Practical Child and Adolescent Psychopharmacology

MMMM This page intentionally left blank Practical child and adolescent psychopharmacology The field of child and adol...

Author: Stan Kutcher

221 downloads 2981 Views 2MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

MMMM

This page intentionally left blank

Practical child and adolescent psychopharmacology The field of child and adolescent psychopharmacology is rapidly growing, but psychopharmacologic treatments for children cannot be straightforwardly extrapolated from adult studies, which presents clinicians with assessment and prescribing challenges. In this important book, a team of expert clinicians synthesizes the most recent research findings about drug treatment of a broad range of psychiatric disorders in children, including attention-deficit hyperactivity disorder, obsessive–compulsive disorder, major depression, schizophrenia, bipolar mania, aggression in pervasive developmental disorder, Tourette’s syndrome, and substance abuse. They examine the issues of tolerability and efficacy, and inappropriate over-use, within a social and developmental context. For each disorder, pharmacotherapy is discussed in the wider context of neurobiology, etiology, diagnosis, and treatment. This will be essential reading for all mental health professionals to inform practice and improve patient outcomes. Stan Kutcher is Professor and Head of the Department of Psychiatry at Dalhousie University, and Chief of Service, Department of Psychiatry and Mental Health Services at the Queen Elizabeth II Health Sciences Center, and Associate Dean of International Medical Development and Research at Dalhousie University, Halifax, Nova Scotia.

Cambridge Child and Adolescent Psychiatry

Child and adolescent psychiatry is an important and growing area of clinical psychiatry. The last decade has seen a rapid expansion of scientific knowledge in this field and has provided a new understanding of the underlying pathology of mental disorders in these age groups. This series is aimed at practitioners and researchers both in child and adolescent mental health services and developmental and clinical neuroscience. Focusing on psychopathology, it highlights those topics where the growth of knowledge has had the greatest impact on clinical practice and on the treatment and understanding of mental illness. Individual volumes benefit both from the international expertise of their contributors and a coherence generated through a uniform style and structure for the series. Each volume provides firstly an historical overview and a clear descriptive account of the psychopathology of a specific disorder or group of related disorders. These features then form the basis for a thorough critical review of the etiology, natural history, management, prevention and impact on later adult adjustment. Whilst each volume is therefore complete in its own right, volumes also relate to each other to create a flexible and collectable series that should appeal to students as well as experienced scientists and practitioners. Editorial board Series editor Professor Ian M. Goodyer University of Cambridge Associate editors Professor Donald J. Cohen Yale Child Study Center

Dr Robert N. Goodman Institute of Psychiatry, London

Professor Barry Nurcombe The University of Queensland

Professor Dr Helmut Remschmidt Klinikum der Philipps-Universita¨t, Germany

Professor Dr Herman van Engeland Academisch Ziekenhuis Utrecht

Dr Fred R. Volkmar Yale Child Study Center

Already published in this series: Psychotherapy with Children and Adolescents edited by Helmut Remschmidt 0 521 77558 2 pb Specific Learning Disabilities and Difficulties in Children and Adolescents edited by Alan and Nadeen Kaufman 0 521 65840 3 pb The Depressed Child and Adolescent second edition edited by Ian M. Goodyer 0 521 79426 9 pb Schizophrenia in Children and Adolescents edited by Helmut Remschmidt 0 521 79428 5 pb Anxiety Disorders in Children and Adolescents: Research, Assessment and Intervention edited by Wendy Silverman and Philip Treffers 0 521 78966 4 pb Conduct Disorders in Childhood and Adolescence edited by Jonathan Hill and Barbara Maughan 0 521 78639 8 pb Autism and Pervasive Developmental Disorders edited by Fred R. Volkmar 0 521 55386 5 hb Cognitive Behaviour Therapy for Children and Families by Philip Graham 0 521 57252 5 hb 0 521 57626 1 pb Hyperactivity Disorders of Childhood edited by Seija Sandberg 0 521 43250 2 hb

Practical child and adolescent psychopharmacology Edited by

Stan Kutcher Dalhousie University, Halifax, Nova Scotia, Canada

   Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge  , United Kingdom Published in the United States by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521655422 © Cambridge University Press 2002 This book is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2002 ISBN-13 ISBN-10

978-0-511-06643-6 eBook (NetLibrary) 0-511-06643-0 eBook (NetLibrary)

ISBN-13 978-0-521-65542-2 paperback ISBN-10 0-521-65542-0 paperback

Cambridge University Press has no responsibility for the persistence or accuracy of s for external or third-party internet websites referred to in this book, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Dedicated to my wife and to my mother – both of whom have put up with me for many years

MMMM

Contents List of contributors Preface and acknowledgements 1

Child and adolescent psychopharmacology at the turn of the millennium

ix xiii 1

Charles W. Popper

2

Developmental psychopharmacology

38

Normand Carrey, Paul Mendella, Frank P. MacMaster, and Stan Kutcher

3

Clinical aspects of child and adolescent psychopharmacology

70

Gabrielle A. Carlson

4

Depression

91

Neal D. Ryan

5

Bipolar mood disorders: diagnosis, etiology, and treatment

106

Vivek Kusumakar, Lorraine Lazier, Frank P. MacMaster, and Darcy Santor

6

Schizophrenia and related psychoses

134

Keith Marriage

7

Obsessive–compulsive disorder

159

Douglas A. Beer, Mai Karitani, Henrietta L. Leonard, John S. March, and Susan E. Swedo

8

Anxiety disorders

187

E. Jane Garland

9

Attention-deficit/hyperactivity disorder

230

Thomas Spencer, Joseph Biederman, and Timothy Wilens

10

Pervasive development disorder

265

Sandra N. Fisman

11

Aggressive behavior

305

Deborah Lynn and Bryan H. King

12

Adolescent substance use disorder K.A. Hussain Mirza

vii

328

viii

13

Contents

Tic disorders and Tourette’s syndrome

382

John T. Walkup

14

Eating disorders and related disturbances

410

Lisa A. Kotler, Michael J. Devlin, and B. Timothy Walsh

15

Medical psychiatric conditions

431

Daniel S. Pine, Elizabeth Cohen, and Yana Brayman

Index

455

Contributors

Douglas A. Beer Department of Psychiatry and Human Behavior Brown University Butler Hospital 345 Blackstone Boulevard Providence, RI 02906 USA [email protected] Joseph Biederman Pediatric Psychopharmacology Unit Massachusetts General Hospital WACC 75 15 Parkman Street Boston, MA 02114 USA Yana Brayman New York Psychiatric Institute 1051 Riverside Drive New York, NY 10032 USA Gabrielle A. Carlson Child and Adolescent Psychiatry State University of New York at Stony Brook Stony Brook, NY 11794-8790 USA [email protected]

ix

Normand Carrey Maritime Psychiatry IWK Health Centre 5850 University Avenue Halifax, NS B3J 3G9 Canada [email protected] Elizabeth Cohen New York Psychiatric Institute 1051 Riverside Drive New York, NY 10032 USA Michael J. Devlin Department of Clinical Psychopharmacology Columbia University New York State Psychiatric Institute 1051 Riverside Drive-Unit 98 New York, NY 10032 USA Sandra N. Fisman Children’s Hospital of Western Ontario PO Box 5375 Stn Ctr CSC London, ON N6A 4G5 Canada sfi[email protected] E. Jane Garland Outpatient Psychiatry 4480 Oak Street Vancouver, BC V6H 3V4 Canada [email protected]

x

List of contributors

Mai Karitani Rhode Island Hospital 593 Eddy Street Providence, RI 02903 USA Bryan H. King Dartmouth Medical School Dartmouth Hitchcock Medical Center One Medical Center Drive Lebanon, NH 03756 USA [email protected] Lisa Kotler Department of Child and Adolescent Psychiatry Columbia University/New York State Psychiatric Institute 1051 Riverside Drive-Unit 74 New York, NY 10032 USA [email protected] Vivek Kusumakar Division of Child and Adolescent Psychiatry IWK Grace Health Centre 5850 University Avenue Halifax, NS B3J 3G9 Canada [email protected] Stan Kutcher Department of Psychiatry Queen Elizabeth II Health Sciences Center Lane Building, Suite 4082 5909 Jubilee Road Halifax, NS B3H 2E2 Canada [email protected] Lorraine Lazier Valley Regional Hospital Western Regional Health Board Kentville, NS Canada

Henrietta L. Leonard Rhode Island Hospital Department of Child Psychiatry 593 Eddy Street Providence, RI 02903-4923 USA Deborah Lynn Department of Child Adolescent Psychiatry UCLA Neuropsychiatric Institute 760 Westwood Plaza Los Angeles, CA 90024 USA [email protected] Frank Petrie MacMaster Mood Disorders Group Dalhousie University Halifax, NS Canada John S. March Duke Child and Family Study Center Duke University Medical Center Box 3527 Durham, NC 27710 USA Keith J. Marriage British Columbia Children’s Hospital WC1-4480 Oak Street Vancouver, BC V6H 3V4 Canada Paul Mendella Dalhousie University Department of Psychology Halifax, NS Canada

xi

List of contributors

K.A. Hussein Mirza University Department of Child and Adolescent Psychiatry Institute of Psychiatry Kings College Denmark Hill London SE5 8AF UK [email protected] Daniel S. Pine Development and Affective Neuroscience Section NIMH Intramural Research Program Building 10, Room 4N-222 MSC-1381 Bethesda, MD 20817 USA [email protected] Charles W. Popper McLean Hospital 115 Mill Street Belmont, MA 02178-9106 USA [email protected] Neal Ryan Western Psychiatric Institute and Clinic 3811 O’Hara Street Pittsburgh, PA 15213-2593 USA [email protected] Darcy Santor Adolescent Inter-Personal Therapy Program Dalhousie University Halifax, NS B3J 3G9 Canada

Thomas J. Spencer Pediatric Psychopharmacology Unit Massachusetts General Hospital WACC 725 15 Parkman Street Boston, MA 02114 USA [email protected] Susan E. Swedo Chief, Pediatrics & Developmental Neuropsychiatry Branch National Institute of Mental Health 9000 Rockville Pike Building 10 Bethesda, MD 20892 USA John T. Walkup Johns Hopkins Hospital CMSC 343 600 N. Wolfe Street Baltimore, MD 21287 USA [email protected] B. Timothy Walsh Department of Clinical Psychopharmacology Columbia University/New York State Psychiatric Institute 1051 Riverside Drive-Unit 98 New York, NY 10032 USA Timothy Wilens Pediatric Substance Abuse Pediatric Psychopharmacology Unit Massachusetts General Hospital WACC 725 15 Parkman Street, Boston, MA 02114 USA

MMMM

Preface

The field of child and adolescent psychopharmacology is rapidly growing and every clinician, physician, and other health provider alike must be informed of new directions and applications in the use of medications as they pertain to the treatment of psychiatric disorders in children and adolescents. To date, considerable research has been conducted which can properly direct the use of a variety of psychotropic compounds in a number of child and adolescent psychiatric disorders. In particular, well-established and effective pharmacologic treatments are available for attention-deficit hyperactivity disorder, obsessive–compulsive disorder, and Tourette’s syndrome. Less well-established but nonetheless frequently applied pharmacotherapies are used to treat a variety of psychiatric illness (such as major depression, schizophrenia, bipolar mania) or specific symptoms which may occur independently or as a component of a particular psychiatric diagnosis – such as aggression in pervasive developmental disorder. Evidence and experience to date clearly indicates that psychopharmacologic treatments for children and teenagers cannot be extrapolated from studies conducted in adult patients. Young people have a different central nervous system development, exhibit different cognitive, behavioral, and affective ‘‘norms’’ and are exposed to different environmental influences. All of these factors can influence the response to pharmacologic treatments – efficacy as well as tolerability. Thus, the study and practice of pharmacologic treatments of child and adolescent psychiatric disorders must become a special and significant area in its own right. These treatments, while demanding proper scientific evaluation, also do not occur within a social vacuum. In many cases, popular sentiments often guided by inadequate knowledge or misinformation about the risks and benefits of the use of psychotropic compounds in children and adolescents can affect the prescription and use of these medications in young people. In some cases, this may lead to inappropriate over-use. In other cases, this may lead to the withholding of potentially effective interventions. In order to avoid both of these unacceptable outcomes, the clinician must be well informed about both xiii

xiv

Preface

the science and the pragmatics of the use of medications in the treatment of child and adolescent psychiatric disorders. This book provides the practicing clinician with important information about the use of medications in treating psychiatric conditions found in young people. It is set in a social and developmental context as the chapters by Popper and Carrey outline. The clinical pragmatics are well summarized by Carlson. The remaining chapters deal with specific psychiatric disorders of children and adolescents and include chapters dedicated to the use of psychotropics in substance abuse and in medical conditions – two areas not well understood by many clinicians. Overall, this volume attempts to provide practical evidencebased information within an understandable clinical context. Acknowledgements I would like to thank all the contributing authors to this text. As is evident, each chapter has been written by an expert in the field and the addition of extra writing in the already ‘‘too busy’’ lives of academics is a burden that is not often appreciated by the reader. Christina Rice and Maria Scott provided valuable organizational support. My colleagues and patients taught me enough about the field to enable me to edit the various contributions with some degree of understanding and knowledge. My wife, as always, provided ongoing support. The positive reflections on this book are due to the expertise of the chapter authors and the publisher. The limitations are my responsibility. Stan Kutcher

1 Child and adolescent psychopharmacology at the turn of the millennium Charles W. Popper McLean Hospital, Belmont, Massachusetts, USA

Child and adolescent psychopharmacology is a leading edge of pediatric psychiatry and is rapidly growing. It has not always been this way. Child and adolescent psychopharmacology essentially began in 1937, when Bradley reported that some children with behavior disorders showed a seemingly paradoxical improvement during treatment with racemic amphetamine (Benzedrine“), which he had exploratorily used to treat 30 mostly preadolescent children in a residential treatment facility (Bradley, 1937). For over 60 years, psychostimulant treatment has basically remained unchanged. The characteristics of stimulant-responsive children have been studied and refined over the decades, and (what is currently called) attention-deficit/hyperactivity disorder (ADHD) has become the psychiatric model or prototype disorder for the medication treatment of children. The prototype treatment: psychostimulants for ADHD Throughout its existence, psychostimulant treatment has also been the prototype treatment used to express uneasiness about children receiving psychiatric medications. Although fully established scientifically, at least as much as antibiotic treatment, psychostimulant treatment is still controversial in some quarters. Concerns include trepidation about the inappropriate management of children in schools and homes, chemical control of children’s minds and behaviors, poisoning of children’s bodies, excessive dosing of medication, overmedicalization of child care, departure from the psychoanalytic or child guidance model, inadequate emphasis on the psychosocial themes, inappropriate attempts to find surrogates for adequate staffing and supervision, and social and psychological stigmatization. Despite such misgivings, Bradley’s approach has evolved into the widespread use of various psychostimulants to treat children with ADHD. 1

2

C.W. Popper

Psychostimulant treatment is no longer viewed as paradoxical, although there are many paradoxical aspects of this treatment. ADHD is one of the most thoroughly studied psychiatric disorders, but its pathophysiology is only roughly understood in terms of neuroanatomic chemistry. Psychostimulants appear to remain effective for years and even decades, but psychostimulants have only recently been demonstrated to sustain improvement over a period of 14–15 months (Arnold et al., 1997; Gillberg et al., 1997; The MTA Cooperative Group, 1999a,b), and longer-term treatment has still not been investigated in a controlled manner. Although ADHD is the most robust of syndromes in child and adolescent psychiatry, most children with ADHD are now recognized to have additional concurrent biopsychiatric disorders. Even with successful drug treatment, stimulant monotherapy is often not sufficient for optimal outcome. For many individuals, psychostimulants need to be combined with additional psychopharmacologic agents in order to have clinically adequate effects. The strategy of treating psychopathology with combinations of psychiatric drugs can be used to ‘‘tickle’’ multiple neuronal systems that underlie different clinical presentations. Yet, as treatment of ADHD becomes more complex, the psychostimulants remain the central element. For many, and probably most, children with ADHD, concurrent educational interventions are needed to remediate the delayed acquisition of learned skills, including social skills, responsiveness to limits, behavioral self-discipline, persistence in effortful activities, self-correcting behavior, study skills, and enjoyment of calmness and quiet pleasures. Although educational interventions combined with psychostimulants are often helpful, the multimodal combination of psychosocial intervention with psychostimulants may not be more advantageous than psychostimulant drugs alone for treating the core symptoms of ADHD (inattention and impulsivity/ hyperactivity). Several studies have indicated that multimodal psychopharmacologic–psychosocial treatment, at least under some circumstances, is not (or only slightly) more effective than stimulant monotherapy for treating the core symptoms of ADHD, but may be more effective for treating features often associated with ADHD, such as academic underperformance, impaired social skills, oppositionality, and aggressivity (Gittelman Klein et al., 1976; Carlson et al., 1992, Ialongo et al., 1993, Pelham et al., 1993; MTA 1999a,b). It is possible that combination treatment might be more effective if inadequate stimulant doses or ineffective psychosocial treatments are used; however, it offers little more than stimulant monotherapy under conditions of optimal or appropriate treatment. Speculatively, though, further refinement

3

Child and adolescent psychopharmacology

of the psychosocial treatments might produce a more potent combination. Over 150 double-blind placebo-controlled studies have demonstrated the efficacy of psychostimulants for both the cognitive and behavioral symptoms of ADHD (Spencer et al., 1996). In addition to psychostimulants, at least 13 different investigative groups over the last 35 years have conducted doubleblind placebo-controlled studies demonstrating the clinical efficacy of tricyclic antidepressants (TCAs) such as imipramine, desipramine, and amitriptyline for treating ADHD (Krakowski, 1965; Winsberg et al., 1972; Rapoport et al., 1974; Waizer et al., 1974; Kupietz and Balka, 1976; Yepes et al., 1977; Yellin et al., 1978; Werry et al., 1980; Garfinkel et al., 1983; Donnelly et al., 1986; Gualtieri and Evans, 1988; Biederman et al., 1989a,b; Gualtieri et al., 1991; Singer et al., 1995). Although TCAs are relatively useful in treating impulsivity and hyperactivity, they are less helpful for cognitive features of the disorder. More than 60 years following their introduction, psychostimulants remain the treatment of choice for ADHD, partially because of their solid effectiveness in treating the behavioral symptoms and especially because of their unmatched effectiveness in ameliorating the cognitive symptoms. In some ways, child and adolescent psychopharmacology has never again reached the peak attainment of its original treatment. No subsequent medication has equaled the psychostimulants for relative diagnostic specificity, target symptom specificity, strength of response, sustained effectiveness over time, the large proportion of patients who respond therapeutically, or the huge number of patients who have benefited from its use. Evolution of child and adolescent psychopharmacology The 1930s marked the beginning of modern child psychopharmacology, a time when few validated psychosocial or drug treatments were available even for adults. Not one of the present-day pharmacotherapies for psychiatric disorders was described in the first textbook of child psychiatry (Kanner, 1935), which advised against using ‘‘toxics and sedatives’’ to control children’s behavior. Two years later, the original papers on amphetamine treatment of behavior disorders of children (Bradley, 1937) were published. In the same year (in fact, in the same issue of the American Journal of Psychiatry), the finding that this drug treatment also improved cognitive functioning in the children and adolescents was reported independently by Molitch and colleagues (Molitch and Eccles, 1937; Molitch and Sullivan, 1937). Two years later, paradoxical phenobarbitalinduced excitation was described in children with behavioral disorders (Cutts and Jasper, 1939).

4

C.W. Popper

In the 1940s, psychostimulants were examined more extensively in children by Bradley and independently by Lauretta Bender (Bradley and Bowen, 1940; Bradley and Green, 1940; Bradley, 1941; Bradley and Bowen, 1941; Bender and Cottington, 1942). By the end of the decade, Bradley had treated 350 preadolescent children with psychostimulants (Bradley, 1950), essentially confirming the earlier findings and spelling out the major features of this treatment. The anticonvulsant phenytoin was reported to help some children with behavior disorders (Brown and Solomon, 1942; Lindsley and Henry, 1942; Walker and Kirkpatrick, 1947). Studies in the 1940s were largely focused on hyperactive children with brain damage, cerebral dysfunction, and developmental disorders. In the 1950s, the biologic revolution in psychiatry began with the initial appearance of antipsychotic and antidepressant agents and a growth spurt of psychopharmacologic research in adults. Chlorpromazine was initially synthesized in 1950 and was reported to have antipsychotic properties in adults in 1952. The first anecdotal description of its use in children was published in 1953 (Heuyer et al., 1953) regarding six children and adolescents (ages 5–14) with psychosis and agitation treated with chlorpromazine in doses up to 2 mg/kg. There were seven additional reports on chlorpromazine for youths in 1955, including a placebo-controlled study of 195 hospitalized children with mixed diagnoses who were treated with doses of 30–100 mg (Freedman et al., 1955). A partial-blind placebo-crossover study was reported the following year (Hunt et al., 1956). Also during the 1950s, the treatment of childhood behavior disorders with diphenhydramine (Effron and Freedman, 1953; Freedman et al., 1955) and meprobamate (Litchfield, 1957; Kraft et al., 1959) was first described, and monoamine oxidase inhibitors (MAOIs) were reported to increase awareness and language production in children with autistic disorder (Freedman, 1958). Reserpine was found to be effective in reducing symptoms of irritable and hypertonic infants (Talbot, 1955). The first review article in the field was published by Freedman et al., 1955. The first National Institute of Mental Health (NIMH) grant in child psychopharmacology was awarded in 1958 to Leon Eisenberg, largely because of his careful methodology, to examine perphenazine treatment of hyperactive children (Eisenberg et al., 1961). The 1960s were a time of large-scale expansion of treatment and research in pedipsychopharmacology. TCAs were first reported to be useful in treating enuresis (MacLean, 1960; Poussaint and Ditman, 1965), ADHD (Krakowski, 1965; Rapoport, 1965), and, seemingly, childhood depression (Lucas et al., 1965; Frommer, 1972). MAOIs were described for treating depressive (Frommer, 1967) and phobic disorders (Kelly et al., 1970) in children. Barbara Fish began to

5


report on various neuroleptics and diphenhydramine, including comparison studies, in hospitalized children with autistic disorder (Fish, 1960a,b). Neuroleptics were first described to treat children with Tourette’s disorder (Chalas and Brauer, 1963; Chapel et al., 1964; Lucas, 1964). Chlordiazepoxide was used clinically (Skynner, 1961) and studied in 130 children (2–17 years old) with mixed diagnoses who were treated with doses of 30–130 mg daily (Kraft et al., 1965). Annell first reported on lithium treatment in a series of children (Annell, 1969a,b), although a single case report had been published previously (Van Krevelen and Van Voorst, 1959). These adventurous times also included some forays by Lauretta Bender into LSD (lysergic acid diethylamide) treatment of children with autistic disorder. Conducted with an intent to ‘‘break through the autistic defenses of severely [disturbed] children,’’ LSD was reported to heighten mood, increase alertness and awareness of reality, improve eye contact and interpersonal responsiveness, and reduce stereotypies, headbanging, and self-injurious behavior without causing psychotic reactions or significant adverse effects (Bender et al., 1962; Bender 1966). Keith Conners, Gabrielle Weiss, and John Werry were leaders in bringing pedipsychopharmacology research on ADHD to a higher plane of methodologic rigor and moving it into the scientific age. Despite the accelerating pace of child psychopharmacologic research, practitioners in the 1960s remained cautious and, in retrospect, overprotective. Medication treatments were viewed as palliative, and clinicians raised concerns over the potential for medication treatments to disrupt psychoanalytically oriented psychotherapies, interfere with a child’s developing sense of selfcontrol and responsibility, foster psychologic and physical dependence on medications, promote or induce drug abuse, expose small vulnerable beings to dangerous medications, and lead to over-reliance on medications to the exclusion of other coping strategies and interventions. These unfounded fears were part of more general doubts about biologic formulations by physicians and simplistic thinking by patients (Robinowitz and Wiener, 1990). In the 1970s, there was another quantum jump in the quantity and quality of psychopharmacotherapy research in youth. Howard Abikoff, Michael Aman, Eugene Arnold, Russell Barkley, Magda Campbell, Dennis Cantwell, Gabrielle Carlson, David Engelhardt, Kenneth Gadow, Laurence Greenhill, Rachel (Gittelman) Klein, William Pelham, Judith Rapoport, Daniel Safer, Robert Sprague, James Swanson, and Paul Wender began their careers and wide-ranging contributions to the field. Imipramine was reported to appear effective in treating children with school phobia and separation anxiety (Gittelman-Klein and Klein, 1971, 1973). Carbamazepine was first used to treat nonepileptic children with

6

C.W. Popper

behavior disorders (Puente, 1976; Remschmidt, 1976), and propranolol was introduced for treating children with brain damage or neurologic abnormalities (Schreier, 1979; Williams et al., 1982). Anecdotal reports on the use of antidepressants and lithium in children were occasionally published, but there was little systematic progress on treating mood disorders in youth, and many clinicians maintained doubt about whether mood disorders even existed in children. The NIMH in the United States held a consensus conference in 1977 which concluded that depression does in fact appear in children, but it could not agree on a definition, and a minority statement dissented with the conclusion that childhood depression exists (Schulterbrandt and Raskin, 1977). Moreover, the budding use of antidepressants was dampened by the report of a fatality (Saraf et al., 1974) in a 6-year-old child being treated with imipramine 15 mg/kg daily, a markedly excessive dose by today’s standards and administered prior to the now routine use of electrocardiography (Saraf et al., 1978) to monitor cardiac conduction. The year 1978 turned out to be a landmark in child and adolescent psychiatry and psychopharmacology. Kim Puig-Antich and colleagues issued an initial report suggesting that a substantial number of children with major depressive disorder, defined by Diagnostic and Statistical Manual of Mental Disorders, Second Edition (American Psychiatric Association, 1975) criteria formulated for adults, improved clinically when treated with imipramine (Puig-Antich et al., 1978). Puig-Antich also noted that these children often had concurrent separation anxiety disorder and that both syndromes appeared to improve with imipramine treatment, echoing the earlier findings of Rachel and Donald Klein, who used a more rigorous design in examining separation anxiety (GittelmanKlein and Klein, 1971, 1973). Puig-Antich’s study was historically pivotal in launching the ongoing surge in the use of psychopharmacologic agents in children, by bringing attention to the potential treatability of childhood depression. Ironically, this finding did not hold up to replication (Puig-Antich et al., 1987) and was not supported by many subsequent controlled trials with various TCAs ( Jensen and Elliott, 1992). Toward the end of the decade, clonidine was first introduced for treating Tourette’s disorder (Cohen et al., 1979, 1980). At the start of the 1980s, the general use of these treatments was still quite limited, largely because psychostimulants remained the only child psychopharmacotherapy with well-demonstrated efficacy. Most residency training programs in child psychiatry taught about psychostimulants but not other medications. Many programs discouraged the use of any psychiatric medications in children, partly due to the dearth of scientific knowledge and partly due

7


to unscientific reasoning and historical tradition, but certainly not out of a lack of well-controlled demonstrations of psychostimulant efficacy. Antipsychotic agents were becoming less stigmatized and were generally used for psychotic disorders and some cases of severe impulsivity. TCAs were employed sparingly, but, over the course of the decade, clinicians gradually became comfortable in using TCA treatments, predominantly for major depression and separation anxiety disorder, as psychopharmacologic research on these disorders expanded. Lithium therapy remained uncommon. At mid-decade, a major thirdparty carrier in the United States was still refusing to pay for lithium treatment, even for hospitalized children, on the grounds that it was too experimental. By the end of the decade, though, a child with bipolar disorder was featured on the videotaped section of the national board examinations in child psychiatry in the United States. Clonidine, which quickly became a common treatment for Tourette’s syndrome, began to be used to treat ADHD (Hunt et al., 1985), but the psychostimulants remained by far the most predominantly prescribed psychiatric medication for children. In parallel with the expansion of psychopharmacologic research in children and adolescents, the clinical use of these treatments became increasingly prevalent during the mid-1980s. By the end of the decade, these treatments had spread far beyond the confines of university clinics, but their widespread use was not based on solid scientific documentation of their safety or efficacy. The extensive use of child psychopharmacologic treatments without adequate documentation in the medical literature became commonplace. In the 1990s, child and adolescent psychopharmacologic treatment entered everyday psychiatric practice. Its speedy expansion led drug treatment, alongside and integrated with psychosocial interventions, to become the prevailing approach in child psychiatry by the mid-1990s. The use of psychostimulants in youth more than doubled between 1990 and 1995 (Safer et al., 1996; Zito et al., 1998). The shift from TCAs toward specific serotonin reuptake inhibitors (SSRIs) for treating children (Ambrosini et al., 1995) proceeded contemporaneously with their swift deployment in adults and, concurrently, the accumulation of studies on TCAs showed their ineffectiveness in treating childhood depression. The newly introduced SSRIs rapidly became the most commonly used child psychopharmacologic treatment, the first time that another medication had surpassed the psychostimulants in prevalence of use. Despite two initially negative studies of SSRI treatment in childhood depression (Simeon et al., 1990; Mandoki et al., 1997), a large-scale study of fluoxetine became the first demonstration of the value of SSRIs for treating children with major depressive episodes (Emslie et al., 1997, 1998). Toward the end of the decade,

8

C.W. Popper

the first and only randomized double-blind, placebo-controlled trial of lithium in treating bipolar disorder in youth yielded a positive outcome (Geller et al., 1998a). This study also showed that lithium reduced the associated substancerelated disorders that appeared during bipolar episodes in those adolescents. In addition, the efficacy of lithium was first demonstrated for treating major depressive disorder in preadolescents who had a family history of bipolar disorder (Geller et al., 1998b). Other mood stabilizers (Ryan et al., 1999), atypical antipsychotics (Toren et al., 1998), and novel antidepressants became routine treatments during the 1990s, despite a relatively small amount of research in youth. Even at present, and despite the widespread use of psychiatric medications in youth, few child psychopharmacologic treatments have been rigorously demonstrated to have efficacy in formal well-designed and well-controlled studies, efficiency in large populations treated in naturalistic clinical settings, or safety in short-term or long-term use. Changing prescribing philosophies Lifting the taboo

The long-standing taboo on psychopharmacologic ‘‘experimentation’’ in children, which had dominated the clinical practice of child and adolescent psychiatry, all but disappeared in the late 1980s. The taboo had long been used to justify reliance on psychodynamic treatments, which then viewed medications primarily in terms of hazards. Only in recent years did psychopharmacologic research come to be viewed as presenting important benefits to youth and not merely risks. It was increasingly recognized that studies in adults were not adequate for extrapolation to children and that the systematic avoidance of innovative treatments for youths was depriving them of important opportunities. Most crucially, clinicians became aware that the current generation of children and adolescents were still missing out on the benefits of the biologic revolution. With the continuing expansion of empirical psychopharmacologic treatment of youth in the 1990s, a type of caution previously exercised by most child and adolescent psychiatrists began to break down and was gradually abandoned. Traditionally, newly developed medications were not generally used for treating children with psychiatric disorders until there was a clear ‘‘track record’’ of their safety and clinical effectiveness in adults, a process that typically required at least several years (Popper, 1987b). This protective strategy began to wear thin with the introduction of the SSRIs, because they offered a clear improve-

9


ment in effectiveness, tolerability, and adverse effects over the previously available antidepressants. With the SSRIs, for the first time, it took only about 1–2 years after the initial commercial introduction of a new drug class in the United States for it to begin to be used in significant numbers in American youths (and, once again, prior to documentation of pediatric efficacy). Concurrently, in the early 1990s, atypical neuroleptics were introduced in the United States and were almost immediately employed for treating children with Tourette’s syndrome, autistic disorder, and psychotic disorders. In addition, there was a shift in approach from ‘‘least restrictive’’ and ‘‘lowest effective dose’’ treatments to ‘‘most effective’’ treatment. The change in level of ‘‘caution’’ reflected the increasing comfort and decreasing rigidity of clinicians employing pedipsychopharmacologic methods. Confronting clinical uncertainty

The scientific and clinical unknowns in child psychopharmacology remain quite broad. There is little available detail on the biochemical development of the brain (especially in humans), drug disposition in children, developmental changes in the responses of target sites of drug action, or developmental differences in drug neurotoxicity (Popper, 1987a). Ethical and legal implications of child psychopharmacologic treatments, the integration of drug and psychosocial child therapies, and the psychotherapeutic implications of these treatments remain poorly understood. However, for better and for worse, current clinical attitudes no longer regard this lack of knowledge as a major obstacle to the use of these medication treatments in children. Instead, it has been customary to view this paucity of information as a challenge requiring child and adolescent psychiatrists to update the field while practicing it. In this situation, clinicians are attuned to watch carefully for potential adverse effects and complications. Exercising such caution in the face of uncertainty, they may be less likely to consider the possibility that some unknown drug effects may be therapeutic. We know from preclinical investigations that psychopharmacologic agents can cause beneficial as well as untoward influences on the central nervous system during development. For example, a medication treatment for acute symptoms might speculatively also delay or reverse brain degeneration associated with a psychiatric disorder. We must realize that potentially serious adverse effects will surely continue to be uncovered in children, but we should also expect currently unknown beneficial drug effects to emerge. The promise of new findings on drug effects, both good and bad, remains an essential part of this field. Despite the scientific unknowns and ethical dilemmas (and impasses), parents and practitioners appear willing

10

C.W. Popper

to take chances – because they judge that the risks of child psychiatric disorders themselves appear, in general, to exceed the risks of the child psychopharmacologic treatments (Popper, 1987b).

The rise of therapeutic empiricism

The case for delaying the use of these treatments until their safety and efficacy are formally demonstrated is logically strong, but compellingly impractical. Such studies would take years or decades to produce results, and the seemingly logical ‘‘conservative’’ approach would prevent the current generation of youths from receiving the new and generally improved modern methods of psychiatric treatment. Empirical treatments have, then, proceeded in concert with studies of efficacy and tolerability, and eventually a selection of ‘‘older’’ treatments can be based on scientific grounds. In psychiatry now, and in pediatrics, research empiricism supplements and augments therapeutic empiricism in clinical practice in developing old drugs for new uses. In contrast, new drugs for initial applications cannot be introduced until they have scientifically demonstrable safety and (in at least some indications) demonstrable value. The preoccupation of child psychiatry with psychoanalysis has given way to a more eclectic and empirical clinical methodology. The former tension between the biologic and psychodynamic conceptualizations, for many years viewed as a substantive division in theoretical understanding and choice in treatment selection, has essentially dissolved. This resolution has allowed these approaches to become coupled and integrated in clinicians’ work. Unified biologic and psychosocial treatment has now become the ‘‘standard of care’’ for most if not all psychiatric disorders of youth. Specific questions about how to balance these treatments are being worked out empirically in clinical practice and research. Therapeutic empiricism (Popper, 1990) has become the watchword by which clinicians decide when to treat and when to delay the use of medication and psychosocial treatments. At the turn of the millennium, clinical knowledge and know-how in pedipsychopharmacology is surprisingly widespread among everyday practitioners. There is increasingly broad, deep, large-scale, and well-funded research in child psychopharmacology, which is now a focus of substantive government effort and financial support. The general discussion and sophisticated questions at national and local conferences demonstrate how extensively child and adolescent psychopharmacology is practiced and understood by large numbers of psychiatrists.

