiving antipsychotic medications often receive concurrent drug therapy because of coexisting depression, anxiety, or other syndromes that necessitate the administration of antidepressants, anxiolytics, or hypnotics. Thus, the potential for a pharmacokinetically mediated DDI is considerable. An example is an increase in plasma levels of clozapine and norclozapine after addition of nefazodone [42]. In this case, the patient’s psychosis was under control with clozapine, and nefazodone was started to treat persistent negative symptoms of schizophrenia. A week later, on this combination, the patient reported increased anxiety and dizziness with mild hypotension. Therapeutic drug monitoring showed increased levels of clozapine and norclozapine consistent with a DDI between clozapine and nefazodone. The clearance of clozapine and norclozapine was reduced by nefazodone through its substantial inhibition for CYP3A4, one of the several enzymes involved in the metabolism of clozapine [42–44]. Drugs such as bupropion, fluoxetine, quinidine, nefazodone, paroxetine, and antipsychotics can under usual dosing conditions produce substantial inhibition of CYP2D6-, CYP2C9/10-, CYP3A3/4-, and CYP2C19-specific CYP enzymes and can produce an average of a 500% increase in the levels of coprescribed drugs which are principally dependent on those inhibited CYP enzymes for their clearance (Table 3). An increase of this magnitude in the levels of coprescribed drugs can lead to serious and even fatal DDIs particularly if the drug has a narrow therapeutic

941

index and its dose is not adjusted for the change in clearance. D.

Elimination Case Example. A 48-year-old bipolar woman, stabilized on lithium 1200 mg/day for the past 6 months, had a plasma level that varied between 0.8 and 1.0 mEq/L. She developed a recurrence of her rheumatoid arthritis, for which her internist prescribed ibuprofen (800 mg TID). A week later she was brought to the emergency room in a confused, disoriented, and lethargic state. She was also ataxic and had periodic generalized myoclonic jerks. TDM revealed a lithium level of 4.0 mEq/L, and despite a rapid fall to under 0.5 mEq/L with plasma dialysis, her neurological status continued to deteriorate. After 5 days, she died.

Failure to account for a critical drug interaction, affecting the renal clearance of lithium, resulted in an otherwise avoidable fatality. Caution should be used when lithium and diuretics or angiotensin-converting enzyme (ACE) inhibitors are used concomitantly because sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity [45]. When such combinations are used, the clinician may need to decrease the dose of lithium and do more frequent monitoring of lithium plasma levels. The simplest definition for elimination is the body’s ability to rid itself of a drug. For the sake of simplicity, one can think of the human body as a central compartment connected to at least two important pump and filter systems—the liver and the kidneys. The final clearance of most psychotropics occurs via kidney. At this stage, most psychotropic drugs, which are almost invariably highly lipophilic, have been converted into more hydrophobic metabolites, which facilitates their final clearance via kidneys. The process of clearance by the kidneys involves a combination of glomerular filtration, tubular secretion, and sometimes tubular reabsorption as well. Concomitant drugs can affect the ability of the renal tubules to excrete a drug and results in the accumulation of higher concentration of polar metabolites. These polar metabolites can be less efficacious, more toxic, or both relative to the parent compound depending on the pharmacological profile of these metabolites. Two examples are the effect of loop diuretics and nonsteroidal antiinflammatory agents on renal clearance of lithium.

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Dehydration can result in the same outcome by diminishing glomerular filtration rate. This chapter has sought to explain why it is important for the clinicians to understand the third variable of Eq. (1) (i.e., interindividual biological variance which is in part determined by concomitant drugs, and dietary substance as well as genetics; concomitant cardiac, renal, and liver diseases; and age). All these factors, by altering the biology of a given patient, shift the dose-response curve for a specific drug in that specific patient to a clinically meaningful degree can result in DDIs by simply increasing or decreasing the rate of clearance of the drug from the body. Half-life and steady state are two pharmacokinetic terms which summarize the major concepts presented in this chapter. 1.

Half-Life

The half-life of a drug is determined by characteristics of the drug and the patient. It is the time necessary to eliminate half of the drug from the body or decrease the concentration of drug in the plasma by 50%. Halflife determines how much time will be needed to achieve steady-state concentration of drug in plasma. The general rule is that the time to reach steady-state concentration of a drug is five times the drug’s half-life, not five times the dosing interval. The half-life of a drug is proportional to the volume of distribution (Vd) of the drug and inversely proportional to the clearance, as shown in Eq. (4). Half life ðt1=2 Þ ¼

2.

Volume of distribution (Vd) Clearance (Cl)

ð4Þ

Steady State

When successive doses of a drug are administered, the concentration of the drug in the body accumulates until equilibrium is achieved: The amount of drug administered during a dosing interval equals the amount of drug eliminated during the dosing interval. That condition is steady state. The time to reach steady state depends on the half-life of the drug. Once steady state is reached, the drug concentration in various body compartments (e.g., adipose tissue, the brain) is at equilibrium. For most clinical purposes, measurement of drug levels under steady state is preferred because the drug level with subsequent doses will remain the same as long as the sample is drawn at the same time in the dosing interval. In addition, if peak and trough levels are measured at steady state, patient’s pharmacoki-

netic variables such as half-life and Vd can be calculated from just two serum levels [4,6]. In contrast, if peak and trough levels are determined before steady state is achieved, one would get only a ‘‘snap shot in time’’ of the serum levels with that particular dose because the levels will change with the next dose. The length of the drug’s half-life determines the time needed to reach steady state, and that can be important in determining the magnitude and nature of the response to the drug (i.e., efficacy versus toxicity). Half-life also determines the time needed to clear the drug. These concepts are important to the issue of DDIs. Drugs interact not so long as they are prescribed but as long as they persist in the body. A lady who had a seizure 10 weeks after the addition of fluoxetine to imipramine is an example of how the time to steady state affects when an adverse event due to a DDI will occur [6,28,34]. In this case, the long half-life of fluoxetine and its active metabolite, norfluoxetine, meant that it took weeks for these substances to reach their eventual steady-state levels [4,6,12,28]. Over this time, the activity of CYP2D6 progressively fell as a result of the competitive inhibition caused by fluoxetine and norfluoxetine [6]. As that enzyme became progressively less functional, the clearance of imipramine progressively diminished and its levels progressively increased [5,12]. In essence, the half-life of imipramine became a function of the half-life of fluoxetine and norfluoxetine. The levels of imipramine increased to the point that it produced its classic concentration-dependent adverse effects which in this case was a grand mal seizure. [12,35]. Returning to Eq. (1), the patient biology (variable 3) was affected by the addition of fluoxetine and norfluoxetine (i.e., progressive CYP2D6 inhibition). That reduced the clearance of imipramine (variable 2), so that the levels of this drug increased to the point that it began affecting ion channels (variable 1) to the point that a clinically meaningful change in clinical effects was observed (i.e., a grand mal seizure) [12].

IV.

CONCLUSION

This chapter reviewed important pharmacokinetic principles and their relationship to DDIs. Understanding the pharmacokinetics of a drug is not only essential to the safe and effective prescribing of medications when used alone but can also helps clinicians to avoid adverse DDIs. Rational clinical therapeutics depends on identification and understanding of


clinically important DDIs. The topic of DDIs, once a medical curiosity, is now one of great clinical importance and growing public interest. The legal profession is also becoming more attentive to the role played by the DDIs in issues of medical liability. For these and other reasons, the clinicians must be attentive to the possibility of adverse DDIs, not only between the drug he or she prescribes, but also between these medications and those prescribed by other physicians, those available over the counter, and those provided by wellintentioned friends and relatives.

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Index

ADAPT, 885 ADC, 102–103 Addicted brain PET, 597–604 Addiction Severity Index (ASI), 590 Addictive disorders animal models, 624 genetics, 615–624 treatment optimization, 591 Addictive drugs mechanisms of action, 586–587 neurotransmitters, 583 pharmacokinetics, 584 rewarding effects, 584 ADHD. see Attention deficit hyperactivity disorder (ADHD) Adolescent anxiety disorders. see Childhood anxiety disorders Adolescent mania outcome, 154 Adolescent mood disorders. see Childhood mood disorders Adolescent psychotic disorders. see Childhood psychotic disorders Adoption studies, 15 alcoholism, 616–618 suicidal behavior, 702 Adrenergic agents alcoholism, 850 Alzheimer’s disease, 869 Adrenocorticotropic hormone (ACTH), 177, 455

AAMR, 57 Academic deficits mental retardation, 58 ACC, 228, 283 Acetylcholine (ACh), 26 affective disorders, 347–357 Alzheimer’s disease, 543–544 catecholamine, 353–355 neuromodulator interactions, 352–353 neurotransmitter interactions, 352–353 personality disorder, 646 second-messenger, 356–357 serotonin, 355–356 Acetylcholinesterase inhibitors Alzheimer’s disease, 866–867 Acetylmethadol opioid dependence, 853 ACh. see Acetylcholine (ACh) Acquired immunodeficiency syndrome (AIDS), 902 ACTH, 177, 455 Activation positron emission tomography aging, 487 Alzheimer’s disease, 487 Acute/brief psychotic disorder DSM and ICD definition, 74 refining, 76–77 Acute mania fosphenytoin, 800–801 Acute stress disorder (ASD), 61 classification, 93 AD. see Alzheimer’s disease (AD) 945

946 Adrenomedullary axes cholinergic mechanisms, 351–352 Adventurous temperament type pharmacological treatment, 142–143 Affective disorders ACh, 347–357 imaging studies, 335–342 kindling, 770–771 putative clinical applications, 921–923 serotonin markers, 400–401 African-Americans comorbid depression, 554 Aggression, 744–745 genetics, 676–677 neuroanatomical correlates, 675–676 neurobiology, 671–677 serotonin, 672–675 Aging activation PET, 487 brain characterization, 478 metabolism, 482–484 healthy definition, 477–478 immaturity, 129 PET image processing, 481–482 structural imaging studies, 336 Agitation childhood depressive disorders, 150 Agoraphobia, 91 clinical genetics, 467–469 comorbidity, 467–468 epidemiology, 467–468 panic disorder, 472 AIDS, 902 AIDS Dementia Complex (ADC), 102–103 AIT-082 (Neotrofin) Alzheimer’s disease, 874–875 Alarm system, 89 Alcohol craving, 565 emotional attachment, 565 mechanisms of action, 586 neurotransmitters, 583 obsession, 564–565 reward centers, 566–569 Alcohol abuse PET, 604 Alcohol/cocaine abuse simultaneous PET, 600–601 Alcohol dependence, 554 GABA, 570 plasma GABA, 365 TCA, 554

Index Alcoholic dementia, 103 Alcohol intoxication characterization, 564 Alcoholism, 128–129 amygdala, 568 biological features, 565–566 brain pathways, 567 clinical features, 564–565 dementia, 103 denial, 565 disorders genetically related to, 618–619 dopamine, 573–574 drug abuse familial relationships, 619–620 etiologic marker studies, 623–624 GABA, 569–571 gene identification, 620–622 genetics, 565, 615–619 glutamate, 571–572 neurobiology, 563–576 pharmacotherapy, 846–850 progression, 565 racial groups, 565 serotonin, 572–573 Alcohol-non-craving animals, 575 Alcohol reward GABA, 570 Alcohol tolerance, 564 Alcohol use disorder (AUD), 553–558 future directions, 557 Alcohol withdrawal, 564 GABA, 570 signs and symptoms, 564 Allele sharing methods, 19–20, 20 Allopregnanolone, 570 Allostatic dysregulation model compulsive drug use, 584–585 Allostatis, 451 Alpha-acetylmethadol opioid dependence, 853 Alpha-secretase inhibitors Alzheimer’s disease, 871 Alpha-synucleinopathies, 107–108 Alprazolam sexual dysfunction, 659 Alzheimer’s disease (AD), 100–101, 865 activation PET, 487 apoptosis, 543 behavioral symptoms treatment, 879–882 biomarkers, 543 brain pathology, function and structure, 484–486 brain imaging, 499–503 functional, 501–503 genotyping, 503