11


New trends Excessive use

Public fears of rampant overmedication of children are quite understandable and hardly unjustified. In 1970, the Washington Post erroneously reported that 5–10% of public school students in Omaha were being treated with stimulants (Maynard, 1970), a revelation that was generally viewed as scandalous. More recently, a careful study examining about 30 000 students in two cities found an 8–10% prevalence of drug treatment for ADHD, with the highest rate, among white boys in fifth grade, at 18–20% (LeFever et al., 1999). Such high rates do not imply generalized overtreatment. It is well known that the use of child psychopharmacologic treatments varies drastically among nations, regional divisions, cities, medical schools, clinics, and individual physicians (Gadow, 1997). In fact, the under-use as well as over-use of psychiatric medications remains a prominent current problem – if over-use means treatment of children who do not have the relevant disorder or need medication, and if under-use means failure to treat youths whose disorders are best treated with medications. Numerous studies have indicated that concerns about massive overmedication are unfounded; even at present, undertreatment appears to be more of a problem than overtreatment ( Jensen et al., 1999). Debates about overtreatment and undertreatment, both in individuals and in populations, highlight the perennial uncertainty and endless process of revision throughout medicine, so practitioners in child and adolescent psychopharmacology can anticipate this to be an ongoing source of tension for decades to come. Money-oriented medicine

Some nations have learned to administer health care in a relatively altruistic and cost-effective manner, but the system of health care in the United States has become dominated by financial rather than medical management. Financially managed medicine is a direct result of the historical inability of physicians to control prices or provide for the needs of the whole population. Caps on costs, often at the expense of quality, have influenced all aspects of medicine, including psychopharmacotherapy, psychosocial treatment, and psychomanagement, with equally injurious effects. Evidence-based medicine, a force emerging from the combined efforts of third-party commercialism and scientific academicism, emphasizes science as the basis for sound or improved practice (Evidence-Based Medicine Working Group, 1992). However, overly rigid use of evidence-based medicine could present a threat to the valuable benefits yielded by therapeutic empiricism for

12

C.W. Popper

psychiatric and general medical treatment. Given the major gaps in the evidence base, especially in child psychiatry, many common clinical decisions must be made on the basis of less rigorous evidence, including qualitative data (Graham, 2000) and clinical practice surveys (Hickie et al., 1999). The risks of evidence-based psychiatry are particularly striking when combined with overly zealous financial management (Berk and Janet, 1999). It is commonly believed that financially based medicine, unless repaired, will lead to ‘‘bargains’’ that weaken and eventually bankrupt the system of care. Third-party managers, questioning the value of the initial psychiatric comprehensive evaluation, have managed to fund clinical evaluations that are shorter than is medically necessary. A thorough child psychiatric/psychopharmacologic evaluation may take 4–7 hours, yet managed care in the United States pays for and expects physicians to make treatment decisions after one hour or less of psychiatric assessment. Shorter evaluations may be hypothetically more cost-effective, but longer evaluations are almost certainly more likely to identify multiple diagnoses, anticipate problems, and avoid setbacks. Evidence-based medicine applies mainly to the needs of the ‘‘‘average’ randomized patient’’ (Feinstein and Horwitz, 1997), leaving others out. In any case, there is little evidence supporting the value of strict evidence-based medicine vs. therapeutic empiricism. Even when there are differences in treatment outcome, they may not be clinically significant. The relative usefulness of these two approaches will be decided empirically, with luck by an equitable balance of medical and administrative research. Changing training programs

Psychopharmacology in residency training programs went from being a luxury frill in 1985 to a staple component in 10 years. Most residents in child psychiatry in the United States are now finishing their training with substantial experience in psychopharmacologic techniques, supplementing other clinical skills. Even for the most biologically oriented trainees, it quickly becomes clear in actual practice that prescribers must talk to children, engage their cooperation in treatment, promote their self-observation and awareness of treatment effects, educate them and their families about psychiatric disorders and interventions, and be prepared to respond effectively to a wide range of potential psychosocial barriers to treatment. Despite the increasing reliance on diagnosis, the gradual de-emphasis of developmental principles in treatment, the decreasing reliance on one-to-one psychodynamic therapies, and the floating of responsibility for individual child psychiatric patients among multiple types of therapists, most residents in child

13


and adolescent psychiatry continue to be trained in psychopharmacology in a manner that promotes a multifaceted approach to treatment. Academic child and adolescent psychopharmacology

Academic medicine continues to provide critical leadership in training and research, and has maintained a superlative record of creating and adapting to new developments in concepts and treatments, but some features of the traditional disdain toward the clinical observations made by nonuniversity practitioners and individual clinicians’ observations have lingered. Nonetheless, in child and adolescent psychopharmacology, as in other fields of medicine, clinical knowledge grows largely by nonacademic mechanisms. In the United States, pedipsychopharmacology is a model medical field whose information explosion has been largely fueled by the empirical observations made by clinicians and whose new findings are rapidly expressed in the daily practice of clinicians throughout the country. Academic research in child and adolescent psychopharmacology consists mainly of controlled clinical trials of medications already in general use, early phase testing of drugs recently marketed or soon to be marketed, neurochemical investigations of children with defined biopsychiatric disorders, and studies in developmental neurobiology. For the most part, ideas for new applications of ‘‘old’’ medications are generated by clinicians in the field. The pace of child psychopharmacologic innovation and academic research is continuing to intensify. The rapid growth of investigation is reflected in the numbers of double-blind placebo-controlled studies, long-term and follow-up research designs, multisite studies, well-organized research departments, specialized research units in pediatric psychopharmacology (RUPPs), young and established contributors, larger case series, original research articles, and medical journals publishing articles on child psychopharmacology. Over forty books whose titles indicate a major focus on child and adolescent psychopharmacology have appeared in English over the last five decades, including textbooks, monographs, trade books, periodicals (except medical journals), and ‘‘book-like’’ special issues of medical journals. Unsurprisingly, the number of such publications has been accelerating: one book in the 1950s, one in the 1960s, 13 in the 1970s, 15 in the 1980s, 23 in the 1990s, and two so far in the 00s (Fisher, 1959; Freed, 1962; Blanco, 1972; National Institute of Mental Health, 1973; Conners, 1974; Gittelman-Klein, 1975; Spiel, 1976; Bosco and Robin, 1977; White, 1977; Wiener, 1977; Mendlewicz and van Praag, 1978; Werry, 1978; Cohen, 1979; Food and Drug Administration, 1979; Gadow, 1979; Klein et al., 1980; Gadow and Gadow, 1981; Raskin et al., 1981; Scruggs et al.,

14

C.W. Popper

1982; Nissen et al., 1984; Campbell et al., 1985; Rapoport et al., 1985; Wiener, 1985; Gadow, 1986a,b; Krasnegor et al., 1986; Popper, 1987; Voss, 1987; Aman and Singh, 1988; Gadow and Poling, 1988; Rothenberger, 1990; Weizman and Weizman, 1990; Green, 1991; Greenhill and Osman, 1991; Shaffer, 1992; Van Hasselt and Hersen, 1993; Werry and Aman, 1993; Rosenberg et al., 1994; Green, 1995; Richardson and Haugland, 1995; Riddle, 1995; Theesen, 1995; Wiener, 1995; Kutcher, 1997; Reiss and Aman, 1997; Rosenberg et al., 1997; Findling and Blumer, 1998; Roemmelt, 1998; Walsh, 1998; Wilens, 1998; Dulcan and Benton, 1999; Greenhill and Osman, 1999; Werry and Aman, 1999; Nutt, 2000; Kutcher, 2001). About 100–150 papers are now published annually on child and adolescent psychopharmacologic treatment, in addition to about another 50-75 studies on other biodevelopmental aspects of pediatric psychiatry. About 80% of these articles are published in two peer-reviewed journals. The Journal of Child and Adolescent Psychopharmacology, which turned 10 years old in 2000, is the first medical journal to focus specifically on pharmacologic and biologic aspects of child and adolescent psychiatry. The Journal of the American Academy of Child and Adolescent Psychiatry, the long-established central journal in the field, is now publishing about 20% of its articles on clinical psychopharmacology. The Child and Adolescent Psychopharmacology Newsletter, founded and edited by Stanley Kutcher since 1997, has become a widely read update and review (Kutcher, 1997). The Brown University Child and Adolescent Psychopharmacology Update, edited by Henrietta Leonard, has been published since 1999 (Leonard, 1999). In addition, a child and adolescent psychopharmacology discussion group (listserv) on the Internet has over 225 subscribers on its mailing list; it can be accessed through [email protected] JOHNS.EDU or its moderator ([email protected]). Beyond quantitative expansion, the quality of funded research has been keeping pace with the expansion of the field. Controlled studies increasingly examine carefully specified populations with systematically assessed diagnoses, explicit clinical inclusion and exclusion criteria, specified comorbidity, multiple observers and observation techniques, a range of clinical outcome measures, and advanced methods of statistical analyses. Efficacy and effectiveness

Clinicians as well as researchers are becoming more familiar with the limitations of double-blind placebo-controlled studies. The relevance of these studies has been called into question by the findings that some drugs that appear efficacious in controlled studies do not render a useful clinical effect in actual

15


‘‘naturalistic’’ treatments and, similarly, that some drugs observed to have value in the hands of clinicians working with real-world patients appear ineffective in controlled studies. The difference between drug ‘‘efficacy’’, as defined in rigorously controlled studies, and drug ‘‘effectiveness,’’ as defined in large-scale naturalistic studies, is emerging as an important distinction in understanding the clinical properties of medications. To a degree, this distinction breaks down in newer and more sophisticated studies that examine formulaic algorithm-based treatments in large populations of children. In general, both drug efficacy and naturalistic effectiveness studies are needed to evaluate fully the clinical promise and valid scope of a drug treatment. Drug–placebo comparisons are essential for the work of the United States Food and Drug Administration (FDA), whose role is to determine whether commercially marketed drugs are safe and efficacious. In contrast, clinical decision-making is often promoted more directly by drug comparison studies (comparing drug against drug), which identify how different drugs or treatments compare in clinical efficacy. Both clinical practitioners and clinical researchers in child and adolescent psychopharmacology contribute essential information that strengthens available treatment. This is not a field where the academics have a hegemony over the production of clinically important findings. Both clinicians and researchers are ahead of each other in certain respects, and both spur the successes of the other. Combined medication treatments

Simplicity and clarity remain important features of optimal care, but the effectiveness of psychopharmacologic monotherapies is quite limited in many cases. The use of multiple concurrent psychiatric medications, though formerly denigrated as ‘‘polypharmacy,’’ has appropriately become a common practice and even a routine part of the ‘‘standard of care.’’ The multipronged approach to influencing different brain neurotransmitter systems goes well beyond the former ‘‘one disease/one treatment’’ model, which is often simplistic in medicine, weakly applicable to most psychiatric disorders, and almost irrelevant to child psychiatric disorders. However, multiple concurrent drug treatments have rarely been studied with regard to safety or therapeutic effect, with methylphenidate/desipramine being the only such combination to have received systematic investigation in children (Rapport et al., 1993; Pataki et al., 1993; Carlson et al., 1995). In addition to the increased likelihood of adverse effects with two or more pharmacotherapies, medical regimens consisting of three or more drugs can give rise to multiple

16

C.W. Popper

concurrent drug interactions, generating at times genuinely unpredictable effects (Fisman et al., 1996). When rigorously conducted, however, multiple concurrent drug treatments can add significantly to the sophistication and effectiveness of child psychopharmacologic treatment. Setbacks The march of progress has not been without setbacks. It was fully predictable that these innovative treatments would be the source of significant problems themselves, including some serious ones. Limited benefits

The widely held, empirically based belief in the 1980s that TCAs can effectively treat major depression in youth has been tempered by the findings of controlled research. Double-blind placebo-controlled studies have repeatedly shown no generalized clinical efficacy of TCAs in childhood depression ( Jensen and Elliott, 1992; Birmaher et al., 1996; Findling et al., 1999; Ambrosini, 2000), even in the recent studies with current methodology (Kye et al., 1996; Birmaher et al., 1998; Klein et al., 1998). Estimates of the pooled effect size of 0.35 standard deviations (95% confidence interval of 0.16–0.86) and the pooled odds ratio of 1.08 (95% confidence interval of 0.53–2.17) indicate no significant clinical value is likely to be uncovered by further controlled trials (Hazell et al., 1995). However, TCAs appear to be decisive in certain youths with depressive disorders, as demonstrated in the responses of individual patients to dose changes as well as to drug discontinuations and restarts. Even some researchers who demonstrated a lack of clinical efficacy of TCAs in controlled trials continue to use the drugs in their own clinical practices. Despite the spate of negative studies which formally demonstrate that they do not work significantly better than placebo, TCAs remain possible secondary and supplementary agents for treating depression in youth. The SSRIs do not have the potential to replace the role of the TCAs in treating enuresis (bedwetting), ADHD, or SSRI-induced frontal release, which includes frontal disinhibition (King et al., 1991; Riddle et al., 1991a) and frontal apathy (Hoehn-Saric et al., 1990; Walkup, 1994; Popper, 1995a). It remains unclear whether TCAs are less effective in treating depression in youths than in adults for developmental pharmacodynamic reasons or perhaps other reasons, including the possibility that the usefulness of TCAs in major depression was historically overvalued in adults. In a similar, but less conspicuous reversal, naltrexone treatment of autistic

17


disorder was another example of overly optimistic estimates of therapeutic drug effects that were later determined to be unfounded or at least overrated. Adverse effects in youth

Certain adverse drug effects in children and adolescents were not anticipated by studies of adults, including the classic example of psychostimulant-induced growth slowing. In a similar manner, valproate-induced polycystic ovary disease appears to be a problem mainly of young women (Isoja¨rvi et al., 1993), resulting from the hormonal consequences of weight gain (Isoja¨rvi et al., 1996, 1998). Lamotrigine is known to be more of a dermatologic risk to children than to adults (Li et al., 1996; Messenheimer, 1998), both with respect to Stevens Johnson syndrome (1/1000 in adults, 1/200 in children) and rash of any type associated with hospitalization (3/1000 in adults, 1/100 in children). The induction of frontal apathy and disinhibition by SSRIs may be more common in youths than adults (Popper, 1995a). TCAs appear more likely to induce increased blood pressure (Kuekes, 1992) and perhaps sinus tachycardia (Leonard et al., 1995) in youths than adults. In addition, there are suggestive data that akathisia may be more prevalent in youths than adults treated with conventional neuroleptics (Keepers et al., 1983). Extrapyramidal symptoms (Mandoki, 1995) and perhaps obsessive–compulsive symptoms may be more common in youths than adults treated with atypical neuroleptics. Nefazodoneinduced hepatic failure might, speculatively, be more common in youths (Aranda et al., 1999). The list of age-related adverse drug effects will enlarge, and the search for other untoward developmental–pharmacodynamic changes will become a staple of this field. Sudden death

Beyond the traditional concerns about the risks of TCA overdose (Frommer et al., 1987), the appearance of sudden medically unexplained deaths in children and adolescents treated with desipramine have raised major concerns with considerable justification. Although the initial three cases (Abramowicz, 1990) identified by the FDA were generally viewed as inconclusive (Elliott et al., 1990; Popper and Elliott, 1990; Biederman, 1991; Elliott and Popper, 1991; Riddle et al., 1991b), three subsequent cases (plus another that could be equally attributed to concurrent neuroleptic treatment) convinced most clinicians that desipramine should be used sparingly in children (Riddle et al., 1993; Zimnitzky and Popper, 1994; Varley and McClellan, 1997), especially for nonlethal disorders such as ADHD and enuresis (Popper and Zimnitzky, 1995). Sudden deaths attributable to desipramine exceed the risks of other TCAs (Biederman

18

C.W. Popper

et al., 1995), but the risks might be comparable in magnitude in both children and adults (Popper, 1994). Although baseline screening and ongoing medical monitoring, including electrocardiography, might be able to prevent some of the deaths due to long Q-T syndrome, even invasive angiography would not necessarily prevent other sudden deaths associated with other cardiac abnormalities (Popper and Zimnitzky, 1995). These rare catastrophes were particularly worrisome because of the previously extensive use of desipramine, whose value in treating childhood depression is now known to be small. Serious questions have also been raised about the combined use of clonidine and methylphenidate (Fenichel, 1995). Although the three initially reported cases were readily attributable to other medical factors (Popper, 1995b), new cases might generate greater concern. The only subsequently reported death on this drug combination involved a 10-year-old boy with a history of several incidents of syncope prior to starting the medication combination (Cantwell et al., 1997). The child went swimming, felt faint, rested for 45 minutes, swam again for another 45 minutes until he felt faint again, and then had a seizure. At autopsy, he was found to have a congenital cardiac abnormality of the left coronary artery. The history of syncope prior to starting the blood pressurelowering medication and the continuing exertion despite hypotensive symptoms that day may have, in retrospect, been a significant risk to a child with potential cardiac vulnerability. In all four cases of methylphenidate–clonidine death, other medical factors presented risks that probably exceeded an unproven risk hypothesized to be associated with the drug combination. The risks associated with psychopharmacologic treatment cannot be stated with certainty, because unknown risks and dangers are likely to be described in the future. Serious overestimation of effectiveness and underestimation of the dangers of these treatments can be expected for years to come, so it is critical to temper enthusiasm or satisfaction in prescribing these treatments with a respectful doubt about the ultimately determined effects of each treatment. Rising expectations While the standards of care are changing, the expectations of care are changing as well. Heightened public understanding of psychiatric disorders and treatments, increasing acceptance of child psychopharmacology, the swelling of newly introduced drugs and drug classes, the unmasking of blindly antipsychiatry and antimedication forces in society, and the new focus in medicine on ‘‘quality of life’’ (in addition to symptom amelioration) have led to a much higher visibility of psychopharmacologic treatments and a sense of promise in

19


child psychiatry. Child psychopharmacology and child psychiatry are now mainstream medicine, and they carry all the attendant hopes, unrealistic expectations, and disappointments. Rush to use

New psychiatric drugs are employed more quickly for clinical treatment of children than in the past. Although it has previously taken years of postmarketing experience before new psychiatric medications were put to use for children, the erosion of this protective delay is certain to bring a comeuppance. Indeed, at this point, a new corner is being turned: new psychiatric drugs are coming into clinical use more rapidly than they can be effectively investigated. New drugs are replacing old drugs while the postmarketing studies on old drugs are not yet completed, and this is especially so for the new psychiatric drugs used in children and adolescents. SSRIs became predominant in child and adolescent psychiatry when TCAs were still being evaluated for the treatment of mood and anxiety disorders. Atypical neuroleptics replaced conventional antipsychotic medications for treating a variety of child psychiatric disorders approximately as quickly as for adult disorders. Anticonvulsant mood stabilizers are now routinely used to treat children with bipolar disorder, starting even before the first adequately controlled prospective study had been conducted of lithium treatment of bipolar disorder in children or adolescents. The potential for rapid drug obsolescence, resulting from the fast expansion of pharmacologic alternatives, might conceivably herald an age when new drugs are quickly replaced before they can be adequately examined and understood. This shift has already begun, and it certainly challenges the traditional manner in which clinical decision-making about medications is made. Whether this shift will pose mainly advantages or disadvantages remains to be seen and will itself require ongoing study. In addition to exposing patients to potentially serious risks, a decreasing reliance on completed formal drug studies might come to make clinical decisions increasingly subject to the subtle effects of pharmaceutical advertising. The role of industry and technology

Major pharmaceutical houses are now quite interested in child and adolescent psychopharmacology, perhaps the clearest and most convincing sign of the ‘‘coming of age’’ of this field, and pharmaceutical manufacturers have for years been reaping benefits from off-label treatments in child psychopharmacology.

20

C.W. Popper

Even though the FDA asserts that approved labeling is specifically intended to regulate pharmaceutical advertising (Food and Drug Administration, 1982), many physicians have regarded them as guides and used them inappropriately as restraints on their prescribing practices. With the FDA now placing more emphasis on the pediatric use of medications in clinical practice and drug trials in children prior to marketing (Food and Drug Administration, 1992), new conduits are being established for new drugs to receive drug package insert labeling for child psychiatric treatment (Laughren, 1996). In the 1997 FDA Modernization Act (Food and Drug Administration, 1997), the US Congress gave clearance for the FDA to grant time extensions on exclusivity patents of already marketed drugs to pharmaceutical houses that conduct clinical research in children. These governmental actions have further spurred the industry to devote resources to research on children (Walkup et al., 1998), which in turn is leading to more advertising of psychiatric drugs for use in children. Medication advertisement

The approaches by pharmaceutical companies to the marketing of medications are generally expected to influence physicians’ prescribing, alter market share, and enhance company revenues. Although largely educational in nature, these approaches still raise concern. Direct-to-consumer advertising on television and magazine pages carries potential advantages (Pines, 1998) and disadvantages (Tsao, 1997; Schommer et al., 1998) for the public, evokes disapproval from most physicians (Lipsky and Taylor, 1997), and poses nettlesome issues for the FDA (Baylor Henry and Drezin, 1998). The detailing techniques of company representatives who promote drugs to physicians include marketing methods whose mechanisms and effects are not well understood by physicians (Roughead et al., 1998). Pharmaceutical advertising in medical journals might appear to be more reliable because of the careful surveillance by the FDA in the United States and similar regulatory agents in other nations (Lexchin, 1997). Nonetheless, certain drug advertisements in medical journals are misleading at best. In some instances, the phrasing and figures in drug advertisements are meaningless or perplexing. More insidious factors in commercial medical advertising include the widespread use of subtle communications pitched to the so-called ‘‘cognitive unconscious’’ and the impact of obvious emotional appeals. (Franz Ingelfinger used to talk about the New England Journal of Medicine receiving an advertisement for an endocrinologic drug that contained the silhouette of a physician looking down, with a banner saying, ‘‘How would you feel, Doctor, if your genitals began to shrink?’’) Drug advertisements in medical journals are

21


unquestionably more colorful and eye-catching than the rest of the contents. Numerous studies have shown that physicians believe that decision-making by other physicians is swayed by medical advertising, but, interestingly, most physicians believe that they themselves are not at all influenced by drug advertisements. This fascinating finding attests to the power of advertising, the strength of denial, and naivety of the target physician audience. An additional problem is probably uncommon, but vexing at any occurrence. Continuing medical education materials and drug company ‘‘throwaway’’ promotional publications are quietly edited by pharmaceutical companies or their ‘‘arm’s length’’ contracted agencies, at times encouraging crucial changes in wording, content, and emphasis that may include potentially significant clinical omissions. Sponsored medical lectures are given at times by physicians who have received implicit or explicit directives from company representatives about what to discuss and what to avoid. Pharmaceutical manufacturers provide unique and essential scientific support for drug research. Certain breakthroughs and types of drug development can come only from the enormous wealth of industry. The relatively smallscale approach of academic medicine and government-funded research cannot provide the necessary resources. Pharmaceutical houses provide the only hope for supra-large-scale research required for the development of new drug products. A balance between the competing and complementary interests of industry, academia, and public need has, for example, resulted in the discovery of increasingly neurotransmitter-specific agents. Innovative treatments

Major drug breakthroughs are, of course, still to come. We still need neuroleptics that cause no (rather than less) tardive dyskinesia and do not induce neuroleptic malignant syndrome. SSRIs are limited by the emergence of frontal release, and none of the antidepressants is free of mania-inducing properties. Pharmacologic research is not the only source of innovative biologic treatments in child and adolescent psychiatry. Light therapies have recently been shown to be potentially successful in treating youths with bipolar disorder (Papatheodorou and Kutcher, 1995) and seasonal affective disorder (Swedo et al., 1997). These therapies might, speculatively, open the way toward psychiatric treatments based on stimulation of other sensory modalities. Electroconvulsive treatment, initially described in children in the early 1980s (Carr et al., 1983; Black et al., 1985; Guttmacher and Cretella, 1988), is now undergoing systematic study in adolescents and children (Cizadlo and Wheaton, 1995; Kutcher and Robertson, 1995; Ghaziuddin et al., 1996; Hill

22

C.W. Popper

et al., 1997). Transcranial magnetic stimulation, a technological improvement on electroconvulsive therapy, has been used to study children with Rett’s syndrome, ADHD, and benign childhood epilepsy, and also to examine the ontogeny of neuronal connections in normal children (Ucle´s et al., 1996; Heinen et al., 1997; Nezu et al., 1997; Heinen et al., 1998). Gene therapy is just beginning in child psychiatric disorders, with the first attempt being directed at Wolfram syndrome (Owen 1998, Swift et al., 1998). Wolfram gene carriers (including heterozygotes) are psychiatrically hospitalized 26 times more frequently than noncarriers. Wolfram syndrome is a primary (progressive) neurogenerative autosomal recessive disorder, first evident in early childhood, which is characterized by generalized brain atrophy, optic atrophy, deafness, juvenile-onset diabetes insipidus, diabetes mellitus, and psychiatric symptoms including behavioral and personality problems, loss of memory function, and frontal release (apathy and disinhibition). A gene has been implicated at chromosome 4p16.1 – particularly, exon 8. The gene, designated as wolframin or WFS1 (Hardy et al., 1999; Ohtsuki et al., 2000), codes for a transmembrane protein expressed in the brain and pancreas, where it appears to promote cell survival (islet beta-cells). Interestingly, a susceptibility gene for bipolar disorder has also been reported at chromosome 4p16 in several linkage studies, but five recent reports have found no association of bipolar disorder with the wolframin gene (Inoue et al., 1998; Furlong et al., 1999; Evans et al., 2000; Middle et al., 2000; Ohtsuki et al., 2000). An additional locus at chromosome 4q22–24 has been suggested (El Shanti et al., 2000), and the disorder has also been proposed to be a mitochondrial DNA disease involving genome deletions (Barrett and Bundey, 1997). Based on the work with the wolframin gene, studies of gene therapy for Wolfram syndrome are progressing. Antibiotic therapy, plasmapheresis, and intravenous immunoglobulins are being found helpful in alleviating psychiatric symptoms in some youths with obsessive–compulsive disorder and Tourette’s syndrome (Matarazzo, 1992; Swedo, 1994; Swedo et al., 1998); anorexia nervosa (Sokol and Gray, 1997), and other disorders in children. These immunologic treatments are based on the neuroimmunological cross-reactivity of antistreptococcal antibodies with central dopaminergic neurons. Nutrition-based medicine is beginning to become assimilated into child psychiatry, based on the recent wave of rigorously designed studies of natural substances and herbals in adults (Stoll et al., 1999a,b) and preliminary findings in children (Horrigan et al., 1998). The treatment of ADHD with fatty acids has been a particular focus of research (Colquhoun and Bunday, 1981; Aman et al.,

23


1987; Burgess et al., 2000). Lower serum levels of omega-3 and omega-6 fatty acids have been reported in children with ADHD (Mitchell et al., 1987; Arnold et al., 1994; Stevens et al., 1995, 1996), with the reductions in fatty acid levels possibly correlating to symptom severity. Double-blind, placebo-controlled studies in youth have suggested some effect of omega-6 gamma-linolenic acid in treating ADHD (Arnold et al., 1989; T Duvner, unpublished data) and of omega-3 docosahexanoic acid in treating aggressive behavior (Hamazaki et al., 1996). In a particularly intriguing recent open-label study (Kaplan et al., 2000), a mixture of 36 minerals and vitamins (modified from a supplement commonly administered to treat aggressive/violent behavior in livestock!) was found to be effective for treating bipolar disorder in adults. Initial results in the doubleblind, placebo-controlled trials have robustly supported this finding (effect size 0.8), but data collection is continuing (Kaplan et al., Nutraceutical treatment of mental disorders: a randomized, placebo-controlled clinical trial in adults with bipolar disorder – funded by the Alberta (Canada) Science and Research Authority, 2000–2002). Open trials of the same supplement were found to rapidly reduce symptom ratings of bipolar disorder in children as well (Bonnie Kaplan, personal communication). The results of my limited use of this supplement in bipolar children have been, simply put, startling and unprecedented. These observations have made me re-think my traditional bias against consideration of nutritional supplementation as a potential treatment of major psychiatric disorders. Tolerability, safety, efficacy, effect size and duration, pharmacokinetics, and drug interactions of all the nutritional treatments will need to be determined, alongside the continuing experimentation with natural substances by the public at large. The turn of the millennium

Technologic advances are not likely to make us wiser, but we can expect to become more knowledgeable and effective in our clinical practices. Just as it may be hard to imagine that child psychopharmacology consisted mainly of psychostimulants and barbiturates 50 years ago, that antidepressants and lithium were scarcely used in youths 15 years ago, or that traditional neuroleptics were still in wide use in children just a few years ago, it will not be long before we will look back on 20th-century psychopharmacology as curious, primitive, and vaguely amusing. Hopefully, we will also be able to look back on these times with a sense of satisfaction about what we were able to accomplish using the knowledge and

24

C.W. Popper

tools available, while perhaps feeling regretful for the currently unknown, perhaps serious or even devastating, toxic effects of our current drug treatments. Possibly in the more distant future, we may wish to disown medication treatments of brain disorders entirely. We may come to regard the era of psychopharmacology as a time when we had nothing better to offer than our old nonspecific chemicals. We should welcome such progress. In the meantime, for the generation or generations of children, adolescents, and adults who are still best treated by psychopharmacologic methods, this book will provide essential knowledge, techniques, and sustenance. Knowing that our clinical reach is limited, we have much to learn.

REFE REN C ES Abramowicz M (1990). Sudden death in children treated with a tricyclic antidepressant. Med Letter Drugs Ther 32:53–4. Aman MG, Singh NN (Eds.) (1988). Psychopharmacology of the Developmental Disabilities. New York: Springer-Verlag. Aman MG, Mitchell EA, Turbott SH (1987). The effects of essential fatty acid supplementation by Efamol in hyperactive children. J Abnorm Child Psychol 15:75–90. Ambrosini PJ (2000). A review of pharmacotherapy of major depression in children and adolescents. Psychiatr Serv 51:627–33. Ambrosini PJ, Emslie GJ, Greenhill LL, Kutcher S, Weller EB (1995). Selecting a sequence of antidepressants for treating depression in youth. J Child Adolesc Psychopharmacol 5:233–40. American Psychiatric Association (1975). Diagnostic and Statistical Manual of Mental Disorders, 2nd edn. Washington, DC: American Psychiatric Association. Annell AL (1969a). Lithium in the treatment of children and adolescents. Acta Psychiatr Scand 207(Suppl):19–30 (Discussion pp. 31–2). Annell AL (1969b). Manic-depressive illness in children and effects of treatment with lithium carbonate. Acta Paedopsychiatry 36:282–301. Aranda MJ, Koehler A, Bejarano PA et al. (1999). Nefazodone-induced liver failure: report of three cases. Ann Intern Med 130:285–8. Arnold LE, Abikoff HB, Cantwell DP et al. (1997). National Institute of Mental Health Collaborative Multimodal Treatment Study of Children with ADHD (the MTA). Design challenges and choices. Arch Gen Psychiatry 54:865–70. Arnold LE, Kleykamp D, Votolato N, Gibson RA, Horrocks L (1994). Potential link between dietary intake of fatty acids and behavior: pilot exploration of serum lipids in attention-deficit hyperactivity disorder. J Child Adolescent Psychopharmacol 4:171–82. Arnold LE, Kleykamp D, Votolato NA, Taylor WA, Kontras SB, Tobin K (1989). Gamma-

25


linolenic acid for attention deficit hyperactivity disorder: placebo-controlled comparison to D-amphetamine. Biol Psychiatry 25:222–8. Barrett TG, Bundey SE (1997). Wolfram (DIDMOAD) syndrome. J Med Genet 34:838–41. Baylor Henry M, Drezin NA (1998). Regulation of prescription drug promotion: direct-toconsumer advertising. Clin Ther 20(Suppl C):C86–95. Bender L (1966). D-lysergic acid in the treatment of the biological features of childhood schizophrenia. Dis Nerv Syst 7(Suppl):43–6. Bender L, Cottington F (1942). The use of amphetamine sulfate (benzedrine) in child psychiatry. Am J Psychiatry 99:116–21. Bender L, Goldschmidt L, Sankar S (1962). Treatment of autistic schizophrenic children with LSD-25 and UML-491. In Recent Advances in Biological Psychiatry, Vol. IV, ed. J. Wortis. New York: Plenum Press, pp. 170–7. Berk M, Janet ML (1999). Evidence-based psychiatric practice: doctrine or trap. J Eval Clin Pract 5: 149–52. Biederman J (1991). Sudden death in children treated with a tricyclic antidepressant. J Am Acad Child Adolesc Psychiatry 30:495–8. Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS (1989a). A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy. J Am Acad Child Adolesc Psychiatry 28:777–84. Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS, Goldblatt A (1989b). A double-blind placebo controlled study of desipramine in the treatment of ADD: II. Serum drug levels and cardiovascular findings. J Am Acad Child Adolesc Psychiatry 28:903–11. Biederman J, Thisted RA, Greenhill LL, Ryan ND (1995). Estimation of the association between desipramine and the risk for sudden death in 5- to 14-year old children. J Clin Psychiatry 56:87–93. Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J (1996). Childhood and adolescent depression: a review of the past 10 years. Part II. J Am Acad Child Adolesc Psychiatry 35;1575–83. Birmaher B, Waterman GS, Ryan ND et al. (1988). Randomized, controlled trial of amitriptyline versus placebo for adolescents with ‘‘treatment-resistant’’ major depression. J Am Acad Child Adolesc Psychiatry 37:527–35. Black DW, Wilcox JA, Stewart M (1985). The use of ECT in children: case report. J Clin Psychiatry 46:98–9. Blanco RF (1972). Prescriptions for Children with Learning and Adjustment Problems. Springfield, IL: CC Thomas. Bosco JJ, Robin SS (Eds.) (1977). Hyperactive Child and Stimulant Drugs. Chicago: University of Chicago Press. Bradley C (1950). Benzedrine and dexedrine in the treatment of children’s behavior disorders. Pediatrics 5:24–37. Bradley C (1941). The behavior of children receiving benzedrine. Am J Orthopsychiatry 11:92–103. Bradley C (1937). The behavior of children receiving Benzedrine. Am J Psychiatry 94:577–85. Bradley C, Bowen M (1941). Amphetamine (Benzedrine) therapy of children’s behavior disorders. Am J Orthopsychiatry 11:92–103.

26

C.W. Popper

Bradley C, Bowen M (1940). School performance of children receiving amphetamine (benzedrine) sulfate. Am J Orthopsychiatry 10:782–8. Bradley C, Green E (1940). Psychometric performance of children receiving amphetamine (benzedrine) sulfate. Am J Psychiatry 97:388–94. Brown WT, Solomon CI (1942). Delinquency and the electroencephalogram. Am J Psychiatry 98:499–503. Burgess JR, Stevens L, Zhang W, Peck L (2000). Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder. Am J Clin Nutr 71:327–30. Campbell M, Green WH, Deutsch SI (1985). Child and Adolescent Psychopharmacology. Beverly Hills, CA: Sage Publications. Cantwell DP, Swanson J, Connor DF (1997). Adverse response to clonidine (case study). J Am Acad Child Adolesc Psychiatry 36:539–44. Carlson CL, Pelham WE, Milich R, Dixon J (1992). Single and combined effects of methylphenidate and behavior therapy on the classroom performance of children with attention-deficit hyperactivity disorder. J Abnorm Child Psychol 20:213–32. Carlson GA, Rapport MD, Kelly KL, Pataki CS (1995). Methylphenidate and desipramine in hospitalized children with comorbid behavior and mood disorders: separate and combined effects on behavior and mood. J Child Adolesc Psychopharmacol 5:191–204. Carr V, Dorrington C, Schrader G, Wale J (1983). The use of ECT for mania in childhood bipolar disorder. Br J Psychiatry 143:411–15. Chalas G, Brauer W (1963). Tourette’s disease: relief of symptoms with R 1625. Am J Psychiatry 120:283–4. Chapel J, Brown N, Jenkins R (1964). Tourette’s disease: symptomatic relief with haloperidol. Am J Psychiatry 121:608–10. Cizadlo BC, Wheaton A (1995). ECT treatment of a young girl with catatonia (case study). J Am Acad Child Adolesc Psychiatry 34:332–5. Cohen MJ (1979). Drugs and the Special Child. New York: Gardner Press. Cohen DJ, Detlor J, Young JG, Shaywitz BA (1980). Clonidine ameliorates Gilles de la Tourette syndrome. Arch Gen Psychiatry 37:1350–7. Cohen DJ, Young JG, Nathanson JA, Shaywitz BA (1979). Clonidine in Tourette’s syndrome. Lancet 8142(2):551–3. Colquhoun I, Bunday S (1981). A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypoth 7:673–9. Conners CK (Ed.) (1974). Clinical Use of Stimulant Drugs in Children. Proceedings of a Symposium Held at Key Biscayne, FL, 1972 (Excerpta Medica 12). New York: American Elsevier. Cutts KK, Jasper HH (1939) Effect of benzedrine sulfate and phenobarbital on behavior problems of children with abnormal electroencephalograms. Arch Neurol Psychiatry 41:1138–45. Donnelly M, Zametkin AJ, Rapoport JL et al. (1986). Treatment of childhood hyperactivity with desipramine: plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response. Clin Pharmacol Ther 39:72–81. Dulcan MK, Benton T (Eds.) (1999). Helping Parents, Youth, and Teachers Understand Medications for Behavioral and Emotional Problems: A Resource Book of Medication Information Handouts. Washing-

27


ton, DC: American Psychiatric Press. Effron AS, Freedman AM (1953). The treatment of behavior disorders in children with Benadryl: a preliminary report. J Pediatr 42:261–6. Eisenberg L, Gilbert A, Cytryn L, Molling P (1961). The effectiveness of psychotherapy alone and in conjunction with perphenazine or placebo in the treatment of neurotic and hyperkinetic children. Am J Psychiatry 117:1088–93. Elliott GR, Popper CW (1991). Tricyclic antidepressants: the QT interval and other cardiovascular parameters (editorial). J Child Adolesc Psychopharmacol 1:187–9. Elliott GR, Popper CW, Frazier SH (1990). Tricyclic antidepressants: a risk for 6–9 year olds? (editorial). J Child Adolesc Psychopharmacol 1:105–6. El Shanti H, Lidral AC, Jarrah N, Druhan L, Ajlouni K (2000). Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am J Hum Genet 66:1229–36. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Carmody T, Mayes TL (1998). Fluoxetine in child and adolescent depression: acute and maintenance treatment. Depress Anxiety 7:32–9. Emslie GJ, Rush AJ, Weinberg WA et al. (1997). A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–7. Evans KL, Lawson D, Meitinger T, Blackwood DH, Porteous DJ (2000). Mutational analysis of the Wolfram syndrome gene in two families with chromosome 4p-linked bipolar affective disorder. Am J Med Genet 96:158–60. Evidence-Based Medicine Working Group (1992). Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA 268:2420–5. Feinstein AR, Horwitz RI (1997). Problems in the ‘‘evidence’’ of ‘‘evidence-based medicine’’. Am J Med 103:529–35. Fenichel RR (1995). Combining methylphenidate and clonidine: the role of post-marketing surveillance. J Child Adolesc Psychopharmacol 5:155–6. Findling RL, Blumer JL (Eds.) (1998). Child and Adolescent Psychopharmacology. Pediatr Clin North Amer 45:1021–1286. Findling RL, Reed MD, Blumer JL (1999). Pharmacological treatment of depression in children and adolescents. Paediatr Drugs 1:161–82. Fish B (1960a). Drug therapy in child psychiatry: pharmacological aspects. Compr Psychiatry 1:212–27. Fish B (1960b). Drug therapy in child psychiatry: psychological aspects. Compr Psychiatry 1:55–61. Fisher S (1959). Child Research in Psychopharmacology. Springfield, IL: Charles C. Thomas. Fisman S, Reniers D, Diaz P (1996). Erythromycin interaction with risperidone and clomipramine in an adolescent. J Child Adolesc Psychopharmacol 6:133–8. Food and Drug Administration, Department of Health and Human Services, United States Government (1997). The Food and Drug Administration Modernization Act of 1997. Federal Register 62(225):62239–494, November 21. Food and Drug Administration, Department of Health and Human Services, United States Government (1992). Specific Requirements on Content and Format of Labeling for Human Prescription Drugs; Proposed Revision of ‘‘Pediatric Use’’ Subsection in the Labeling [21 CFR Part 201]. Federal Register 57(201): 47423–7, October 16.

28

C.W. Popper

Food and Drug Administration, Department of Health and Human Services, United States Government (1982). Use of approved drugs for unlabeled indications. FDA Drug Bull 12:4–5. Food and Drug Administration (1979). Guidelines for the Clinical Evaluation of Psychoactive Drugs in Infants and Children. Washington, DC: United States Government Printing Office. Freed H (1962). The Chemistry and Therapy of Behavior Disorders in Children. Springfield, IL: CC Thomas. Freedman AM (1958). Drug therapy in behavior disorders. Pediatr Clin North Am 5:573–94. Freedman AM, Effron AS, Bender L (1955). Pharmacotherapy in children with psychiatric illness. J Nerv Ment Dis 122:479–86. Frommer EA (1972). Indications for antidepressant treatment with special reference to depressed preschool children. In: Depressive States in Childhood and Adolescence, Ed. AL Annell. New York: John Wiley & Sons, pp. 449–54. Frommer EA (1967). Treatment of childhood depression with antidepressant drugs. BMJ 1:729– 32. Frommer DA, Kulig KW, Marx JA, Rumack B (1987). Tricyclic antidepressant overdose: a review. J Am Med Assoc 257:521–6. Furlong RA, Ho LW, Rubinsztein JS et al. (1999). A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases. Neurosci Lett 277:123–6. Gadow KD (1997). An overview of three decades of research in pediatric psychopharmacoepidemiology. J Child Adolesc Psychopharmacol 7:215–36. Gadow KD (1986a). Children on Medication (Vol. 1): Hyperactivity, Learning Disabilities, and Mental Retardation. Austin, TX: PRO-ED (initially published by College-Hill Press, Baltimore). Gadow KD (1986b). Children on Medication (Vol. 2): Epilepsy, Emotional Disturbance, and Adolescent Disorders. Austin, TX: PRO-ED (initially published by College-Hill Press, Baltimore). Gadow KD (1979). Children on Medication: A Primer for School Personnel. Reston, VA: Council for Exceptional Children. Gadow KD, Gadow JL (Eds.) (1981). Psychosocial Aspects of Drug Treatment for Hyperactivity. Boulder, CO: Westview Press. Gadow KD, Poling AG (1988). Pharmacotherapy and Mental Retardation. Austin, TX: PRO-ED (initially published by College-Hill Press, Baltimore). Garfinkel B, Wender PH, Sloman L, O’Neill I (1983). Tricyclic antidepressant and methylphenidate treatment of attention deficit disorder in children. J Am Acad Child Psychiatry 22:343–8. Geller B, Cooper TB, Sun K et al. (1998a). Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 37:171–8. Geller B, Cooper TB, Zimerman B et al. (1998b). Lithium for prepubertal depressed children with family history predictions of future bipolarity: a double-blind, placebo-controlled study. J Affect Disord 51:165–75. Ghaziuddin N, King CA, Naylor MW et al. (1996). Electroconvulsive treatment in adolescents with pharmacotherapy-refractory depression. J Child Adolesc Psychopharmacol 6:259–71. Gillberg C, Melander H, von Knorring A et al. (1997). Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. Arch Gen Psychiatry 54:857–64.

29


Gittelman-Klein R (1975). Recent Advances in Child Psychopharmacology. New York: Human Sciences Press. Gittelman-Klein R, Klein DF (1973). School phobia: diagnostic considerations in the light of imipramine effects. J Nerv Ment Dis 156:199–215. Gittelman-Klein R, Klein DF (1971). Controlled imipramine treatment of school phobia. Arch Gen Psychiatry 25:204–7. Gittelman Klein R, Klein DF et al. (1976). Relative efficacy of methylphenidate and behavior modification in hyperkinetic children: an interim report. J Abnorm Child Psychol 4:361–79. Graham P (2000). Treatment interventions and findings from research: bridging the chasm in child psychiatry. Br J Psychiatry 176:414–19 [discussion 420]. Green WH (1995). Child and Adolescent Clinical Psychopharmacology, 2nd edn. Baltimore, MD: Williams and Wilkins. Green WH (1991). Child and Adolescent Clinical Psychopharmacology, 1st edn. Baltimore, MD: Williams and Wilkins. Greenhill LL, Osman BB (Eds.) (1999). Ritalin: Theory and Practice, 2nd edn. New York: Mary Ann Liebert. Greenhill LL, Osman BB (Eds.) (1991). Ritalin: Theory and Patient Management, 1st edn. New York: Mary Ann Liebert. Gualtieri CT, Evans RW (1988). Motor performance in hyperactive children treated with imipramine. Percept Motor Skills 66:763–9. Gualtieri CT, Keenan PA, Chandler M (1991). Clinical and neuropsychological effects of desipramine in children with attention deficit hyperactivity disorder. J Clin Psychopharmacol 11:155–9. Guttmacher LB, Cretella H (1988). Electroconvulsive therapy in one child and three adolescents. J Clin Psychiatry 49:20–3. Hamazaki T, Sawazaki S, Itomura M et al. (1996). The effect of docosahexaenoic acid on aggression in young adults: a placebo-controlled double-blind trial. J Clin Invest 97:1129–34. Hardy C, Khanim F, Torres R et al. (1999). Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet 65:1279–90. Hazell P, O’Connell D, Heathcote D, Robertson J, Henry D (1995). Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. BMJ 310:897–901. Heinen F, Glocker FX, Fietzek U, Meyer BU, Lu¨cking CH, Korinthenberg R (1998). Absence of transcallosal inhibition following focal magnetic stimulation in preschool children. Ann Neurol 43:608–12. Heinen F, Petersen H, Fietzek U, Mall V, Schulte Mo¨nting J, Korinthenberg R (1997). Transcranial magnetic stimulation in patients with Rett syndrome: preliminary results. Eur Child Adolesc Psychiatry 6(Suppl 1):61–3. Heuyer G, Gerard G, Galibert J (1953). Traitement de l’excitation psycho-motrice chez l’enfant par le 4560 R.P. Arch Franç Pediatr 9:961–3. Hickie IB, Scott EM, Davenport TA (1999). Enhancing the evidence base for clinical psychiatry: are practice surveys a useful tool? Med J Aust 171:315–18.

30

C.W. Popper

Hill MA, Courvoisie H, Dawkins K, Nofal P, Thomas B (1997). ECT for the treatment of intractable mania in two prepubertal male children. Convuls Ther 13:74–82. Hoehn-Saric R, Lipsey JR, McLeod DR (1990). Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol 10:343–5. Horrigan JP, Sikich L, Courvoisie HE, Barnhill LJ (1998). Alternative therapies in the child psychiatric clinic. J Child Adolesc Psychopharmacol 8:249–50. Hunt BR, Frank T, Krish TP (1956). Chlorpromazine in the treatment of severe emotional disease of children. Am J Dis Child 91: 268–77. Hunt RD, Minderaa RB, Cohen DJ (1985). Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial. J Am Acad Child Psychiatry 24:617–29. Ialongo NS, Horn WF, Pascoe JM et al. (1993). The effects of a multimodal intervention with attention-deficit hyperactivity disorder children: a 9-month follow-up. J Am Acad Child Adolesc Psychiatry 32:182–9. Inoue H, Tanizawa Y, Wasson J et al. (1998). A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nature Genet 20:143–8. Isoja¨rvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyla¨ VV (1996). Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 39:579–84. Isoja¨rvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla¨ VV (1993). Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–8. Isoja¨rvi JI, Ra¨ttya¨ J, Myllyla¨ VV et al. (1998). Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 43:446–51. Jensen PS, Elliott GR (Eds.) (1992). Why don’t antidepressants seem to work for depressed adolescents? (Special section) J Child Adolesc Psychopharmacol 2:7–45. Jensen PS, Kettle L, Roper MT et al. (1999). Are stimulants overprescribed? Treatment of ADHD in four U.S. communities. J Am Acad Child Adolesc Psychiatry 38:797–804. Kanner L (1935). Child Psychiatry. Baltimore, MD: Charles C. Thomas. Kaplan BJ, Simpson JSA, Ferre RC, Gorman CP, McMullen D (2000). Successful treatment of bipolar disorder with a nutritional supplement: ten cases (abstract). Proceedings of the 50th Annual Meeting of the Canadian Psychiatric Association, October, 2000, Victoria, British Colombia, p. 61. Keepers GA, Clappison VJ, Casey DE (1983). Initial anticholinergic prophylaxis for neurolepticinduced extrapyramidal syndromes. Arch Gen Psychiatry 40:1113–17. Kelly D, Guirguis W, Frommer E, Mitchell-Heggs N, Sargeant W. (1970). Treatment of phobic states with antidepressants. Br J Psychiatry 116:387–98. King RA, Riddle MA, Chappell P et al. (1991). Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 30:179–86. Klein DF, Gittelman R, Quitkin F, Rifkin A (1980). Diagnosis and Drug Treatment of Psychiatric Disorders: Adults and Children. Baltimore, MD: Williams and Wilkins. Klein RG, Mannuzza S, Koplewicz HS et al. (1998). Adolescent depression: controlled desipra-

31


mine treatment and atypical features. Depress Anxiety 7:15–31. Kraft IA, Ardali C, Duffy JH, Hart JT, Pearce P (1965). A clinical study of chlordiazepoxide used in psychiatric disorders of children. Int J Neuropsychiatry 1:433–7. Kraft IA, Marcus IM, Wilson W, Swander DV, Rumage NS, Schulhofer E (1959). Methodological problems in studying the effect of tranquilizers in children with specific reference to meprobamate. South Med J 52:179–85. Krakowski AJ (1965). Amitriptyline in treatment of hyperkinetic children: A double blind study. Psychosomatics 6:355–60. Krasnegor NA, Gray DB, Thompson T (Eds.) (1986). Developmental Behavioral Pharmacology. Hillsdale, NJ: Erlbaum. Kuekes ED, Wigg C, Bryant S, Meyer WJ (1992). Hypertension is a risk in adolescents treated with imipramine. J Child Adolesc Psychopharmacol 2:241–8. Kupietz S, Balka E (1976). Alterations in vigilance performance of children receiving amitriptyline and methylphenidate. Psychopharmacology 50:29–33. Kutcher S (Ed.) (2001). Practical Child and Adolescent Psychopharmacology. Cambridge: Cambridge University Press. Kutcher SP (Ed.) (1997). Child and Adolescent Psychopharmacology Newsletter. New York: Guilford Press. Kutcher S, Fletcher J (Eds.) (1997). Child and Adolescent Psychopharmacology, 1st edn. Philadelphia, PA: W.B. Saunders. Kutcher S, Robertson HA (1995). Electroconvulsive therapy in treatment-resistant bipolar youth. J Child Adolesc Psychopharmacol 5:167–75. Kye CH, Waterman GS, Ryan ND et al. (1996). A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression. J Am Acad Child Adolesc Psychiatry 35:1139–44. Laughren TP (1996). Regulatory issues in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry 35:1276–82. LeFever GB, Dawson KV, Morrow AL (1999). The extent of drug therapy for attention deficithyperactivity disorder among children in public schools. Am J Public Health 89:1359–64. Leonard HL (Ed.) (1999). The Brown University Child and Adolescent Psychopharmacology Update (Newsletter). Providence, RI: Manisses Communications Group. Leonard HL, Meyer MC, Swedo SE et al. (1995). Electrocardiographic changes during desipramine and clomipramine treatment in children and adolescents. J Am Acad Child Adolesc Psychiatry 34:1460–8. Lexchin J (1997). Enforcement of codes governing pharmaceutical promotion: what happens when companies breach advertising guidelines? CMAJ 156:351–6. Li LM, Russo M, O’Donoghue MF, Duncan JS, Sander JW (1996). Allergic skin rash with lamotrigine and concomitant valproate therapy: evidence for an increased risk. Arq Neuropsiquiat 54:47–9. Lindsley DB, Henry CE (1942). The effects of drugs on behavior and the electroencephalograms of children with behavior disorders. Psychosom Med 4:140–9. Lipsky MS, Taylor CA (1997). The opinions and experiences of family physicians regarding

32

C.W. Popper

direct-to-consumer advertising. J Fam Pract 45:495–9. Litchfield HR (1957). Clinical evaluation of meprobamate in disturbed and prepsychotic children. Ann NY Acad Sci 67:828–31. Lucas AP, Lockett HJ, Grimm F (1965). Amitriptyline in childhood depression. Dis Nerv Sys 28:105–13. Lucas AR (1964). Gilles de la Tourette’s disease in children: treatment with phenothiazine drugs. Am J Psychiatry 121:606–8. MacLean REG (1960). Imipramine hydrochloride (Tofranil) and enuresis. Am J Psychiatry 117:551. Mandoki M (1995). Risperidone treatment of children and adolescents: increased risk of extrapyramidal side effects? J Child Adolesc Psychopharmacol 5:49–67. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL (1997). Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull 33:149–54. Matarazzo EB (1992). Tourette’s syndrome treated with ACTH and prednisone: reports of two cases. J Child Adolesc Psychopharmacol 2:215–26. Maynard R (1970). Omaha pupils given ‘‘behavior’’ drugs. Washington Post, June 29. Mendlewicz J, van Praag HM (Eds.) (1978). Childhood Psychopharmacology: Current Concepts, Symposium on Childhood Psychopharmacology, Amsterdam, October 1977. New York: S Karger AG. Messenheimer JA (1998). Rash in adult and pediatric patients treated with lamotrigine. Can J Neurol Sci 25:S14–18. Middle F, Jones I, McCandless F et al. (2000). Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene. Am J Med Genet 96:154–7. Mitchell EA, Aman MG, Turbott SH, Manku M (1987). Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr 26:406–11. Molitch M, Eccles AK (1937). The effect of benzedrine sulfate on the intelligence scores of children. Am J Psychiatry 94:587–90. Molitch M, Sullivan JP (1937). The effect of benzedrine sulfate on children taking the New Stanford Achievement Test. Am J Orthopsychiatry 7:519–22. MTA Cooperative Group (1999a). A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 56:1073–86. MTA Cooperative Group (1999b). Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the Multimodal Treatment Study of children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1088–96. National Institute of Mental Health, Department of Health, Education, and Welfare, United States (1973). Special Issue on Pharmacotherapy of Children. Psychopharmacol Bull 9:1–241. Nezu A, Kimura S, Ohtsuki N, Tanaka M (1997). Transcranial magnetic stimulation in benign childhood epilepsy with centro-temporal spikes. Brain Dev 19:134–7. Nissen G, Eggers C, Martinius J (1984). Kinder- und Jugendpsychiatrische Pharmakotherapie in Klinik und Praxis. Berlin: Springer-Verlag. Nutt D (2000). Child and Adolescent Psychopharmacology. London: Martin Dunitz. Ohtsuki T, Ishiguro H, Yoshikawa T, Arinami T (2000). WFS1 gene mutation search in

33


depressive patients: detection of five missense polymorphisms but no association with depression or bipolar affective disorder. J Affect Disord 58:11–17. Owen MJ (1998). Psychiatric disorders in Wolfram syndrome heterozygotes. Mol Psychiatry 3:12–13. Papatheodorou G, Kutcher S (1995). The effect of adjunctive light therapy on ameliorating breakthrough depressive symptoms in adolescent-onset bipolar disorder. J Psychiatry Neurosci 20:226–32. Pataki CD, Carlson GA, Kelly KL, Rapport MD, Biancaniello TM (1993). Side effects of methylphenidate and desipramine alone and in combination in children. J Am Acad Child Adolesc Psychiatry 32:1065–72. Pelham WE, Carlson C, Sams SE, Vallano G, Dixon MJ, Hoza B (1993). Separate and combined effects of methylphenidate and behavior modification on boys with attention deficit-hyperactivity disorder in the classroom. J Consult Clin Psychol 61:506–15. Pines WL (1998). Direct-to-consumer promotion: an industry perspective. Clin Ther 20(Suppl C):C96–103. Popper C (1995a). Balancing knowledge and judgment: a clinician looks at new developments in child and adolescent psychopharmacology. Special Issue: Pediatric Psychopharmacology II, ed. MA Riddle. Child Adolesc Psychiatr Clin North Amer 4:483–513. Popper C (Ed.) (1987a). Psychiatric Pharmacosciences of Children and Adolescents. Washington, DC American Psychiatric Press. Popper CW (1995b). Combining methylphenidate and clonidine: pharmacologic questions and news reports about sudden death. J Child Adolesc Psychopharmacol 5:157–66. Popper CW (1994). Desipramine deaths may be adrenergic (abstract). New Research Program and Abstracts, Annual Meeting of the American Psychiatric Association, p. 182. Popper CW (1990). Therapeutic empiricism and therapeutic basics. J Child Adolesc Psychopharmacol 1:3–5. Popper CW (1987b). Medical unknowns and ethical consent: prescribing psychotropic medication for children in the face of uncertainty. In Psychiatric Pharmacosciences of Children and Adolescents, ed. CW Popper. Washington, DC: American Psychiatric Press, pp. 127–61. Popper CW, Zimnitzky B (1995). Sudden death putatively related to desipramine treatment in youth: a fifth case and a review of speculative mechanisms. J Child Adolesc Psychopharmacol 5:283–300. Popper CW, Elliott GR (1990). Sudden death and tricyclic antidepressants: clinical considerations for children. J Child Adolesc Psychopharmacol 1:125–32. Poussaint AF, Ditman KS (1965). A controlled study of imipramine (Tofranil) in the treatment of childhood enuresis. J Pediatr 67:283–90. Puente RM (1976). The use of carbamazepine in the treatment of behavioral disorders in children. In Epileptic Seizures – Behavior – Pain, ed. W Birkmayer. Berne: Hans Huber, pp. 243– 52. Puig-Antich J, Blau S, Marx N, Greenhill LL, Chambers W (1978). Prepubertal major depressive disorder: a pilot study. J Am Acad Child Psychiatry 17:695–707. Puig-Antich J, Perel JM, Lupatkin W et al. (1987). Imipramine in prepubertal major depressive

34

C.W. Popper

disorders. Arch Gen Psych 44:81–9. Rapoport J (1965). Childhood behavior and learning problems treated with imipramine. Int J Neuropsychiatry 1:635–42. Rapoport JL, Conners CK, Reatig N (Eds.) (1985). Rating scales and assessment instruments for use in pediatric psychopharmacology research (Special Issue). Psychopharmacol Bull 21:713– 1125. Rapoport JL, Quinn PO, Bradbard G, Riddle KD, Brooks E (1974). Imipramine and methylphenidate treatments of hyperactive boys: a double-blind comparison. Arch Gen Psychiatry 30:789– 93. Rapport MD, Carlson GA, Kelly KL, Pataki CS (1993). Methylphenidate and desipramine in hospitalized children: II. Separate and combined effects on cognitive function. J Am Acad Child Adolesc Psychiatry 32:333–42. Raskin A, Robinson DS, Levine J (Eds.) (1981). Age and the Pharmacology of Psychoactive Drugs. New York: Elsevier. Reiss S, Aman MG (1997). Psychotropic Medications and Developmental Disabilities: The International Consensus Handbook, Vol. 1 ( J Intellect Disabil Res). Columbus, OH: Ohio State University Nisonger Center. Remschmidt H (1976). The psychotropic effect of carbamazepine in non-epileptic patients with particular reference to problems posed by clinical studies in children with behavior disorders. In Epileptic Seizures – Behavior – Pain, ed. W Birkmayer. Berne: Hans Huber, pp. 235–42. Richardson MA, Haugland G (Eds.) (1995). Use of Neuroleptics in Children. Washington, DC: American Psychiatric Press. Riddle MA, Geller B, Ryan N (1993). Another sudden death in a child treated with desipramine. J Am Acad Child Adolesc Psychiatry 32:792–7. Riddle MA, King RA, Hardin MT et al. (1991a). Behavioral side effects of fluoxetine in children and adolescents. J Child Adolesc Psychopharmacol 1:193–8. Riddle MA, Nelson JC, Kleinman CS et al. (1991b). Sudden death in children receiving Norpramin“: a review of three reported cases and commentary. J Am Acad Child Adolesc Psychiatry 30:104–8. Riddle MR (Ed.) (1995). Pediatric psychopharmacology I and II. Child Adolesc Psychiatr Clin North Am 4:1–520. Robinowitz CB, Wiener J (1990). Learning about innovations in clinical treatment. J Child Adolesc Psychopharmacol 1:165–8. Roemmelt AF (1998). Haunted Children: Rethinking Medication of Common Psychological Disorders. Albany: State University of New York Press. Rosenberg DR, Holttum J, Gershon S (1994). Textbook of Pharmacotherapy for Child and Adolescent Psychiatric Disorders. New York: Brunner/Mazel. Rosenberg D, Holttum J, Ryan N, Gershon S (1997). Pocket Guide for the Textbook of Pharmacotherapy for Child Adolescent Psychiatric Disorders. Washington, DC: Taylor and Francis (Brunner/Mazel). Rothenberger A (Ed.) (1990). Brain and Behavior in Child Psychiatry. New York: Springer-Verlag. Roughead EE, Harvey KJ, Gilbert AL (1998). Commercial detailing techniques used by pharma-

35


ceutical representatives to influence prescribing. Aust N Z J Med 28:306–10. Ryan ND, Bhatara VS, Perel JM (1999). Mood stabilizers in children and adolescents. J Am Acad Child Adolesc Psychiatry 38:529–36. Safer DJ, Zito JM, Fine EM (1996). Increased methylphenidate usage for attention deficit disorder in the 1990s. Pediatrics 98:1084–8. Saraf KR, Klein DF, Gittelman-Klein R, Gootman N, Greenhill P (1978). EKG effects of imipramine treatment in children. J Am Acad Child Psychiatry 17:60–9. Saraf KR, Klein DF, Gittelman-Klein R, Groff S (1974). Imipramine side effects in children. Psychopharmacology (Berl) 37:265–74. Schommer JC, Doucette WR, Mehta BH (1998). Rote learning after exposure to a direct-toconsumer television advertisement for a prescription drug. Clin Ther 20:617–32. Schreier H (1979). Use of propranolol in the treatment of postencephalitic psychosis. Am J Psychiatry 136:840–1. Schulterbrandt JG, Raskin A (Eds.) (1977). Depression in Childhood: Diagnosis, Treatment, and Conceptual Models. New York: Raven Press. Scruggs EE, Poling A, Mastropien MA, Gadow KD, Bialer I (Eds.) (1982). Advances in Learning and Behavioral Disabilities: Methodological Issues in Human Psychopharmacology, Volume 1. Greenwich, CT: JAI Press. Shaffer D (Ed.) (1992). Pediatric psychopharmacology. Psychiatr Clin North Am 15:1–281. Simeon JC, Dinicola VF, Ferguson HB, Copping W (1990). Adolescent depression: a placebocontrolled fluoxetine treatment study and follow-up. Prog Neuropsychopharm Biol Psychiatry 14:791–5. Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED, Denckla MB (1995). The treatment of attention-deficit hyperactivity disorder in Tourette’s syndrome: a double-blind placebocontrolled study with clonidine and desipramine. Pediatrics 95:74–81. Skynner ACR (1961). Effects of chlordiazepoxide. Lancet 7186:1110. Sokol MS, Gray NS (1997). An infection-triggered, autoimmune subtype of anorexia nervosa. J Am Acad Child Adolesc Psychiatry 36:1128–33. Spencer T, Biederman J, Wilens T, Harding M, O’Donnell D, Griffin S (1996). Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry 35:409–32. Spiel W (1976). Therapie in der Kinder- und Jugendpsychiatrie. Stuttgart: Thieme. Stevens LJ, Zentall SS, Abate ML, Kuczek T, Burgess JR (1996). Omega-3 fatty acids in boys with behavior, learning, and health problems. Physiol Behav 59:915–20. Stevens LJ, Zentall SS, Deck JL (1995). Essential fatty acid metabolism in boys with attentiondeficit hyperactivity disorder. Am J Clin Nutr 62:761–8. Stoll AL, Locke CA, Marangell LB, Severus WE (1999a). Omega-3 fatty acids and bipolar disorder: a review. Prostaglandins Leukot Essent Fatty Acids 60:329–37. Stoll AL, Severus WE, Freeman MP et al. (1999b). Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56:407–12. Swedo SE (1994). Sydenham’s chorea: a model for childhood autoimmune neuropsychiatric disorders. JAMA 272:1788–91.

36

C.W. Popper

Swedo SE, Allen AJ, Glod CA et al. (1997). A controlled trial of light therapy for the treatment of pediatric seasonal affective disorder. J Am Acad Child Adolesc Psychiatry 36:816–21. Swedo SE, Leonard HL, Garvey M et al. (1998). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 154:264–71. Swift RG, Polymeropoulos MH, Torres R, Swift M (1998). Predisposition of Wolfram syndrome heterozygotes to psychiatric illness. Mol Psychiatry 3:86–91. Talbot MW (1955). The use of reserpine in irritable and hypertonic infants. Ann NY Acad Sci 61:188–97. Theesen KA (1995). The Handbook of Psychiatric Drug Therapy for Children and Adolescents. Binghamton, NY: Haworth Press. Toren P, Laor N, Weizman A (1998). Use of atypical neuroleptics in child and adolescent psychiatry. J Clin Psychiatry 59:644–56. Tsao JC (1997). Informational and symbolic content of over-the-counter drug advertising on television. J Drug Educ 27:173–97. Ucle´s P, Lorente S, Rosa F (1996). Neurophysiological methods testing the psychoneural basis of attention deficit hyperactivity disorder. Childs Nerv Syst 12:215–17. Van Hasselt VB, Hersen M (Eds.) (1993). Handbook of Behavior Therapy and Pharmacotherapy for Children: A Comparative Analysis. Needham Heights, MA: Allyn and Bacon. Van Krevelen DA, Van Voorst JA (1959). Lithium in der Behandlung einer Psychose unklarer Genese bei einem Jugendlichen (Lithium in the treatment of a psychosis of unknown etiology in a young person). Acta Paeopsychiatry 26:148–52. Varley CK, McClellan J (1997). Two additional sudden deaths with tricyclic antidepressants (case study). J Am Acad Child Adolesc Psychiatry 36:390–4. Voss R (1987). Anpassung auf Rezept: die fortschreitende Medizinisierung auffa¨lligen Verhaltens von Kindern und Jugendlichen. Stuttgart: E Klett-Cotta. Waizer J, Hoffman SP, Polizos P, Engelhardt D (1974). Outpatient treatment of hyperactive school children with imipramine. Am J Psychiatry 131:587–91. Walker CF, Kirkpatrick BB (1947). Dilantin treatment for behavior problem children with abnormal electroencephalograms. Am J Psychiatry 103:484–92. Walkup JT (1994). A differential diagnosis of the adverse behavioral effects of fluoxetine. Am Acad Child Adolesc Psychiatry News 25: 28–30. Walkup JT, Cruz K, Kane S, Geller B (1998). The future of pediatric psychopharmacology. Child Psychiatr Clin North Am 5:1265–78. Walsh BT (Ed.) (1998). Child Psychopharmacology. Washington, DC: American Psychiatric Press. Weizman A, Weizman R (Eds.) (1990). Application of Basic Neuroscience to Child Psychiatry. New York: Plenum Medical Books. Werry JS (Ed.) (1978). Pediatric Psychopharmacology: The use of behavior modifying drugs in children. New York: Brunner/Mazel. Werry JS, Aman MG (Eds.) (1999). Practitioner’s Guide to Psychoactive Drugs for Children and Adolescents, 2nd edn. New York: Plenum Press. Werry JS, Aman MG (Eds.) (1993). Practitioner’s Guide to Psychoactive Drugs for Children and

37


Adolescents. New York: Plenum Press. Werry JS, Aman MG, Diamond E (1980). Imipramine and methylphenidate in hyperactive children. J Child Psychol Psychiatry 21:27–35. White JH (1977). Pediatric Psychopharmacology: A Practical Guide to Clinical Application. Baltimore, MD: Williams and Wilkins. Wiener JM (Ed.) (1995). Diagnosis and Psychopharmacology of Childhood and Adolescent Disorders, 2nd edn. New York: John Wiley. Wiener JM (Ed.) (1985). Diagnosis and Psychopharmacology of Childhood and Adolescent Disorders. New York: John Wiley. Wiener JM (Ed.) (1977). Psychopharmacology in Childhood and Adolescence. New York: Basic Books. Wilens TE (1998). Straight Talk About Psychiatric Medications for Kids. New York: Guilford Press. Williams DT, Mehl R, Yudofsky S, Adams D, Roseman B (1982). The effect of propranolol on uncontrolled rage outbursts in children and adolescents with organic brain dysfunction. J Am Acad Child Psychiatry 21:129–35. Winsberg BG, Bialer I, Kupietz S, Tobias J (1972). Effects of imipramine and dextroamphetamine on behavior of neuropsychiatrically impaired children. Am J Psychiatry 128:1425–31. Yellin AM, Spring C, Greenberg LM (1978). Effects of imipramine and methylphenidate on behavior of hyperactive children. Res Commun Psychol Psychiatry Behav 3:15–25. Yepes LE, Balka EB, Winsberg BG, Bialer I (1977). Amitriptyline and methylphenidate treatment of behaviorally disordered children. J Child Psychol Psychiatry 18:39–52. Zimnitzky B, Popper CW (1994). A fifth case of sudden death in a child taking desipramine (abstract). New Research Program and Abstracts, Annual Meeting of the American Psychiatric Association, p. 181. Zito JM, Safer DJ, Riddle MA, Johnson RE, Speedie SM, Fox M (1998). Prevalence variations in psychotropic treatment of children. J Child Adolesc Psychopharmacol 8:99–105.

2 Developmental psychopharmacology Normand Carrey, Paul Mendella, Frank MacMaster, and Stan Kutcher Maritime Psychiatry, IWK Health Centre, Halifax, Canada

Introduction Developmental psychopharmacology takes place within the context of developmental neurobiology. Normal maturation of the brain is characterized by complex anatomic, molecular, and organizational changes which are required to prepare the individual for optimal adaptive behavior (Chugani et al., 1996). The practicing clinician should strive to understand evolving psychopathology and psychopharmacologic treatments within this context as both may affect central nervous system (CNS) developmental processes. Advances in our understanding of brain development in experiments derived from both animals and humans have started to shed some light on certain underlying principles which could serve as the rational basis for developmental psychopharmacology. In this chapter, we will review briefly the normal development of the CNS, developmental aspects of neurotransmitters and receptors, developmental neuroimaging, and experimental studies involving psychotropic compounds in young animals.