Index [Alzheimer’s disease] structural, 499–501 brain metabolism, 484–486 characterization, 478 chromosome 9 gene, 529–530 chromosome 10 gene, 529 chromosome 12 gene, 527–529 cost, 521 vs. frontosubcortical dementia, 108 vs. frontotemporal dementia, 501 genetics, 104, 521–530 incidence, 521, 537 mild cognitive impairment pathological correlates, 545–546 neurobiology, 537–546 neuronal death, 543 neurotransmitter abnormalities, 543–545 pathological diagnosis, 542 pathology, 521–522 pathophysiology, 107 PET, 480, 484–485 prevalence, 537 sleep, 718 structural abnormalities, 538–542 treatment, 866–879 vs. vascular dementia, 505 in vivo imaging techniques, 478–479 Amantadine cocaine dependence, 589 sexual dysfunction, 662 Amenorrhea antipsychotics, 659 American Association of Mental Retardation (AAMR), 57 American Psychiatric Association (APA) bipolar disorder practice guidelines, 160 Amfebutamone. see Bupropion (Amfebutamone) Amitriptyline bulimia nervosa, 833 childhood mood disorders, 159 Amphetamine model, 324 neurotransmitters, 583 psychoses, 318, 320–321 Amygdala, 179 aggression, 675–676 alcoholism, 568 hyperresponsivity, 453 measurement, 337 PTSD, 451–453, 453 viscerosensory information, 441 Amyloid aggregation inhibitors, 871–873 immunization, 873 protein, 544 Amyloid-beta protein, 108

947 Amyloid deposition inflammatory reaction Alzheimer’s disease, 540 Amyloid metabolism Alzheimer’s disease, 538–540 Amyloid precursor protein (APP) early-onset Alzheimer’s disease, 522 metabolism, 541 Androgens sexual dysfunction, 660 Angular gyrus syndrome, 102 Animal models, 1–10 changing role, 7–8 cholinergic-behavioral effects, 347–348 definitional/conceptual issues, 4–5 ethological context, 3–4 genetics, 8–9 historical context, 3 new therapies, 9 psychoses, 317–329 developmental viral infection, 326 early limbic lesion models, 325 evoked immune response, 326 perinatal distress models, 326 pharmacological, 323 schizophrenia, 319 future directions, 328 significance, 6 types, 4–5 validation criteria, 5–6 Animal rights, 9 Anorexia nervosa, 633 behavioral traits, 635 course, 634–635 genetics, 635–636 neurotransmitters, 636–639 osteoporosis, 831 pharmacological intervention, 827–831 phenomenology, 634 ANP, 436 Anterior cingulate cortex (ACC), 228, 283 Antiamyloid treatments Alzheimer’s disease, 869–873 Antibiotics, 903 Anticholinergic agents antidepressants, 350–351 Anticipation trinucleotide repeat sequences, 401–402 Anticonvulsants alcoholism, 850 bimodal effects, 769–770 biochemical effects, 768–769 contingent tolerance model, 782–785 mechanisms of action, 767–785 vs. psychotropic mechanisms, 767–768 sexual dysfunction, 661

948 Antidepressants, 95 Alzheimer’s disease, 881–882 anorexia nervosa, 828–829 bulimia nervosa, 832–834 cellular and molecular mechanism, 814–815 mechanistic approaches, 811–814 nicotine dependence, 845–846 response studies, 340 sexual dysfunction, 657–659 Antidopaminergic neuroleptic agents anorexia nervosa, 828 Antiepileptics childhood bipolar disorders, 162 Antihypertensives, 903 Anti-inflammatory agents Alzheimer’s disease, 876–877 Anti-Inflammatory Prevention Trial (ADAPT), 885 Antioxidants Alzheimer’s disease, 875–876 Antipsychotics Alzheimer’s disease, 879–881 childhood psychotic disorders, 201–202 receptor effects, 734 receptor occupancy, 245–246 receptor pharmacology, 733 sexual dysfunction, 659–660 side effects, 201–202, 734 weight gain, 747–748 Antisocial personality, 142–143 Antisocial personality disorders (ASPD), 647 Anxiety disorder proneness, 471 alcoholism, 618 Anxiety disorders, 61–62, 128–129, 923–924 benzodiazepine, 815 childhood, 175–188 vs. childhood mood disorders, 153 with childhood mood disorders, 152 classification, 89–97 current, 90–91 comorbid SUDs, 555–556 new treatments, 815–816 Anxiolytics Alzheimer’s disease, 882 sexual dysfunction, 659 APA bipolar disorder practice guidelines, 160 Apolipoprotein E (ApoE) Alzheimer’s disease, 874 late-onset Alzheimer’s disease, 524–527 racial groups, 526 structure, 525 Apoptosis Alzheimer’s disease, 543 prevention, 757–758 APP early-onset Alzheimer’s disease, 522

Index [APP] metabolism, 541 Appetite childhood depressive disorders, 151 Appetite stimulants anorexia nervosa, 828 Aretaeus of Cappadocia, 69 Arginine vasopressin (AVP) personality disorder, 646 Aripiprazole schizophrenia, 737 Arizona Sexual Experiences Scale (ASEX), 663 ASD, 61 classification, 93 ASEX, 663 ASI, 590 Asians alcoholism, 565 ASPD, 647 Asperger’s disorder, 59 neurobiology, 211–212 Association studies, 17–18, 298–299, 397–398 Atorvastatin Alzheimer’s disease, 878 Atrial natriuretic peptide (ANP), 436 Attention deficit hyperactivity disorder (ADHD), 18, 55–56, 61 with childhood bipolar disorders, 152 vs. childhood mood disorders, 153 comorbidity, 56 prevalence, 56 Attention deficits schizophrenia, 225–226 Atypical antipsychotics pathological gambling, 693 schizophrenia dopamine hypothesis, 261 Atypical neuroleptic agents anorexia nervosa, 830 AUD, 553–558 Autism, 59 biochemical factors, 206–207 electroencephalography, 207–208 eye movement, 208 functional MRI, 210 genetic factors, 206 immunological factors, 208 magnetic resonance spectroscopy, 209 morphometric neuroimaging, 209 neurobiology, 205–211 neuroimaging, 208–210 neurophysiology, 207–208 pathology, 206 positron emission tomography, 209–210 quantitative MRI, 208–209 single-photon emission computed tomography, 209–210

Index [Autism] therapeutic intervention, 210–211 Aversive therapy alcoholism, 849–850 nicotine dependence, 845 Avoidant personality, 141 AVP personality disorder, 646 Baddeley’s model of working memory, 226 Basal ganglia, 735 BDNF, 778 Behavioral inhibition, 180 Behavioral similarity models, 4 Behavioral therapy, 911 Rett’s disorder, 213 Benperidol, 912 Benzodiazepines, 95 alcoholism, 570, 850 anxiety disorders, 815 childhood social phobia, 181 comorbid SUDs and anxiety disorders, 556 obsessive personality, 140 panic disorder, 438–439 psychotic disorders, 735 PTSD, 458 sexual dysfunction, 659, 660–661 Beta-amyloid aggregation inhibitors, 871–873 immunization, 873 protein, 544 Beta blockers performance anxiety, 181 Beta-endorphin alcoholism, 565 Beta-secretase inhibitors Alzheimer’s disease, 870 Binswanger’s disease, 102 Biobehavioral animal models, 2 Biochemical signaling, 308 Biofeedback sleep, 720 Biogenic amine reuptake, 27–33 transport, 28 transporters, 32, 741 mechanisms, 31 Biological markers Alzheimer’s disease, 543 family studies, 468 panic disorder, 442 Biological preparedness theory, 92 Biopsychosocial view, 1 Bipolar disorders, 60–61 adolescents

949 [Bipolar disorders] prevalence, 150 childhood, 151–152, 160–164 outcome, 154 trauma, 650 comorbid SUDs, 555 cyclic AMP-generating pathway, 372 cyclic AMP-signaling pathway, 380–381 ERK/MAP kinase signaling pathway, 376 functional imaging, 341–342 GABA system, 279–281, 367–368 gene expression regulation, 385 GH, 409 G-proteins, 378–380 hyperintensities, 341 imaging studies, 340–342 intracellular calcium signaling, 373–375, 383–385 intracellular responses integration, 376 phenytoin, 795–796 prophylactic study, 800 phosphoinositide pathway, 372–373, 381–383 prevalence adolescents, 150 signal transduction abnormalities, 371–386, 378–385 sodium channel abnormalities, 802 structural imaging studies, 340–341 clinical significance, 341 vs. unipolar disorder, 407–415 volumetric studies, 340–341 Bleuler, Eugen, 70 Blockers. see also Calcium channel blockers performance anxiety, 181 Blood oxygen level dependent (BOLD), 687 BOLD, 687 Borderline personality, 140–141 Brain aging characterization, 478 function exploration, 479–481 5HT, 676 hypometabolism Alzheimer pattern, 485–486 metabolism, 479 aging, 482–484 Alzheimer’s disease, 484–486 atrophy corrected, 486–487 pathology, function and structure Alzheimer’s disease, 484–486 phospholipid metabolism spectroscopy studies, 312 tumors dementia, 103 Brain-derived neurotrophic factor (BDNF), 778 Brain voltage-gated sodium channels, 798–799

950 Brief psychotic disorder DSM and ICD definition, 74 refining, 76–77 Brofaromine bulimia nervosa, 832 Bromocriptine alcoholism, 847 cocaine dependence, 589 Bulimia nervosa, 633, 831–836 behavioral traits, 635 course, 634–635 genetics, 635–636 neurotransmitters, 636–639 phenomenology, 634 Buprenorphine (Subutex) opioid dependence, 588, 853–854 Bupropion (Amfebutamone) bulimia nervosa, 833 childhood bipolar disorders, 164 cocaine dependence, 589 cyclothymic-dependent personality, 144 histrionic personality, 143 nicotine dependence, 845–846 sexual dysfunction, 658, 661, 663 sustained-release nicotine dependence, 589 Buspirone alcoholism, 848 autism, 211 childhood social phobia, 181 comorbid SUDs and anxiety disorders, 555–556 generalized anxiety disorder, 815 nicotine dependence, 589 sexual dysfunction, 659, 661 CADASIL, 105 Calcium differential target, 775 Calcium-binding peptides cerebral cortex, 282 GABA system schizophrenia, 281–282 hippocampus, 282 Calcium carbimide alcoholism, 849–850 Calcium channel blockers alcoholism, 850 childhood bipolar disorders, 163 vascular dementia, 883 Calcium signaling pathway abnormalities, 384 Cancer, 902 Candidate chromosomal regions, 398–400 Candidate genes, 398–400 alcoholism, 620–621 panic disorder, 470

Index [Candidate genes] panic syndrome, 442 Cannabinoids anorexia nervosa, 828 mechanisms of action, 587 Carbamazepine alcoholism, 850 anticonvulsant effects, 768 anticonvulsant tolerance, 785 bipolar disorders comorbid SUDs, 555 bulimia nervosa, 834 childhood bipolar disorders, 162 contingent tolerance model, 782–783 differential target, 775 drug interactions, 742 mechanism of action, 772–776 pharmacological properties, 793–794 Rett’s disorder, 213 sexual dysfunction, 661 substance P, 776 Carbon dioxide hypersensitivity, 434 Cardiovascular disease pharmacological interventions, 900–901 Castration surgical, 912 Catatonic type schizophrenia, 200 Catecholamines ACh interactions, 353–355 stress-induced increases, 177 Cautious temperaments, 137, 141 CBD, 105 brain imaging, 509 pathophysiology, 107 CBF. see Cerebral blood flow (CBF) CBT. see Cognitive behavior therapy (CBT) CCK-4, 470–471 CDD, 59 neurobiology, 213–214 Cell death. see Apoptosis Central choline imaging studies, 350 Central nervous system immune system, 410 Central pathways panic disorder, 435 Central sleep apnea syndrome, 719 CERAD, 542 Cerebral autosomal-dominant angiopathy subcortical infarcts and leucoencephalopathy (CADASIL), 105 Cerebral blood flow (CBF), 439–440, 479, 480 model, 480 Cerebral cortex calcium-binding peptides, 282 Cerebral hyperintensity depression, 337

Index Character, 644 psychobiology, 117–148 psychotherapy, 136, 137 scores, 118 vs. temperament, 119 treatment guidelines, 134–148 Character immaturity mental disorder, 126–129 Character traits psychobiological summary, 129 Chemical neuroimaging development, 46–49 Childhood anxiety disorders, 175–188 Childhood bipolar disorders, 151–152, 160–164 outcome, 154 Childhood depressive disorders symptoms, 150–151 Childhood disintegrative disorder (CDD), 59 neurobiology, 213–214 Childhood generalized anxiety disorder, 178–180 Childhood mania, 61 Childhood mood disorders, 149–164 biology, 154–159 clinical characteristics, 149–150 comorbidity, 152–153 differential diagnosis, 153 epidemiology, 149–150 future directions, 164 future research, 188 natural course, 153–154 pharmacotherapy, 159–160 prevalence, 150 psychotherapy, 160 signs and symptoms, 150–151 treatment, 159–164 guidelines, 160 Childhood obsessive-compulsive disorder, 182–185 brain chemistry/glutamate, 184–185 volumetric studies, 182–184 Childhood panic disorder, 181 Childhood posttraumatic stress disorder, 185–187 with separation anxiety, 186 Childhood psychiatric disorders classification, 55–59 Childhood psychotic disorders, 63, 197–202 clinical picture, 198–200 etiology, 200–202 historical background, 198 neuroimaging, 200–201 pathophysiology, 200–202 treatment, 201–202 guidelines, 202 Childhood schizophrenia, 198 delusions, 63 Childhood social anxiety disorder, 180–181 Childhood social phobia, 180–181

951 Childhood specific phobias, 187–188 Childhood trauma bipolar disorders, 650 Children’s Medication Algorithm Project, 161 Chlordiazepoxide alcoholism, 850 sexual dysfunction, 659 Chlorpromazine cocaine dependence, 589 Cholecystokinin receptor antagonists, 818 Cholecystokinin tetrapeptide (CCK-4), 470–471 Cholesterol aggression, 675 personality disorder, 646–647 Cholesterol-lowering agents Alzheimer’s disease, 878–879 Choline, 349 Cholinergic innervation Alzheimer’s disease, 544 Cholinergic neurons Alzheimer’s disease, 544 Cholinergic pathways, 47 Cholinergic receptors Alzheimer’s disease, 544 Cholinesterase inhibitors Alzheimer’s disease, 867–868 vascular dementia, 884 Cholinomimetics mood-depressing effects, 348–349 Chromosome 4, 400–401 Chromosome 5, 399 Chromosome 11, 399–400 Chromosome 12, 401 linkage studies, 527 Chromosome 18, 398–399 Chromosome 19 late-onset Alzheimer’s disease, 524–527 Chromosome 21, 401 Chromosome 9 gene Alzheimer’s disease, 529–530 Chromosome 10 gene Alzheimer’s disease, 529 Chromosome 12 gene Alzheimer’s disease, 527–529 Chromosome X, 398 Chronic alcoholism dementia, 103 Cigarette smoking comorbidity, 557 genetics, 619 Cisapride anorexia nervosa, 830–831 Citalopram alcoholism, 849 Alzheimer’s disease, 881 anorexia nervosa, 829

952 [Citalopram] bipolar disorders, 413 bulimia nervosa, 834 childhood obsessive-compulsive disorder, 184 obsessive personality, 139 Citric acid nicotine replacement, 845 CJD, 103 brain imaging, 510 Classification systems future research, 76–77 validity, 75 Clinical diagnoses, 74–76 Clinical disorders animal models, 7–8 Clioquinol Alzheimer’s disease, 872–873 Clomipramine, 911–912 anorexia nervosa, 828–829 autism, 211 OCD, 815 pathological gambling, 686 schizophrenia, 740–741 serotonin, 738 Clonazepam childhood obsessive-compulsive disorder, 184 sexual dysfunction, 659 Clonidine, 455 childhood panic disorder, 181 nicotine dependence, 589, 845 panic disorder, 437 Clozapine childhood bipolar disorders, 163 pharmacological profile, 732 schizophrenia, 259–260, 731–732, 735, 736 dopamine hypothesis, 261 serotonin receptors, 271 sexual dysfunction, 659 Cluster A personality disorders, 647 Cocaine, 27 administration pharmacokinetics, 584 mechanisms of action, 586 neurotransmitters, 583 time activity curves, 596 Cocaine abuse comorbidity, 556–557 Cocaine addiction PET, 598–600 Cocaine/alcohol abuse simultaneous PET, 600–601 Cocaine dependence pharmacological treatment, 854 pharmacotherapy, 589–590

Index Cogeners mechanisms of action, 586 Cognition repetitive transcranial magnetic stimulation, 925 Cognitive behavior therapy (CBT) for childhood generalized anxiety disorder, 179 childhood mood disorders, 160 childhood social phobia, 181 pathological gambling, 690 Cognitive catastrophe, 435 Cognitive deficit model compulsive drug use, 585 Cognitive deficits schizophrenia, 223–231 amphetamine-induced DA release, 242–244 baseline DA release, 244 clinical significance, 229–230 DA transporters, 244 DOPA decarboxylase, 242 functional imaging, 239–240 imaging DA transmission, 240 MRS, 246–249 neurochemical imaging, 240–249 neuropharmacological imaging, 240–249 nondopaminergic receptors, 244–245 PET, 240–246 phosphorus spectroscopy, 246–247 prefrontal DA transmission, 244 proton spectroscopy, 247–248 resting-state studies, 239–240 SPECT, 240–246 striatal DA transmission, 240–242 task-related activation studies, 239–240 Cognitive disability schizophrenia treatment, 230–231 Cognitive disorders protein aggregation, 106 Cognitive therapy sleep, 720 Collagen vascular disease, 901 Collimator, 46 Combat-related posttraumatic stress disorder (PTSD), 455 Combat-related PTSD, 455 Communication disorders, 58–59 Comorbid AUDs and bipolar disorders, 555 Comorbid depression African-Americans, 554 Comorbid SUDs and anxiety disorders, 555–556 and bipolar disorders, 555 psychiatric disorders, 554 psychotic disorders, 556 Complex genetics, 296

Index Complex phenotype, 296–297 Compulsions, 92 Compulsive drug use biological theory, 584–585 Computed tomography (CT) advent of, 44 childhood mood disorders, 157 personality disorder, 649 Conduct disorder, 56 with childhood bipolar disorders, 152 vs. childhood mood disorders, 153 Confusional arousals, 722 Congenital hypoventilation syndrome, 177 Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), 542 Construct validity, 5 Continuous-performance task (CPT), 225 Convergence, 4 Cortex GABAergic interneurons, 277–279 Cortical dementia, 109 Corticobasal degeneration (CBD), 105 brain imaging, 509 pathophysiology, 107 Corticosteroids, 903 immune response, 411 Corticostriatothalamocortical circuits OCD, 424 Corticotrophin-releasing factor (CRF), 177, 436, 455, 818 antagonist depression, 814 Cortisol, 455, 457 aggression, 675 Cost Alzheimer’s disease, 521 CPA, 913 CPT, 225 Craving alcohol, 565 Creutzfeldt-Jakob disease (CJD), 103 brain imaging, 510 CRF. see Corticotrophin-releasing factor (CRF) CT. see Computed tomography (CT) Cushing’s syndrome, 457 Cyanocobalamin dementia, 103 Cyclic AMP-generating pathway bipolar disorders, 372 Cyclic AMP-signaling pathway bipolar disorders, 380–381 Cyclo-oxygenase-2 inhibitors Alzheimer’s disease, 877 Cyclothymic-dependent personality, 144 Cyclothymic type, 137 CYP drug-drug interactions, 938–939

953 [CYP] enzyme induction, 939–940 enzyme inhibition, 940–941 Cyproheptadine sexual dysfunction, 662, 663 Cyproterone acetate (CPA), 913 Cytochrome P450 (CYP) drug-drug interactions, 938–939 enzyme induction, 939–940 enzyme inhibition, 940–941 Cytogenetic abnormalities, 300–301 Cytokines mood disorders, 412 DA. see Dopamine (DA) d-amphetamine psychoses, 318, 320–321 DAT, 27 DBS, 919 DBT, 651 Declarative memory, 227 Deep brain stimulation (DBS), 919 Degenerative dementia, 100–102 Delusional disorder DSM and ICD definition, 74 Delusions, 199 childhood schizophrenia, 63 Dementia brain imaging, 497–511 functional, 498–499 structural, 497–498 classification, 99–110 clinical profile, 109 etiology, 100 clinical classification, 108–110 definition, 99 etiology, 99–104 genetics, 104–105, 106 pathophysiology, 105–108, 107 pharmacological treatment, 865–886 protein aggregation, 106 Dementia infantilis. see Childhood disintegrative disorder Dementia praecox, 70 Dementia syndromes brain imaging abnormalities, 512 contributions, 513 Dementia with Lewy bodies (DLB), 101, 884–885 brain imaging, 506 Demyelinating disorders, 103–104 Denial alcoholism, 565 Deoxyglucose model, 480–481 Dependence, 845–846 Dependent personalities, 137 Depo-Provera, 913

954 Depot neuroleptics, 748–749 Depression, 60 alcoholism, 618 animal models, 366–367 cerebral hyperintensity, 337 comorbid African-Americans, 554 CRF antagonist, 814 functional imaging studies, 339–340 GABA, 364 GH, 409 imaging studies, 335 muscarinic interactions, 352 neuroimaging clinical significance, 338–339 nicotine receptor agonist, 813–814 nicotinic interactions, 352 regional brain measurements, 336–338 sleep, 714–716 structural imaging studies, 336 valproate, 366 Depressive disorders childhood symptoms, 150–151 Desipramine bulimia nervosa, 832, 833 cocaine dependence, 589 comorbid major depressive disorder and alcohol use disorder, 554 DESNOS, 450 Developmental coordination disorder, 58 Developmental models implications, 327–328 Deviant personalities vs. normal personalities, 120–122 Dexamethasone, 457 Dexamethasone suppression test (DST), 408 Dextroamphetamine sexual dysfunction, 663 DFP, 8, 348 Diabetes, 901–902 antipsychotics, 748 Diagnosis threshold international differences, 74 Diagnostic and Statistical Manual of Mental (DSM), 71–73 challenges, 93–95 comorbidity, 94–95 treatment discrimination, 95 Diagnostic and Statistical Manual of Mental (DSM-1), 71 Diagnostic and Statistical Manual of Mental (DSM-II), 72 Diagnostic and Statistical Manual of Mental (DSM-III), 73