Microdevelopment Models and concepts

It is well recognized that various neuroanatomic regions and neurotransmitter systems develop at different rates and mature at different times (Teicher and Baldessarini, 1987). Neural development can be traced through four overlapping processes: cell birth (neurogenesis), cell migration, formation of connectivity (including elaboration of processes, synapse formation, cell death, and axonal regression), and myelination (Insel, 1995). In many areas of the immature brain, more neurons and neurites are produced than in the mature brain. Significant numbers of neurons die prenatally whereas neurite elimination goes on at least until late childhood or early adolescence (Huttenlocher, 1979; Rakic et al., 1986), with myelination extending across the life cycle (Benes, 1998; 38

39


Yakovlev and Lecours, 1967). Although there are variations across mammalian species as to the exact timing of these events, all species follow the basic pattern of overshoot (overproduction) followed by widespread pruning of both neurons and cell processes (Insel, 1995). Much of this ‘‘pruning’’ occurs during that period of development corresponding to early childhood. In adolescence, further pruning occurs as well as other organizational changes of a qualitatively different nature. For example, Andersen et al. (1997) have noted that D1 and D2 receptors in the male rat striatum are at their highest levels at day 40 (corresponding to puberty), with receptors pruned to adult levels subsequently. Plasticity and sensitive periods

The complementary concepts of brain plasticity and sensitive periods are two important frameworks which inform our understanding of many aspects of brain development. Plasticity is conceptualized as the brain’s ability to shape itself in response to environmental or chemical input during the sensitive period (the period during which experience can alter neural representation before so-called hard wiring occurs) and also as the ability to compensate for cortical damage by ipsilateral or contralateral reconnections. An example of experience-dependent plasticity in development is the study by Hubel et al. (1977) demonstrating that monocular deprivation leads to lasting changes in ocular dominance columns in the cortex. Similarly, levels of neurotransmitters can be developmentally programmed to alter during sensitive periods, as shown by transiently elevated levels of N-methyl-D-aspartate (NMDA) receptors in the visual cortex of kittens during the period critical for experiencedependent modification of the cortex (Bode-Greuel and Singer, 1989). Thus, the model that emerges is that of a complex relationship between preordained changes in brain function interacting with particular environmental stimuli during specific periods of neural development. In most species studied to date, immature animals have been found to be able to sustain damage to large areas of the cerebral cortex and show remarkably little functional deficit (Chugani et al., 1996). This has been attributed to the reorganizational potential of the developing brain and is known as the Kennard effect. As a general rule, mammalian brains (because of bilateral interhemispheric connections) can re-establish connections between intact cortical areas and subcortical structures to compensate for loss of function secondary to damaged or destroyed cortical areas. Small neocortical lesions are associated with recovery mediated by intact ipsilateral brain areas, whereas larger lesions trigger compensatory changes in the contralateral hemisphere. The degree of compensation depends on: the age of the organism (the more

40

N. Carrey et al.

immature an organism is, the greater are the chances for compensation); the size and location of the lesion; and the sensitive period for the specific neural pathway in which the lesion occurred. For example, there can be near complete recovery of language function in infants whereas motor and visual functions do not recover as well with lesions of comparable size occurring at a comparable age. Different brain areas can reconfigure themselves to compensate for lost function – such as the caudate assuming the delayed response of the lesioned dorsolateral prefrontal cortex following bilateral frontal cortical lesions in neonatal monkeys (Kling and Tucker, 1967). Interestingly, at least in adults, certain medications such as the amphetamines promote recovery in reorganization after some types of brain injury (Crisostomo et al., 1988) whereas neuroleptics and antihypertensives may not. Apoptosis

Many of the intracellular events in neurons are genetically programmed to unfold as part of the developmental sequence. This has been demonstrated in studies of the nematode Caenorhabditis elegans which have demonstrated that a certain family of genes is associated with programmed cell death whereas another family of genes is associated with cellular survival (Sulston, 1976). This process of cell death or survival can be subsumed under the conceptual framework identified as ‘‘apoptosis.’’ Apoptosis is a normal part of cell development where cells may self-destruct (commit suicide) by orderly self-disassembly, avoiding an inflammatory reaction (Barnes and Mackenzie, 1999). Jacobsen et al. (1997) have identified five overlapping functions of apoptosis in animals. These are: development of functionally necessary structures; deleting functionally unnecessary structures; controlling cell numbers; eliminating abnormal or harmful cells; and producing differentiated cells without organelles. Cell homeostasis depends in part on inhibitory mechanisms responsible for stopping or delaying apoptosis such as the protein NF-kB, a protein capable of activating the transcription of specific genes as part of the molecular and cellular response to noxious stimuli. An example of normal apoptosis in the CNS is the controlled harvesting of 50% of the original complement of alpha-motor neurons occurring in the process of modeling skeletal muscle motor end units. Disturbance of the processes which regulate apoptosis is now being investigated as one of the central mechanisms in several disease processes occurring in both CNS and nonCNS disorders. These include atherosclerotic heart disease, cancer, tuberculosis, Alzheimer’s disease, diabetes, HIV-AIDS, and,

41


possibly, schizophrenia. Cell-damaging effects of some toxins and drugs such as ethanol and barbiturates which lead to hepatic dysfunction may be due to their effect on the intracellular mechanisms which regulate apoptosis. In amyotrophic lateral sclerosis, disordered apoptosis may be induced by the effect of free radicals, intracellular calcium entry, and excitatory amino acids such as glutamate and N-methyl-D-aspartate. Apoptosis of the dopaminergic neurons in the nigrostriatal pathways results in Parkinson’s disease. MPP (1-methylphenyl-pyridium), an agent used to induce Parkinson’s in experimental animals, and reserpine, which causes Parkinson’s by depleting dopamine, both induce apoptosis. Thus, factors which influence cellular survival or cell death through apoptosis contribute to brain developmental plasticity both in health and in disease. Following from this understanding of apoptosis, a variety of clinical or pathoetiologic mechanisms can be developed or understood. For example, the first human gene capable of inhibiting apoptosis was identified by Mackenzie and Korneluk in 1995 (Barnes and Mackenzie, 1999). Called NAIP (neuronal apoptosis inhibitory protein), this compound may have potential clinical applications. Microinjections of NAIP-expressing adenovirus introduced into the rat hippocampus protects populations of sensitive neurons from ischemia-induced cell death (Xu et al., 1997). From a pathoetiologic perspective, disordered apoptosis may be part of the mechanism by which extreme environmental stress such as child abuse leads to elevated corticosteroid levels, hippocampal granule cell death, and cognitive dysfunction. In the future, NAIP analogs may be used to mitigate the effects of in utero exposure to ethanol and cocaine or to offset the adverse effects of dopamine antagonists used in the treatment of childhood schizophrenia or Tourette’s syndrome. Cellular migration and growth

Many aspects of cell migration, axon outgrowth, and neural pathway formation are also under genetic control (Morilak et al., 1995). In the cortex, neurons are helped to their final destinations by an interactive scaffolding structure of radial glial cells which extend their processes to both pial and ventricular surfaces. It has been suggested that migration along these glial cells forms the developmental basis for the vertical, columnar organization of functional cortical modules in the brain. Genetic mouse mutants have been developed which show separate defects in the ability of CNS neurons to attach or detach from this radial glia scaffold (Caviness and Rakic, 1978; Hatten, 1990). In patients with dyslexia, autism, schizophrenia, and fetal alcohol syndrome, the

42

N. Carrey et al.

presence of ectopic cells and migratory arrests in postmortem tissue suggest that abnormal migration may be of pathoetiologic significance (Nowakowski, 1991). Thus, neural programming errors can result in disturbances in normal cell growth and connectivity. Axon outgrowth and pathway formation toward the final genetically predetermined destination are guided along by complex interactions between cellsurface proteins, extracellular matrix proteins, and attractant and repellant factors secreted by target regions in the brain (Dodd and Jesell, 1988; TessierLavigne et al., 1988). In Drosophila, axonal pathfinding defects have been demonstrated to arise from defects in the genes coding for the cell-adhesion proteins neuroglian and the fascilins-1, -2, and -3 (Bieber et al., 1989; Harrelson and Goodman, 1988; Snow et al., 1989; Zinn et al., 1988). The process of establishing and maintaining patterns of cell survival, cell growth, and cell connectivity is also influenced by nerve growth factors. These ‘‘target-derived neurotrophic growth factors’’ are secreted by the innervated targets of nerve fibers and are specific to neuron populations and receptors. These trophic factors are then taken up into the nerve terminal by receptors and transported retrogradely to the cell body where they may affect cell growth and differentiation. Neurons, in turn, may affect their targets anterogradely by the release of neurotransmitters and neuropeptides which seek to establish the appropriate connection points. Failure to establish connection successfully may result in cell death or inappropriate pruning. At the current time, insufficient study of these processes has occurred and the particular effects of specific tropic factors on pathoetiology or treatment of particular psychiatric disorders have not been determined. The relative contributions of intrinsic, genetically ordered processes and the effects of environmental stimuli on the outcomes of cell migration and connectivity are at this time unknown. For the clinician, however, an appreciation of the complexity of these developments and their potential for enhancing understanding of treatment and disease is necessary. Neurotransmitters

At the more microscopic level, neural development is orchestrated by a cascade of events affecting the brain’s intracellular signaling system. This involves a variety of neurotransmitters, receptors, second messengers (such as inositol, cGMP, and calcium), nerve growth factors, and neuropeptides. Many of these neural elements play a role during early CNS development that is very different than their function in the mature brain. For example, it is known that neurotransmitters and receptors are expressed at their highest levels in the immature

43


brain and in anatomic regions different than in the mature brain, even in the absence of fully functional synapses. It is important to understand their changing role as this may affect the expression of psychopathology or the response to psychopharmacologic interventions. Monoamine-secreting neurons (serotonin, noradrenaline, and dopamine) are detectable by embryonic day 13 in rats and catecholamines appear as early as gestational week 5 in humans (Zecevic and Verney, 1995). These cells distribute afferents to the cerebral cortex where their processes may play an important but time-limited role by providing an orientation target to other axons arriving later on in cortical development ( Jones, 1991). In the cortex, the serotonin (5-HT) fibers are the first afferent fibers to arrive, but the last to fully establish their innervation pattern (Lidow and Molliver, 1982). Thus, different monoamine neurons may exhibit different and unique patterns of programmed development. Species-specific patterns also exist, such as the more extensive innervation of the cerebral cortex by dopaminergic terminals in primates compared with rodents (Gaspar et al., 1989). The final outcome is that monoaminergic brainstem cells contain processes that innervate extensive areas of the brain either by synaptic contact or secretion of neurotransmitter substances into the neuropil – thus demonstrating that monoaminergic neurotransmitters have structural and functional, as well as trophic, roles in CNS development. Serotonin levels in the postnatal cortex of the young mouse are roughly twice the adult concentrations (Hohman et al., 1988). Chugani et al. (1997) examined serotonin synthesis rates, using alpha-methyl-l-tryptophan, in a pediatric population and found that from age 3 months to 3 years children demonstrated levels that were 200% higher than those found in adults. These levels remained high until age 5, when they began the decline leading toward adult levels. Conversely, depletion of serotonin from birth to postnatal days 10–20 in rats has been demonstrated to result in a permanent decrease in synaptic density and learning deficits persisting into adulthood (Mazer et al., 1997). This has led some researchers to hypothesize that serotonin in the developing brain acts as a developmental signal (Lauder et al., 1983; Whitaker-Azmitia et al., 1996). It has been proposed by these investigators that serotonin autoregulates its own development and that changes in 5-HT levels during development alter the final morphology of the 5-HT system (via inhibition of outgrowth of 5-HT terminals). Prenatal depletion of 5-HT with p-chlorophenylalanine, an irreversible inhibitor of tryptophan hydroxylase, delays the onset of neurogenesis in 5-HT target regions by delaying the onset of differentiation of raphe serotonergic neurons (Lauder and Krebs, 1976), while serotonin stimulation with 5-methoxytryptamine produces dose-dependent effects on

44

N. Carrey et al.

neurite outgrowth (Shemer et al., 1991). Development of mesencephalic dopamine neurons (targets of raphe serotonergic axons) are also delayed. 5-HT can thus be conceptualized as playing a dual role in development: autoregulation of the serotonergic neurons and development of target tissues for neurons containing other monoamine neurotransmitters. Serotonin may have effects on other neurotransmitter systems. Ascending serotonergic systems from the median and dorsal raphe innervate areas of the brain rich in dopamine neurons (Pineyro and Blier, 1999) where they regulate the firing rate and release of dopamine. In human subjects from 21 to 49 years of age, Wang et al. (1995) demonstrated a correlation between frontal 5-HT-2 decline and number of striatal dopamine D2 receptors. Liu and Lauder (1992) have shown that serotonin, through regional effects on either raphe glia or mesencephalic glia, will promote nerve growth factors affecting the maturity of serotonergic neurons or tyrosine hydroxylase neurons, respectively. Alternatively, D1 receptors have been shown to be inhibitory to growth cone motility in serotonergic terminals; if rat pups are treated prenatally with a D1 agonist, as adults they have greatly reduced serotonin-uptake sites (Whitaker-Azmitia et al., 1990). If the dopamine system is depleted in the neonate, through 6hydroxydopamine lesions in the caudate, then overgrowth of 5-HT terminals occurs (Breese et al., 1984). Interestingly, in these animals as adults, the effect of dopamine is increased whereas the effect of serotonin is decreased suggesting adaptive changes secondary to the changes in neurotransmitter level ( Jackson et al., 1988). Receptors

(1)

(2)

Neuroreceptors evolve different developmental functions as the organism matures and there is regional as well as receptor subtype specificity whose functional properties change across maturational time. Whitaker-Azmitia (1991) hypothesizes that receptors can be conceptualized as fitting into two categories or roles: Programmable receptors – these are thought to need appropriate amounts of stimulation to develop their functions. The D2 receptor is an example of this and an over- or understimulated receptor may be functionally impaired permanently. For example, in adults, chronic neuroleptic administration generally results in an increase in D2 receptors, but neonates deprived of dopamine stimulation do not show this effect (Duncan et al., 1987; Saleh and Kostrzewa 1988). Receptors that affect development – these are mostly transiently expressed receptors since they play a specific developmental role, possibly through

45


coupling with second messenger systems. The dopamine D2 receptor, absent in the frontal cortex in adult rats, is transiently expressed in the immature brain (Noisin and Thomas, 1988). Insel (1995) offers the following insights about the role of transient receptors in development: (a) receptor binding may develop independently of innervation; (b) the pattern of binding is diverse with specific brain regions showing intense binding transiently in the first to third week postnatally; and (c) the expression of binding precedes receptor–effector (second messenger) coupling. Serotonergic receptors in rats attain peak levels in fetal or early postnatal life and then decrease to adult levels (Whitaker-Azmitia, 1991). For some receptor subtypes, the highest number of receptors occurs during brain development at a time when properly functioning synapses are not present. Additionally, structurally similar receptors may be involved in different developmentally important functions; for example, in the serotonergic neuron, the 5-HT-1C receptor may regulate cell division, whereas 5-HT-1A receptors may regulate cell differentiation (Whitaker-Azmitia, 1991). The 5-HT-1A receptor subtype has been thought to play a critical role in both neuronal and glial cell growth through trophic effects on nerve growth factors. Whitaker-Azmitia and Azmitia (1994) have shown that astroglial cells promote immature neuronal growth through the secretion of S-100, a nerve growth factor, but the effect is mediated through 5-HT-1A receptors on brain astroglial cells. As the serotonergic neuron matures, the level of S-100 decreases – as does the number of 5-HT-1A receptors found on astroglia. Drugs which act as agonists to the 5-HT-1A receptor, such as 8-OH-DPAT, promote astroglial cell maturity. In the developing rat, 5-HT-2 receptor levels have been shown to increase dramatically between embryonic day 17 (E17) and postnatal day 13 (P13), and then to decline until P27 to then stabilize at adult levels. These ontogenetic variations in 5-HT-2 receptor levels have been accompanied by similar changes in 5-HT-2 mRNA (Roth et al., 1991). This developmental pattern of 5-HT-2 receptors corresponds to the pattern of innervation of the cortex, peaking at postnatal day 14 (D’Amato et al., 1987) and pruned back to adult levels around postnatal day 27. In other studies using positron emission tomography (PET) scanning of human subjects aged 21–49 years, Wang et al. (1995) have shown that 5-HT-2 receptors decrease with age in frontal cortex and striatum. This decrease over time was relatively specific as it was not found to occur at a similar rate in the occipital cortex. Gross-Isseroff et al. (1990) confirmed these findings in postmortem autoradiographic analyses of 12 healthy brains which showed sharp decreases in prefrontal and hippocampal 5-HT-2 receptors over the second and

46

N. Carrey et al.

third decade. These receptor numbers reached a minimum around age 50, but began to increase again in the sixth and seventh decade, showing the dynamic nature of receptor changes over the entire lifespan and raising implications for medication treatment including both efficacy and adverse effects. A similar developmentally sensitive role for dopamine and the dopamine receptor has also been documented. The level of hyperactivity and its persistence into adulthood is correlated positively with the degree of dopamine depletion as induced by 6-hydroxydopamine in neonate rodents (Miller et al., 1981). However, contrary to high levels of 5-HT in mouse neocortex neonatally, dopamine levels in rat forebrain slowly rise to adult levels by postnatal day 45 (Rodriguez et al., 1994). Mesencephalic levels of dopamine, however, reach adult levels prenatally, reflecting dopamine turnover in cells, whereas postnatal forebrain dopamine reflects axonal growth and synaptogenesis (Santana et al., 1992). The highest numbers of both dopamine 1 and dopamine 2 receptors occur in the immature brain in rats, baboons, and humans (Whitaker-Azmitia, 1991). The D1 receptor has been localized on growth cones which are located on the tip of the growing nerve terminal, suggesting a role in influencing neuronal differentiation and maturation (Lockerbie et al., 1988). D2 receptors are transiently expressed in the frontal cortex of the immature rat but are absent in the adult brain (Noisin and Thomas, 1988). However, if dopaminergic receptors are deprived of stimulation then permanent changes in binding or compensatory receptor expression may occur in adults, such as demonstrated when neonates are lesioned with 6-hydroxydopamine (Duncan et al., 1987). Profound depletion of forebrain dopamine by 6-hydroxydopamine in neonatal rats was associated with an 82% loss of D1 receptors, but administration of a D1 agonist abolished this effect (Gelbard et al., 1990). Gelbard and coworkers speculate that D1 receptor density may be regulated by reciprocal processes during normal development, but may fail to develop in the absence of an adequate level of stimulation. In human studies, D1 receptor density decreased 48% between childhood and adulthood (Seeman et al., 1987) and then continued to decrease throughout the life span from 20 to 72 years, in both the striatum and frontal cortex (Iyo and Yamasaki, 1993). The D2 receptor has also been shown to depend on the input of a dopamine terminal for development (Broaddus and Bennett, 1990). As a result of D2 agonist and antagonist actions, it has been shown that stimulation of D2 receptors results in increased length and branching of neurites in a subset of frontal cortical neurons (Todd, 1992). Stimulation of 5-HT-1A receptors in the same culture system resulted in a decrease in neurite branch growth. Most

47


cortical cells express 5-HT-1A receptors, whereas only a small percentage have D2 receptors. Accordingly, the same neurotransmitter may elicit different morphogenic responses in different cells depending on the receptor subtype the cell expresses and the second messenger system to which the receptor couples. In human subjects, striatal D2 receptors fell by 59% between childhood and adulthood (Seeman et al., 1987). Additionally, it has been shown that between 21 and 49 years of age striatal D2 receptors also decrease significantly with age (Iyo and Yamasaki, 1993; Wang et al., 1995). Sex effects are evident in these processes as the decrease is greater for males than for females: 43% vs. 25% (Wong et al., 1984). There are also animal data to indicate that the period of adolescence may show a unique developmental profile that differentiates this portion of the lifespan from either childhood or adulthood. These findings have suggested that, in the adolescent years, changes may occur in specific brain regions, may be preferentially directed toward specific receptor types, and may be sex sensitive. For example, Andersen et al. (1997) investigated D1 and D2 receptors in male and female rats at ages 25, 35, 40, 60, 80, 100, and 120 postnatal days in both the striatum and nucleus accumbens. Both D1 and D2 receptors were increased in striatum for males during the periadolescent period, but were pruned back as the animal matured. In the nucleus accumbens, D1 receptors dramatically increased at the onset of puberty and this increase was sustained into adulthood. In females, D1 and D2 receptors in striatum and nucleus accumbens also increased in periadolescence, although the increase was notably less than that found in males. Possibly, as a consequence of this smaller change in receptor numbers, the investigators noted that there was practically no pruning of receptors as the animals matured. The authors speculate that these receptor changes are, if not necessary, then at least permissible factors in the expression of various disorders which exhibit psychiatric symptomatology prepubertally (such as in attention-deficit/hyperactivity disorder [ADHD]/ and Tourette’s syndrome) that tend to wane after adolescence, especially in males. Amino acids and neuropeptides

The amino acid neurotransmitters GABA (gamma-aminobutyric acid) and glutamate are thought to play important roles in development because of their ubiquitous and time-sensitive distribution throughout the brain. They have been observed in two telencephalic neuron populations that demonstrate early maturation, and Cameron et al., (1998) hypothesize that their function is to direct the development of later maturing neuronal populations. That both of these neuron populations appear only transiently supports the hypothesis of a

48

N. Carrey et al.

specific developmental role in the formation of CNS structures for these two neurotransmitters. It has been further proposed that glutamate plays a role in neuron cell migration and survival, but other studies suggest a role for glutamate in controlling cell proliferation. According to Lo Turco and colleagues (1995), when nonNMDA receptors are stimulated, there is a significant decrease in proliferation (up to 60%) of cortical progenitor cells in rat cortical explants. Blockade of NMDA receptors by antagonists in the first week postnatally results in increased proliferation of granule cells in the rat dentate gyrus (Gould et al., 1994). The rat dentate gyrus, which continues to produce granule cells throughout life, apparently retains its sensitivity to NMDA antagonists in adulthood. Similarly, GABA has a multifaceted and complex role in neurodevelopment. The GABA receptor changes its role from being excitatory during childhood to becoming inhibitory during adulthood. This may help to explain the clinical observation of the increased disinhibitory effect of benzodiazepines in children. Similarly to glutamate, GABA can decrease proliferation of cortical progenitors (LoTurco et al., 1995) during a specific developmental time window. There is evidence to suggest that the GABAa receptor may exert its effect by modulating a growth factor, bFGF (fibroblast growth factor; reviewed in Cameron et al., 1998), but the clinical significance of this is not known. Similarly to the role of glutamate and GABA in development, endogenous opioid peptides inhibit CNS cell proliferation. This process is thought to be routed through a receptor only expressed during early development, the zeta receptor (Zagon and McLaughlin, 1991). Naltrexone treatment increases the total number of neurons generated postnatally in the dentate gyrus and the subventricular zone (Zagon and McLaughlin, 1986). Neuropeptides work in concert with other neurotransmitters to regulate neurogenesis. Neuropeptides and their receptors are expressed at their highest level in the immature brain as shown for substance P, oxytocin, and neurotensin which can be as high as 2000 times the adult value (Insel, 1995). Many of these peptides are expressed early on in the developing brain in regions undergoing proliferation, but some continue to be expressed postnatally and may persist into adulthood. For example, FGF or the FGF family, consisting of at least 15 members, acting through tyrosine kinase receptors, are expressed early in development and persist into adulthood in the granule layer of the hippocampal dentate gyrus and the subventricular zone lining the lateral ventricles of the forebrain (Cameron et al., 1998). A similar pattern of persistence into adulthood in regions undergoing neurogenesis has been found for

49


other peptide growth factors including epidermal growth factor, transforming growth factor-alpha and beta-2, insulin-like growth factor-1, and plateletderived growth factor (Cameron et al., 1998). The thyroid hormone T3 has also been implicated in regulating neurogenesis pre- and postnatally and into adulthood. In summary, then, a complex array of neuropeptides interacts with neurotransmitters to regulate neurogenesis. Although our understanding of their expression, interrelationships, and function is incomplete, it seems that many of these growth factors continue to function into adulthood and continue to modulate areas of the brain responsible for adaptive functioning such as the dentate gyrus of the hippocampus. Coupling

An important aspect of neurodevelopmental signaling is the coupling of neurotransmitters and receptors to second messenger systems. While later in development a cell’s survival may depend on establishing functional synapses, earlier in development transiently expressed receptors, through their coupling with second messengers, may play a role in directing development (WhitakerAzmitia, 1991). The activity level of phospholipase C, the enzyme responsible for the production of inositol phosphates, is much greater in the immature compared with the mature rat brain. Cell proliferation may be regulated through receptors that stimulate phosphotidylinositol hydrolysis whereas cellular differentiation may be regulated by receptors that stimulate adenylyl cyclase. However, not all systems operate in this manner, as it has been found that the developmental patterns of various G proteins are independent of their coupling to receptors (Insel et al., 1988). Macrodevelopment Recent advances in neuroimaging techniques have confirmed existing data on microscopic neuroanatomic growth patterns in cell processes and synapses. Hashimoto et al. (1995) used magnetic resonance (MR) spectroscopy to study 47 children ranging in age from 1 month to 18 years. Their findings demonstrated a rapid increase in the NAA/Cho (N-acetyl aspartate/choline) ratio occurring over the period from 1 month to 2–3 years in the right parietal area, after which time it increased more slowly. The increase in the right frontal area was evident until 4 years, but was slower than the right parietal area, indicating the slower maturational curve of the frontal cortex. These findings were consistent with the MR findings of Barkovich et al. (1988) and the postmortem findings of Yakovlev and Lecours (1967). van der Knaap et al. (1990) found a

50

N. Carrey et al.

similar increase in NAA/Cr (N-acetyl aspartate/creatine) and NAA/Cho and a decrease in Cho/Cr. The most powerful changes were seen by age 3, but were still evident at age 16. More recently, Pouwels et al. (1999) found an increase in NAA in gray matter while white matter remained constant during infancy and childhood. As this increase in NAA was concurrent with an increase of taurine, which plays a role in synapse formation, it was hypothesized that NAA might not just mark the presence of neurons, but the presence of functioning neurons. Additionally, these investigators found that N-acetyl-aspartyl-glutamate increased in the thalamus and white matter, while glutamate itself decreased in white matter. Creatine, choline, myo-inositol, and glutamate were found to be fairly constant during development. All of these substances are implicated in the metabolism of neural cell membrane synthesis or membrane breakdown. The ratio of creatine to phosphocreatine in these studies, however, showed longitudinal consistency and remained a constant 2:1 regardless of developmental state. Minshew and Pettegrew (1996) found a reduction of phosphomonoesters and an increase in phosphocreatine in a population ranging from adolescence to young adulthood. It was posited that this indicated a reduction in the synthesis of neural cell membranes and an increase in their breakdown. The increased phosphocreatine was hypothesized to be the result of a decrease in utilization of high-energy phosphates (thus, an increase in the metabolic pool), presumably a reflection of a reduction in synapse number, which is a change consistent with maturation. Chugani et al. (1987) studied local cerebral metabolic rates for glucose utilization (ICMRGlc) with PET in 29 children between the ages of 5 days and 15.1 years. In infants less than 5 weeks old, ICMRGlc was highest in sensorimotor cortex, thalamus, brainstem, and cerebellar vermis. By 3 months, ICMRGlc had increased in parietal, occipital, and temporal cortices, the basal ganglia, and the cerebellar cortex. Interestingly, frontal and dorsolateral occipital cortices displayed later maturational rises onsetting at 6–8 months. The anatomic distribution was similar to adult patterns by 1 year of age, but adult values were not reached until 2 years of age. ICMRGlc values then surpassed adult values by 3–4 years of age and were maintained until 9 years of age where they declined again to adult values by the end of the second decade. Overall, the cerebral cortex underwent the highest proportional increase in ICMRGlc over its adult mature rates when compared with other portions of the brain, but the frontal and dorsolateral occipital cortices matured more slowly than other cortical areas. Chugani et al. interpreted these findings as evidence that, in general, a rise in

51


metabolic rate of a particular part of the brain is highly correlated with that part of the brain’s effect on the animal. Given this argument, their data show that over the lifespan different brain regions may ‘‘phase in’’ or ‘‘phase out’’ in terms of their relative contribution to the control of a variety of functions. Chugani et al. further speculated that the cause of the increase then decrease of metabolic rates in developing brain structures is a reflection of the protracted process of overproduction followed by pruning of synapses and dendritic processes. For example, at age 7, when the child’s brain is almost identical in size and weight to that of the adult, the average synaptic density in the frontal cortex is 1.4 times the adult value. Over the teenage years, loss of density occurs which leads to the establishment of ‘‘adult’’ levels. These findings support earlier postmortem findings by Huttenlocher (1990) who found the highest synaptic density in the first 3 years of life, followed by a gradual decline over the course of childhood and adolescence. Similar patterns of results have been identified by other investigators using other methods of CNS evaluation. In a study of magnetic resonance imaging (MRI) scanning of 121 normal children between 4 and 18 years of age, Giedd et al. (1997) found that males had mean cerebral volumes 9% larger than females, but that females had relatively larger basal ganglia. There were sex differences in maturational rates, with males showing greater increases in lateral ventricular volumes especially after age 11. There was a decrease in left globus pallidus volume and increased amygdala volume with age for males, whereas hippocampal volumes increased for females, findings that indicate the possible organizational dimorphic roles of sex steroids. Giedd et al. (1999b) further examined corpus callosal development in 139 healthy children. These investigators found that corpus callosal area increased with age, especially in the posterior CNS regions between the ages of 5–18 years. No sex differences in corpus callosum development were noted. Perhaps the most interesting finding from these studies was the large variability in brain structure sizes in this normal, carefully evaluated population. Pfefferbaum et al. (1994) studied cerebral volumes (using MRI) in children and adults. A 300 ml increase in intracranial volume was noted from 3 months to 10 years. Gray matter peaked at 4 years of age and dropped after this. White matter increased past age 20 years. Cerebral spinal fluid (CSF) volumes remained constant throughout the age range. When adjusted for head size, the older probands in the sample demonstrated a reduction in gray matter (0.7 ml/year) while white matter remained constant for five decades. More recently, Sowell et al. (1999) found decreases with age in the striatal and prefrontal areas in children and adolescents. The changes were most apparent in the

52

N. Carrey et al.

putamen and globus pallidus. The frontal lobe differences arose from changes in gray matter. In another study, Giedd et al. (1999a) found a sharp increase in brain gray matter occurring during the adolescent years, with females peaking approximately 1 year earlier than males. Klingberg et al. (1999) utilized the new technology of diffusion tensor imaging (DTI) to examine the in vivo development of white matter tracts in children and adults. DTI can be used to measure the anisotropy of a sample – anisotropy is the movement of water along tissues. With increased myelin, one would expect an increase in anisotropy as the water moves along the myelin sheath rather than against it. In this study, the anisotropy in frontal white matter was lower in children relative to adults, indicating less myelin in the children. Right frontal lobe coherence (the orientation of myelin sheaths) was less than that of the left frontal lobe in children and adults. These findings further demonstrate that myelination occurs over the lifespan. In MRI studies of ADHD, three groups of investigators have reported a smaller right prefrontal cortex in probands compared with controls, (Castellanos et al., 1994; Filipek et al., 1997; Hynd et al., 1990), but these same investigators found contradictory results regarding either loss or reversal of normal asymmetry in caudate volumes in the ADHD group. It is not clear, therefore, if these findings are evidence of abnormalities or simply exaggerated phenotypic variants of normal developmental patterns. While much work remains to be done before MRI can be considered to be a useful clinical tool, MRI findings as currently available can perhaps be correlated to clinical characteristics (such as severity or comorbidity) or used to help guide treatment interventions. Another application of MRI would be to monitor for potential brain changes accompanying chronic pharmacologic interventions. For example, Frazier et al. (1996) found that children with a diagnosis of schizophrenia and who were treated with typical neuroleptics had an increase in basal ganglia volume which decreased 2 years later when these same patients were treated with clozapine. Similar effects were noted by Keshavan et al. (1994) and Chakos et al. (1995) with first-episode schizophrenics. Rosenberg et al. (1998) reported a reduction in striatal glutamate after 12 weeks of paroxetine treatment in children with pediatric obsessive–compulsive disorder (OCD). Structural changes were also noted in the nucleus accumbens (Bailey et al., 1998) and thalamus (Gilbert et al., 2000) with paroxetine treatment. At this time, the clinical meaning of these findings has not been clarified and the relationship of these changes to outcome or adverse effects of treatment still needs to be established.