Index

Disorders

Disorders-1 Disorders-II Disorders-III

Diagnostic and Statistical Manual of Mental Disorders-IIIR (DSM-IIIR), 73 Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV), 73–74 Diagnostic and Statistical Manual of Mental Disorders-IVTR (DSM-IV-TR), 73–74 Diagnostic criteria DSM, 71–73 ICD, 73–74 international differences, 74–75 Diagnostic hierarchies international differences, 74 Dialectical Behavior Therapy (DBT), 651 Diazepam sexual dysfunction, 659 Diffusion tensor imaging (DTI), 46 DiGeorge syndrome, 301 Digoxin, 903 Dihydroxyphenylacetic acid (DOPAC) pathological gambling, 687 Di-isopropylfluorophosphate (DFP), 8, 348 Discriminant analysis, 487 Disintegrative disorder childhood, 59, 213–214 Disintegrative psychosis. see Childhood disintegrative disorder Disorders of Extreme Stress (DESNOS), 450 Disorganized type schizophrenia, 200 Disruptive behavior disorders, 55 Dissocial alcoholics, 648 Distractibility childhood bipolar disorders, 152 Disulfiram alcoholism, 849 cocaine dependence, 589–590 schizophrenia comorbid SUDs, 556 Divalproex autism, 211 childhood bipolar disorders, 162 side effects, 162 DLB, 101, 884–885 brain imaging, 506 DLPFC, 228 DMD gene, 16 DNA epigenetic manipulations, 327 Donepezil, 354 Alzheimer’s disease, 867 autism, 211 DOPAC pathological gambling, 687 Dopamine (DA), 25, 26, 27 aggression, 674 alcohol, 565

Index [Dopamine] alcoholism, 573–574 Alzheimer’s disease, 545 anorexia nervosa, 828 autism, 207 bipolar disorders, 413–414 D3 receptor genes, 299–300 eating disorders, 639 histrionic personality, 143 neuroimaging studies pathological gambling, 687–688 pathological gambling, 687–688 genetics studies, 688 personality disorder, 646 Dopamine model compulsive drug use, 585 Dopaminergic agonists cocaine dependence, 589 Dopaminergic neuroleptic agents anorexia nervosa, 828 Dopaminergic pathways, 47 Dopaminergic reward system regulation, 597 Dopaminergic system, 735–738 PTSD, 454 Dopamine transporter (DAT), 27 Dorsolateral prefrontal cortex (DLPFC), 228 Dothiepin, 901 Douchene muscular dystrophy (DMD) gene, 16 Doxapram panic disorder, 437 Drug abuse alcoholism familial relationships, 619–620 definition, 581–582 genetics, 619 Drug-addicted individuals clinical assessment of, 588–591 Drug addiction biological basis, 581–591 definition, 581–582 neural substrates, 582–584 Drug dependence definition, 581–582 gene identification, 622–623 understanding, 596–597 Drug-drug interactions, 933–934 cytochrome P450, 938–939 Drug holiday, 661 Drugs absorption, 934–936 addictive, 583–587 development, 807–811 rationale, 809–811

955 [Drugs] discovery, 9 distribution, 936–937 dosage vs. concentration, 934–942 elimination, 941–942 mechanism PET, 597–604 metabolism, 937–941 Drug user with psychiatric comorbidity, 590–591 DSM. see Diagnostic and Statistical Manual of Mental Disorders (DSM) DST, 408 DTI, 46 Dysthymia, 60 Early-onset Alzheimer’s disease, 522–524 APP gene, 522 presenilin genes, 522–523 Eating disorders. see also Anorexia nervosa; Bulimia nervosa biological basis, 633–639 etiology, 633 pharmacological intervention, 827–837 ECA study, 553 Ecstasy. see Methylenedioxymethamphetamine ECT, 919 EEG, 50 autism, 207–208 Ejaculation dysfunction, 658 Electroconvulsive therapy (ECT), 919 Electroencephalography (EEG), 50 autism, 207–208 Electrogenic process, 29 Elevated mood childhood bipolar disorders, 151 Emotional core, 119 Empirical validity models, 5 Endogenous opiate PTSD, 458 Endogenous opioid peptide (EOP) alcohol, 566 pathways drug addiction, 582 Endorphin alcoholism, 565 self-injurious behavior, 646 Enkephalin-containing neurons alcoholism, 574 Environment immaturity prevention, 134–135 EOP alcohol, 566 pathways drug addiction, 582

956 Epidemiologic Catchment Area (ECA) study, 553 Erectile dysfunction haloperidol, 663 ERK/MAP kinase signaling pathway bipolar disorders, 376 ERPs, 50 Esquirol, Jean Etienne, 69 Estrogen, 910, 913 Alzheimer’s disease, 877–878 Event-related potentials (ERPs), 50 Evoked immune response animal models psychoses, 326 Excessive worry, 90 Excitatory amino acids, 761–762 agonists Alzheimer’s disease, 869 Expansive mood childhood bipolar disorders, 151 Explosive temperament type, 140–141 Extreme harm avoidance pharmacological treatment, 139–142 Extreme temperament variants causal pharmacotherapy, 138–139 pharmacological guidelines, 138–139 pharmacotherapy guidelines, 137 symptomatic pharmacotherapy, 137–138 Eye movement autism, 208 Face validity, 5 Facilitation, 226 FAD, 522 False alarm, 91 False suffocation alarm hypothesis, 434–435 Familial Alzheimer’s disease (FAD), 522 Familiality genetic risk, 295–296 Family-based linkage studies alcoholism, 621–622 drug dependence, 622–623 Family studies, 14 affective disorders, 702 alcoholism, 615–616 biological markers, 468 depression, 702 eating disorders, 635–636 panic disorder, 468 suicidal behavior, 702–703 Fatal familial insomnia, 103 Fatigue childhood depressive disorders, 151 Fatty acids childhood bipolar disorders, 163 Fear structures, 188

Index Fear processing structures involving, 180 Feedback, 277 Feedforward, 277 Felbamate pharmacological properties, 795 Fenfluramine aggression, 672 autism, 211 bulimia nervosa, 832, 835 Fibromyalgia, 901 Field trials clinical diagnoses, 75 5-hydroxytryptamine (5HT), 25, 26, 27 transporter, 27 Flickering-light sensation, 920–921 Flinders Resistant Line (FRL), 348 Flinders-sensitive line (FSL) rats, 8 Fluoxetine, 911–912 alcoholism, 849 Alzheimer’s disease, 882 bipolar disorders, 413 bulimia nervosa, 833 childhood mood disorders, 159 childhood obsessive-compulsive disorder, 184 cocaine abuse comorbidity, 556–557 comorbid major depressive disorder and alcohol use disorder, 554 drug holiday, 661 obsessive personality, 139 OCD, 815 pathological gambling, 690–692 pindolol, 812 Fluphenazine, 912 Fluvoxamine autism, 211 bipolar disorders, 413 bulimia nervosa, 834 for childhood generalized anxiety disorder, 179 childhood social phobia, 181 drug interactions, 742 obsessive personality, 139 OCD, 815 pathological gambling, 692 fMRI. see Functional magnetic resonance imaging (fMRI) Food restriction, 638 Fosphenytoin, 802 acute mania, 800–801 Freud’s project, 650–652 FRL, 348 Frontal cortex, 735 Frontal lobe measurement, 336 Frontosubcortical dementia (FSCD), 108 vs. Alzheimer’s disease, 108

Index Frontotemporal dementia (FTD), 101 vs. AD, 501 brain imaging, 506–507 genetics, 104–105 treatment, 885 FSCD, 108 FSL rats, 8 FTD. see Frontotemporal dementia (FTD) Functional magnetic resonance imaging (fMRI) autism, 210 childhood mood disorders, 157 dopamine pathological gambling, 687 personality disorder, 649 Functional neuroimaging, 49–51 childhood mood disorders, 158 GABA. see Gamma-aminobutyric acid (GABA) GABAergic interneurons cortex, 277–279 discriminative processing, 279–280 hippocampus, 277–279 network oscillations, 279 phenotypical differentiation, 279 GABAergic pathways, 47 PET, 48 GABAergic terminals markers, 282–284 Gabapentin, 780–781, 784 alcoholism, 850 borderline personality, 141 childhood bipolar disorders, 163 pharmacological properties, 794–795 GABHS infections, 182 GAD. see Generalized anxiety disorder (GAD) Galanin (GAL), 35 Galantamine Alzheimer’s disease, 867 Gamblers Anonymous (GA), 689–690 Gambling defined, 683–684 Gambling Symptom Assessment Scale (G-SAS), 692 Gamma-aminobutyric acid (GABA), 95, 364–365, 816 alcohol, 565 alcohol dependence, 365 alcoholism, 569–571 Alzheimer’s disease, 545 bipolar disorders, 414 depression, 364 nicotine dependence, 844 panic disorder, 438–439 pathological gambling, 689 personality disorder, 646 pharmacology, 365–366 plasma, 364–365 receptor-binding, 284–285 system

957 [Gamma-aminobutyric acid] altered inputs, 285–286 bipolar disorders, 279–281, 367–368 cell migration, 286 cortical lamination, 286 extrinsic afferents postnatal ingrowth, 286–287 hippocampus activity driven changes, 287 neurodevelopmental hypothesis, 286–287 reelin, 286 schizophrenia, 279–281 postmortem evidence, 281–286 stress, 287 Gamma-secretase inhibitors Alzheimer’s disease, 870–871 Gene expression gene expression regulation, 376–378 regulation bipolar disorders, 376–378 Generalized anxiety disorder (GAD), 61–62 buspirone, 815 childhood, 178–180 classification, 90 paroxetine, 815 SAD, 177 venlafaxine, 815 Genes identification, 14 Genetic knockout, 32 Genetic models, 5 Genetic panic syndrome comorbid medical conditions, 441–442 Genetic risk familiality, 295–296 Genetics, 2. see also Adoption studies; Family studies; Twin studies addictive disorders, 615–624 alcoholism, 565, 615–619 Alzheimer’s disease, 521–530 animal models, 8–9 psychoses, 326–327 anorexia nervosa, 635–636 autism, 206 bipolar disorder, 648 childhood mood disorders, 155 childhood psychotic disorders, 201 epidemiology, 295–296, 395–396 panic disorder, 440–442 personality disorder, 647–648 phospholipid metabolism, 312–313 psychotic disorders, 295–302 schizophrenia serotonergic dysfunction, 267–268 smoking, 619 Genetic studies classification, 96 dopamine

958 [Genetic studies] pathological gambling, 688 pathological gambling, 686, 689 suicidal behavior, 702–705 Genome scan studies panic disorder, 470–471 Genotyping brain imaging Alzheimer’s disease, 503 Gerstmann-Straussler-Scheinker disease, 103 Gerstmann syndrome, 102 Ginkgo biloba Alzheimer’s disease, 875–876 sexual dysfunction, 664 Ginseng sexual dysfunction, 664 Glucocorticoids Alzheimer’s disease, 876 stress-induced increases, 177 Glucose dysregulation antipsychotics, 748 Glutamate, 200 alcoholism, 571–572 Alzheimer’s disease, 545 panic disorder, 439 Glutamate excitatory amino acid system schizophrenia, 739–740 Glutamatergic function schizophrenia cognitive disability, 231 Glutamate systems panic disorder, 438–439 Glutamine bipolar disorders, 414 Glycine cycloserine schizophrenia cognitive disability, 231 Glycogen synthase kinase-3, 762–763 GnRH analogs, 914 Gosereline (Zoladex), 914 G-proteins, 372 bipolar disorders, 378–380 Grandiosity childhood bipolar disorders, 151 Granulovacuolar degeneration Alzheimer’s disease, 542 Group A beta-hemolytic streptococcal (GABHS) infections, 182 Growth hormone bipolar disorders, 409 depression, 409 mood disorders, 350 G-SAS, 692 Guam-Parkinson-dementia complex, 541 Guanine-nucleotide binding proteins. see G-proteins

Index Guided imagery sleep, 720 Guilt childhood depressive disorders, 150

Haloperidol Alzheimer’s disease, 880 childhood obsessive-compulsive disorder, 184 cocaine dependence, 589 erectile dysfunction, 663 schizophrenia, 741–742 Haloperidol-clozapine childhood psychotic disorders, 201 Haplotype Relative Risk (HRR), 18–19, 397–398, 469 Hard-wired transmission, 25–27 Harm avoidance psychobiological correlates, 130 psychobiology, 129–130 HD brain imaging, 508 gene, 21 genetics, 105 Headache repetitive transcranial magnetic stimulation, 926 Healthy aging definition, 477–478 Hearing repetitive transcranial magnetic stimulation, 926 Heart period variability (HPV), 436 Heinroth, Johann Christian, 70 Heller, Theodor, 213 Hereditary dysphasic dementia pathophysiology, 106–107 High blood pressure panic attacks, 436 High harm avoidance, 137 High novelty seeking pharmacological treatment, 142–144 High reward dependence high harm avoidance, 137 pharmacological treatment, 144 Hippocampus calcium-binding peptides, 282 GABAergic interneurons, 277–279 GABA system activity driven changes, 287 schizophrenia, 281–282 measurement, 337 neuritic plaques, 539 normal afferent connections, 539 PTSD, 457 Hirano bodies Alzheimer’s disease, 541 Histrionic personality, 143–144

Index HIV-related dementia (HRD), 102–103, 902 brain imaging, 511 Homology, 4 Homovanilic acid (HVA) pathological gambling, 687 Hormonal therapy, 913–915 HPV, 436 HRD, 102–103, 511, 902 HRR, 18–19, 397–398, 469 Human Genome Project, 18 Huntington’s chorea, 282 Huntington’s disease (HD) brain imaging, 508 gene, 21 genetics, 105 HVA pathological gambling, 687 5-Hydroxytryptamine (5HT), 25, 26, 27 transporter, 27 Hyperactivity alcoholism, 618 Hyperglycemia antipsychotics, 748 Hyperintensity location, 338 Hyperphosphorylation Alzheimer’s disease, 873–874 Hyperresponsivity amygdala, 453 Hypersomnia childhood depressive disorders, 150–151 Hypertension panic attacks, 436 Hypnotics Alzheimer’s disease, 882 mechanisms of action, 586 Hypothalamic-growth hormone axis, 409 Hypothalamic-pituitary-adrenal axis, 407–408, 408–409, 451 cholinergic mechanisms, 351–352 drug addiction, 582 hyperactivity, 408 panic disorder, 436–437 Hypothalamic-pituitary-gonadal axis, 410 Hypothyroidism dementia, 103 Iatrogenic sexual dysfunction, 657–665 Ibuprofen, 901 ICD. see International Classification of Diseases (ICD) Idebenone Alzheimer’s disease, 876 Iloperidone schizophrenia, 740 Imagery, 92

959 Imipramine bulimia nervosa, 832 childhood mood disorders, 159 sexual dysfunction, 659 Immature character relative risk, 123 Immature fantasy, 199 Immaturity age, 129 prevention, 134–135 Immune response mood disorders, 411 PTSD, 459 stress, 410–411 Immune system central nervous system, 410 mood disorders, 410–411 PTSD, 458–459 Impaired cognition schizophrenia, 228–230 Impaired executive functions schizophrenia, 228–229 Impulses, 92 Impulsive aggression serotonin, 645–647 tryptophan hydroxylase, 648 Incentive-sensitization model compulsive drug use, 585 Independent temperament type pharmacological treatment, 144–145 Infectious agents genes, 13 Inflammatory reaction amyloid deposition Alzheimer’s disease, 540 Inflated self-esteem childhood bipolar disorders, 151 Inhalant abuse PET, 603 Inositol, 778 Inositol depletion hypothesis, 759–761 Insomnia childhood depressive disorders, 150–151 Interference, 226 International Classification of Diseases (ICD), 73 International Classification of Diseases-9 (ICD-9) vs. International Classification of Diseases-10 (ICD-10), 73–74 International Classification of Diseases-10 (ICD-10) vs., 73–74 vs. International Classification of Diseases-9 (ICD-9), 73–74 Interpersonal therapy (IPT) childhood mood disorders, 160 Intracellular calcium signaling bipolar disorders, 373–375, 383–385

960 Intracellular responses integration bipolar disorders, 376 Intravenous immunoglobulin autism, 211 Ipsapirone, 645 bulimia nervosa, 835 IPT childhood mood disorders, 160 Irritability childhood bipolar disorders, 151 childhood depressive disorders, 150 Kernberg’s Transference Focused Therapy, 650–651 Ketamine, 322 mimicking schizophrenia, 739 schizophrenia, 318 Ketamine abuse PET, 602 Ketoconazole, 903 cardiovascular safety, 747 Ketogenic diet Rett’s disorder, 213 Kindling, 770–771 Kraeplin, Emil, 70 Kraeplin’s systematic classification of psychoses, 70 Kuru, 103 Laboratory advances, 21 Lacunar state, 102 L-alpha-acetylmethadol opioid dependence, 853 Lamotrigine, 778–779, 784, 903 anticonvulsant tolerance, 785 autism, 211 childhood polar disorders, 162 pharmacological properties, 794 side effects, 162 Late-onset Alzheimer’s disease, 522, 524–530 apolipoprotein E gene, 524–527 chromosome 19, 524–527 susceptibility genes, 524 LC, 35, 454–455 LDP, 279 Learning disorders, 58–59 Leuprolide (Lupron), 914 Levetiracetam, 781 Lewy bodies Alzheimer’s disease, 542 dementia, 884–885 LHPA, 451, 456 Life events, 135 Light absorption, 51 scattering, 51

Index Limbic-hypothalamic-pituitary-adrenal (LHPA), 451, 456 Linehan’s Dialectical Behavior Therapy, 651 Linkage disequilibrium, 297–298 isolated populations, 20–21 Linkage method, 396–397 Lipska-Weinberger model, 325 Lithium, 757–764, 903 Bcl-2 upregulation, 758 bipolar disorders comorbid SUDs, 555 childhood bipolar disorders, 160–162, 163–164 loading, 800 neurotrophic effects, 777 pathological gambling, 693 serotonin, 761 sexual dysfunction, 660–661 side effects, 162 substance P, 776 vs. valproate, 776–778 Locus coeruleus (LC), 35 PTSD, 454–455 stress, 454–455 Long-term depression (LDP), 279 Long-term memory models, 226 Long-term potentiation (LTP), 279 Lorazepam, 802 psychotic disorders, 735 Lovastatin Alzheimer’s disease, 878 Low character variants psychotherapy guidelines, 134 Low harm avoidance high reward dependence, 137 Low reward dependence pharmacological treatment, 144–145 Loxapine schizophrenia, 742 LSD schizophrenia, 318 LTP, 279 Lupron, 914 Lysergic acid diethylamide (LSD) schizophrenia, 318 Magnetic resonance imaging (MRI), 45 advent, 44 autism, 208–209 brain Alzheimer’s disease, 500 childhood mood disorders, 157 clinical application, 46 personality disorder, 649 quantitative autism, 208–209 quantitative volumetric

Index [Magnetic resonance imaging (MRI)] brain Alzheimer’s disease, 500 Magnetic resonance spectroscopy (MRS), 48, 312 autism, 209 childhood mood disorders, 157, 158 childhood psychotic disorders, 201 cognitive deficits schizophrenia, 246–249 Magnetic seizure therapy (MST), 919 Magnetization transfer imaging (MTI), 49 Magnetoencephalography (MEG), 51 Major depression, 554 comorbidity, 554–555 vs. panic disorder, 436–437 TCA, 554 Major depressive disorder (MDD), 60, 128–129 comorbidity, 60 Maladaptation, 122 Mania childhood, 61 fosphenytoin, 800–801 MAO pathological gambling, 686–687 MAOIs comorbid SUDs and anxiety disorders, 556 cyclothymic-dependent personality, 144 sexual dysfunction, 658 Marchiafava-Bignami, 103 Marijuana neurotransmitters, 583 Marijuana abuse PET, 603 Mature character protecting against personality disorder, 122 Maturity higher level, 129 Mazindol cocaine dependence, 589 McCrae and Costa’s model of personality, 645 m-CPP pathological gambling, 686 MDD, 60, 128–129 MDMA, 27 mechanisms of action, 587 neurotransmitters, 583 Mecamylamine nicotine dependence, 589, 846 Mechanistic models, 5 Medial prefrontal cortex PTSD, 453–454 Medication. see Drugs Meditation sleep, 720 Medroxyprogesterone acetate (MPA), 913

961 MEG, 51 Melancholy definition, 69 Melatonin childhood bipolar disorders, 163 Membranes biology, 307–308 phospholipid metabolism phospholipase A2, 308–310 remodeling, 308 Memory neurobiology, 226–228 Mendelian inheritance, 16–17 Menstrual irregularities antipsychotics, 659 Mental disorder character immaturity, 126–129 Mental retardation, 57–58 comorbidity, 57 Mental rituals, 92 Mescaline schizophrenia, 318 Mesolimbic dopamine drug addiction, 582 pathways, 584 Metabolic dementia, 103 Metabotropic glutamate, 437 receptor agonists, 817–818 Metachlorophenylpiperazine (m-CPP) pathological gambling, 686 Methadone opioid dependence, 588, 851–853, 854 Methamphetamine mechanisms of action, 586 Methamphetamine abuse PET, 601 Methodical temperament type, 139–140 Methylenedioxymethamphetamine (MDMA), 27 mechanisms of action, 587 neurotransmitters, 583 Methylphenidate cocaine dependence, 854 histrionic personality, 143 mechanisms of action, 586 sexual dysfunction, 663 Metyrapone, 903 Mianserin bulimia nervosa, 832 sexual dysfunction, 662 MID, 102 Milameline Alzheimer’s disease, 868 Mild cognitive impairment Alzheimer’s disease pathological correlates, 545–546 treatment, 885