53


Effects of stress, early experience, and hippocampal neurogenesis An exciting area for the neurodevelopmentalist is the convergence of clinical and basic science in studying the effects of early environmental stress on developing CNS neurotransmitters, hormones, and anatomic structures. For the sake of this discussion, we will limit ourselves to the role of the impact of early stress on the hormones (cortisol, adrenocorticotrophic hormone [ACTH] and corticotrophin-releasing factor [CRF]) of the limbic–hypothalamic–pituitary–adrenal axis (or LHPA axis). The neurophysiologic adaptation or maladaptation to stress following a critical period of development may be modified by psychopharmacologic treatments with immediate and subsequent long-term effects on psychopathology and level of functioning. In general, adults who have experienced severe and longstanding early adverse childhood experiences are more susceptible to experience mood and anxiety symptoms in later adult life (McCauley et al., 1997). Certain investigators have postulated that changes in CRF may mediate the association between stressful experiences and the later development of mood and anxiety disorders (Heim and Nemeroff, 1999). CRF immunoreactivity has been measured in the brainstem, implicating this hormone’s role in modulating monoamines and their projections to the forebrain. An interesting limbic connection is between CRF neurons in the amygdala and noradrenergic neurons of the locus ceruleus (van Bockstaele et al., 1996). Acute and chronic stress increase CRF concentrations in many brain areas including the amygdala and the locus ceruleus. Some types of stress activate the LHPA axis, where neurotransmitters stimulate the synthesis and release of CRF which then stimulates corticotrophs to produce ACTH, which, in turn, stimulates the synthesis and release of glucocorticoids from the adrenal cortex. While few human studies exist to elucidate the relationships between the effects of significant early stress and LHPA dysfunction, DeBellis et al. (1994) found that sexually abused girls exhibited blunted ACTH responses to a CRF challenge. Animal studies have documented that separation of young rat pups from their mothers may make them susceptible to increased ACTH and corticosterone responses to a variety of stressors in adult life (Plotsky and Meaney, 1993). Interestingly, Plotsky et al. (in press) found that the excessive stress response of the LHPA axis is reversed by treating the maternally separated rats with the antidepressants paroxetine and reboxetine. Fluoxetine treatment decreases CSF CRF concentrations in recovering depressed patients (DeBellis et al., 1993). Finally, Gould and Tanapat (1999) have put forth several interesting propositions based on their experimental animal work about the effects of early stress

54

N. Carrey et al.

on hindering hippocampal neurogenesis. The granule cells of the dentate gyrus undergo rapid development beginning in gestation and continuing postnatally, but new granule cell production has been documented in adulthood as well. Adrenal steroid levels decrease and remain low for the first 2 postnatal weeks in the rat (the hyporesponsive period) which coincides with maximal granule cell production in the dentate gyrus, but, subsequently, as the adrenal steroid levels increase, granule cell production slows to the rate observed in adults. In animals exposed to chronic stress, there is persistent inhibition of granule cell production with resulting changes in the structure of the dentate gyrus. The researchers propose that the elevated levels of glucocorticoids activate excitatory NMDA receptors in the entorhinal cortex which suppress granule cell formation in the hippocampus via the perforant path. Investigators have hypothesized that stressful experiences during development may have a long-term effect on the hippocampus by directly altering its structure and functioning (particularly learning and memory). Cognitive impairments in children who have been sexually and physically abused have indeed been documented (Carrey et al., 1995). It is not yet clear if some psychotropics, such as antidepressants which impact on the serotonin system, have a protective effect on susceptible developing brain regions by dampening an over-reactive LHPA axis resulting from child abuse. Additionally, it is not known if some psychosocial interventions such as family therapy may affect the child’s environment in such a manner as to modify the stress effects of that environment on hippocampal development. Genetic evidence for some psychiatric developmental disorders and pediatric pharmacogenetics Although it is beyond the scope of this chapter to review all the genetic findings emerging now in molecular genetic psychiatry, identification of a few genetic mechanisms has implications for advancing our understanding of these disorders and guiding the future development of psychopharmacologic interventions. Two areas of research that are of immediate application in the child and adolescent age group are the theory of genetic anticipation and the identification of candidate genes in ADHD. The concept of anticipation in genetics is dependent on the action of trinucleotide repeats over generations. Triplets or trinucleotides consist of 3 nucleotides consecutively repeated either within genes or in the large stretches of DNA that lie between genes. Many of the trinucleotide repeats are the same length in all individuals, but other repeats are of variable length. These repeats,

55


even the variable or polymorphic areas, are transmitted unchanged from one generation to the next. However, some repeats may change in length when passed on and, when this occurs, gene expression is disrupted. This is referred to as a dynamic or expansion mutation. One group of diseases is characterized by a number of repeats above which (40) the expansion causes the disease, as in neurodegenerative diseases such as Huntington’s chorea. The excessively long stretches of glutamine residues encoded by the CAG repeat are apparently neurotoxic to a particular set of cortical or subcortical neurons. The second group of triplet repeat diseases consists of skeletal developmental disorders which result from one or two additional triplets which result in abnormal conformational changes to produce an abnormal protein product. A third group of disorders results from repeat expansions outside the protein-coding region, such as in fragile X syndrome. The discovery of triplet repeat disorders helped to explain the phenomenon of anticipation – where certain diseases have an earlier age of onset and/or a more severe phenotype – since repeat mutations are unstable and tend to get longer with each successive generation. An anticipation pattern of inheritance has been used to explain the earlier age of onset and increased severity in bipolar disorder and schizophrenia (Margolis and Ross, 1999). These earlier onset disorders may be more difficult to treat with the usual psychopharmacologic agents compared with adult onset disorders. Pharmacologic interventions in the future could target the development of small molecules capable of upregulating or downregulating the expression of faulty genes. A more recent approach to pharmacogenetics has been to assess responders vs. nonresponders to a specific pharmacologic intervention and test candidate genes that might distinguish the two groups. This approach has been used for lithium in bipolar patients (Grof et al., 1994), and fluvoxamine for mood disorder for the 5-HT transporter gene (Smeraldi et al., 1998), and, more recently, ritalin response in ADHD for the dopamine transporter gene or DAT1 (Winsberg and Comings, 1999). These latter authors found that ritalin nonresponders were more frequently homozygous for the ‘‘10 copy of the DAT1 gene’’ (86%) compared with the responders (31%), although overall, in their sample of 30, only 53% of the total group were responders, lower than the 75–80% response rate found in other studies. In an accompanying editorial, Cook (1999) pointed out the difficulty in interpreting these results since this approach utilized response as a categorical clinical variable, whereas ADHD and its response to treatment are multidimensional. Cook also mentioned that, although the symptoms of hyperactivity and impulsivity are highly heritable, the mode of transmission is likely to be polygenic as other studies have found

56

N. Carrey et al.

positive associations for the dopamine receptor genes (D4 and D5) and the dopamine beta hydroxylase gene. He also cautioned that other variables such as family environment, comorbidity, and access to health care may add to the complexity of interpreting these early results. Developmental psychopharmacology Finally, in terms of developmental neuropharmacology, it has now been reasonably well established that the nervous system shows different responses depending on the age of the organism and the level of plasticity. For unclear reasons, certain drugs are extremely toxic, others that would be predicted to be toxic have no effect, and others have enduring organizational effects or developmental phase-specific effects. Therefore, medications may have different effects if received in utero, in the neonatal period, prepubertally, peripubertally, in adulthood, or in old age. For example, cocaine and ethanol produce specific developmental syndromes when the fetus is exposed in utero. Concerning ethanol, as early as gestational day 15 (G15), there is a demonstrated toxic effect on raphe (serotonergic) neurons in cell cultures. At G19, it has been found that cortical neurons are impaired, possibly due to a 5-HT-1A deficit. 5-HT-1A receptors in the brainstem of rat pups exposed in utero to alcohol are increased at postnatal day 5, as this may represent a developmental delay in expression of these receptors. Cultured rhombencephalon astrocytes exposed to ethanol secrete fewer growth factors; these teratogenic effects may be prevented by pretreating with buspirone pregnant mother rats who are fed ethanol (reviewed in Whitaker-Azmitia et al., 1996). In the immature brain, the 5-HT system appears to be particularly vulnerable to the teratogenic effects of cocaine (Akbari et al., 1992). There are fewer 5-HT-1A receptors in cortical astrocytes exposed to cocaine. Concomitant decrease in S-100b protein, a nerve growth factor, leads to cortical thinning. These abnormalities may, in turn, lead to abnormal pharmacologic responses to other drugs later on in development. On the other hand, certain excitotoxins such as quinolinate, which cause degeneration in the adult rat hippocampus, have no effect when injected during the first 2 postnatal weeks (Keilhoff et al., 1990). In the adult brain, receptor blockade usually leads to homeostatic compensatory upregulation whereas receptor stimulation has the opposite effect. Exposure to agonists and antagonists prenatally or perinatally can give paradoxical and long-term effects. Early blockade of a neurotransmitter system can lead to permanent downregulation, whereas early stimulation results in upregulation

57


that can persist into adulthood. This has been demonstrated with morphine, neuroleptics, antidepressants, substance P, vasopressin, benzodiazepines, and corticotropin releasing hormone (Insel, 1995). Recently, investigators have shown that treatment of neonate rats with fluoxetine has resulted in an increase of paroxetine binding consistent with outgrowth of serotonergic projections in the frontal cortices persisting into adulthood (Wegerer et al., 1999). Insel (1995) proposes that exposure to an agonist during the neonatal period induces enduring functional increases in receptor responsiveness or a type of ‘‘chemical imprinting.’’ Whether the effects of agonists or antagonists confer an advantage or disadvantage to certain neuron populations during the developmental trajectory, especially neurons with terminals in areas of high pruning or neurons with extensive terminal fields, is not known at the current time. The developmental specificity of a drug response is the result of multiple interacting factors including the status of receptors and their effectors, metabolic enzymes, and the role of the blood–brain barrier. The motor response to clonidine, an alpha-2 adrenergic agonist, is an example of a developmentally determined drug response. From day 1 to day 14 postnatally, clonidine increases locomotor activity whereas, afterwards, it suppresses locomotor activity. Hartley and Seeman (1983) speculate that this effect is due to the late maturation of alpha-2 receptors in motor pathways. Teicher and Baldessarini (1987) have interpreted the observation that acute administration of imipramine to the adult rat produces sedation, whereas this is not shown until 4 weeks of age in the younger rat, as due to the delayed development of a serotonin-mediated inhibitory response. Similarly, McCracken and Poland (1995) found that in prepubertal rats the prolactin response to a serotonin agonist was not enhanced by pretreatment with amitryptiline whereas in adult rats the prolactin response was enhanced. They suggested that immature organisms may lack the full capacity to upregulate a 5-HT receptor-coupled response. These ontologic differences in the development of monoamine systems may help to explain the documented differences in clinical response in antidepressant–placebo studies in children and teenagers compared with adults. It seems logical to conclude that a drug effect may be beneficial at one developmental stage, but may either have no effect or adverse effects at another developmental period. For example, periadolescent rats appear to be more sensitive to the behavioral (cataleptic) effects of catecholamine antagonists such as haloperidol while at the same time displaying hyposensitivity to dopamine agonists (Spear and Brake, 1983). This parallels the human clinical situation which demonstrates adolescents’ increased sensitivity to dystonic reactions and parkinsonism. In clinical studies, the incidence of drug-induced

58

N. Carrey et al.

dystonias and bradykinetic reactions diminishes strikingly with maturation from ages 10–19 years to adulthood (Keepers et al., 1983) whereas neurolepticinduced akathisia is less common in children. Richardson et al. (1991) found a prevalence of parkinsonism of 34% and tardive dyskinesia of 12% in a mixed sample of inpatient children and adolescents, with only 18% of the sample having been given a diagnosis of psychosis or bipolar disorder. The incidence of drug-related dyskinesias ranges from 12% to 34% (Campbell et al., 1997) and neuroleptic-withdrawal dyskinesias are more common in children and can be as high as 51% (Campbell et al., 1988). Children may be at higher risk for developing neuroleptic malignant syndrome; in children less than 6 years of age, almost all cases here occurred after ingestion of a single dose of neuroleptic (Latz and McCracken, 1992). Spear and Brake hypothesize that the lagging of certain neurotransmitter systems or the immaturity of feedback loops responsible for neuronal homeostasis such as the various autoreceptors may explain why, clinically, younger children and adolescents may be more prone to some medication side effects which are either exaggerated or paradoxical drug reactions. The psychostimulants appear to be safe medications when appropriately prescribed (Tosyali and Greenhill, 1998), but there are concerns about their ability to induce dysphoric affect in the very young. There is evidence to suggest that global developmental disturbances may alter the child’s response to pharmacotherapy. For example, Handen et al. (1999) found that, while methylphenidate was effective in reducing ADHD symptoms in a group of developmentally delayed children, five out of 11 children had significant adverse effects of severe social withdrawal, increased crying, and irritability, especially at the 0.6 mg/kg dosage. Children under 3 years old who have the diagnosis of ADHD are frequently prescribed psychotropics. Rappley et al. (1999) in a review of Medicaid health records from Michigan over a 15-month period identified 223 children with the diagnosis of ADHD of whom 57% were prescribed psychotropics with the most common medications prescribed being methylphenidate and clonidine. From the developmental perspective, it is not known whether the stimulants acquire their euphorigenic effects and addictive properties as the brain matures because of the confounding variable of route of administration (oral vs. intranasal or intravenous route). In an article with the provocative title ‘‘Is Methylphenidate like Cocaine’’, Volkow and colleagues (1995) investigated with PET scanning the pharmacokinetics of methylphenidate injected intravenously into eight healthy male subjects. The findings were compared with a previous PET study where subjects had PET scans taken after intravenous cocaine was administered. Cocaine and methylphenidate had

59


similar affinities, similar rates of uptakes for blocking the dopamine transporter, and a similar subjective experience of the ‘‘high’’, but the rate of clearance was much slower for methylphenidate. The authors concluded that it is the rate of clearance of the drug from the brain which may limit its frequent selfadministration. While this offers a theoretical rationale as to why methylphenidate is not abused more compared with its widespread availability, the clinician should maintain a high index of suspicion with older adolescents or adults suspected of drug abuse. Antidepressant mechanisms of action in children and adolescents are different than those in adults, presumably reflecting underlying developmental differences in neurotransmitter and receptor maturation. Tricyclic antidepressants (TCAs) have not been shown to be any more efficacious than placebo in controlled trials (Ryan, 1990), whereas only two placebo-controlled trials involving a selective serotonin reuptake inhibitor (SSRI) (fluoxetine and paroxetine) showed the medication to be superior to inactive drug (Emslie et al., 1997; Keller et al., in press). While the SSRIs as a category are considered to be safer and better tolerated than TCAs, the whole gamut of side effects present in adults can also become manifest in children – including movement disorders and drug-induced mania (DeVane and Sallee, 1996; Leonard et al., 1997). A side effect which appears to be more common in children, especially if the initiation dose is too high, is activation or agitation, which can be seen in as many as 50% of those children who are improperly prescribed excessive initial doses of an SSRI (Riddle et al., 1992). High dosages of the SSRIs may in effect override release-inhibiting autoreceptors and stimulate postsynaptic receptors to produce activation. These findings serve to remind clinicians of the importance of using age-appropriate medication dosing strategies and not applying dosing models used in adults to children or adolescents. Conclusions and future directions From the above survey, the following considerations will be put forth cautiously while we await more definitive neurodevelopmental research. While ongoing research is establishing the timetables of neurodevelopment for certain species (rodents and other primates), the processes of neural growth in humans extend over many years, making it difficult to study and, in particular, difficult to determine experimentally sensitive periods for the growth of different neuronal processes and regional brain differences. What has to date been established is that brain organization continues for many years postnatally, with an intense period of activity occurring during the first 3 years of life

60

N. Carrey et al.

followed by decreased growth in the next few decades. However, growth is only one of a number of important processes that affect CNS functioning. Over the course of development, such phenomena as cell death, changes in receptor functioning, and ongoing organizational refinements all provide substantial contributions to how the brain functions. Additionally, such changes occur within different brain regions over different points of developmental time. For example, the cerebral cortices are slower to mature and, among these, the frontal lobes show an even slower development. Certain brain areas retain plasticity throughout life – such as the hippocampus, presumably as a reflection of its role in adaptive functioning – while others (such as the motor cortex) demonstrate less of an ability to do so. Superimposed on these genetically determined patterns of development, a variety of stressors (ranging from toxic substances to severe life experiences) internal to or external to the organism may affect neural organization. While animal and some human data show the negative effects of in utero exposure to some drugs or other maternally ingested substances, no overall conclusions as to the effect of specific compounds can be made ‘‘a priori’’ in the absence of data obtained from carefully constructed experiments. For example, according to longitudinal research, few if any significant negative long-term effects on cognition, behavior, or functioning have been observed in those individuals who were exposed to SSRIs in utero. Maternal alcohol abuse, however, may result in fetal alcohol syndrome with significant long-term cognitive, behavioral, and functional disturbances to the child. There may be lifespan-specific effects of medications known to affect CNS functioning and these may be dose related. For example, some anticonvulsants such as phenobarbital may have effects on children’s IQ after 2 years of treatment, an effect that lasts 6 months after the drug is stopped (Farwell et al., 1990). Such effects have not, however, been demonstrated for all anticonvulsants and the long-term effects of these disturbances are not well established. Benzodiazepines may exhibit disinhibitory effects in many children, but at a lower frequency in adults. Lithium may have a neuroprotective effect on the CNS at lower doses, but may be neurotoxic at abnormal or supratherapeutic levels or in combination with some antipsychotics. A further complication of this information is that these phenomena may be expressed in greater or lesser extent or not at all depending on the individual exposed. Antipsychotic medications, when given at an early age in animals, may have enduring effects on receptor changes later on in adulthood. When haloperidol is administered pre- and neonatally to rats, there is decreased D2 binding in the striatum and a decreased response to apomorphine – changes that persist

61


until adulthood (Hill and Engblom, 1984; Rosengarten and Friedhoff, 1979). The atypical neuroleptics when given prophylactically may confer protection against relapse. Early evidence from ongoing research by McGorry and colleagues (2000) suggests that low-dose ‘‘novel’’ antipsychotic medications when given to populations at high risk for psychosis may have a neuroprotective effect. These changes may occur in the cerebral cortex and, while these may be positive in terms of treating an ongoing psychotic illness, effects of the same compound may be different in another brain region, such as the striatum. For example, some ‘‘typical’’ neuroleptics when used in young persons may cause an increase in volume of the basal ganglia. This may not occur with the use of the ‘‘atypical’’ compounds. It has now been established that there is a high prevalence of parkinsonian symptoms in young people associated with the use of ‘‘typical’’ antipsychotics. However, the newer ‘‘novel’’ antipsychotic medications may be less likely to cause such effects which may be due to differential effects of ‘‘novel’’ and ‘‘traditional’’ antipsychotic medications in the striatum. Additionally, it is also well established that psychotic illnesses such as schizophrenia are associated with movement disorders that are present prior to the use of any antipsychotic medications, perhaps due to abnormal functioning of the cortico–cerebellar–thalamic–cortical circuit. These data serve to illustrate the complexity of the issue and caution against simplistic pronouncements regarding the long-term positive or negative effects on neurodevelopment of these and, by extension, any medications in young people. Antidepressants such as the TCAs and the SSRIs may have neuroprotective effects, not only by downregulating receptors in mood disorders but also by decreasing elevated corticosteroid levels associated with stress. Their excessive usage in the child population may, however, kindle an activation or hypomanic response in predisposed individuals although at rates lower than those noted in adults. NMDA antagonists seem to have neuroprotective effects in animals. Stimulants, which have not undergone extensive preclinical study despite their widespread use, appear to be safe in both long- and short-term use, but may induce dysphorias in younger children and may have abuse potential in some, but not most, teenagers, particularly as part of multiple substance abuse. Knowledge of neurodevelopment from animal studies may have implications both for our understanding of the pathoetiology of child and adolescent psychiatric disorders and the possible salutary or deleterious effects of psychotropics on brain development. For example, Andersen et al. (1997) have shown that D1 and D2 receptors are overproduced and pruned to a greater extent in the striatum of male compared with female rats. DA receptors reach their peak

62

N. Carrey et al.

at day 40, then decrease dramatically by day 60, the period of time corresponding to puberty in the rat. From this observation, Andersen et al. have speculated that the onset of symptoms and gender disparity that occur in ADHD and Tourette’s syndrome may stem from developmental receptor density changes. At the same time, generalizations from a single species must be interpreted with caution because of the much more extensive dopaminergic terminal fields in the primate cortex compared with the rodent cortex. We are only now starting to understand the multilevel influences of acute and long-term effect of drugs on neuron cell factors. Since most of the treatments in child psychiatry are of a long-term nature (ADHD, depression, OCD), pharmacotherapy has the potential to alter signal transduction pathways including altered levels of and altered types of proteins expressed in target neurons (Nestler and Duman, 1995). At least three mechanisms have been identified, including regulation of gene transcription, regulation of RNA translation/turnover, and regulation of protein turnover, as potential sites of action for drug effects. As such, drug treatments may interact at the neuronal level with psychopathologic influences and environmental factors to produce positive or negative loops leading to CNS recalibration, long-term neuroprotection, or negative effects. As child and adolescent psychiatrists are consulted to treat more severe cases at earlier ages, it is imperative that they possess not only an in-depth knowledge of psychopharmacology, neurosciences, genetics, developmental psychology, and environmental systems, but also demonstrate the conceptual rigor necessary to integrate these sources of knowledge in order to tailor treatments to individual patients, families, and clinical settings. The intuitive logic of prescribing to children psychotropic drugs known to be effective in adults, without knowledge of their relationship to neurodevelopment, should be tempered by careful clinical research, arising not from ‘‘top down’’ strategies but rather from ‘‘bottom up’’ strategies in which the development of psychopharmacologic interventions is informed by an understanding of the ontology of the central nervous system.

REFE REN C ES Akbari H, Kramer H, Whitaker-Azmitia P, Spear L, Azmitia E (1992). Prenatal cocaine exposure disrupts the development of the serotonergic system. Brain Res 572:57–63. Andersen S, Rutstein M, Benzo J, Hostetter J, Teicher M (1997). Sex differences in dopamine receptor overproduction and elimination. Neuroreport 8:1495–8.

63


Bailey CY, Stewart CM, Paulson LD, MacMaster FP, MacDonald AD, Rosenberg DR (1998). Basal ganglia and treatment response in pediatric obsessive compulsive disorder. AACAP Meeting, Volume IVX: 119. Barkovich A, Kjos B, Jackson D, Norman D (1988). Normal maturation of the neonatal and infant brain: MR imaging at 1.5T. Radiology 166:173–80. Barnes D, Mackenzie A (1999). Recent recognition and molecular delineation of apoptosis: beginnings of a therapeutic revolution? Ann Roy Coll Phys Surg Canada 32:376–82. Benes FM (1998). Brain development, VII. Human brain growth spans decades. Am J Psychiatry 155:1489–92. Bieber A, Snow P, Hortsch M et al. (1989). Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to a vertebrate adhesion molecule L1. Cell 59:447–60. Bode-Greuel K, Singer W (1989). The development of N-methyl-D-aspartate receptors in cat visual cortex. Dev Brain Res 46:197–204. Breese G, Baumeisster A, McCown T et al. (1984). Behavioral differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: relevance to neurological symptoms in clinical syndromes with reduced brain dopamine. J Pharmacol Exp Ther 231:343–54. Broaddus W, Bennett J (1990). Postnatal development of striatal dopamine function. Dev Brain Res 52:273–7. Cameron H, Hazel T, McKay R (1998). Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36:287–306. Campbell M, Adams P, Perry R, Spencer E, Overall J (1988). Tardive and withdrawal dyskinesia in autistic children: a prospective study. Psychopharmacol Bull 24:251–5. Campbell M, Armemeteros J, Malone R, Adams P, Eisenberg Z, Overall J (1997). Neurolepticrelated dyskinesias in autistic children: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 36:835–43. Carrey N, Butter H, Bialik R, Persinger M (1995). Physiological and cognitive effects of child abuse. J Am Acad Child Adolesc Psychiatry 34:1067–75. Castellanos F, Giedd J, Eckburg P et al. (1994). Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder. Am J Psychiatry 151:1791–6. Caviness V, Rakic P (1978). Mechanisms of cortical development: a view from mutations in mice. Annu Rev Neurosci 1:297–326. Chakos M, Lieberman J, Bilder R et al. (1995). Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry 151:1430–6. Chugani DC, Muzik O, Chakraborty P, Mangner T, Chugani HT (1997). Human brain serotonin synthesis capacity measured in vivo with alpha-[C-11]methyl-L-tryptophan. Synapse 28:33–43. Chugani H, Muller RA, Chugani D (1996). Functional brain reorganization in children. Brain Dev 18:347–56. Chugani H, Phelps M, Mazziotta J (1987). Positron emission tomography study of human brain functional development. Ann Neurol 22:487–97. Cook E (1999). Commentary; the early development of child pharmacogenetics. J Child Adolesc Psychiatry 38:1478.

64

N. Carrey et al.

Crisostomo E, Duncan P, Propst M, Dawson D, Davis J (1988). Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol 23:94–7. D’Amato R, Blue M, Largent B et al. (1987). Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas. Proc Nat Acad Sci (USA) 84:4322–6. DeBellis M, Chrousos G, Dorn L, Burke L, Helmers K, Kling M (1994). Hypothalamic-pituitary adrenal dysregulation in sexually abused girls. J Clin Endocrinol Metab 78:249–55. DeBellis M, Gold P, Geracioti T, Listwack S, Kling M (1993). Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 150:656–7. DeVane C, Sallee F (1996). Serotonin selective reuptake inhibitors in child and adolescent psychopharmacology: a review of published experience. J Clin Psychiatry 57:55–66. Dodd J, Jessell TM (1988). Axon guidance and patterning of neuronal projections in vertebrates. Science 242:692–9. Duncan G, Criswell H, McKown T, Paul I, Mueller R, Breese G (1987). Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine. J Pharmacol Exp Ther 243:1027–34. Emslie G, Rush J, Weinberg W et al. (1997). A double blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–7. Farwell R, Lee Y, Hirtz D, Sulzbacher S, Ellenberg J, Nelson J (1990). Phenobarbital for febrile seizures: effects on intelligence and on seizure recurrence. N Engl J Med 322:364–9. Filipek P, Semrud-Clikeman M, Steingard R, Renshaw P, Kennedy D, Biederman J (1997). Volumetric MRI analysis comparing subjects having attention deficit disorder with controls. Neurology 48:589–601. Frazier J, Giedd J, Kaysen D et al. (1996). Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment. Am J Psychiatry 153:564–6. Gaspar P, Berger B, Febvret A, Vigny A, Henry JP (1989). Catecholamine innervation of the human cerebral cortex as revealed by comparative immunochemistry of tyrosine hydroxylase and dopamine-beta-hydroxylase. J Comp Neurology 279:249–71. Gelbard H, Teicher M, Baldessarini R et al. (1990). Dopamine D1 receptor development depends on endogenous dopamine. Develop Brain Res 56:137–40. Giedd JN, Blumenthal J, Jeffries NO et al. (1999a). Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 2(10):861–3. Giedd JN, Blumenthal J, Jeffries NO et al. (1999b). Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study. Prog Neuropsychopharmacol Biol Psychiatry 23(4):571–88. Giedd JN, Castellanos FX, Rajapakse JC, Vaituzis AC, Rapoport JL (1997). Sexual dimorphism of the developing human brain. Prog Neuropsychopharm Biol Psychiatry 21:1185–201. Gilbert AR, Moore GJ, MacMaster FP et al. (2000). Decrease in thalamic volumes in pediatric patients with obsessive-compulsive disorder who are taking paroxetine. Arch Gen Psychiatry 5:449–56. Gould E, Tanapat P (1999). Stress and hippocampal neurogenesis. Biol Psychiatry 46:1472–9.

65


Gould E, Cameron H, McEwen B (1994). Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol 340:551–65. Grof P, Alda M, Grof E (1994). Lithium response and genetics of affective disorders. J Affect Disord 32:85–95. Gross-Isseroff R, Salama D, Israeli M, Biegon A (1990). Autoradiographic analysis of age dependent changes in serotonin 5-HT-2 receptors in human brain post-mortem. Brain Res 519:223–7. Handen B, Feldman H, Lurier A et al. (1999). Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD. J Am Acad Child Adolesc Psychiatry 38:805–12. Harrelson A, Goodman C (1988). Growth cone guidance in insects; fascilin II is a member of the immunoglobulin superfamily. Science 242:700–8. Hartley E, Seeman P (1983). Development of receptors for dopamine and noradrenaline in rat brain. Eur J Pharmacol 1:391–7. Hashimoto T, Tayama M, Miyazaki M et al. (1995). Developmental brain changes investigated with proton magnetic resonance spectroscopy. Dev Med Child Neurol 37:398–405. Hatten M (1990). Riding the glial monorail: a common mechanism for glial guided neuronal migration in different regions of the developing mammalian brain. Trends Neurosci 13:179–84. Heim C, Nemeroff C (1999). The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biol Psychiatry 46:1509–22. Hill H, Engblom J (1984). Effects of pre-and postnatal haloperidol administration to pregnant and nursing rats on brain catecholamine levels in their offspring. Dev Pharmacol Therap 7:188–97. Hohman C, Hamon R, Batshaw M, Coyle J (1988). Transient postnatal elevation of serotonin levels in mouse neocortex. Devain Br Res 43:163–6. Hubel D, Weisel T, Levay S (1977). Plasticity of ocular dominance columns in monkey genesis. Phil Trans R Soc Lond:278. Huttenlocher P (1979). Synaptic density in human frontal cortex developmental changes and effects of aging. Brain Res 163:195–205. Huttenlocher PR (1990). Morphometric study of human cerebral cortex development. Neuropsychologia 28:517–27. Hynd G, Semrud-Clikeman M, Lorys A, Novey E, Eliopulos D (1990). Brain morphology in developmental dyslexia and attention deficit disorder/hyperactivity. Arch Neurology 47:919–26. Insel T (1995). The development of brain and behavior. In F Bloom, D Kupfer (Eds.) Psychopharmacology, The Fourth Generation Of Progress. New York: Raven Press, pp. 683–94. Insel T, Battablia G, Fairbanks D, DeSouza E (1988). The ontogeny of brain receptors for corticotropin releasing factor and the development of their functional association with adenylate cyclase. J Neurosci 8:4151–8. Iyo M, Yamasaki T (1993). The detection of age-related decrease of dopamine D1 and D2 and serotonin 5-HT-2 receptors in living human brain. Prog Neuropsychopharm Biol Psychiatry 17:415–21. Jacobsen M, Weil M, Raff M (1997). Programmed cell death in animal development. Cell 88:347–54.

66

N. Carrey et al.

Jackson D, Bruno J, Stachowiak M, Zigmond M (1988). Inhibition of striatal acetylcholine release by serotonin and dopamine after the intracerebral administration of 6-hydroxydopamine to neonatal rats. Brain Res 457:267–73. Jones E (1991). The development of the primate neocortex – an overview. In SA Mednick, TD Cannon, CE Barr, M Lyon (Eds.) Fetal Neurodevelopment and Adult Schizophrenia. New York: Cambridge University Press, pp. 40–65. Keepers G, Clappison V, Casey D (1983). Initial anticholinergic prophylaxis for acute neuroleptic induced extrapyramidal syndromes. Arch Gen Psychiatry 40:1113–17. Keilhoff G, Wolf G, Stastny F, Schmidt W (1990). Quinolate neurotoxicity and glutamatergic structures. Neurosci 34:235–42. Keller M, Ryan N, Stroker M et al. (in press). Efficacy of paroxetine in the treatment of adolescent major depression: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. Keshavan M, Bagwell W, Haas G, Sweeney J, Schooler N, Pettegrew JW (1994). Changes in caudate volume with neuroleptic treatment. Lancet 344:1434. Kling A, Tucker T (1967). Effects of combined lesions of frontal granular cortex and caudate nucleus in the neonatal monkey. Brain Res 6:428–39. Klingberg T, Vaidya CJ, Gabrieli JD, Moseley ME, Hedehus M (1999). Myelination and organization of the frontal white matter in children: a diffusion tensor MRI study. Neuroreport 10:2817–21. Latz S, McCracken J (1992). Neuroleptic malignant syndrome in children and adolescents: two case reports and a warning. J Child Adolesc Psychopharmacol 2:123–9. Lauder J, Krebs H (1976). Effects of p-chlorophenylalanine on time of neuronal origin during embryogenesis in the rat. Brain Res 107:638–44. Lauder J, Wallace J, Wilkie M, Dinome A, Krebs H (1983). Roles for serotonin in neurogenesis. Monog Neural Sci 9:3–10. Leonard H, March J, Rickler K, Allen A (1997). Pharmacology of the selective serotonin re-uptake inhibitors in children and adolescents. J Am Acad Child Adolesc Psychiatry 36:725–36. Lidow HGW, Molliver ME (1982). An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields. Brain Res Bull 8:389–430. Liu J, Lauder J (1992). Serotonin promotes region-specific glial influences on cultured serotonin and dopamine neurons. Glia 5:306–17. Lockerbie R, Beujouan J, Saffroy M, Glowinski J (1988). An isolated growth cone-enriched fraction from developing rat brain has substance P binding sites. Brain Res 468:1–9. LoTurco J, Owens D, Heath M, Davis M, Kriegstein A (1995). GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15:1287–98. Margolis R, Ross C (1999). Genetics of childhood disorders: triplet repeat disorders. J Am Acad Child Adolesc Psychiatry 38:1598–600. Mazer C, Muneyyireci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997). Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits. Brain Res 760:68–73. McCauley J, Kern D, Kolodner K et al. (1997). Clinical characteristics of women with a history of childhood abuse. JAMA 277:1362–8.

67


McCracken J, Poland R (1995). Reduced effect of antidepressant on prolactin response to a serotonin agonist in prepubertal rats. J Child Adolesc Psychopharmacol 5:115–20. McGorry P, Phillips A, Yung S et al. (2000). A randomised control trial of interventions in the pre-psychotic phase of psychotic disorders. Schizophrenia Res 41:9. Miller F, Heener T, Kotake C, Seiden L (1981). Magnitude and duration of hyperactivity following neonatal 6-hydroxydopamine is related to the extent of brain dopamine depletion. Brain Res 229:123–32. Minshew NJ, Pettegrew JW (1996). Nuclear magnetic resonance spectroscopic studies of cortical development. In RW Thatcher, GR Lyon (Eds.) Developmental Neuroimaging: Mapping the Brain. Morilak D, Porteus M, Ciaranello R (1995). Molecular and cellular mechanisms of brain development. In F Bloom, D Kupfer (Eds.). Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 671–81. Nestler E, Duman R (1995). Intracellular messenger pathways as mediators of neural plasticity. In F Bloom, D Kupfer (Eds.), Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 695–704. Noisin E, Thomas W (1988). Ontogeny of dopaminergic function in the rat midbrain tegmentum, corpus striatum and frontal cortex. Brain Res 469:241–52. Nowakowski R (1991). Genetic disturbances of neuronal migration: some examples from the limbic system of mutant mice. In S Mednick, T Cannon, C Barr, M Lyon (Eds.) Fetal Neural Development and Adult Schizophrenia, New York: Cambridge University Press, pp. 69–96. Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO (1994). A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol 51:874–87. Pineyro G, Blier W (1999). Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51:534–75. Plotsky P, Meaney J (1993). Early postnatal experience alters hypothalamic corticotropin-releasing factor mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res 18:195–200. Plotsky P, Thrivikraman K, Caldji C, Sharma S, Meaney M (in press). The effects of neonatal rearing environment on CRF mRNA and CRF receptor levels in adult rat brain. J Neurosci. Pouwels PJ, Brockmann K, Kruse B et al. (1999). Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS. Pediatr Res 46:474–85. Rakic P, Bourgeois JP, Eckenhoff M, Zecevic N, Goldman-Rakic P (1986). Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 232:232–4. Rappley M, Mullan P, Alvarez F et al. (1999). Diagnosis of ADHD and use of psychotropic medication in very young children. Arch Pediatr Adolesc Med 153:1039–45. Richardson MA, Haugland G, Craig T (1991). Neuroleptic use, parkinsonian symptoms, tardive dyskinesia, and associated factors in child and adolescent psychiatric patients. Am J Psychiatry 148:1322–8. Riddle M, Scahill L, King R et al. (1992). Double-blind trial of fluoxetine and placebo in children and adolescents with obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry 31:1062–9.

68

N. Carrey et al.

Rodriguez M, Martin L, Santana C (1994). Ontogenic development of brain asymmetry in dopaminergic neurons. Brain Res Bull 33:163–71. Rosenberg DR, MacMaster FP, Parrish JC et al. (1998). Caudate glutamatergic changes with paroxetine therapy for pediatric obsessive compulsive disorder. Biol Psychiatry (Suppl) 43:78. Rosengarten H, Friedhoff A (1979). Enduring changes in dopamine receptor cells of pups from drug administration to pregnant and nursing rats. Science 203:1133–5. Roth B, Hamblin M, Ciaranello R (1991). Developmental regulation of 5-HT-2 and 5-HT-1C mRNA and receptor levels. Dev Brain Res 58:51–8. Ryan N (1990). Pharmacotherapy of adolescent major depression: beyond TCAs. Psychopharmacol Bull 26:75–9. Saleh M, Kostrzewa R (1988). Impaired striatal dopamine receptor development: differential D-1 regulation in adults. Eur J Pharmacol 154:305–11. Santana C, Rodriguez M, Afonso D, Arevelo R (1992). Dopaminergic neuron development in rats: biochemical study from prenatal life to adulthood. Brain Res Bull 29:7–13. Seeman P, Bzowej N, Guan HC et al. (1987). Human brain dopamine receptors in children and aging adults. Synapse 1:399–404. Shemer A, Azmitia E, Whitaker-Azmitia P (1991). Dose-related effects of pre-natal 5-methoxytryptamine on development of serotonin terminal density and behavior. Dev Brain Res 59:59– 63. Smeraldi E, Zanardi R, Benedetti F, DiBella D, Perez J, Catalano M (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 3:508–11. Snow P, Bieber A, Goodman C (1989). Fascilin III: a novel homophilic adhesion molecule in Drosophila. Cell 59:313–23. Sowell ER, Thompson PM, Holmes CJ, Jernigan TL, Toga AW (1999). In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nature Neurosci 2:859–61. Spear L, Brake S (1983). Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83–109. Sulston J (1976). Postembryonic cell lineages of the nematode C. elegans. Dev Biology 56:110–56. Teicher M, Baldessarini R (1987). Developmental pharmacodynamics. In (C. Popper (ed.). Psychiatric Pharmacosciences of Children and Adolescents, Washington, DC: American Psychiatric Press. Tessier-Lavigne M, Placzek M, Lumsden A, Dodd J, Jesell T (1988). Chemotropic guidance of developing axons in the mammalian central nervous system. Nature 336:775–8. Todd R (1992). Neural development is regulated by classical neurotransmitters: dopamine D2 receptor stimulation enhances neurite outgrowth. Biol Psychiatry 31:794–807. Tosyali C, Greenhill L (1998). Child and adolescent psychopharmacology: important developmental issues. Pediatric Clin North Am 45:1021–35. van Bockstaele E, Colago E, Valentino R (1996). Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus ceruleus in the rat brain. J Comp Neurol 364:523–34.