962 Mild personality disorder, 128–129 Mirtazapine autism, 211 sexual dysfunction, 658, 662 Mitral valve prolapse (MVP), 441 Mixed expressive-receptive disorder, 58 Moclobemide nicotine dependence, 589, 846 sexual dysfunction, 658 Molecular genetics, 297–300 aggression, 677 Monoamine neuropeptides, 34 transporter structures, 27 Monoamine oxidase inhibitors (MAOIs) comorbid SUDs and anxiety disorders, 556 cyclothymic-dependent personality, 144 sexual dysfunction, 658 Monoamine oxidase (MAO) pathological gambling, 686–687 Monoaminergic regulation, 25–36 Monoaminergic neurotransmission neuropeptide modulation, 33–36 Monodrug user, 590 Mood disorders, 60–61 childhood. see Childhood mood disorders cytokines, 412 GAMA, 363–369 growth hormone, 350 hypothalamic-pituitary-gonadal axis, 410 immune response, 411 immune system, 410–411 molecular genetics, 395–402 Mood disturbance, 199 Mood stabilizers anorexia nervosa, 830 bulimia nervosa, 834 mechanisms, 773, 779 pathological gambling, 692–693 sexual dysfunction, 660–661 Morel, Benedict Augustin, 70 Motive circuit alcoholism, 569 Motor disorders, 58–59 Motor stereotypy, 320 MPA, 913 MRI. see Magnetic resonance imaging (MRI) MRS. see Magnetic resonance spectroscopy (MRS) MS, 103–104 MSA, 107 brain imaging, 510 MST, 919 MTI, 49 Multifinality, 126

Index Multi-infarct dementia (MID), 102 Multiple sclerosis (MS), 103–104 Multiple system atrophy (MSA), 107 brain imaging, 510 MVP, 441 Myocardial infarction panic attacks, 436 Myoinositol bulimia nervosa, 835 Nalmephene alcoholism, 848 Naloxone personality disorder, 646 PTSD, 458 Naltrexone (Trexan) alcoholism, 848 autism, 211 bulimia nervosa, 835 opioid dependence, 588, 851 pathological gambling, 692 personality disorder, 646 Narcolepsy, 720–721 NARP, 76–77 National Comorbidity Survey (NCS), 553, 554 NCS, 553, 554 NE. see Norepinephrine (NE) Nefazodone sexual dysfunction, 658 Neoplastic dementia, 103 Neostigmine, 354 Neotrofin Alzheimer’s disease, 874–875 Nerve growth factor Alzheimer’s disease, 874 NET, 27 Neumann, Heinrich, 70 Neural circuitry selective vulnerability, 537–538 Neurobiological insights classification, 96–97 Neurobiological status, 2 Neuroendocrine hypothesis, 407 Neuroendocrine studies childhood mood disorders, 156–157 Neurofibrillary tangles (NFRTs), 100 Alzheimer’s disease, 538, 540 Neuroimaging childhood mood disorders, 157–158 classification, 95–96 Neuroleptics psychotic disorders, 735 Neuromodulator ACh interactions, 352–353 Neuronal death Alzheimer’s disease, 543

Index Neuropeptides, 33–34 autism, 207 bipolar disorders, 415 monoamines, 34 OCD, 427–428 schizophrenia, 740–741 Neuropeptide Y (NPY), 35 galanin norepinephrine, 35–36 Neuropil threads Alzheimer’s disease, 541 Neuropsychiatric disorders repetitive transcranial magnetic stimulation, 919 sleep, 714–718 Neurosciences animal models, 7 Neurosurgery, 912 Neurotensin schizophrenia, 740–741 Neurotransmitter ACh interactions, 352–353 bipolar disorders, 415 Neurotransmitter studies childhood mood disorders, 155–156 Neurotrophic agents Alzheimer’s disease, 874–875 Neurotrophins autism, 207 New-variant CJD (vCJD), 103 NFRTs, 100 Alzheimer’s disease, 538, 540 Nicardipine vascular dementia, 883 Nicergoline vascular dementia, 884 Nicotine mechanisms of action, 586–587 neurotransmitters, 583 Nicotine abuse PET, 601 Nicotine dependence pharmacotherapy, 588–589, 843–846 Nicotine gum, 844 Nicotine receptor agonist depression, 813–814 Nicotine replacement therapy, 588–589, 844 Nicotine use genetic studies, 623 Nicotinic acetylcholine receptor agonists Alzheimer’s disease, 868 Nightmares, 722–723 Nimodipine childhood bipolar disorders, 163 differential target, 775 vascular dementia, 883 NMDA. see N-methyl-D-aspartate (NMDA)

963 N-methyl-D-aspartate (NMDA), 457 glutamate receptor antagonists psychoses, 318, 321–323 receptor antagonists, 813 receptor channel blockers alcoholism, 850 NMR advent of, 44 Nonaffective acute remitting psychosis (NARP), 76–77 Nonalcohol SUDs comorbidity, 556–557 Nondegenerative dementia, 102–104 Nonparametric methods, 17–19 Nonsteroidal anti-inflammatory drugs (NSAIDs) Alzheimer’s disease, 876–877 Nootropics vascular dementia, 883–884 Noradrenaline Alzheimer’s disease, 545 Norepinephrine (NE), 25, 27 aggression, 674 anorexia nervosa, 828 bipolar disorders, 415–416 histrionic personality, 143 personality disorder, 646 Norepinephrine transporter (NET), 27 Normal personalities vs. deviant personalities, 120–122 Normal pressure hydrocephalus (NPH), 102 Normal sleep, 713–714 Nortriptyline childhood mood disorders, 159 nicotine dependence, 589, 846 vs. paroxetine, 901 Novelty seeking psychobiological correlates, 131 psychobiology, 130–131 NPGi, 437 NPH, 102 NPY, 35 galanin norepinephrine, 35–36 NREM parasomnias, 721–722 NSAIDs Alzheimer’s disease, 876–877 Nuclear magnetic resonance (NMR) advent of, 44 Nucleus accumbens, 596 Nucleus paragigantocellularis (NPGi), 437 Nutrition genes, 13 Obsession alcohol, 564–565 Obsessive-compulsive disorder (OCD), 61–62, 911–912, 923–924

964 [Obsessive-compulsive disorder (OCD)] autoimmune pathology, 425–426 childhood, 182–185 classification, 92–93 clomipramine, 815 dopaminergic systems, 427 fluoxetine, 815 functional studies, 424–425 neuroanatomical models, 423–425 neurobiology, 423–428 neurochemistry, 426–428 neuropeptides, 427–428 neuropharmacology, 426–428 serotonin, 426–427 structural studies, 424 Obsessive personality, 139–140 Obstructive sleep apnea syndrome, 719 OCD. see Obsessive-compulsive disorder (OCD) ODD. see Oppositional defiant disorder (ODD) Olanzapine Alzheimer’s disease, 880–881 childhood bipolar disorders, 163 dementia with Lewy bodies, 885 pathological gambling, 693 psychotic disorders, 735 schizophrenia, 737, 742, 746 serotonin, 738 sexual dysfunction, 660 Olivopontocerebellar atrophy, 107 Omega-3 fatty acids childhood bipolar disorders, 163 Ondansetron alcoholism, 573, 848 bulimia nervosa, 835 Opiate abuse PET, 602 Opiates anorexia nervosa, 828 Opioid alcoholism, 574–576 bulimia nervosa, 834–835 mechanisms of action, 587 neurotransmitters, 583 pathological gambling, 689 self-injurious behavior, 646 Opioid antagonists alcoholism, 847–848 nicotine dependence, 846 pathological gambling, 692 Opioid dependence pharmacological treatment, 850–854 pharmacotherapy, 588 Opioid maintenance therapy, 851–854 Opioid pathways, 47 Oppositional defiant disorder (ODD), 56–57 vs. childhood mood disorders, 153

Index [Oppositional defiant disorder (ODD)] comorbidity, 57 prevalence, 56 Orgasm dysfunction, 658 Osteoporosis anorexia nervosa, 831 Overanxious disorder. see Generalized anxiety disorder Oxcabamazepine childhood bipolar disorders, 163 Oxcarbazepine mechanism of action, 772–776 pharmacological properties, 794 Pallidal-thalamocortical pathway alcoholism, 569 Panic attacks, 62, 436 situationally bound, 433 symptoms, 91 Panic disorder (PD), 61–62, 91 agoraphobia, 472 biological markers, 442 biological systems, 434–439 candidate gene studies, 470 central pathways, 435 childhood, 181 classification, 90–91 clinical genetics, 467–469 comorbidity, 440–442, 467–468 epidemiology, 467–468 future directions, 442 GABA/glutamate systems, 438–439 genetics, 440–442 genome scan studies, 470–471 heritability, 468 molecular studies, 470–471 neurobiology, 433–443 neuroimaging studies, 439–440 noradrenergic system, 437–438, 438 paroxetine, 815 respiratory physiology, 434–436 risk loci, 469–470 SAD, 177 sighing, 435 SSRI, 439 syndrome, 471 trait markers neurodevelopmental studies, 434 Panic syndrome candidate gene, 442 PAP phosphatase, 758–759 Paracrine transmission, 25–27 Paralimbic system OCD, 423–424 Parametric methods, 15–17

Index Parametric stress tests, 487 Paranoid type schizophrenia, 200 Paraphilias, 909 Parkinson’s disease, 101–102 sleep, 718 Parkinson’s disease with dementia brain imaging, 509–510 Paroxetine Alzheimer’s disease, 881 bipolar disorders, 413 childhood mood disorders, 159 childhood social phobia, 181 drug holiday, 661 vs. nortriptyline, 901 obsessive personality, 139 panic disorder, 815 pathological gambling, 690–692 social anxiety disorder, 815 Partial volume effect (PVE) correction, 482–484 Passionate temperament type, 143–144 Passionate type, 137 Passive-aggressive personality, 142 Passive-aggressive temperaments, 137 Pathological gambling, 683–693 behavioral treatment, 690 classification, 685–686 comorbidity, 684–685 conceptualization, 685–686 defined, 684–685 definition, 683–685 diagnostic criteria, 684 genetic studies, 686, 689 high-risk groups, 685 neurobiology, 686–689 neurochemical studies, 686 norepinephrine systems, 688–689 opioid antagonists, 692 opioid systems, 689 pharmacological challenge studies, 686 pharmacotherapy, 690–693 prevalence, 684 self-help, 689–690 treatment, 689–693 PCOS, 661 divalproex, 162 PCP. see Phencyclidine (PCP) PD. see Panic disorder (PD) Pedigree linkage analysis, 16 Pentoxifylline vascular dementia, 883 Peptides neurotransmitters Alzheimer’s disease, 545 Performance anxiety beta blockers, 181

965 Persistence psychobiological correlates, 133 psychobiological data, 132–133 Personality production, 120 Personality development fifteen-step, 127 hierarchical model, 128 Personality disorder biological basis, 643–652 categorical and dimensional assessment, 124 genetics, 647–648 life events, 649–650 neuroimaging studies, 649 neurotransmitters, 645–647 psychobiological integration of treatment, 145–148, 146–147 social vs. clinical diagnosis, 124–125 symptoms predictors, 121 Pervasive developmental disorder not otherwise specified, 59 vs. childhood mood disorders, 153 neurobiology, 214 Pervasive developmental disorders, 59 PET, 46 Pettersen Mania Rating Scale, 801, 802 PFC aggression, 675 alcohol, 566 OCD, 423 Pharmacoeconomics drug development, 811 Phasic/tonic dopamine model compulsive drug use, 585 Phencyclidine (PCP), 322, 324 abuse PET, 602 mechanisms of action, 587 mimicking schizophrenia, 739 neurotransmitters, 583 schizophrenia, 318 Phenelzine bulimia nervosa, 832 Phenobarbital, 802 Phenotypes definition, 14, 644 Phenytoin bipolar disorders, 795–796 prophylactic study, 800 drug interactions, 742 pharmacological properties, 795–796 Phonological disorder, 58 Phosphoadenosine phosphate (PAP) phosphatase, 758–759 Phosphoinositide pathway bipolar disorders, 372–373, 381–383

966 Phospholipase A2 membrane phospholipid metabolism, 308–310 Phospholipids metabolism genetic studies, 312–313 molecular structure, 308 schizophrenia, 310–313 Phosphomonoesters (PME), 312 Physostigmine, 801 bipolar disorders, 349 Pick’s disease, 101 pathophysiology, 106 Pilocarpine supersensitive pupillary responses, 351 Pimozide autism, 210–211 childhood obsessive-compulsive disorder, 184 Pindolol fluoxetine, 812 obsessive personality, 139 Pinel, Philippe, 69 Piribedil mild cognitive impairment, 885 PKC alcoholism, 570 drug effects, 777 Plasma GABA, 364–365 alcohol dependence, 365 PM, 396 31P magnetic resonance spectroscopy, 312 PME, 312 Polycystic ovarian syndrome (PCOS), 661 divalproex, 162 Polydrug user, 590 Polygenic Model (PM), 396 Polymorphism, 18, 32 Population stratification, 469 Positron emission tomography (PET), 46 activation, 487 AD, 480, 484–485 aging, 487 Alzheimer’s disease, 487 autism, 209–210 childhood mood disorders, 157, 158 childhood psychotic disorders, 201 cognitive deficits schizophrenia, 240–246 dopamine pathological gambling, 687 image processing aging, 481–482 personality disorder, 649 PTSD, 453 scanner, 47 Posttraumatic stress disorder (PTSD), 61–62, 185–187, 455, 923–924

Index [Posttraumatic stress disorder (PTSD)] amygdala, 451–453 benzodiazepine, 458 childhood, 185–187 vs. childhood mood disorders, 153 classification, 93 clinical factors, 450–451 combat-related, 455 dopamine system, 454 endogenous opiate, 458 epidemiology, 449–450 hippocampus, 457 HPT, 459–460 immune system, 458–459 LHPA axis, 455–457 locus ceruleus, 454–455 medial prefrontal cortex, 453–454 neurobiology, 449–460 vs. panic disorder, 436–437 with separation anxiety, 186 serotonin system, 457–458 sertraline, 815 trauma, 459–460 PPA, 109 PPI, 225, 320 Precession, 45 Predictive validity, 5 Prefrontal cortex, 283 Prefrontal cortex (PFC) aggression, 675 alcohol, 566 OCD, 423 Preparatory attention, 225 Prepulse inhibition (PPI), 225, 320 Primary insomnia, 719–720 Primary progressive aphasia syndrome (PPA), 109 Prion diseases, 102–103 Problem gambling defined, 684–685 prevalence, 684 Progesterone, 910 Programmed cell death. see Apoptosis Progressive muscle relaxation sleep, 720 Progressive supranuclear palsy (PSP), 108–109 brain imaging, 508–509 vs. frontotemporal dementia, 501 genetics, 105 tau lesions, 107 Prolactin schizophrenia, 260 Prolyloligopeptidase, 760 Propanolol autism, 211 Propentofylline vascular dementia, 883

Index Propositional memory, 119 Protein kinase C (PKC) alcoholism, 570 drug effects, 777 Proton MRS childhood mood disorders, 158 PSP. see Progressive supranuclear palsy (PSP) Psychiatric comorbidity, 553–558 Psychiatric disorders childhood classification, 55–59 comorbid SUDs, 554 genes predisposing to, 15–21 genetic etiology, 14–15 medical conditions, 903 pharmacological interventions, 899–904 most common, 554 Psychiatric genetics methodological advances, 13–22 Psychiatric neuroimaging developments, 43–52 Psychobiological model, 644 Psychoses, 127–128 animal models, 317–329 early limbic lesion models, 325 pharmacological, 323 drug-induced models, 318–323 Psychosocial stresses genes, 13 Psychostimulants mechanisms of action, 586 Psychotherapy advanced stages, 137 Psychotic disorders, 62–63 childhood. see Childhood psychotic disorders comorbid SUDs, 556 genetic findings, 295–302 membrane abnormalities, 307–313 Psychotropic drugs, 911–912 Psychotropic-induced sexual dysfunction treatment, 661–662 PTSD. see Posttraumatic stress disorder (PTSD) Pulmonary disease, 902–903 PVE correction, 482–484 Quality of life drug development, 811 Quantitative MRI autism, 208–209 Quantitative trait loci (QTL), 21 Quantitative volumetric MRI brain Alzheimer’s disease, 500 Quetiapine childhood bipolar disorders, 163

967 [Quetiapine] schizophrenia, 259, 736, 740 serotonin, 738 sexual dysfunction, 659 Rabi, Isaac, 44 Racial groups alcoholism, 565 apolipoprotein E gene, 526 Racing thoughts childhood bipolar disorders, 152 Raclopride schizophrenia dopamine hypothesis, 261 rCBF, 49 Reactive psychosis, 76 psychobiological correlates, 132 Reelin protein, 326 Regional cerebral blood flow (rCBF), 49 Region of interest (ROI), 45 Relaxation techniques sleep, 720 Reliability clinical diagnoses, 75 Reliable temperament type pharmacological treatment, 144 REM sleep behavior disorder, 723–724 Renal disease, 902 Repetitive transcranial magnetic stimulation (rTMS) effects induced by, 927–928 neuropsychiatric disorders, 919–929 safety guidelines, 926–927 side effects, 925–926 Residual type schizophrenia, 200 Resting studies, 339–340 Restless legs syndrome/periodic limb movement disorder, 721 Rett’s disorder, 59 neurobiology, 212–213 Reversible monoamine oxidase A inhibitor (RIMA) sexual dysfunction, 658 Reward addictive drugs, 584 Reward dependence psychobiological data, 132 psychobiology, 131 Rheumatoid arthritis, 901 Rifampin drug interactions, 742 RIMA sexual dysfunction, 658 Risperidone Alzheimer’s disease, 880 childhood bipolar disorders, 163 childhood obsessive-compulsive disorder, 184 serotonin, 738 sexual dysfunction, 659, 660

968 Ritanserin schizophrenia dopamine hypothesis, 261 serotonin receptors, 271 Rivastigmine Alzheimer’s disease, 867 RLA, 348 ROI, 45 Roman Low Avoidance rats (RLA), 348 rTMS. see Repetitive transcranial magnetic stimulation (rTMS) Sabcomeline Alzheimer’s disease, 868 Sabril, 605 pharmacological properties, 795 SAD, 62, 177–178 Safety drug development, 810 Salivary cortisol, 436 SANS, 200, 238 Scale for the Assessment of Negative Symptoms (SANS), 200, 238 Scanditronix PC 1024-7B, 484 Schizoaffective disorder, 63 DSM and ICD definition, 74 erectile dysfunction, 663 Schizoid personality pharmacological treatment, 144–145 Schizophrenia, 62–63, 924 affective symptoms, 746–748 animal models, 319 future directions, 328 attention deficits, 225–226 catatonic type, 200 childhood, 198 delusions, 63 classification systems, 69–77, 199–200 diagnostic criteria, 71–73 evolution, 69–70 symptoms, 71 twentieth century, 70–71 clozapine, 259–260 cognitive deficits, 223–231 amphetamine-induced DA release, 242–244 antipsychotic drugs, 245–246 baseline DA release, 244 clinical significance, 229–230 DA transporters, 244 DOPA decarboxylase, 242 functional imaging, 239–240 imaging DA transmission, 240 MRS, 246–249 neural basis, 228–229 neurochemical imaging, 240–249 neuropharmacological imaging, 240–249

Index [Schizophrenia] nondopaminergic receptors, 244–245 PET, 240–246 phosphorus spectroscopy, 246–247 prefrontal DA transmission, 244 proton spectroscopy, 247–248 resting-state studies, 239–240 SPECT, 240–246 striatal DA transmission, 240–242 task-related activation studies, 239–240 cognitive disability treatment, 230–231 cognitive symptoms, 746 comorbid SUDs, 556 D2 block, 262 developmental manipulations, 323–328 disorganized behavior, 746 dopamine depletion, 260 dopamine hypothesis, 259–263 atypical antipsychotics, 261 effect lag, 260–261 isomers, 260 molecular genetics, 263 dopamine receptors, 262–263 D1 receptor, 263 drug-induced, 318 ejaculatory dysfunction, 659 GABA system, 279–281 genetic model, 328 glutamate excitatory amino acid system, 739–740 impaired cognition, 228–230 impaired executive functions, 228 international pilot study, 75–76 negative symptoms, 745–746 neuroimaging findings, 237–240 perceptual disturbances, 224–225 pharmacological treatment, 731–750 genotyping, 748 older, 732–738 switching patients, 742–744 phospholipids, 310–313 positive symptoms, 744–745 prolactin elevation, 260 psychopathology, 319 quetiapine, 259 serotonergic dysfunction, 267–272 atypical antipsychotics, 271–272 challenge studies, 268 genetics, 267–268 serotonin receptors, 268–271 serotonin transporters, 271 serotonin, 738–739 sleep, 717–718 SPD, 647 structural imaging, 237–239 symptoms, 732

Index [Schizophrenia] categories, 318 cross-cultural groups, 75–76 School performance childhood depressive disorders, 151 Secretase inhibitors Alzheimer’s disease, 870, 871 Sedatives mechanisms of action, 586 neurotransmitters, 583 Segregation analysis, 15 panic disorder, 469 Seizures repetitive transcranial magnetic stimulation, 925 Selective attention, 226 Selective breeding, 8 Selective M1 receptor agonists Alzheimer’s disease, 868 Selective serotonin uptake inhibitors (SSRIs), 138, 901, 911–912 aggression, 673 alcoholism, 573 borderline personality, 140–141 cautious temperaments, 141 childhood mood disorders, 159 childhood obsessive-compulsive disorder, 185 cocaine dependence, 589 comorbid SUDs and anxiety disorders, 556 cyclothymic-dependent personality, 144 obsessive personality, 139 panic disorder, 439 Selegeline cocaine dependence, 854 Self-deprecation childhood depressive disorders, 150 Self-injurious behavior endorphin system, 646 opioids, 646 Selye, Hans, 451 Semantic priming tasks, 227 Senile plaques (SPs), 100 Alzheimer’s disease, 538 Sensitive temperament type, 142 Separation anxiety disorder (SAD), 62, 177–178 Serotonin, 25, 910 ACh, 355–356 aggression, 672–675 agonists, 324 psychoses, 321 alcoholism, 572–573, 848–849 Alzheimer’s disease, 545, 869 anorexia nervosa, 828, 829 augmentation, 811–812 autism, 206–207 bipolar disorders, 413

969 [Serotonin] eating disorders, 636–639 lithium, 761 markers affective disorders, 400–401 OCD, 426–427 pathological gambling, 686–689 pathways, 47 personality disorder, 645–647 PTSD, 457–458 receptor agonists, 816–817 psychoses, 318 receptors, 299 schizophrenia serotonergic dysfunction, 268–271 schizophrenia, 738–739 transporter gene suicidal behavior, 704 transporters schizophrenia, 271 Serotonin reuptake inhibitors (SRIs), 95 autism, 211 pathological gambling, 690–692 Sertraline, 911–912 Alzheimer’s disease, 881–882 anorexia nervosa, 830 bipolar disorders, 413 childhood mood disorders, 159 comorbid major depressive disorder and alcohol use disorder, 554–555 drug holiday, 661 obsessive personality, 139 PTSD, 815 sexual dysfunction, 658 Severely disorganized behaviors, 127–128 Severe personality disorders, 128 Sex hormone binding globulin (SHBG) sexual dysfunction, 661 Sexual behavior brain regions, 910–911 Sexual dysfunction antidepressants, 657–659 anxiolytics, 659 iatrogenic, 657–665 pharmacotherapy, 661–664 treatment, 661–662, 665 SHBG sexual dysfunction, 661 Shprintzen syndrome, 301 Shy-Drager syndrome, 107 Shyness, 92 Sibpair analysis, 20, 397 Sighing panic disorder, 435 social phobia, 435