69


van der Knaap MS, van der Grond J, van Rijen PC, Faber JA, Valk J, Willemse K (1990). Age-dependent changes in localized proton and phosphorus MR spectroscopy of the brain. Radiology 176:509–15. Volkow N, Ding Y-S, Fowler J et al. (1995). Is methylphenidate like cocaine? Arch Gen Psychiatry 52: 456–63. Wang J, Volkow N, Logan J et al. (1995). Evaluation of age-related changes in serotonin 5-HT-2 and dopamine D2 receptor availability in healthy human subjects. Pharmacol Letts 56:249–53. Wegerer V, Moll G, Bagli M, Rothenberger A, Ruther E, Muether G (1999). Persistently increased density of serotonin transporters in the frontal cortex of rats treated with fluoxetine during early juvenile life. J Child Adolesc Psychopharmacol 9:13–24. Whitaker-Azmitia P (1991). Role of serotonin and other neurotransmitter receptors in brain development: basis of developmental pharmacology. Pharmacol Rev 43:553–61. Whitaker-Azmitia P, Azmitia E (1994). Astroglial 5-HT-1a and S-100beta in development and plasticity. Perspect Dev Neurobiol Vol2:233–8. Whitaker-Azmitia P, Druse M, Walker P, Lauder J (1996). Serotonin as a developmental signal. Behav Brain Res 73:19–29. Whitaker-Azmitia P, Quartermain D, Shemer A (1990) Prenatal treatment with SKF 38393, a selective D1 agonist: longterm consequences on 3H-paroxetine binding and on dopamine and serotonin receptor sensitivity. Dev Brain Res 57:181–5. Winsberg B, Comings D (1999). Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 38:1474–77. Wong D, Wagner H Jr, Dannals R et al. (1984). Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science 226:1393–6. Xu D, Crocker S, Doucet J et al. (1997). Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus. Nature Med 3:997–1004. Yakovlev P, Lecours A (1967). The myelogenetic cycles of regional maturation of the brain. In A Minkowski (Ed.) Regional Development of the Brain in Early Life. Oxford: Blackwell, pp. 3–69. Zagon I, McLaughlin P (1986). Opioid antagonist-induced modulation of cerebral and hippocampal development: histological and morphometric studies. Dev Brain Res 28:233–46. Zagon I, McLaughlin P (1991). Identification of opioid peptides regulating proliferation of neurons and glia in the developing nevous system. Brain Res 542:318–23. Zecevic N, Verney C (1995). Development of the catecholamine neurons in human embryos and fetuses, with special emphasis on the innervation of the cerebral cortex. J Comp Neurol 351:509–35. Zinn K, McAllister L, Goodman C (1988). Sequence analysis and neuronal expression of fascilin I in grasshoppers and Drosophila. Cell 53:577–87.

3 Clinical aspects of child and adolescent psychopharmacology Gabrielle A. Carlson State University of New York, Stony Brook, USA

Introduction When his car stopped running, a man had his car towed to the mechanic. The mechanic opened the hood, contemplated the interior for a minute or two, took out his wrench, and tightened a bolt. When he turned on the ignition, the car miraculously started. The bill was for $95.98. The man asked how the bill was figured, given how little effort was involved. The mechanic said it cost 98 cents to turn the bolt and $95 to know which bolt to turn. Similarly, psychopharmacologic treatment is not simply writing prescriptions; it is knowing how and when to do so. Knowing ‘‘when to do so’’ is at the core of a psychiatric assessment. Making the correct diagnosis is akin to solving a murder-mystery. Just as one needs to have a considerable amount of information about the murder and its victim in order to discover who did it, there needs to be considerable understanding of the problem in order to give it a diagnosis. In both situations, it is necessary to be active in obtaining information. The more complicated the case, the more information sources must be contacted. One must sort through a considerable body of evidence, not all of which carries equal weight. There may be several suspects or other diagnoses that must be eliminated. There may be accomplices (comorbidity). In the end, one may only have circumstantial evidence (information from other informants) rather than incontrovertible fact (a reliably completed interview from the patient, validated by other information sources). Finally, in both situations, it is important to understand the context in which the crime/illness occurred. This analogy is particularly apt for child/adolescent psychiatry. The cases of children referred for psychiatric evaluation are becoming more complex not only because the intertwining of family, psychosocial, and individual pathology is becoming more complex, but also because the health care system is increasingly defining child psychiatrists as the professionals who are referred the most diagnostically complicated, treatment refractory children. In addition, while 70

71

Clinical aspects

the rest of medicine relies increasingly on procedures, tests, and the like to define diagnosis, psychiatry must still live by its wits. Success is determined by one’s ability to obtain the trust of the informants in order to obtain reliable information, to be a good observer, to have knowledge of psychopathology, knowledge of the diagnostic tools available, an ability to integrate a complicated body of information, and plain, old fashioned thought. One can develop screening tools, symptom lists, decision trees, algorithms, and manuals, but the point at which those are all that is needed to make a diagnosis is the point at which the discipline of psychiatry and child psychiatry defines its extinction. The framework of diagnosis in itself is not universally agreed upon. It implies that a deviation from normal (however that is defined) has occurred which is of sufficient magnitude to produce functional impairment. It implies a recognizable pattern of deviation. It is hoped that, by recognizing the pattern, the clinician will be able to advise the patient about what is accounting for the complaints for which help is sought, how the problems should best be treated, what is likely to occur if the problems are not treated, and what the likely outcome will be when treatment is applied. There are two basic schemata by which diagnosis is conceptualized: dimensional and categorical. Dimensions describe symptom clusters and behavior. Pathology is operationally defined by a set of rating scales which address the dimension at issue. There is the assumption of normal distribution of the dimension within the population and, at a certain point, ‘‘pathology’’ is said to occur. IQ is the most obvious example. At a certain point (2 standard deviations below or above the ‘‘norm’’), mental retardation (at the low end) and giftedness (at the high end) are said to occur. In psychiatry, many dimensions are measured with rating scales e.g., anxiety, depression, hyperactivity, impulsivity, inattention, aggressiveness, extroversion, introversion, and emotional lability. Rating scales have the advantage of being easy to complete, of providing a level of severity, and, in general, of quantifying the level of impairment. Since, at our level of ignorance, we are frequently treating symptoms, not entire illnesses, there is a definite place for well-normed, systematic rating scales in a psychiatric evaluation. In most clinical situations, they are used as a reliable method of quantifying observations originally made during a series of interviews. Categoric diagnosis is how we conceptualize illness. A disorder is assumed to be a single entity with a characteristic group of signs and symptoms, an onset (history), course, and conclusion. It presumably has a cause and, until an etiology or confirmatory test is found, it presumably can be distinguished from another disorder by its history, symptoms, course, and treatment response. One final concept needs emphasis. Symptoms and disorders happen in

72

G.A. Carlson

individuals. The individual’s genetic make-up and life circumstances color which symptoms predominate, or the manner in which they manifest. They may also significantly impact on the course of illness and treatment response. They certainly influence attitude toward illness, doctor, and treatment. To reiterate then, giving medication is the easy part. The hard part is to determine what should be given, to whom, when, for what reasons, how, and for how long. Information gathering Evaluating disturbed children remains a relatively labor-intensive task. However, it can be made considerably more efficient by obtaining as much information in advance, and as precisely as possible (Table 3.1). In the best of circumstances, that means obtaining biographic information, standardized rating scales from parents and teachers which evaluate symptoms and functioning, and having in advance any other assessments that have already been completed (e.g., IQ testing and written consultations from other mental health professionals). Sometimes, report cards dating back to kindergarten are important in ascertaining the child’s early behavior, educational attainments, or attendance. Such detailed assessments are more easily completed in an office or clinic setting. However, even in an emergency room, it is possible to have parents and/or older child or teenager complete a comprehensive rating scale like the Child Symptom Inventory (Gadow and Sprafkin, 1995), the Child Behavior Checklist (Achenbach, 1991), or the Connors Parent Rating Scale (Conners, 1989). The formermost has the advantage of being DSM based and can be used as a semi-structured interview (Grayson and Carlson, 1991). The latter two have the advantage of having been normed on many children, giving informative cut-off scores for severity of multiple dimensions. The point is that, even before the clinician says hello to the family, the ‘‘wheels’’ should be turning regarding what information to elicit and what should be observed. In our clinic, we also ask children over the age of 10 (provided they have a fourth grade reading level) to complete rating scales addressing their overall behavior, and areas of depression and anxiety. If the history suggests other problems, specific rating scales are given. Kutcher’s text, Child and Adolescent Psychopharmacology (Kutcher, 1997) has a wonderful appendix with many forms or examples of forms used for this purpose. If we are conducting the evaluation on one day, children are asked to complete a variety of evaluation tools while we concurrently obtain collateral information from parents. If two separate appointments are used, parents are asked to have the child complete the

73

Clinical aspects

Table 3.1. Systematic evaluation of children and adolescents Step 1:

Step 2:

Step 3:

Step 4a:

Step 4b:

Step 5:

Step 6:

Step 7:

Parents and teacher complete the Stony Brook Child Symptom Inventory (CSI; Gadow and Sprafkin, 1995), and a standardized behavior rating scale such as the Achenbach CBCL (Achenbach, 1991) and teacher report form (TRF) (Edelbrock and Achenbach, 1987) or Conners Parent/Teacher Rating Scales (Conners, 1989). Clinician reviews checklists and scales prior to meeting with patient/family assessing: (a) Diagnostic domains endorsed on the CSI; (b) Whether total symptom scores and relevant factor scores on the standardized rating scales are significant; and (c) Areas of agreement and disagreement between informants. Parents and child/adolescent are interviewed initially together to ascertain reasons for evaluation, set gound rules for the assessment, and provide an understanding of the presenting problem. Level of child cooperation and cognitive ability briefly assessed. If youth is competent and agreeable, he/she completes self-rating scales covering depression, anxiety, and the Adolescent Symptom Inventory (Gadow and Sprafkin, 1995) while parents are separately interviewed. A Sentence Completion Test is useful to judge the young person’s written language, handwriting, and spontaneous thoughts. Parents are interviewed either clinically, using the CSI to pursue significant areas further, or with a semistructured interview (such as the K-SADS) with time organized to concentrate on areas of clinical significance. After parents are interviewed, the child/adolescent is interviewed. Rating scales are visually inspected for significant responses (which are discussed) and scored. Mental status exam is completed including neurodevelopmental screen as relevant. If there are discrepancies between parent and child, they are resolved at the subsequent informing session during which diagnosis and treatment recommendations are made and agreed upon. Rating scales are then used as baselines for subsequent treatment monitoring.

evaluation instruments at home. In the case of children between the ages of 6–10 where attention-deficit/hyperactivity/disorder (ADHD) is one of the differential diagnoses, we conduct a Restricted Academic Playroom observation where the child’s off-task behavior, time out of seat, and ability to inhibit certain responses are observed (Roberts, 1990). We also observe for tics. If there are concerns about development and/or academic performance, a specific developmental examination assessing motor, language, memory, and visual– spatial difficulties is done (Levine, 1998).

74

G.A. Carlson

The decision about whether to complete the evaluation all at once, or seeing parents one day and child the next, should be based on what kind of information one is looking for, not how the insurance company or other third-party payer reimburses. If in advance of face to face assessment one has obtained demographic information and some idea of the symptoms/behaviors causing problems, one can organize this rationally. For instance, if one has a single parent with a hyperactive 5 year old, it might be better to schedule two separate visits because there will be no supervision for the child while the parent is being interviewed. However, if there is a question of a diagnosis where ‘‘relatedness’’ is of primary concern, it will be important to have a period of time where the parent(s) and child are seen together. Similarly, if parents are dealing with a teenager who will be upset at having parents talk to the doctor while he/she waits in the waiting room completing forms, it makes more sense to interview parents on a different day. History taking, in some jurisdictions, seems, unfortunately, to have become the province of social workers, and the child/adolescent psychiatrist is given the task of ‘‘doing the mental status.’’ This is an old division of labor, reinforced in the United States by managed care companies because social work time is considered ‘‘cheaper.’’ It has been exacerbated by research protocols where there is the need to have the child interviewer ‘‘blind’’ to parent information for a variety of experimental or statistical reasons. However, in a clinical setting, ‘‘blindness’’ is not a virtue – it is a handicap. Simultaneous interviewing is also conducted for logistic reasons. If both parties are seen simultaneously by two people, the family can leave more quickly and child supervision is not a problem. However, in such a scenario, professional time needs to be spent integrating the two sets of data, and, if information obtained has varied as to the informant, statisticians and myriads of other well-meaning professionals can engage in obsessive wrangling about who to believe. Using the same person to conduct both segments, or to gather enough history to put the mental status in a diagnostic framework, allows the person who evaluates the child to have a clear history in mind at the time he/she is seeing/interviewing the child. If there are discrepancies in information, these can be immediately resolved with the pertinent issues clarified. The problem of confidentiality is confronted at the outset by meeting everyone together and saying to the child, ‘‘I am going to be spending the next hour getting information about you from your parents. Then I am going to talk to you about what has been going on in your life.’’ Ground rules regarding confidentiality should be defined at the outset of the assessment. If an issue arises in either interview that potentially raises concern about confidentiality

75

Clinical aspects

(e.g., one parent is having an affair; a relative committed suicide; divorce is being contemplated; the child is using drugs or alcohol, is sexually active, is engaged in antisocial behavior, has made suicide attempts, or is thinking about suicide), the advisability for continued secrecy can be discussed with the person being interviewed. Ironically, the one party who thinks the information is a secret is often unaware that the other person knows about it already or is highly suspicious. In the United States, the imposition of managed care into child/adolescent evaluations and treatment is considered by many to be having a detrimental effect on the diagnostic process. If one clinician is paid to spend only 30 minutes with a child to obtain information, that is likely to be the time spent. However, those directives must change and those who need to change it are the clinicians on whom treatment responsibility falls in the end. Even with a complete database (and it has taken a good deal of time on the part of the clerical staff to make sure this is the case – and that time is not free), it is not possible to do a thorough, comprehensive psychiatric evaluation of a child, arrive at a diagnosis, consider a treatment plan, and provide feedback to parents, in less than 60 minutes, even in simple cases. This is partly because the purpose of assessment is not only to discover if pertinent diagnoses are present – it is also necessary to ensure that others are absent. For instance, even though ADHD in many cases is a relatively easy disorder to diagnose, ascertaining the presence of mild pervasive developmental disorders, anxiety disorders, and depression is not quickly conducted. Similarly, children with co-occurring learning and language disorders, especially those that have not been diagnosed by others prior to the psychiatric evaluation, need more time in order for a clinician to conduct those assessments properly or to ensure that they are done. Distinguishing a language disorder from a thought disorder is germane to the diagnosis of psychosis; knowing whether a child has a receptive language disorder is germane to how easily he/she will understand what you tell him/her; whether the child has an expressive language disorder is germane to how much you can trust the ‘‘output’’ the child gives you. These issues are not quickly evaluated and most often require the careful elicitation of information from a variety of sources including the child, parent, or significant third party. Rating scales and structured interviews can be used during this process, but cannot be relied on in the absence of a clinical assessment. Where psychiatric evaluations of children are limited by structured interviews rather than enhanced by them is one of the great travesties of psychiatric diagnosis. Complicated cases take longer than simple ones, just as heart transplants take longer than uncomplicated appendectomies. This process is summarized in Table 3.1.

76

G.A. Carlson

Additionally, diagnosis may become relatively clear within the first portion of the assessment. However, getting the parent/child to have enough confidence in your conclusion so that they will, finally, follow through with treatment takes much longer even when the diagnosis is straightforward. This is especially true when psychopharmacologic treatment is recommended. Although some parents are comfortable with the ‘‘medical model’’, and are hoping for a ‘‘magic bullet’’ that will provide symptom removal, many are not. Parents often appear to be much more likely to take the recommendations of someone they hear on talk shows pushing unproved treatment on their child than they are to follow recommendations of qualified doctors to treat their hyperactive, impulsive, and inattentive child with a proven and well-tolerated medication such as methylphenidate. Structured and unstructured interviews

The diagnostician’s job is first to connect the symptoms/problems with which the patient presents with the possible disorders that might be responsible for the symptoms/problems. The next step is to narrow the possibilities down to the ‘‘correct’’ one(s). Sometimes, the connection is easy to make. A parent will say his/her child is sleeping all the time and seems depressed, or the child will not sit still and is constantly in trouble for not finishing school work. Connecting these symptoms with a differential diagnosis that includes depression or ADHD is relatively straightforward. However, sometimes the symptoms are less easy to connect with a diagnosis. For instance, ‘‘my son spends all his time on the internet with white supremacist chat groups’’, or ‘‘my daughter has always made up tall stories. I got a call from the teacher saying she was sorry I had broken my leg. I didn’t know what she was talking about. I was fine.’’ A single, specific diagnosis does not leap to mind from these identified concerns. On the other hand, a symptom or behavior can be cited as problematic and can connect with many different diagnoses. For instance, ‘‘my son/daughter cannot tolerate change of any sort’’ (e.g., obsessive–compulsive disorder; pervasive developmental disorder; some cases of ADHD; intermittent explosive disorder), or ‘‘my son/daughter has always been aggressive but, since s/he has become a teenager, it is much worse’’ (e.g., oppositional defiant disorder; mania; depression; ADHD). One of the reasons it is necessary to have a good understanding of psychopathology is to know what questions to ask next. However, for people with less knowledge, one of the innovations that have developed from research studies has been the availability of structured interviews. Although people trained at university centers engaged in research often

77

Clinical aspects

know what ‘‘structured interviews’’ are, many people in clinical practice are aware only of acronyms like ‘‘Kiddie-SADS’’ (Schedule for Affective Disorders and Schizophrenia–Childhood Version; Orvaschel et al., 1982; Kaufman et al., 1994), ‘‘DICA’’ (Diagnostic Interview for Children and Adolescents; Reich et al., 1991), and ‘‘DISC’’ (Diagnostic Interview Schedule for Children; National Institute of Mental Health, 1992). However, structured interviews are merely the setting forth of the diagnostic criteria developed by the American Psychiatric Institute’s Diagnostic committees (DSM III–IV; American Psychiatric Association 1980, 1987, 1994) in a systematic manner and a language that is supposed to be understood by lay people. By consistently going through every question, it is often possible to stumble on the diagnosis/diagnoses by sheer thoroughness. If the interviewer follows the rules, he/she is ‘‘forced’’ to ask all the questions, not merely the ones thought to be relevant. For the child or adolescent, if one has had the foresight to obtain completed rating scales before the interview, the answers themselves should be read and discussed. Questions about suicidal behavior should be asked even if the question seems like it is from ‘‘left field.’’ Similarly, homicidal ideation should be asked about. If the diagnosis is clear or it is considered by the clinician that medication will be of use in treatment, it is useful to get the parent’s and child’s perspective on its use early on in the course of the assessment. Children often reflect their parents’ biases. In teenagers, their viewpoint is often colored by the perspective of their peers. A hopeful comment is ‘‘my best friend takes ‘Zoloft’.’’ On the other hand, one cringes at ‘‘all the dorks go down to the nurse to get their fix.’’ Unfortunately, the latter is a frequent quote from youths about their peers taking stimulants.

(1) (2) (3)

(4)

(5)

The parental interview The parental interview should cover the following: Chief complaint/presenting problem/reason for referral. When did the problem start, what has perpetuated it, and what has made it better? What was your child like as a baby/toddler/preschooler-school aged child, followed by a brief review of questions addressing cognitive development, anxious behaviors, sociability with adults and peers, activity level and impulse control, and physical/medical history. Psychiatric review of symptoms either from a structured interview or the Child Symptom Inventory starting with the diagnoses that one thinks are most probable based on the information to that point. What treatments have been tried? In addition to asking what medications have

78

G.A. Carlson

been used in the past, obtain information about doses, duration of treatment, response to treatment of various behaviors in question, and side effects. It is not just a question of cure vs. no cure, but what the degree of response was of a particular symptom or symptom cluster. Interview with the child By the time the child is interviewed (Table 3.2), the clinician should have some hypotheses about what disorders might be accounting for the problem. During the interview, where the child is being asked about him/herself, fun things, friends, school, parents, what he/she thinks the problems are, and psychiatric symptom review/structured interview questions, the clinician is also observing the following to address the disorders under consideration: Appearance Separation from parents Relationship with familiar/unfamiliar people Activity level/impulse control Cognitive ability (including approach to tasks like copying, writing, reading) Language Thought process Thought content Mood/affect Neurologic status (handedness, fine and gross motor control, specific tasks if there is some sign or history of difficulty). In my experience as a specialty board examiner and a supervisor, the biggest gap in the young clinician’s diagnostic ability is the understanding of what one is supposed to be doing with the child/adolescent during the mental status examination. The mental status examination is often recited from memory with no idea of why one should or should not do ‘‘serial 7s’’ or a ‘‘draw-aperson.’’ Most surprising is the active avoidance of the obvious such as following up on leads provided by the patient or increasing the scope of the examination when a particular problem area has been identified. Table 3.1 outlines the evaluation process and Table 3.2 summarizes significant areas of the mental status that should be assessed for the major diagnostic categories. Baseline assessment for psychopharmacologic treatment

Over and above the information needed for diagnostic purposes, it is necessary to delineate which symptoms/behaviors are causing difficulty, which will then be the target of treatment. The more these behaviors can be operationalized in

Overly familiar with examiner

Relationship with examiner/parents Activity level

Possibly sullen and uncooperative

May have difficulty

Unremarkable

Unremarkable

Poverty of speech; poverty of content of speech; blocking; latency of response; ‘‘pseudo-intellectual’’ Words often slower than mind is thinking; Unremarkable Evasive; vague; irrelevant; illogical; verbally impulsive circumstantial; tangential; neologisms Nonspecific Often complains; power struggles Hallucinations; delusions; paranoid ideation Silly; inappropriate; unchanging facial Appropriate; often quite cheerful and Depends on how cooperative; may be playful euthymic; may be irritable, manipulative, expression; poor eye contact; fails to smile evasive or laugh when prompted; lack of vocal inflection (flat affect); suspicious; can appear ‘‘depressed’’ Recognition of inattention, hyperactivity, Distinguish impulsive/affective aggression Psychotic symptoms; depression; anxiety; physical symptoms easy boredom; anxiety, depression; from predatory aggression; distinguish from mania/depression/anxiety/PDD psychosis; grandiosity ‘‘Soft neurologic signs’’ Not relevant to primary diagnosis ‘‘Soft neurologic signs’’

Depends on if there is a comorbid learning disability; distractible (visual/auditory) Often problems with written language; in speaking, blurts out answers; interrupts

Disheveled; unkempt; bizarre; confused–perplexed May or may not have trouble depending on how withdrawn and disinterested May vary from disinterested to inappropriate; guarded; evasive May be overactive or underactive; inactivity is both lack of energy and lack of interest May be inattentive; vague

Schizophrenia

* Any of these disorders can co-occur with a learning disability which needs separate evaluation. ODD = oppositional defiant disorder; OLD = obsessive–compulsive disorder; PDD = pervasive developmental disorder. The above observations are not always present but should be looked for systematically.

Neuro status*

Symptom review

Mood/affect

Thought content

Thought process

Language*

Cognitive ability/attention*

Disinhibited; goes with strangers

Separation

Unremarkable

ODD/OCD

Physical restlessness; fidgety – out of seat; Unremarkable touches everything

Unremarkable to disorganized

Appearance

ADHD

Table 3.2. Mental status chart—a

Uncaring/oblivious; if PDD NOS, may be catastrophically anxious No eye contact; oblivious to examiner; withdraws from interaction attempt Very over- or underactive; whirls, flaps, hits self, rocks, toe-walks; aimless/disorganized Depends on how retarded; social/language much lower than motor abilities

Separation

Cognitive ability/attention

Relationship with examiner/ parents Activity

Depends on level of mental retardation if present

Appearance

PDD

Table 3.2. Mental status chart – b

Distractible; may seem smarter than is

Increased; may be purposeful but may not be; impulsive

Disinhibited; overly familiar; silly

Possibly disheveled; sometimes dressed outlandishly or sexually provocatively Age appropriate

Mania

May seem dull, distracted, indecisive

Not relevant to primary diagnosis

Won’t be able to separate; may have to do it gradually Very shy, slow to warm up; unassertive with examiner; clingy with parents Unremarkable to tense, fidgety

Age appropriate unless also has separation anxiety Lack of spontaneity; reponds but does not initiate Fewer spontaneous movements; long latencies; sluggish

Hypervigilant; tense

No smile; little facial expression; looks dejected

Depression

Anxiety disorders, separation anxiety disorder, social phobia etc.

Symptom review Neuro status

Mood/affect

Thought content

Thought process

Speech/ language

Cries, laughs, smiles without external stimuli; unpredicable outbursts; no facial expression Not applicable with child Neurodevelopmental signs; clumsy; odd sensory responses – sniffs, rubs, stares, covers ears, studies small details

May be absent; echolalic; poor voice modulation; pronoun reversal; odd words/jargon; sticks to certain topics; poor pragmatic language Concrete; in PDD NOS may be pedantic; poverty of content Doesn’t use toys appropriately; agitated by change

Rule out substance intoxication Not relevant to primary diagnosis

Irritable; labile; silly; giddy; clowning, playful; elated

Flight of ideas; disjointed thoughts; distracted responses Grandiose; paranoid; silly; check psychotic

Rapid/pressured speech which can appear disjointed; overproductive

Check for somatic symptoms and panic Not relevant to primary diagnosis

Grumpy/irritable; sad, blah, bored

Check for somatic symptoms Not relevant to primary diagnosis

Unremarkable

May be pressured; nervous laugh

Reflective of worry + fears; somatic complaints; check fears, phobias, panic; compulsions/ obsessions Hyperaroused; overcompliant

Self depreciatory; morbid; check psychotic symptoms; check suicidal/ homicidal

Limited; possibly slowed

Slowed speech; underproductive; response latency; quiet voice; mumbling

82

G.A. Carlson

Table 3.3. Behavioral variables sometimes amenable to pharmacotherapy Mental retardation self-abusive behavior – rarely aggression/hyperactivity – sometimes Autism/PDD self-abusive behavior – rarely aggression/hyperactivity – sometimes ‘‘withdrawn’’ behavior – sometimes Attention deficit/hyperactivity disorder inattention/distractibility – often hyperactivity/impulsivity – often aggression – sometimes Conduct disorder aggression (impulsive) – sometimes Anxiety disorders separation anxiety – sometimes panic attacks – often obsessions / rarely compulsions / sometimes Depressive disorders depressed mood – sometimes irritability – sometimes vegetative symptoms – often psychomotor retardation – often Psychosis/ schizophrenia ‘‘positive symptoms’’ – often ‘‘negative symptoms’’ – sometimes Mania hyperactivity – often volatility/irritability – sometimes psychosis – often

terms of intensity, frequency, and duration, the easier it will be to measure the impact of medication treatment. Table 3.3 lists behaviors that are frequently the object of treatment and this author’s experience with their responsiveness to psychopharmacologic treatment. In addition to rating the potential targets of treatment, it is also wise to obtain a baseline measure of potential side effects (which often merge with

83

Clinical aspects

disorder anyway). If you do not know a child’s bedtime, or how picky their eating is, or how often they get headaches, or whether they occasionally are still enuretic, it will be easy to attribute symptoms in these areas to medication side effects. Psychoeducational aspects There are two groups of children a psychopharmacologist is likely to see – those in need of medication but who have not yet begun treatment, and those referred already on a regimen that is not working adequately. Those who have not yet begun treatment need to understand the disorder being treated (i.e., its signs and symptoms), treatments available for the disorder, what happens if it is not treated, and why the clinician is suggesting the course of treatment he/she is suggesting. This needs to be put into plain English. If an informed consent is necessary, parent and older child need to be able to say back in their own words what their understanding is of the problem and its treatment. Harold Koplewicz, MD, has helped to simplify this task for many disorders with his book Its Nobody’s Fault (Koplewicz, 1996). He not only provides information about the medications likely to be used, he also describes in a language that ordinary people will understand how the various disorders present. For parents who consider medication treatment as the court of last resort, it may be sensible to recommend a trial of psychologic treatment with a time period built in such that a continuation of problems after x number of weeks warrants a reconsideration of medication. I like to recommend no more than 8–12 weeks. Often, psychotherapists themselves will request adjunctive medication to enhance the psychotherapeutic process. Fortunately, most people have progressed past the ‘‘either/or’’ philosophy of medication and psychologic treatment. When a child is referred having been partially treated, it is necessary to find out what kinds of treatments have been tried. Frequently, parents will say ‘‘we’ve tried everything.’’ It turns out that two stimulants have been used, at too low a dose and for too short a time. It is therefore necessary to have a careful accounting of what has been tried, and what results have accrued. This must also include the adverse effects experienced, the attitude of the child/ parent to the treatment, and the degree of adherence to previous treatments. One can then plan with the family whether it is appropriate to stop all medication and determine whether the medications used have simply not helped or if they have, in fact, worsened various problems. A flow sheet like that in Table 3.4 can be of use.

84

G.A. Carlson

Table 3.4. Medication flow chart

Medication + dose

Response (CGI score)

Methylphenidate/Ritalin

−3−2−1 0+1+2+3

dextroamphetamine/Dexedrine

−3−2−1 0+1+2+3

Other stimulants

−3−2−1 0+1+2+3

imipramine/Tofranil

−3−2−1 0+1+2+3

Other TCAs

−3 – 2−1 0+1+2+3

clonidine/Catapres

−3−2−1 0+1+2+3

guanfacine/Tenex

−3−2−1 0+1+2+3

Lithium

−3−2−1 0+1+2+3

valproate/Depakote

−3−2−1 0+1+2+3

carbamazepine/Tegretol

−3−2−1 0+1+2+3

clorpromazine/Thorazine

−3−2−1 0+1+2+3

thioridazine/Mellaril

−3 – 2−1 0+1+2+3

haloperidol/Haldol

−3−2−1 0+1+2+3

Other neuroleptics

−3−2−1 0+1+2+3

respiradone/Risperidal

−3−2−1 0+1+2+3

olanzepine/Zyprexa

−3−2−1 0+1+2+3

clozapine/Clozaril

−3−2−1 0+1+2+3

Other atypical neuroleptics

−3−2−1 0+1+2+3

fluoxetine/Prozac

−3 – 2−1 0+1+2+3

paroxetine/Paxil

−3−2−1 0+1+2+3

sertraline/Zoloft

−3−2−1 0+1+2+3

clomipramine/Anafranil

−3−2−1 0+1+2+3

Other antidepressants

−3−2−1 0+1+2+3

Combinations

−3−2−1 0+1+2+3 −3−2−1 0+1+2+3 −3 – 2−1 0+1+2+3 −3−2−1 0+1+2+3

Side effects/reason for discontinuation

85

Clinical aspects

Deciding which medication to use As can be seen in Table 3.5, there are several considerations to deciding what medication(s) should be tried and in what order. Targets of treatment and measures needed to quantify change have already been discussed. It is important to target psychosocial functioning separately from change in psychopathology. Although the two are related, it has become clear that symptoms remit long before change takes place in psychosocial functioning. In cases where the child had previously been a good student, or had decent peer relationships, remission of symptoms might enable a return to the previous level of functioning. If those areas had always been problematic, remission of symptoms enables focus to be put into these deficits, but one should not assume that they will automatically improve. They may require additional, specific psychosocial interventions. Other parts of the decision tree regarding medication selection include the amount of information available on the safety and efficacy of any specific medication in young people. Until recently, such data were rare. In fact, systematic data are still rare in children under the age of 12 for anything but stimulants and a few antipsychotic medications. Fortunately, in the United States, the Food and Drug Administration has mandated that this situation be rectified. A good psychopharmacologist will update his/her knowledge base periodically as information becomes available. This information is important to share with parents. A chart like that in Table 3.4 for major psychiatric disorders is one approach to organizing the information. The age of the child in question may impact on medication response. There is some evidence to suggest that preschool children, while responding to stimulant treatment, have higher rates of side effects than older children (Musten et al., 1997; Greenhill, 1998). This is also true for lithium in young children (Hagino et al., 1995). Children with early-onset schizophrenia respond less well to typical antipsychotic medication (Kumra et al., 1996). Whether these observations are the result of an earlier onset of disorder and, by implication, more severe disorder or whether there is something about the developing brain that leads to different medication responses is unknown (Vitiello, 1998). Clinically, however, it is wise to prepare oneself and the family for the fact that young children may be more complicated to treat with medication. Other issues that complicate treatment include the presence of multiple disorders, which is the rule rather than the exception for children requiring medication treatment. Some comorbidities respond to the same approach.

86

G.A. Carlson

Table 3.5. What to consider in initiating pharmacologic treatment for major depressive disorder Givens: 1. Accurate diagnosis 2. Adequate psychoeducation/patient preparation How to decide what medication to use: 1. What is the target of treatment? (e.g., major depressive episode) depressed mood – sometimes responds irritability – sometimes responds sleep/appetite symptoms – often respond low energy – often responds 2. How do you measure it? Children’s Depression Rating Scale (Poznanski et al., 1984): Hamilton is used but does not rate teen-appropriate behaviors Self-rating scales: (a) Childrens Depression Inventory (Kovacs, 1992); (b) Beck Depression Inventory (Beck, 1967); Depression Self Rating Scale (Birleson, 1981); (c) Visual analog scale for target symptoms; (d) Clinical Global Improvement Scale. Measure psychosocial function separately 3. What is known of therapeutic efficacy? Drug

Trial status

fluoxetine paroxetine sertraline fluvoxamine bupropion nefazadone

double-blind study – published double-blind study finished, abstract published 75% effective in many open studies; double-blind study; complete? double-blind study in OCD; not depression studied only in ADHD small, open study double-blind study planned small open trial – no better than placebo no information of any sort double-blind study planned

venlafaxine mirtazepine

4. What medications are best tolerated? 5. What has been tried already? 6. Concurrent other issues: Young child vs. older child vs. adolescent Comorbidity – medical and psychiatric Baseline labs should include: CBC; liver function tests; pregnancy test for sexually active females; EKG; thyroid-stimulating hormone

87

Clinical aspects

Table 3.5. (cont.) Environmental variables: A. Is the family receptive or hostile? If hostile, why? B. Does the family somaticize or deny? C. Is the drug being thought of as a ‘‘magic bullet’’ or facilitator? D. Will the drug be used at school? Home? Both? E. What is the effect of structure vs. no structure? F. Is there someone competent to administer and follow the medication? 7. Cost and availability.

Anxiety and depression, for instance, may respond to serotonin-specific reuptake inhibitors. Combined depression and ADHD may respond to a medication with dopamine and noradrenergic effects. An aggressive, manic young person may respond to medications which treat both aggression and mania. However, a child with tics and attention deficit, or with hyperactivity and anxiety, or with depression and psychosis may need more than one medication. Children with medical conditions which impair liver metabolism or renal clearance will need closer monitoring and possibly different medications than healthy children. Another common-sense consideration to decide which medication to select has to do with where and when medication will be used. Having someone competent to administer and follow the medication becomes more important as the type of medication becomes more complicated. One of the most useless contributions to child treatment is an inpatient admission where the discharge plan describes a regimen of administering four medications at five precise time points during the day, and returning a child to a single mother with two jobs, several children, and a 3-month follow-up at the local mental health clinic – this is a house of cards that will collapse on discharge. How long to treat

A final consideration in any kind of treatment is how long to continue it. Unfortunately, there are no child-specific studies to guide the clinician. Since the most serious psychiatric disorders in children are fairly chronic, it is safe to assume that medication treatment should not cease with the onset of response. Families are often concerned about the ‘‘will s/he need medicine for the rest of his/her life’’ question. That question should be anticipated in discussing the diagnosis and natural history of the disorder. Beyond that, it makes more sense to worry about how long treatment needs to be once remission of symptoms is achieved. The more protracted this period is, the more reluctant one should be to discontinue treatment prematurely. Treatment should be at least as long as

88

G.A. Carlson

the condition has existed and as long as symptoms continue. When the period of stability has allowed not only for symptomatic relief but also persistent psychosocial gains, it may be worth beginning to discuss medication discontinuation. Even then, discontinuation should be done with gradual cessation of medication, with parent and child knowledgeable about withdrawal symptoms and return of target symptoms, and with adequate supports in place. In other words, do not discontinue medication right before a child goes to overnight camp in the summer. In some disorders, such as schizophrenia, medication discontinuation may not be indicated. Summary Psychopharmacologic treatment of children has come a long way in the past 10 years. It still has a long way to go, however. The nagging concern we all have about the long-term effects of medication on the developing brain cannot be dismissed. What puts the concern in perspective is that the conditions we are treating are not trivial. With the rare exception of a parent with Munchausen By Proxy, almost no parent brings a child to a child/adolescent psychiatrist for no reason. The disorders are generally significantly impairing and, at least in this day and age, have often been addressed by another professional first with less ‘‘invasive’’ treatments. Additionally, the potential neuroprotective effects of medication on the developing brain should not be discounted. By making a careful diagnosis, it is possible to circumvent useless medication trials as well as giving the family confidence that the clinician is not merely ‘‘pill pushing.’’ By informing the family about the therapeutic efficacy and liabilities of medication, one can have a collaborative relationship rather than an adversarial one. Understanding the natural history of the disorders in question will inform the clinician about how long to continue treatment. Finally, it is important to remind oneself that illnesses, be they ‘‘medical’’ or ‘‘mental’’, are at the minimum inconvenient and, at the maximum, frightening and disabling. The medications we use, singly or in combination, have some empirical data to back them up, but not as much as we would like. A rule of thumb worth considering is – if I had a child or sibling with this disorder, would I allow him to be treated with this regimen? It has been my experience that families respond more to the honest answer to that question than to all of the data we can quote.

89

Clinical aspects

REFE R EN C ES Achenbach TM (1991). Manual for the Child Behavior Checklist. Burlington: University of Vermont. Achenbach TM, Edelbrock C (1987). Manual for the Youth Self-Report and Profile. Burlington: University of Vermont. American Psychiatric Association. (1980). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. Washington, DC: American Psychiatric Association. American Psychiatric Association. (1987). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn (revised). Washington, DC: American Psychiatric Association. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Beck AT (1967). Measurement of Depression: The Depression Inventory. Philadelphia, PA: University of Pennsylvania Press, Chapter 12. Birleson P (1981). The validity of depressive disorder in childhood and the development of a self-rating scale: a research report. J Child Psychol Psychiatry 22:73–86. Conners CK (1989). The Conners Rating Scales: Instruments for the Assessment of Child Psychopathology. Toronto, Ont: Multi-Health Systems. Edelbrock C, Achenbach TM (1987). Manual for the Teacher. Burlington: University of Vermont. Gadow KD, Sprafkin K (1995). Adolescent Supplement to the Child Symptom Inventor(ies) Manual, 3rd edn. New York: Dx Checkmate. Grayson P, Carlson GA (1991). The utility of a DSMIIIR-based checklist in screening child psychiatric patients. J Am Acad Child Adolesc Psychiatry 30:669–73. Greenhill LI (1998). The use of psychotropic medication in preschoolers: indications, safety, and efficacy. Can J Psychiatry 43:576–81. Hagino OR, Weller EB, Weller RRA, Washing D, Fristad MA, Kontras SB (1995). Untoward effects of lithium treatment in children aged four through six years. J Am Acad Child Adolesc Psychiatry 34:1584–90. Kaufman J, Birmaher B, Brent D, Rau U, Ryan N (1994). Schedule for Affective Disorders – Schizophrenia for School-aged Children (6–18 years) Kiddie SADS – Lifetime Version (K-SADS-PL). Pittsburgh, PA: Western Psychiatric Institute of Psychiatry, Division of Child and Adolescent Psychiatry. Koplewicz HS (1996). It’s Nobody’s Fault: New Hope and Help for Difficult Children and Their Parents. Toronto, Ont: Times Books/Random House. Kovacs M (1992). Children’s Depression Inventory – Manual. Toronto, Ont: Multi-Health Systems. Kumra S, Frazier JA, Jacobsen LK et al. (1996). Childhood onset schizophrenia: a double-blind comparison. Arch Gen Psychiatry 53:1090–7. Kutcher SP (1997). Child and Adolescent Psychopharmacology. Philadelphia, PA: WB Saunders. Levine MD (1998). Developmental Variation and Learning Disorders. Cambridge, Mass and Toronto: Educators Publishing Service. Musten LM, Firestone P, Pisterman S, Bennett S, Mercer J (1997). Effects of methylphenidate on preschool children with ADHD; cognitive and behavioral functions. J Am Acad Child Adolesc

90

G.A. Carlson

Psychiatry 36:1407–15. National Institute of Mental Health (1992). Diagnostic Interview Schedule for Children (NIMH DISC-C, P), Version 2.3. Orvaschel H, Puig-Antich J, Chambers W et al. (1982). Retrospective assessment of prepubertal major depression with Kiddie-SADS-E. J Am Acad Child Adolesc Psychiatry 21:392–7. Poznanski EO, Grossman JA, Buchsbaum Y, Banegus M, Freeman L, Gibbons R (1984). Preliminary studies of the reliability and validity of the children’s depression rating scale. J Am Acad Child Psychiatry 23:191–7. Reich W, Shayka JJ, Taibleson C (1991). Diagnostic Interview for Children and Adolescents (Parent and Child) DSMIIIR-version. St. Louis: Washington University Division of Child Psychiatry. Roberts MA (1990). A behavioral observation method for differentiating hyperactive and aggressive boys. J Abnorm Child Psychol 18:131–42. Vitiello B (1998). Pediatric psychopharmacology and the interaction between drugs and the developing brain. Can J Psychiatry 43:582–4.

4 Depression Neal D. Ryan Western Psychiatric Institute, Pittsburgh, Pennsylvania, USA

Child and adolescent depression: overview

Does child and adolescent depression exist?

Perhaps surprisingly, this was a contentious question as recently as 15 years ago. One influential line of thought argued that children did not have the cognitive development necessary to become depressed and, while they might have transient dysphoria, did not have long-duration, adult-like depressions. In fact, today’s best available estimates suggest that perhaps 2% of prepubertal children and 4% of adolescents may suffer depression at any one time (Fleming and Offord, 1990). Before puberty, there appears to be an approximately equal sex ratio, with an adult-type pattern of more depression in girls than boys beginning in adolescence. What is the naturalistic course? Is the course severe enough that treatment is warranted?

Obviously, if the naturalistic course is brief enough or mild enough, treatment with its costs and potential side effects may be unwarranted. The data suggest that child and adolescent depression is a persistent and recurring disorder. The natural course of clinic-referred depression appears to last 6–9 months on average with a significant minority lasting years (Kovacs et al., 1984a,b; Ryan et al., 1987). Most children and adolescents who suffer a single episode get future recurrent episodes and grow up to be adults with depression (Harrington et al., 1990, 1993; Kovacs et al., 1984 a,b; Weissman et al., 1999). Estimates from various studies suggest that about 20–40% of children and adolescents who have a first episode of major depression will turn out to be bipolar (Birmaher et al., 1996b). The phenomenon of ‘‘kindling’’ has been hypothesized to occur in adult unipolar depression – each episode of depression is thought to lower the threshold for future episodes so that prior depressions make future depressions more likely in the same individual. There are not yet strong data as to whether or not this occurs with child or adolescent depression, but it is, at least, a 91

92

N.D. Ryan

potential hazard. In adults, there appears to be more depression now than in prior decades (a secular increase) (Hagnell et al., 1982; Klerman et al., 1985) and the author and others have shown that there also appears to be more child and adolescent depression now than in the past (Kovacs and Gatsonis, 1994; Lewinsohn et al., 1993; Ryan et al., 1992). There is a high rate of attempted and completed suicide with child and adolescent depression, seen especially as these subjects are followed over time (Harrington et al., 1994; Rao et al., 1993; Ryan et al., 1987). During and after the acute episode, children and adolescents suffer impairment in their psychosocial functioning seen in school and with friends and family (Puig-Antich et al., 1985a,b). Even after recovery of the clinical episode, depressed youths have more other adverse health consequences and higher rates of smoking (Rohde et al., 1994). Who is at risk for child depression?

Child depression is strongly familial with depressed children having more depressed adult relatives and young depressed adults having more depression in their children than would be expected by chance (Puig-Antich et al., 1989; Weissman et al., 1984a,b; Williamson et al., 1995c). There are no available twin studies to help distinguish between family genetic transmission and family environmental transmission in children, but, in adults, depression appears to be both genetic (almost certainly involving several or many genes) and from nonshared environmental factors, with a relatively small contribution from shared family environment. Childhood adverse life events appear to play a role in the onset of depression both in childhood and subsequently (Kessler and Magee, 1993; Williamson et al., 1995a,b, 1996). In summary, depressive disorders in childhood and adolescence are protracted, recurrent illnesses which persist into adulthood. They are associated with suffering, functional impairment, and suicide both during the episode and afterwards. Current episodes may increase the hazard for future episodes. This is a morbid disorder strongly deserving of our best efforts at treatment. Child and adolescent depression: diagnosis

∑ ∑

To understand how to diagnose depression in children and adolescents we will address two questions: How does the clinical picture of depression change between childhood and adulthood? How does one adapt interviewing techniques for children?

93

∑

∑

Depression

Surprisingly enough, the answer to the first question appears to be that there is a relatively constant picture of the clinical syndrome of depression through development and into adulthood. In one large study by Ryan and colleagues (Ryan et al., 1987), a large sample of children and adolescents presenting to a research clinic were evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS) semistructured diagnostic interview. The frequencies of both the symptoms required for diagnosis and other depressive symptoms were examined to see how they varied with age and maturation. Of over 30 depression-related symptoms examined, two-thirds did not show age-related differences in their severity or frequency and only a third showed some differences. For example, there was no maturational effect on depressed mood, guilt, negative self-image, fatigue, concentration problems, anger, irritability, insomnia, or suicidal ideation. Prepubertal children showed a greater frequency of anxiety, somatic complaints, phobias, and depressed appearance, while adolescents showed more hopelessness and helplessness, anhedonia, hypersomnia, and lethality of suicide attempt. While there were differences between the age groups in the frequency of these particular symptoms, the differences overall were not very large. The frequency of all these symptoms also was similar to that reported in adult studies (Carlson and Kashani, 1988). At first, one might think that this is simply tautological – these symptoms were used to diagnose the children as depressed, so, of course, they had the same frequency of these symptoms. However, this is not the case because the associated depressive symptoms which were not used in the diagnosis also showed stability with age and, obviously, some of the symptoms used to make the diagnosis could still vary with age and yet the diagnosis still be met. In the same group of almost 200 children and adolescents, it appeared that the symptom factors (using principle component analysis) strongly paralleled those seen in adult depression with an overall endogenous factor, a factor for negative cognitions, and a factor for anxiety, among others. How then do we need to adapt our interview to elicit these symptoms? In the development of the K-SADS-P and its successor the K-SADS-PL, which is available at http://www.wpic.pitt.edu/ksads, the author and colleagues have suggested that the following are key to interviewing the child and adolescent who may have a depression successfully (Kaufman et al., 1997; Puig-Antich and Chambers, 1986): Obtain information from all sources of information particularly including the parent and child, but also including the school, prior medical and psychiatric charts, etc. Interview the parent without the child present and interview the parent before

94

∑

∑

∑ ∑

∑

N.D. Ryan

the child. The information that the parent conveys helps you to structure the interview with the child and helps you efficiently and completely to elicit symptoms from the child. If you interview the child first, there are whole periods of time that you do not know to ask about while, if you have the information of the parent, you can successfully get the child to tell you about these impaired or symptomatic intervals. Interview the child, if at all possible, without the parent or parents present who tend to inhibit the child’s full and frank discussion of symptoms. Ask the parent and child together to help you clarify large discrepancies and use your best clinical judgment on those items where the parent and child reports differ. For example, while in general the parents are likely to be better reporters of behavior and the child perhaps a better reporter of internal affect states, this varies from family to family. Use child-specific terms and use multiple terms for the same phenomena or affect state in case the child has not generalized the meaning of one term. For example, one child, when asked if he was ‘‘depressed’’, said no but then I went on to ask if he was ‘‘sad’’ (again he answered no) and then ‘‘blue’’ to which he responded in the affirmative. When asked to clarify, this 8-year-old boy said that he felt sad when his grandparent had died and now he felt a bad feeling, but it was a different one, so it was not ‘‘sad’’ but ‘‘blue.’’ It is frequently useful to develop a time-line using parent data and then to add data that the child provides. In general, start with an unstructured introductory interview during which you concentrate on what the child and family finds most problematic (the chief complaint). After the family and child understand that you are out to help them with what they identify as important, they will put up with the long stream of questions one needs to ask to elicit all the positive and negative symptoms. Especially with younger children, questions about time intervals have to be worded in a way that makes sense to the child. For example, intervals of weeks or months may be linked to external events in the year (e.g., the beginning of school, the child’s birthday, a particular holiday), while time intervals for an individual day may be linked to events within the day (e.g., ‘‘Does your depression last from breakfast time until lunch time?’’) rather than asking the child for the number of hours that she is blue every day. These are general guidelines which, overall, appear to be useful. However, the astute clinician will tailor the interview to the child and family, being sensitive to their language abilities, their cultural background, their degree of fatigue, especially as the evaluation goes on, etc. Overall reliability on the K-SADS and other instruments (Kaufman et al.,

95

Depression

1997) suggests that using methods such as this, the diagnosis of depression in children and adolescents could be made as reliably as these diagnoses are made in adults. Hypothesized central nervous system mechanisms Multiple central nervous system (CNS) mechanisms have been associated with depression in adults including the serotonin and noradrenaline neurotransmitter systems, the HPA axis and other stress-related endocrine systems, intracellular messengers and neurotrophic factors, and specific neurocircuitry (e.g., prefrontal cortical circuits) (Drevets et al., 1997, 1998). Early studies focused on monoamines after noting that drugs such as reserpine, which depleted monoamines, induced depression in many individuals and noting that most of the antidepressants discovered by trial-and-error affected monoaminergic systems, including monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). Further support for these hypotheses included evidence that these same monoaminergic systems were involved in those brain systems regulating sleep, appetite, and aggression. Despite this evidence and the remarkable productivity of the monoaminergic hypotheses of depression, after several decades of work it is still not entirely possible to make a hypothesis which accounts for the antidepressant effect of all antidepressants or the time course of all antidepressants with putative dysregulation of specific neurotransmitter systems. Other proposed mechanisms for depression have looked at dysregulation of second messenger systems including cAMP and neurotrophic factors (Duman et al., 1997). While consideration of hypothesized CNS mechanisms in the etiology and maintenance of depression will, hopefully, soon provide new therapeutic strategies, currently available and soon to be available agents have primarily been targeted at the monoaminergic system. Psychopharmacologic treatments for depression in adults The first pharmacologic antidepressant, discovered over 50 years ago, was an MAOI. Agents in this class are now third- or fourth-line agents in the treatment of adult depression and have been extremely rarely used in adolescent and child depression since (Ryan et al., 1988b). Therefore, the use of these agents in adults is not further discussed. TCAs have been available for approximately 40 years. The majority of studies of TCAs in adults have been of amitriptyline and imipramine with about two-thirds of studies showing these compounds to be significantly more

96

N.D. Ryan

effective than placebo and one-third failing to find medication superiority. In those finding medication superiority, in general, there is approximately a 30% drug minus placebo difference (Burke and Preskorn, 1995). The tertiary amine TCAs amitriptyline and imipramine are equally effective and are also, overall, equally effective as the secondary amine TCAs desipramine and nortriptyline (Burke and Preskorn, 1995). This is important because the tertiary TCAs are relatively serotonergic and the secondary TCAs are relatively more noradrenergic. Of note, and discussed below, in children and adolescents, because of the greater hepatic metabolism of the tertiary compounds compared with the secondary compounds, all of these agents are relatively noradrenergic. The selective serotonin reuptake inhibitors (SSRIs) are newer agents which offer a significantly better side effect profile and much less hazard of death with an accidental or deliberate overdose. They are significantly better than placebo and approximately equivalent in efficacy to the TCAs. Other agents include trazodone and nefazodone (both phenylpiperazines) and bupropion (an aminoketone), all of which appear to be effective antidepressants and roughly of equal efficacy to the TCAs or SSRIs. While the release of many new antidepressants is heralded by assertions that the particular antidepressant acts more rapidly than currently available agents, this has not in general proven to be the case. Available pharmacologic treatment shows a several-week delay between initiating treatment and significant improvement in the underlying depression. Currently available SSRIs in North America include fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram. While there have been considerable efforts to identify subgroups who may be more medication responsive or who may respond better to one pharmacotherapeutic approach than another, in general, this has not resulted in clear answers. Those with the mildest depressions (e.g., Hamilton Depression Rating Score under 12) may not show medication superiority to placebo. In part, this may be due to a floor effect; they just may not have enough room to demonstrate improvement so as to separate the medication effect out. The one area where the SSRIs may be superior to the TCAs in adult depression is the treatment of depression with comorbid anxiety (Montgomery, 1995). Adult depression unresponsive to the first pharmacologic agent may be treated by switching from one antidepressant to another in the same class, switching to another antidepressant in a different class, augmentation with lithium or thyroid hormone, or, less frequently, the use of MAOIs, electro-convulsive therapy, or other less well-studied pharmacologic approaches. Several theoretically based combination strategies have been put forward including combining a noradrenergic agent with an SSRI (Shader et al., 1997), or combining pindolol,

97

Depression

a potent 5-HT-1A receptor agonist, with SSRIs (Artigas et al., 1994, 1996; Blier and Bergeron, 1995). These approaches are theoretically interesting and clinically promising but require more investigation. Some of the newer agents including venlafaxine and mirtazapine may have a combination of neurotransmitter effects which in theory could result in superior efficacy or more rapid action (Shader et al., 1997). While one study has found venlafaxine superior to fluoxetine in melancholic major depressives (Clerc et al., 1994), in general, these agents need more investigation before such a hypothesis can be confirmed or refuted. Psychopharmacologic treatment of depression in children and adolescents: efficacy and tolerability Given the overwhelming evidence for efficacy of TCAs in adult depression, it is quite surprising that aggregating together controlled studies of TCAs in children and adolescents suggests that they may not work or, at best, may work much less well in youth. While the open clinical trials of TCAs in children looked promising, the available randomized controlled trials of TCAs in both children and adolescents have been essentially uniformly negative (Birmaher et al., 1996a). The total number of children and adolescents in these studies of TCAs is only a few hundred, most of the studies are small, and there are methodological issues which could limit generalizability and the ability to find medication–placebo difference in some of the studies. Nevertheless, combining all available data in a meta-analytic approach suggests a difference in efficacy from TCAs used in adults (Hazell et al., 1995). The recent reporting of a large randomized study of adolescent depression including imipramine and placebo cells (Keller et al., in press), which showed absolutely no evidence for superiority of imipramine to the placebo, does further reduce the estimated effect of these compounds. Several possible reasons for this asserted lack of efficacy of the TCAs have been advanced (Ryan and Varma, 1998). The TCAs are all relatively noradrenergic and relatively less serotonergic in children and adolescents than they are in adults because of the rapid metabolism. Thus, they may not have a necessary component for action in children where the serotonergic system matures relatively early but the noradrenergic system is not yet mature – and so may not yet offer the same opportunity for therapeutic intervention. Adolescents may be relatively more likely to show atypical symptoms of depression which may be relatively less TCA responsive because of the age of onset curves of bipolar vs. unipolar disorder. The onset of depression in childhood or adolescence has a higher chance of signaling

98

N.D. Ryan

eventual bipolar disorder, even though it is not yet diagnosable, than does the onset of a first depression in adulthood; some 20–40% of child- and adolescentonset depression may turn out to be bipolar. Such latent bipolar disorder may be less TCA responsive than a depression which continues to be unipolar over time. Since the tricyclic compounds are all off patent, it is unlikely that we will have more controlled data with these compounds in the treatment of depression in children because they are significantly more hazardous in overdose than the newer agents, even if they were effective, they would be second- or third-line treatment choices. Newer, more noradrenergic antidepressants will receive industry testing in child and adolescent major depression so we will, over the next few years, have data about the relative opportunity for noradrenergic vs. serotonergic pharmacologic strategies in this age group. SSRIs are clearly efficacious in the treatment of adult depression. Three randomized controlled trials of SSRIs in children and adolescents have been reported. The first (Simeon et al., 1990) failed to show superiority of fluoxetine vs. placebo in a relatively small study that had a high placebo and medication response rate. The second found a clinically and statistically significant superiority of fluoxetine to placebo in an 8-week trial (Emslie et al., 1997). The response rates (56% on fluoxetine and 33% on placebo) were similar to those seen in adult trials of antidepressants. The fluoxetine was superior to placebo beginning at week 5 of the trial. Both children and adolescents appeared to respond equally well. Recently, a multisite study of paroxetine vs. imipramine vs. placebo found statistical and clinical superiority of paroxetine to placebo and no superiority of imipramine to placebo (Keller et al., in press). There was one small placebo-controlled study of venlafaxine in children (Mandoki et al., 1997) which failed to show a superiority of the medication to placebo. A number of other industry-sponsored studies are ongoing and should be available soon. Due to a change in United States Food and Drug Administration regulations, it is likely that there will be efficacy trials in children and adolescents of more or all antidepressants that have become available in the United States recently or which will become available over the next several years. While MAOIs are efficacious in adult depression, there is very limited open experience with their use in child depression. The one open report (Ryan et al., 1988b) of irreversible MAOIs alone or used as augmentation with TCAs suggested that, at least openly, there was some possibility that they were efficacious. However, despite apparent efficacy in some children, there was still a significant hazard for accidental or deliberate dietary indiscretions. For most children, the hazards of these compounds may outweigh their

99

Depression

benefits and so they are very rarely used today in children or adolescents. There are scant data on lithium augmentation of TCAs in adolescents nonresponsive to TCAs (Ryan et al., 1988a; Strober et al., 1992). Other augmentation strategies, similarly, only have clinical anecdote to support them. Therefore, it is challenging to know what to do for the third- and fourth-line treatments in child or adolescent depression unresponsive to SSRIs or other modern antidepressants. The half-lives in adults of these compounds are as follows: fluoxetine has a half-life of 1–4 days with norfluoxetine having a half-life of 4–16 days (DeVane, 1992; Leonard et al., 1997); paroxetine has a half-life of about 24 hours with no active metabolites; sertraline has a half-life of about 24 hours, and the desmethylsertraline metabolite has a half-life of about 66 hours but is 5–10 times less potent than the parent compound; fluvoxamine has a half-life of 12–24 hours in adults; and citalopram has a half-life of about 33 hours in adults. All of these compounds are metabolized primarily in the liver and hepatic metabolism in children (e.g., 6–10 years old) may be about twice that seen in adults. These compounds are metabolized by cytochrome P450 isoenzymes with the 2D6 isoenzyme important in the metabolism of fluoxetine, paroxetine, and sertraline, the 3A3/4 isoenzyme important in the metabolism of fluoxetine, nefazodone, and fluvoxamine, 1A2 important in the metabolism of fluvoxamine, 2C9 important in the metabolism in fluoxetine, and the 2C19 isoenzyme important in the metabolism of fluvoxamine and fluoxetine. The most common side effects from these compounds include nausea, vomiting, diarrhea, agitation, headaches, insomnia, disinhibition, jitteriness, and tremor. Even taken in aggregate, the cardiovascular and gastrointestinal side effects of the SSRIs are much less frequent and severe than of the TCAs, while insomnia may occur with similar frequency to that seen in TCAs (Emslie et al., 1999). All of the SSRIs are relatively nontoxic in adults or children even when taken in large overdoses and deaths from overdose are extremely rare. There was one case reported of a 13-year-old boy who ingested 1.8 g of fluoxetine, suffered a tonic clonic seizure and had ST suppression on an EKG, but had a complete recovery (Riddle et al., 1989). In one analysis of deaths per million prescriptions in England (in adults), all the TCAs as a group were at least an order of magnitude more hazardous than all the SSRIs (Henry et al., 1995). Do SSRIs provoke suicide? Two meta-analyses strongly suggest that SSRIs do not lead to an increase in suicide and may, in fact, be somewhat protective (Beasley et al., 1991; Montgomery et al., 1995). A SSRI withdrawal syndrome has been described consisting of dizziness, anxiety and agitation, lethargy, fatigue, paraesthesia, nausea, insomnia, vivid

100

N.D. Ryan

dreams, irritability, and dysphoria. It can be mistaken as an exacerbation of depression especially if a short half-life SSRI is used. This syndrome may occur as early as a few days or as late as 1–2 weeks after discontinuation, it may occur despite tapering, and it may persist for up to 3 weeks. It is self-limited. In some individuals, the clinician may decide to restart the medication and taper it more slowly (Coupland et al., 1996). Sexual dysfunction including anorgasmia and impotence are not infrequent side effects of SSRIs. One needs to question directly the adolescent about this potential side effect, since he/she is not likely to tell you even if present. Open data suggest that bupropion may reverse this SSRI side effect (Balon et al., 1993) and other pharmacologic approaches have also been suggested in the literature. Behavioral activation or disinhibition appear to occur in about 20% of children treated with SSRIs and are dose related. Some children can be managed by decreasing but not stopping the medication. Mania may occur with SSRI treatment as well as with TCA treatment in children and adolescents. There is one report that it may be particularly frequent with adolescents with obsessive–compulsive disorder plus depression (Go et al., 1998). Clinical guidelines for psychopharmacological treatment of child depression

∑ ∑

∑

There is not yet a clear consensus in the field on the treatment of child and adolescent depression. For example, some experts would argue that a trial of psychotherapy should be tried before antidepressants at least in the more mild or moderate depressions, while others would suggest that medication and psychotherapy should be started simultaneously, and yet others suggest a trial of antidepressants first, with psychotherapy added to those who achieve less than optimal response. This particular question probably engenders more debate than any of the other questions surrounding current best practices. That being said, a reasonable treatment approach would consist of the following steps. Obtain a clear history including information from parents, teachers, and other sources to confirm the diagnosis of major depression. Explore the possibility of other syndromes that could be confused with the diagnosis of major depression, but might require different treatment – including sequelae of abuse, bipolar disorder, or medical condition. Consider a 1 or 2 week treatment delay with re-evaluation before starting treatment. It is not unusual to see the child or adolescent have enormous positive impact from the first evaluation. Obviously, this may not eventually be

101

∑

∑

∑

∑

∑

Depression

sustained, but clinical evidence suggests that, at least in some children, they will achieve a long-term sustained response simply from the evaluation and not require further treatment. This interval can be used for education of the child and family about this disorder. Treatment of first choice is frequently an SSRI. There is debate between experts as to whether this should be one of the two with some controlled trial evidence for efficacy (fluoxetine or paroxetine) or any of the group. Others would start venlafaxine or another novel antidepressant as the first treatment. As a result of the unfavorable side effect profile and lack of efficacy data, it is difficult to support the use of TCAs as a first-line treatment in children and adolescents. As a result of the more rapid metabolism seen in youth for the hepatic metabolic systems which form the main route of elimination of these compounds, children and adolescents generally require adult-type doses. Since the half-lives of the compounds are somewhat shorter in children, the dosage schedule should be at least as frequent in adults, particularly for those compounds with the shortest half-lives. While the effective dose appears to be an adult-like dose for most of these agents, increased anxiety and agitation in the first week after starting treatment is seen relatively frequently. Clinical experience suggests that starting with a low dose (e.g., 10 mg of fluoxetine) and then building up may avoid this unpleasant side effect. Barring clinically significant adverse side effects, treatment should be continued for at least 8 weeks and not more than 12 weeks before declaring failure if there is inadequate or little improvement. Without any available controlled research data in children and adolescents, the choice of what to do if the first pharmacologic agent is unsuccessful is derived from expert consensus and extrapolating from data in adults. Many clinicians would switch to a different SSRI or try venlafaxine, remeron, or bupropion.

Summary and conclusions In summary, depression in childhood and adolescence is a chronic, recurring, and highly morbid disorder associated with poor psychosocial functioning, suffering, and attempted and completed suicide. The current scientific database is certainly inadequate. Nevertheless, the average course of this disorder precludes taking the nihilistic approach, saying to oneself, ‘‘Since we don’t really know what to do yet, just wait.’’ Therefore, the clinician is compelled to use available research data, mixed with expert consensus and personal experience, to plan a treatment course.

102

N.D. Ryan

The role of psychotherapy and medication, which should be used first, and how they should be combined is a completely open question at present. There is one ongoing study, led by Dr. John March at Duke University, which addresses this question. No data will be available from that study for several years. Another ongoing study by Harrington and Goodyear in the UK is also expected to assist clinicians with regard to this issue within the next 2 years. Once a medication is to be used, an SSRI is most likely the first choice. In general, the SSRIs are used much like they would be in an adult with the most notable frequent differences being starting at a slightly lower dose (though going to a full adult-type dose) and making sure that the child does not have medication withdrawal given the shorter half-life of these compounds in children. Despite excellent and aggressive therapy with first antidepressant, a significant number of children, perhaps as many as 30–40%, will not have a sufficient response to the first SSRI treatment and so will require other medication or psychotherapeutic approaches. How to treat childhood depression which is unresponsive to the first-line treatment is, as yet, unstudied.

REFE REN C ES Artigas F, Perez V, Alvarez E (1994). Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 51:248–51. Artigas F, Romero L, de Montigny C, Blier P (1996). Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19:378–83. Balon R, Yeragani VK, Pohl R, Ramesh C (1993). Sexual dysfunction during antidepressant treatment. J Clin Psychiatry 54:209–12. Beasley CM Jr, Dornseif BE, Bosomworth JC et al. (1991). Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 303:685–92. Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J (1996a). Childhood and adolescent depression: a review of the past 10 years. Part II. J Am Acad Child Adolesc Psychiatry 35:1575–83. Birmaher B, Ryan ND, Williamson DE et al. (1996b). Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry 35:1427–39. Blier P, Bergeron R (1995). Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol 15:217–22. Burke M, Preskorn SH (1995). Short-term treatment of mood disorders with standard antidepressants. In FE Bloom, DJ Kupfer (Eds.) Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 1053–65. Carlson GA, Kashani JH (1988). Phenomenology of major depression from childhood through adulthood: analysis of three studies. Am J Psychiatry 145:1222–5.

103

Depression

Clerc GE, Ruimy P, Verdeau-Palles J (1994). A double-blind comparison of venlafaxine and fluoxetine in patients. Int Clin Psychopharmacol 9:139–43. Coupland NJ, Bell CJ, Potokar JP (1996). Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 16:356–62. DeVane CL (1992). Pharmacokinetics of the selective serotonin reuptake inhibitors. J Clin Psychiatry 53 (Suppl):13–20. Drevets WC, Ongur D, Price JL (1998). Reduced glucose metabolism in the subgenual prefrontal cortex in unipolar depression. Mol Psychiatry 3:190–1. Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824–7. Duman RS, Heninger GR, Nestler EJ (1997). A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606. Emslie G, Rush A, Weinberg W et al. (1997). A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–7. Emslie GJ, Walkup JT, Pliszka SR, Ernst M (1999). Nontricyclic antidepressants: current trends in children and adolescents. J Am Acad Child Adolesc Psychiatry 38:517–28. Fleming JE, Offord DR (1990). Epidemiology of childhood depressive disorders: a critical review. J Am Acad Child Adolesc Psychiatry 29:571–80. Go FS, Malley EE, Birmaher B, Rosenberg DR (1998). Manic behaviors associated with fluoxetine in three 12- to 18-year-olds with obsessive-compulsive disorder. J Child Adolescent Psychopharmacol 8:73–80. Hagnell O, Lanke J, Rorsman B (1982). Suicide and depression in the male part of the Lundby study. Changes over time during a 25-year observation period. Neuropsychobiology 8:182–7. Harrington R, Bredenkamp D, Groothues C, Rutter M, Fudge H, Pickles A (1994). Adult outcomes of childhood and adolescent depression. III. Links with suicidal behaviours. J Child Psychol Psychiatry 35:1309–19. Harrington R, Fudge H, Rutter M, Bredenkamp D, Groothues C, Pridham J (1993). Child and adult depression: a test of continuities with data from a family study. Br J Psychiatry 162:627–33. Harrington R, Fudge H, Rutter M, Pickles A, Hill J (1990). Adult outcomes of childhood and adolescent depression. I. Psychiatric status. Arch Gen Psychiatry 47:465–73. Hazell P, O’Connell D, Heathcote D, Robertson J, Henry D (1995). Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. BMJ 310:897–901. Henry JA, Alexander CA, Sener EK (1995). Relative mortality from overdose of antidepressants. BMJ 310:221–4. Kaufman J, Birmaher B, Brent D et al. (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–8. Keller M, Ryan ND, Strober M et al. (in press). Efficacy of paroxetine in the treatment of adolescent major depression: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. Kessler RC, Magee WJ (1993). Childhood adversities and adult depression: basic patterns of association in a US national survey. Psychol Med 23:679–90. Klerman GL, Lavori PW, Rice J et al. (1985). Birth-cohort trends in rates of major depressive

104

N.D. Ryan

disorder among relatives of patients with affective disorder. Arch Gen Psychiatry 42:689–93. Kovacs M, Feinberg TL, Crouse-Novak M, Paulauskas SL, Pollock M, Finkelstein R (1984a). Depressive disorders in childhood. II. A longitudinal study of the risk for a subsequent major depression. Arch Gen Psychiatry 41:643–9. Kovacs M, Feinberg TL, Crouse-Novak MA, Paulauskas SL, Finkelstein R (1984b). Depressive disorders in childhood. I. A longitudinal prospective study of characteristics and recovery. Arch Gen Psychiatry 41:229–37. Kovacs M, Gatsonis C (1994). Secular trends in age at onset of major depressive disorder in a clinical sample of children. J Psychiatr Res 28:319–29. Leonard HL, March J, Rickler KC, Allen AJ (1997). Pharmacology of the selective serotonin reuptake inhibitors in children and adolescents. J Am Acad Child Adolesc Psychiatry 36:725–36. Lewinsohn PM, Rohde P, Seeley JR, Fischer SA (1993). Age-cohort changes in the lifetime occurrence of depression and other mental disorders. J Abnorm Psychol 102:110–20. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL (1997). Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull 33:149–54. Montgomery SA (1995). Selective serotonin reuptake inhibitors in the acute treatment of depression. In FE Bloom, DJ Kupfer (eds), Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 1043–51. Montgomery SA, Dunner DL, Dunbar GC (1995). Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo. Eur Neuropsychopharmacol 5:5–13. Puig-Antich J, Chambers WJ (1986). Schedule for Affective Disorders and Schizophrenia for School-Age Children (6-18). K-SADS-P Fourth Working Draft. Puig-Antich J, Goetz D, Davies M et al. (1989). A controlled family history study of prepubertal major depressive disorder. Arch Gen Psychiatry 46:406–18. Puig-Antich J, Lukens E, Davies M, Goetz D, Brennan-Quattrock J, Todak G (1985a). Psychosocial functioning in prepubertal major depressive disorders. I. Interpersonal relationships during the depressive episode. Arch Gen Psychiatry 42:500–7. Puig-Antich J, Lukens E, Davies M, Goetz D, Brennan-Quattrock J, Todak G (1985b). Psychosocial functioning in prepubertal major depressive disorders. II. Interpersonal relationships after sustained recovery from affective episode. Arch Gen Psychiatry 42:511–17. Rao U, Weissman MM, Martin JA, Hammond RW (1993). Childhood depression and risk of suicide: a preliminary report of a longitudinal study. J Am Acad Child Adolesc Psychiatry 32:21–7. Riddle MA, Brown N, Dzubinski D, Jetmalani AN, Law Y, Woolston JL (1989). Fluoxetine overdose in an adolescent. J Am Acad Child Adolesc Psychiatry 28:587–8. Rohde P, Lewinsohn PM, Seeley JR (1994). Are adolescents changed by an episode of major depression? J Am Acad Child Adolescent Psychiatry 33:1289–98. Ryan ND, Varma D (1998). Child and adolescent mood disorders – experience with serotoninbased therapies. Biol Psychiatry 44:336–40. Ryan ND, Meyer V, Dachille S, Mazzie D, Puig-Antich J (1988a). Lithium antidepressant augmentation in TCA-refractory depression in adolescents. J Am Acad Child Adolesc Psychiatry 27:371–6.