970 Signal transduction abnormalities bipolar disorders, 371–386 Signal transduction systems, 371–372 Sildenafil sexual dysfunction, 663–664 Simultaneous cocaine/alcohol abuse PET, 600–601 Simvastatin Alzheimer’s disease, 878 Single Major Locus (SML) model, 396 Single-photon emission computed tomography (SPECT), 46 autism, 209–210 childhood mood disorders, 157, 158 cognitive deficits schizophrenia, 240–246 personality disorder, 649 scanner, 47 Situationally bound panic attacks, 433 Sleep cholinomimetic effects, 349–350 neuropsychiatric disorders, 714–718 Sleep apnea syndrome, 718–719 Sleep disorders, 713–724 Sleep disturbance childhood bipolar disorders, 151 childhood depressive disorders, 150–151 Sleep restriction therapy, 720 Sleep studies childhood mood disorders, 157 Sleep terrors, 722 Sleepwalking, 722 SML model, 396 Smoking comorbidity, 557 genetics, 619 SNS, 451 Social anxiety disorder childhood, 180–181 paroxetine, 815 Social functioning, 2 Socialization childhood depressive disorders, 151 Social phobia, 61–62 childhood, 180–181 classification, 91–92 clinical genetics, 467–469 comorbidity, 467–468 epidemiology, 467–468 sighing, 435 Sodium channel abnormalities bipolar disorders, 802 antibipolar AC plasma level, 799–800 antibipolar potency, 802–803 gating mechanism, 798 pharmacological agent, 798

Index Somatic complaints childhood depressive disorders, 151 Somatostatin bipolar disorders, 415 Specific phobias categories, 92 SPECT. see Single-photon emission computed tomography (SPECT) Spinning, 45 Spin-spin relaxation, 45 Spontaneous panic attacks, 91 Spontaneous panic disorder, 433 Sporadic Alzheimer’s disease, 522 SPs, 100 Alzheimer’s disease, 538 SRIs, 95 autism, 211 pathological gambling, 690–692 SSRIs. see Selective serotonin uptake inhibitors (SSRIs) Stage fright beta blockers, 181 Statistical parametric mapping, 481–482 Stepwise character development, 135–136 Stevens-Johnson syndrome, 162 STG, 200 Stimulants bulimia nervosa, 834 sexual dysfunction, 663 Stimulus control therapy sleep, 720 Stress immune response, 410–411 locus ceruleus, 454–455 plasma cortisol, 459 Stress vulnerability animal models, 7 Striatonigral degeneration, 107 Striatum OCD, 424 Stroke panic attacks, 436 Stroop task, 226, 453 Structural MRI, 45 Structural neuroimaging childhood mood disorders, 157–158 development, 44–46 Subcortical dementia, 108–109 Subcortical gray matter measurement, 337 Substance abuse disorders (SUDs), 553–558 and anxiety disorders, 555–556 comorbidity, 554–555 future directions, 557 pathological gambling, 684–685 psychiatric disorders, 554 psychotic disorders, 556

Index [Substance abuse disorders (SUDs)] treatment strategy PET, 604–606 Substance P antagonists antidepressant/anxiolytic drugs, 34–35 bipolar disorders, 415 carbamazepine, 776 lithium, 776 neurokinin receptor antagonist, 812–813 receptor antagonists, 817 schizophrenia, 740–741 Substance use with childhood mood disorders, 152 Subutex opioid dependence, 588, 853–854 SUDs. see Substance abuse disorders (SUDs) Suicidal behavior cholesterol, 706 future directions, 707 genetic studies, 702–705 molecular genetic research, 702–705 postmortem studies, 705–706 psychotropic medications, 706–707 stress-diathesis model, 701–702 in vivo biochemical studies, 705 Suicidal comorbid populations, 557 Suicidal ideation childhood depressive disorders, 151 Suicide genetics, 648 neurobiology, 701–707 Superior temporal gyrus (STG), 200 Surgical castration, 912 Susceptibility genes late-onset Alzheimer’s disease, 524 Sustained-release bupropion nicotine dependence, 589 Sympathetic nervous system (SNS), 451 Symptom domain, 138 Synapse loss Alzheimer’s disease, 540–541 Synuclein family, 107 Synucleinopathies, 107–108 Tachycardia, 436 Tacrine Alzheimer’s disease, 867 Talairach space, 481 Talkative childhood bipolar disorders, 151–152 Talsaclidine Alzheimer’s disease, 868, 871 Tauopathies pathophysiology, 105–107 TBI, 103

971 TCAs. see Tricyclic antidepressants (TCAs) TCI, 118 scales, 120 TDT, 19, 469 Technetium-99m hexamethylpropylene amine oxime childhood mood disorders, 158 Teenagers. see Adolescent Temperament vs. character, 119 character outcome, 125–126 protecting against personality disorder, 122–124 psychobiology, 117–148, 129–133 scores, 118 stimulus-response patterns, 125 treatment guidelines, 134–148 Temperament and Character Inventory (TCI), 118 scales, 120 Temporal lobe aggression, 676 atrophy Alzheimer’s disease, 500 epilepsy, 453 measurement, 336–337 Testosterone, 910 aggression, 674 Thalamus, 183 Theory-driven models, 4–5 Thiamine deficiency dementia, 103 Thioridazine, 912 cardiovascular safety, 747 childhood psychotic disorders, 201 sexual dysfunction, 659 Thiothixene childhood psychotic disorders, 201 31P magnetic resonance spectroscopy, 312 Thyroid hormone metabolism, 459–460 Tiagabine, 780–781 childhood bipolar disorders, 163 pharmacological properties, 795 Tiapride alcoholism, 847 Tics, 177 TMS, 919–929 Tobacco mechanisms of action, 586–587 neurotransmitters, 583 Tolerability drug development, 810 Tonic dopamine model compulsive drug use, 585 Topiramate, 779–780 childhood bipolar disorders, 163 pharmacological properties, 794 Tourette syndrome, 17

972 Tower of London, 229 Toxic dementia, 103 Toxic epidermal necrolysis, 162 Toxins genes, 13 Transcranial magnetic stimulation (TMS), 919–929 Transmission disequilibrium test (TDT), 19, 469 Transporters, 27–33 anatomical localization, 29–30 models, 27–29 regulation, 30–33 Trauma, 451 childhood bipolar disorders, 650 neurobiology, 451 PTSD, 459–460 Traumatic brain injury (TBI), 103 Traumatic stress response neurobiology, 452 Trazodone Alzheimer’s disease, 881 bulimia nervosa, 833 sexual dysfunction, 658 Trexan. see Naltrexone (Trexan) Tricyclic antidepressants (TCAs) autism, 211 childhood mood disorders, 159 cocaine dependence, 589 comorbid major depressive disorder and alcohol use disorder, 554 comorbid SUDs and anxiety disorders, 556 cyclothymic-dependent personality, 144 sexual dysfunction, 658 Trinucleotide repeats anticipation, 300 sequences anticipation, 401–402 Triptorelin, 914 Tryptophan hydroxylase, 637, 638 impulsive aggression, 648 suicidal behavior, 704 Tuberoinfundibular projections, 735–736 Tuberous sclerosis, 471 Twin studies, 15 aggression, 676 alcoholism, 616 eating disorders, 636 panic disorder, 468 suicidal behavior, 702 Undifferentiated type schizophrenia, 200 Unexpected panic disorder, 433 Unipolar disorder vs. bipolar disorder, 407–415 Universal addiction site, 566–567

Index Upper-airway resistance syndrome (UARS), 719 Urinary free cortisol (UFC), 455 Vagus nerve stimulation (VNS), 919 Valproate, 364 alcoholism, 850 bipolar disorders comorbid SUDs, 555 depression, 366 vs. lithium, 776–778 loading, 800 pharmacological properties, 794 sexual dysfunction, 661 Vancomycin autism, 211 Vascular dementia, 102 vs. Alzheimer’s disease, 505 brain imaging, 503–506 functional, 504 structural, 504 white matter changes, 504–505 treatment, 882–884 Vascular depression, 339 Vasopressin aggression, 674 bipolar disorders, 414–415 vCJD, 103 Velocardiofacial syndrome (VCFS), 301, 471 Venlafaxine for childhood generalized anxiety disorder, 179 generalized anxiety disorder, 815 Ventral tegmentum (VTA), 596 alcohol, 566 VietNam Era Twin Registery, 689 Vietnam veterans PTSD, 459 Vigabatrin (Sabril), 605 pharmacological properties, 795 Vineland Adaptive Behavior Scales, 58 Violence neurobiology, 671–677 Vitamin B12 deficiency dementia, 103 Vitamin E Alzheimer’s disease, 875 VNS, 919 Voltage-gated sodium channels, 796–799 Voltage-sensitive sodium channels structure, 796–798 Volume transmission (VT), 25–27 VTA, 596 alcohol, 566 Weight antipsychotics, 747–748 childhood depressive disorders, 151

Index Wernicke-Korsakoff syndrome, 103 Wilson’s disease genetics, 105 Wistar Kyoto (WKY) rats, 8 Wolfram syndrome, 471 Women’s Health Initiative Memory Study (WHIMS), 878 Women’s Health Initiative Randomized Trial, 878 Working memory, 226 Worthlessness childhood depressive disorders, 150 Xanomeline Alzheimer’s disease, 868 Xanthine derivatives vascular dementia, 883

973 Yohimbine childhood panic disorder, 181 panic disorder, 437 sexual dysfunction, 662–663 Young Rating Mania Scale, 802 Zinc anorexia nervosa, 831 Ziprasidone cardiovascular safety, 746 psychotic disorders, 735 schizophrenia, 737 Zoladex, 914 Zonisamide, 781–782 childhood bipolar disorders, 163

About the Editors

JAIR C. SOARES is Associate Professor of Psychiatry and Chief, Division of Mood and Anxiety Disorders, University of Texas Health Science Center, San Antonio. The author or coauthor of many journal articles, book chapters, and books, including Bipolar Disorders and Brain Imaging in Affective Disorders (both titles, Marcel Dekker, Inc.), Dr. Soares is a member of the American Psychiatric Association, the International Society for Neuroimaging in Psychiatry, the Society for Neurosciences, the Society of Biological Psychiatry, the International Society for Bipolar Disorders, and the Society for Nuclear Medicine. He received the M.D. degree (1990) from the University of Saõ Paulo School of Medicine, Brazil.

SAMUEL GERSHON is Professor of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. The author or coauthor of numerous journal articles, book chapters, and books, including Bipolar Disorders and Pharmacotherapy for Child and Adolescent Psychiatric Disorders, Second Edition (both titles, Marcel Dekker, Inc.), Dr. Gershon is a Fellow of the American College of Neuropsychopharmacology, the Royal College of Psychiatrists, U.K. He received the M.B.B.S. degree (1950) from the Faculty of Medicine, University of Sydney, Australia.

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