105

Depression

Ryan ND, Puig-Antich J, Ambrosini P et al. (1987). The clinical picture of major depression in children and adolescents. Arch Gen Psychiatry 44:854–61. Ryan ND, Puig-Antich J, Rabinovich H et al. (1988b). MAOIs in adolescent major depression unresponsive to tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry 27:755–8. Ryan ND, Williamson DE, Iyengar S et al. (1992). A secular increase in child and adolescent onset affective disorder. J Am Acad Child Adolesc Psychiatry 31:600–5. Shader RI, Fogelman SM, Greenblatt DJ (1997). Newer antidepressants: hypotheses and evidence. J Clin Psychopharmacol 17:1–3. Simeon JG, Dinicola VF, Ferguson HB, Copping W (1990). Adolescent depression: a placebocontrolled fluoxetine treatment study and follow-up. Prog Neuropsychopharm Biol Psychiatry 14:791–5. Strober M, Freeman R, Rigali J, Schmidt S, Diamond R (1992). The pharmacotherapy of depressive illness in adolescence. II. Effects of lithium augmentation in nonresponders to imipramine. J Am Acad Child Adolesc Psychiatry 31:16–20. Weissman MM, Leckman JF, Merikangas KR, Gammon GD, Prusoff BA (1984a). Depression and anxiety disorders in parents and children. Results from the Yale family study. Arch Gen Psychiatry 41:845–52. Weissman MM, Prusoff BA, Gammon GD, Merikangas KR, Leckman JF, Kidd KK (1984b). Psychopathology in the children (ages 6–18) of depressed and normal parents. J Am Acad Child Psychiatry 23:78–84. Weissman MM, Wolk S, Goldstein RB et al. (1999). Depressed adolescents grown up. JAMA 281:1707–13. Williamson DE, Birmaher B, Anderson BP, al-Shabbout M, Ryan ND (1995a). Stressful life events in depressed adolescents: the role of dependent events during the depressive episode. J Am Acad Child Adolesc Psychiatry 34:591–8. Williamson DE, Birmaher B, Dahl RE, al-Shabbout M, Ryan ND (1996). Stressful life events influence nocturnal growth hormone secretion in depressed children. Biol Psychiatry 40:1176– 80. Williamson DE, Dahl RE, Birmaher B, Goetz RR, Nelson B, Ryan ND (1995b). Stressful life events and EEG sleep in depressed and normal control adolescents. Biol Psychiatry 37:859–65. Williamson DE, Ryan ND, Birmaher B et al. (1995c). A case-control family history study of depression in adolescents. J Am Acad Child Adolesc Psychiatry 34:1596–607.

5 Bipolar mood disorder: diagnosis, etiology, and treatment Vivek Kusumakar1, Lorraine Lazier2, Frank P. MacMaster1, and Darcy Santor1 1

Dalhousie University, Halifax, Nova Scotia, Canada Valley Regional Hospital, Kentville, Nova Scotia, Canada

2

Introduction Bipolar disorder in adolescents and children has recently become the focus of increasing study. Debate about its age of onset, phenomenology, comorbidity, course, outcome, and treatment is vigorous and yet, in many cases, still uninformed by sufficient evidence. The ‘‘classic’’ prototype of bipolar I disorder has emerged with some clarity in this population. Less is known about bipolar II or the spectrum of biphasic mood lability of mood dyscontrol. Diagnostic issues Epidemiology

There have only been a small number of reports regarding bipolar mood disorder (BMD) in children and adolescents. A retrospective study of adult BMD patients estimated that 0.5% had an age of onset of 5–9 years and 7.5% had an onset of 10–14 years when the first manic episode struck (Loranger and Levine, 1978; Geller et al., 1995). North American studies estimate the point prevalence at 0.2–0.4% for the prepubertal population and about 1.0% in adolescents (Lewinsohn et al., 1995; Zarate and Tohen, 1996; Bland, 1997) with no identified gender differences in prevalence. Diagnosis and phenomenology

Case reports of mania in preschool and prepubertal children have appeared dating back to the mid-19th century and early Greek writers identified this disorder as being of adolescent onset (Weller et al., 1995). However, explicit criteria to diagnose mania in children first came into practice only in 1960. Currently, DSM-IV (adult) criteria for bipolar disorder are used for children and adolescents without any modifications apart from minor modifications 106

107

Bipolar mood disorders

for the criteria of a major depressive episode, and the duration of symptoms for cyclothymia and dysthymia (American Psychiatric Association, 1994). Clinically, the major differential psychiatric diagnoses to consider are attentiondeficit/hyperactivity disorder (ADHD), conduct disorder (CD), and schizophrenia (Weller et al., 1995). ADHD has an onset in preschool with a chronic course and no psychotic symptoms. Any difficulty in sleeping in ADHD is not a change from the usual pattern. The behavior problems in CD are more hurtful and vindictive, with little or no guilt or remorse. Flight of ideas, pressured speech, or psychosis is not present, although children with CD may demonstrate suspiciousness, usually related to fear of getting caught. Schizophrenia has a more insidious onset, usually has a family history of schizophrenia rather than BMD, and presents with bizarre psychosis rather than manic affective symptomatology. The features providing the best distinction between BMD, and ADHD, CD, and oppositional defiant disorder are the presence of flight of ideas, grandiosity, and the episodic nature of the former (Carlson, 1996). Rapid cycling BMD and borderline personality functioning can pose a diagnostic challenge. However, the presence of biphasic mood difficulties, rather than uniphasic depressive symptoms, can support the diagnosis of BMD. Useful diagnostic instruments are the Diagnostic Interview for Children and Adolescents–Revised (DICA-R), Diagnostic Interview Schedule for Children (DISC), Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS), and the Mania Rating Scale. Developmental issues

Three main theories have been advanced to explain the major onset of bipolar illnesses in the decade following puberty (for a review see McMahon and DePaulo, 1996). These theories are triplet repeat expansion, mitochondrial damage, and age-related gene expression. It is believed that mitochondrial DNA damage is secondary to oxygen radicals. Damaged mitochondrial DNA alters cellular respiration and is especially detrimental to those cells with the greatest oxygen supply, such as neurons. When cumulative damage reaches a certain threshold, which may take years, the illness manifests. Research into age-dependent gene expression is only in the initial stages, but it has been suggested that gene expression is influenced by variables such as hormonal changes and exogenous chemicals. A number of developmental issues complicate the diagnosis of a mood disorder in children and adolescents. Undeveloped verbal communication skills hinder the interviewing process, and the clinician’s utilization of the observations of collateral informants becomes critical. Additionally, ADHD,

108

V. Kusumakar et al.

the disruptive behavior disorders, and BMD share many features, and the periods of peak onset for other phenomologically similar mental illnesses that may be confused for BMD occur during childhood and adolescence. During adolescence, normal developmental mood shifts may complicate the diagnosis of mood disorders (Golombeck and Kutcher, 1990). Substance abuse symptoms may lead to symptoms difficult to distinguish from manic or depressive states. Screening for illicit substances thus becomes a necessary laboratory investigation in the mood-disordered youth. Presentation in childhood and adolescence

The most common presentation in children and adolescents is not the classic picture seen in adults. In preadolescence, the course is characterized by mixed episodes, rapid/ultrarapid cycling, and ultradian or chaotic subthreshold biphasic mood dysregulation. Hence, the alternating episodes of depression and mania/hypomania are not easily identified, and may be mistakenly diagnosed as ADHD or another disruptive behavior disorder. Chaotic biphasic mood dysregulation may present without meeting diagnostic criteria for either depression or hypo/mania and may manifest for months to years through adolescence before the episodes become more clinically distinguishable. In the majority of adolescent-onset bipolar disorder cases, the initial episode is one of major depression (Kutcher, 1994). Kutcher et al. (in press), in a sample of adolescent-onset subjects, report that 75% experienced depression as the first affective episode, with a mean age of onset of 15.8 years. Interestingly, the mean age of onset for the first manic episode was 16.7 years. The majority of this sample presented with either mixed mania (74%) or a rapid cycling (76%) picture at the first manic episode. Although not well studied as yet, initial reports do indicate some differences in presentation noted between prepubertal children, adolescents, and adults (McGlashan, 1988; Weller et al., 1995; Sax et al., 1997). Prepubertal manic children may more commonly present with irritability and lability of mood, whereas adolescents are more likely to present euphoric, grandiose, and paranoid features. Prepubertal manic children with psychosis are more likely than adults to exhibit hallucinations, which are usually visual (70%) rather than auditory (50%). In reviewing DSM-III case reports, Carlson (1984) described differences between the presentations of BMD in young prepubertal children (15 months– 8 years old) and older prepubertal children (9–12 years old). Carlson (1984) found that younger children more commonly had comorbid disorders (especially hyperactivity); their manic/hypomanic phases were marked more by

109


irritability (as opposed to elation) and they lacked grandiosity or paranoia. The depressive phase in younger children was also predominantly irritable and lacked the ‘‘typical’’ adult features such as guilt and psychomotor retardation. The sample of older children presented in more ‘‘typical’’ fashion with more easily identifiable episodes of euphoria. Neither group demonstrated vegetative symptoms consistently in either phase; however, both groups did display distractability and pressured speech in the manic/hypomanic phase. In a comparison of 26 adult-onset ( 19 years old) and 28 adolescent-onset cases, McGlashan (1988) identified that the latter had more psychotic symptoms and were more likely to have been assaultive while psychotic and in trouble with the law. Certain symptoms in youths with major depressive disorder appear to predict BMD. They include positive family history for BP, combined with: sudden onset, psychomotor retardation, mood incongruent psychotic symptoms, and pharmacologically induced switch to hypomania or mania (Strober and Carlson, 1982; Papatheodoru and Kutcher, 1996). Misdiagnosis and underdiagnosis

Bowring and Kovacs (1992) present four reasons for the difficulty in diagnosing bipolar disorder in the child and adolescent population. They are as follows: (1) the low incidence rate in children may mean that the more common disorders, such as ADHD, may be preferentially diagnosed in a child presenting psychomotor overactivity or irritability; (2) there is considerable variance in presentation, both cross-sectionally and longitudinally; (3) the influence of developmental factors on clinical presentation, such as ‘‘excessive involvement in pleasurable activities that have a high potential for painful consequences’’ will differ in meaning or presentation between an 8 year old, 15 year old, and 30 year old, and the definition of grandiosity will be in flux for these ages, given that the definition for developmentally appropriate play and fantasizing differs throughout one’s lifetime; and (4) the commonality of symptoms associated with a variety of childhood disorders (especially ADHD) confuses the diagnostic process. Conventional perspectives have held that schizophrenia has an earlier age of onset than BMD and that BMD is rare in adolescents and is virtually unknown in childhood. These notions may explain why children and adolescents presenting with psychotic symptoms are commonly diagnosed with schizophrenia. Carlson et al. (1994) in their sample of 231 hospitalized psychotic patients (15–60 years old) found that more than 50% of youth BMD cases were initially misdiagnosed. An earlier study by Joyce (1984) produced similar results in that 48% of males and 69% of females with onset of affective disorder before the age

110

V. Kusumakar et al.

of 20 had been previously diagnosed with schizophrenia. Akiskal (1996) described the common reasons for misdiagnosis of BMD as schizophrenia as follows: (1) there is over-reliance on cross-sectional instead of longitudinal presentation; (2) incomplete inter-episode recovery is equated with schizophrenia; (3) bizarreness of psychotic symptoms is equated with schizophrenia; (4) clinicians presume irritability to be due to paranoid delusions; (5) clinicians often label depressive symptoms and apathy as negative schizophrenia symptomatology; (6) flights of ideas are misperceived as loosening of associations; and (7) there is the presumption that Schneiderian symptoms are diagnostic of schizophrenia psychosis. Comorbidity

Comorbidity in psychiatric conditions can be ‘‘true’’ (two or more separate disorders occur concurrently), ‘‘developmental’’ (one disorder leads to the development of another separate disorder while persisting), or ‘‘spurious’’ (diagnostic classification of symptom overlap or symptoms reaching ‘‘threshold’’ levels for more than one diagnosis, leading to multiple diagnosis instead of a single diagnosis). Apart from Kutcher et al. (1989) and Quackenbush et al. (1996), the available literature on comorbidity in juvenile BMD fails to deal with these categories. For example, West et al. (1996) examined 36 adolescents (12–18 years) hospitalized with an acute manic episode for comorbidity. Eightysix percent of the adolescent inpatients had at least one comorbid disorder (ADHD in 69%, substance abuse/dependence in 39%, anxiety disorders in 31%, Tourette’s syndrome in 8%, and bulimia nervosa in 3%). The onset of ADHD predated the onset of bipolar disorder by several years (average of 5.4 years) in the majority of cases with comorbid ADHD. The age of onset of bipolar disorder ranged from 4 to 18 years, with a mean age of approximately 11.5 years. Confusion regarding comorbidity can also occur if cross-sectional rather than longitudinal analyses are conducted. Similarly, retrospective accounting of symptoms and impairment is less likely to be valid than prospective evaluations. In some cases, prodromal symptoms of BMD may be mistakenly attributed to another diagnosis. The available literature exemplifies these confusions. For example, a number of authors describe a high degree of comorbidity between BMD and ADHD (Biederman et al., 1995; Geller et al., 1995; Wozniak et al., 1995; Faraone et al., 1997). Others, controlling for the above features, do not find similar comorbidities (Quackenbush et al., 1996; Kutcher, 1994; Reddy et al., 1997; Duffy et al., 1998, in press). CD (Kutcher et al., 1989), Tourette’s disorder (Kerbeshian et al., 1995), substance abuse (Maier

111


and Merikangas, 1996; Strakowski et al., 1996; Todd et al., 1996), and personality disorders (Kutcher and Marton, 1996) and some anxiety disorders have been described in BMD youth, but similar caveats to their ‘‘comorbidity’’ apply.

Etiology Etiologic models of potential importance to models of treatment of juvenile BMD include genetic, neurobiologic, psychosocial, and family environmental factors.

Genetics

There is suggestive evidence, arising from numerous studies using a variety of methods, including family studies, twin and adoption studies, and segregation, linkage, and association analyses (summarized in Alda, 1997), supporting a genetic basis for BMD. Concordance for BMD in monozygotic twins is estimated to be as high as 79% (Bertelsen et al., 1977; Reus and Freimer, 1997). Several chromosomal regions have been implicated in BMD including X, 4p, 5p, 6, 11p, 13, 15, 16p, 18p, 18q, and 21q. It should be noted that the findings for several of these studies have not been replicated, or were not supported by subsequent studies (Alda, 1997). The chromosomes showing the most promise currently appear to be 18 and 21. Studies of chromosome 18 are suggesting separate loci, one of which is believed to be dominant and paternally transmitted (Alda, 1997; Reus and Freimer, 1997). Anticipation is the worsening of illness severity and an earlier age of onset seen in successive generations (Alda, 1997). This has been suggested for several medical disorders and neurologic conditions, as well as schizophrenia and BMD. Anticipation is associated with genetic mutations involving an expansion of trinucleotide repeat sequences (Alda, 1997). Genetic imprinting is the differential gene expression depending on whether the illness is transmitted maternally or paternally (Grigoroiu-Serbanescu et al., 1995); this is believed to be the result of methylation during meiosis (Alda, 1997). The presence of anticipation or imprinting phenomena in BMD has been suggested by genetic studies conducted by Mendelwicz and colleagues (1997), MacInnis et al. (1993), and Grigoroiu-Serbanescu et al. (1997). For a more detailed summary of genetic factors, see Reus and Freimer (1997), Alda (1997), Rutter (1997), and Lombroso et al. (1994).

112

V. Kusumakar et al.

Neurobiology

Laterality Flor-Henry (1986) identified the bilateral orbital and mesial frontal regions and the nondominant fronto-temporal region as centers for affective expression and mood regulation. An increased prevalence of sinistrality in the offspring of bipolar patients in the absence of familial sinistrality is suggestive of subtle damage to the left hemisphere. This damage results in a compensatory preferential use of the left hand and visuospatial deficits. Furthermore, it is also suggested that subtle left hemisphere dysfunction is associated with a decrease in right hemisphere inhibition by the left hemisphere. The result of this imbalance is affective dysregulation. Mania is hypothesized to be related to the failure of the nondominant hemisphere to control/inhibit the dominant hemisphere. The reverse is hypothesized for the depressive phase of the illness. Neuroimaging A review of the mood disorders neuroimaging literature proposes a model including circuits involving the prefrontal cortex, mediodorsal thalamus, amygdalaen hippocampus complex, ventral palladium, striatum, and cerebellum (Soares and Mann, 1997). A lesion at any region in this circuit could hypothetically result in a primary dysregulation of mood or a vulnerability to mood disorders in the face of environmental stressors. The lesion could be developmental or acquired. The evidence favors localized abnormalities as opposed to generalized or global disease (Soares and Mann, 1997). There is evidence of ventricular enlargement in some BMD cases, and subcortical white matter and periventricular hyperintensities have been identified in some BMD patients. Observed on spin-echo (T2) weighted images, they are related to histopathologic abnormalities such as myelin pallor, small vascular malformations, dilated perivascular spaces, lateral ventricle diverticula, minute cysts, infarctions, and necrosis (Awad et al., 1986; Kirkpatrick and Hayman, 1987; Braffman et al., 1988; Marshall et al., 1988; Grafton et al., 1991). Their exact significance in the pathoetiology of BMD is not known. Structural abnormalities of frontal lobes have been detected in adult BMD patients (Drevets et al., 1997, 1998; Ongur et al., 1998; Sax et al., 1998). Temporal lobe changes have been identified, but the results have not been consistent with regards to volume or lateralization. Some evidence suggests cerebellar atrophy in both unipolar and bipolar individuals. Although a smaller corpus callosum has been detected in psychotic BMD, consistent with similar findings in schizophrenia (Coffman et al., 1990), it appears normal in aggregated studies of all subtypes of BMD (Hauser et al., 1989). The general consensus is that mania is associated more commonly with right hemispheric

113


lesions, whereas depression is more commonly associated with left (especially frontal) hemispheric lesions (Soares and Mann, 1997). Studies involving children and adolescents are sparse. Botteron et al. (1995) compared eight (8–16-years-old) manic patients and five controls using T1 and T2 weighted magnetic resonance imaging (MRI). Four (50%) of the eight BMD group demonstrated abnormalities on scanning, as compared with one (20%) of the control subjects. The sample was too small to demonstrate statistical significance. The petalia (an indication of cerebral asymmetry) appeared to be different between the two groups. In a retrospective review of MRI scans, Woods et al. (1995) compared 52 bipolar (DSM-III-R) patients (14–65 years old) and 38 controls (21–65 years old). Controls had no history of major psychiatric illness in themselves or their first-degree relatives. MRI scans were scored for deep white matter hyperintensities (DWMH), periventricular hyperintensities (PVH), ventricular enlargement, and sulcal widening. The BMD group had significantly higher total, DWMH, and PVH scores. There was also a positive correlation between age and each of these scores. However, several methodological limitations were present and the meaning of these findings is unclear. More recently, Friedman et al. (1999), compared 20 patients with schizophrenia and 15 patients with BMD (10–18 years old) with 16 normal adolescents. No differences between BMD and schizophrenia groups were observed. Both patient groups, when combined, had reduced intracranial volume and increased size of frontal and temporal sulci. Electrophysiology An electrophysiologic investigation of 11 pairs of same-sex siblings (16–62 years old), with one of each pair having received a diagnosis (DSM-III) of bipolar affective disorder (Knott et al., 1985), showed that the BMD siblings spent a significantly smaller percentage of time in alpha wave activity on EEG. Significantly larger positive auditory-evoked potential at 40–60 ms was also demonstrated. It was concluded that these results suggest hyperarousal in the brainstem and hippocampus. Knott et al. (1985) supposed that these characteristics represented a vulnerability trait as opposed to a state-dependent feature of the illness as all of the bipolar subjects were free of symptoms at the time of testing and only three had received medication in the month prior to the study. Cognition Cognitive impairment has typically been associated with schizophrenia and considered uncommon in BMD, although some studies suggest otherwise (Coffman et al., 1990; Albus et al., 1996). In these investigations, BMD

114

V. Kusumakar et al.

individuals with psychotic symptoms demonstrated both visuomotor and attentional difficulties. Similarly, in a study of bipolar I youth followed up for a mean of 4.5 years following their first manic episode, Robertson et al. (1998) demonstrated that the BMD group differed significantly from controls on WISC (Wisconsin Card Sorting Test) III raw score verbal, performance, and full scale analysis. A number of subscales thought to measure executive functioning (such as coding, symbol search, picture arrangement, and processing speed index) were found to be particularly compromised. As there is evidence of cognitive impairment early in the course of psychotic BMD, it can be surmised that these persons may present with academic difficulties. Kutcher et al. (in press), in a series of studies of a cohort of adolescent-onset bipolar patients, have described a number of academic problems. Although this group was characterized by good to excellent academic functioning prior to onset, after a mean illness length of 4.6 years, academic achievements were significantly decreased compared with age- and sex-matched controls (Quackenbush et al., 1996; Robertson et al., 1998; Kutcher et al., in press). Female BMD subjects were more severely affected in terms of grade delay (Robertson et al., 1998). Reading and spelling ability (as assessed by the Wide Range Achievement Test [WRAT]) did not significantly differentiate bipolars from controls. Of interest is that mathematical achievement and mathematical scores on the WRAT-R2 were significantly below that of controls (p = 0.009) (Bird et al., 1998). Quackenbush et al. (1996) have outlined a number of useful school-based educational interventions for this group as specific remedial educational programs may be necessary for young people with bipolar disorder. Psychosocial factors

Separation or loss of attachment figures prior to puberty have been linked with adult-onset depression, but not specifically to BMD, as current hypotheses suggest that early-onset BMD may be more influenced by genetic factors than is late-onset BMD. Psychosocial functioning in bipolar youth has been described premorbidly and postillness onset (4.6 years) in a cohort of BMD I teenagers. BMD I illness persons in the teen years demonstrate a relatively high level of premorbid peer relationships (Quackenbush et al., 1996; Kutcher et al., in press). These high premorbid function findings are consistent with those reported by Werry et al. (1991) and Reddy et al. (1997). After a mean illness duration of only 4.6 years, significant difficulties in peer relationships compared with normal controls arose. Problems included attitudes towards school, teachers, and peers; lower self-esteem; fighting; feeling excluded; and attention

115


seeking (Robertson et al., 1998). Thus, it may be concluded that it is indeed the illness that negatively impacts on peer relationships, and that it may cause personality dysfunction when present during critical stages of personality development. Therapeutic interventions directed at psychosocial functioning need to be incorporated into illness management strategies. Family

Robertson et al. (1998), in a longitudinal follow-up study of a sample of 44 adolescent bipolar I (DSM-IV) subjects, did not find significant differences between patients and controls with respect to either relationship with mother or relationship with father. A significantly increased level of minor conflicts with parents (p = 0.004) and significantly poorer relationships with siblings (p = 0.05) were reported. Family cohesion, as reported by the bipolar subjects, and family adaptability as measured by Family Adaptability and Cohesion Evaluation Score (FACES II) showed that they were significantly more likely than controls to report families as less connected (p = 0.05), but there were no significant differences in family adaptability; youth to parent communication, also, did not differentiate groups. These findings suggest that there is little evidence of severe family dysfunction that could be specifically attributed to BMD. Hence, family functioning is unlikely to be a primary etiologic factor for BMD in young people. Problems with family functioning are more likely to be a result of the disorder itself. Clinical implications from these findings are supportive of the need for family psychoeducation and supportive interventions rather than for any explorative family therapy that assumes that family functioning issues have primary etiologic significance. Treatment of bipolar mood disorder in young people Establishing a therapeutic relationship

As BMD is a recurrent, relapsing, and chronic condition, a longitudinal approach to therapy is the cornerstone of effective treatment (Kusumakar et al., 1997a). Goals of the therapeutic relationship should include: (1) the recognition of symptoms and dysfunction early (so effective interventions can be instituted early to control symptoms); (2) prevention of deterioration; and (3) promotion of healthy development and achievement of reasonable functioning. Family involvement is essential in understanding the illness and the scope and limitations of treatment interventions. Just as the patient requires support, so do families need help to cope with the burden of illness. BMD in a young person can pose many challenges to families’ emotional energy and financial reserves,

116

V. Kusumakar et al.

and it is not uncommon for more than one family member to be affected by a psychiatric disorder. As families can play a major role in the promotion of treatment adherence in the young person, the early detection of symptoms and or dysfunction, support of healthy functioning, and an inclusive therapeutic approach are needed. Discordant family relationships and attitudes can jeopardize healthy supports for the young person, decrease treatment adherence, and, also, increase stress in an already vulnerable young person. For effective long-term treatment, a relaxed and supportive relationship with the young person, which promotes open dialog, is an important interpersonal foundation. Young people may be unwilling and reluctant attendees at the clinic. It may take many months to years before the young person and the clinical team develop an effective relationship. As illness and treatment can conflict with the quest for autonomy, the young person may experience the treatment itself and the clinical team as a further restriction. The clinician should be prepared to contain and deal with passive–deferential attitudes or even oppositional–defiant stances. Some of these attitudes and behaviors may be part of the young person coming to an accommodation with the illness and treatment. The professional jargon used by healthcare professionals can be a barrier for the young person and families, so simple and clear (but not slang) language should be used. Teens with BMD may go through stages of denial, fear, self-blame or blaming others, and despair before learning to become active participants in the management of the illness. This may, at various stages, create unhealthy demands on or rejection of one or more interventions. Clinicians and team need to help the young person, family, and significant others understand the recurrent and fluctuating nature of BMD, the associated morbidity and mortality, and the opportunities presented by participation in effective treatment. Effective and empathic management of feelings of denial, guilt, self-blame, and hostility can improve the potential of a collaborative and individualized treatment plan. It is also critical to assist the young person and family to identify a supportive network of people who will help the young person seek, and continue in, treatment. Young people and families benefit significantly from making plans that, while instilling hope, are directed toward realistic and attainable goals with regards to school, relationships, and other activities. They may require active assistance to maintain key relationships in school or work situations. Issues of transference, countertransference, and challenges to interpersonal boundaries are likely to impact positively and negatively at different times on the therapeutic relationship, even though clinicians may not see themselves as

117


offering formal individual or family psychotherapy. The importance of these relationships in effective treatment should not be underestimated. Kutcher et al. (in press), in a consumer-based study of bipolar teenagers, identified that the most useful therapeutic intervention reported was the young person’s relationship with nursing and medical staff. Psychoeducation and psychotherapy

The value of psychoeducation and psychotherapy as an adjunct to medication cannot be overemphasized. Many young people experience subthreshold dysfunction in emotions and behavior, even when their symptoms are apparently under control. They may have also suffered a decline in scholastic and relationship functioning. It is not uncommon for there having been months, if not years, of different diagnoses and unsuccessful attempts at treatment before a diagnosis of BMD is made and appropriate treatment initiated. Families often experience considerable frustration, loss of hope, and inappropriate labeling of their problems during this protracted pathway into appropriate care. Hence, psychoeducation should form a core element of psychosocial support and intervention. Psychoeducation is best received after a degree of stability has been achieved in the acute phase of either a mania or depression. While there are no specific studies of the effectiveness of psychoeducation in young people and their families, clinical experience suggests that psychoeducation can increase the potential for a relationship between the young person, family, and the treatment team, improve treatment adherence, and allow for early detection of symptoms of relapse or recurrence. With reduced hospital admissions, improved compliance with medication, and increased family support, there is considerable support for the effectiveness of psychoeducation in adult bipolar patients (Cochran, 1984; Harvey and Peet, 1991; Peet and Harvey, 1991; Huxley et al., 2000). Psychoeducation should consist of the following: (1) clinical presentations; (2) diagnostic criteria; (3) the recognition of subsyndromal symptoms; (4) lifestyle factors that affect mood and functioning; (5) the course of illness with and without treatment; and (6) the beneficial and adverse effects of medication, electro-convulsive therapy (ECT), and psychosocial treatments. Both interpersonal therapy (IPT) and social rhythm therapy attempt to unify the social and interpersonal models of mood disorder, and the rhythm stability hypothesis (Miklowitz et al., 1996). The latter hypothesis proposes that mood regulation is in part a function of regular daily activity and social stimulation patterns, as these patterns affect biologically based circadian rhythms. In adults, preliminary evidence suggests that this therapy, as an adjunct to medication, is associated with improved regulation of daily rhythms and functioning (Frank et

118

V. Kusumakar et al.

al., 1997). Results of interpersonal therapy trials, using IPT (Klerman–Weissman model) in young people with unipolar depression and bipolar disorder, are beginning to demonstrate the value of this type of treatment (Muffson et al., 1999; Santor and Kusumakar, 1999). The cognitive–behavior therapy (CBT) literature is scant, although there is growing evidence of its possible efficacy in young people with unipolar depression (Harrington et al., 1998). Healthy daily routines, good sleep hygiene, and reduction or discontinuation of alcohol, substances, caffeine, and nicotine can be beneficial, particularly in rapid cycling or mixed states. Acute mania, mixed states, and rapid cycling

Significant numbers of young people (approximately two-thirds) with mania present with atypical features (marked by irritability rather than euphoria), mixed states, and/or have a rapid cycling course of illness (Ryan et al., 1987; Kutcher, 1993; Geller et al., 1993; Kutcher, 1994). Conditions such as acute mania and mixed state, particularly dysphoric mania, may carry with them the danger of risk-taking behaviors and self-harm. An inpatient admission is often required to help stabilize the patient and to provide a safe environment while initiating antimanic treatment where a team evaluation can not only clarify diagnoses and comorbidity by using instruments like the K-SADS-PL (Kaufman et al., 1997), but also assess the range and severity of symptoms with an instrument like the Modified Mania Rating Scale (MMRS; Blackburn, 1977) or the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962). There is little evidence for the need for extensive laboratory investigations in the absence of findings on a good history and physical examination. However, most clinics conduct a complete blood count including platelets, serum electrolytes, liver enzymes, thyroid-stimulation hormone, serum creatinine, urine analysis, and urine toxicology for substance use (Kusumakar et al., 1997a,b). A serum pregnancy test should be done as clinically indicated. Antimanic treatment should be initiated within 72 hours of the manic or mixed episode being diagnosed. Highly belligerent or combative patients can benefit from a low stimulus environment and sedating medications that can be administered orally or parenatally, such as lorazepam, chlorpromazine, or clopenthixol. In some patients, lorazepam can exacerbate disinhibition, while neuroleptics can produce acute dystonic reactions. Despite evidence that lorazepam, chlorpromazine, and clopenthixol have antimanic effects, they should only be used in the short term. In extreme cases, electroconvulsive therapy (ECT) may be necessary to deal with an extremely disturbed patient. Considerable debate exists regarding the use of antipsychotics in mania with

119


psychotic symptoms. In a review of adult studies, Kusumakar et al. (1997a,b) found that there appears to be reasonable evidence that lithium and divalproex have therapeutic effects even in the presence of mood congruent psychotic symptoms within a mania or dysphoric manic mixed state. There are few published data, however, on the effects of mood stabilizers on bizarre or mood incongruent symptoms in mania or a mixed state. There is growing evidence for the efficacy of the newer generation of neuroleptics (olanzapine, risperidone) in acute mania with or without psychotic symptoms in adults and young people (Segal et al., 1998; Tohen et al., 1999; Kusumakar et al., 1999). Significant adverse effects that may negatively affect compliance in young people using these medications are dramatic weight gain, with both olanzapine and risperidone, and galactorrhea with risperidone (Kusumakar et al., 1997b). No published double-blind placebo-controlled study of the antimanic effects of mood stabilizers in mania in young people has yet been completed, but there are currently studies under way with both lithium and divalproex in adolescent mania. Strober et al. (1988, 1995) studied two sets of adolescents who were treated with lithium during acute mania and found that 68% responded well to this medication, while preadolescent mania was less responsive. While lithium can be effective in pure adolescent mania, it has a narrow therapeutic range, with reduced efficacy below 0.8 mmols/l, and increased adverse effects above 1.1 mmols/l. Lithium can be lethal in overdose. Lithium likely has a shorter half-life in children than in adults due to more efficient renal clearance in children (Vitiello et al., 1988), the onset of action of lithium can be from 7 to 14 days, and patients do not tolerate oral loading doses of lithium. Hence, it can take days to weeks to achieve therapeutic levels with lithium. Lithium doses can be titrated either by using a nomogram technique (Cooper et al., 1973; Fetner and Geller, 1992) or a linear proportional titration technique (Fetner and Geller, 1992) using the first serum lithium level and total daily dose as a baseline. The predictors of lithium response include pure mania, family history of response to lithium, and mania as the first mood disorder episode. The predictors of lithium nonresponse include mixed states, rapid cycling, and depression as the first mood disorder episode (Kusumakar et al., 1997b). Due to the narrow safety range of lithium, it is not a drug of choice in impulsive, actively suicidal young people, or in chaotic families where the monitoring of serum levels and side effects can be problematic. Commonly reported side effects of lithium by young people include acne, tremor, weight gain, and cognitive side effects (‘‘fog in the head’’). Cognitive impairment due to lithium treatment has been well documented in children with aggression and depres-

120

V. Kusumakar et al.

sion (Silva et al., 1992; and Geller et al., 1994, respectively); long-term use is associated with hypothyroidism, and there is an increased risk of renal dysfunction in patients who have a history of overdose on lithium, and/or family or personal history of renal disease. In open studies with adolescents, divalproex sodium (DVP) has been shown to be potentially effective (Papatheodoru and Kutcher, 1993) and there are data in adult mania showing that DVP and lithium are equal in efficacy and superior to placebo (Bowden et al., 1994). DVP is well tolerated in loading doses of 20–30 mg/kg per day in mania in adults as well as in adolescents (McElroy et al., 1996). Although there is no set therapeutic range for DVP, published data show it to be less effective when serum levels are below 45 grams/ml (approximately 350 mmols/l) and it is associated with increased adverse effects when serum levels exceed 125 grams/ml (approximately 800 mmols/l) (Bowden et al., 1994). In adult studies, DVP is efficacious in pure mania, mixed states, and rapid cycling bipolar disorder (Kusumakar et al., 1997b). Adolescents generally tolerate DVP better than lithium. This also results in better compliance with DVP compared with lithium. With DVP, lithium, and carbamazepine monotherapy, weight gain is reported. Reports of hepatic failure with DVP are primarily in preadolescents on polypharmacy regimens. Blood dyscrasias with DVP are as rare as with tricyclic antidepressants (TCAs) and transient thrombocytopenia is a well-recognized phenomenon associated with DVP treatment. Thrombocytopenia may warrant a discontinuation of medication if it is persistent, severe, and/or clinically relevant. It has been reported that young females receiving valproic acid for epilepsy are significantly more likely to develop obesity and polycystic ovary syndrome when compared with those not being treated with DVP (Isojarvi et al., 1993, 1996). Young female patients should be monitored carefully as the relationship between BMD, treatment with DVP, obesity, and polycystic ovary syndrome warrants further study. There are published data with adult manics treated with carbamazepine, but there is only limited evidence of the efficacy of carbamazepine in adolescents with BMD. The efficacy of carbamazepine in lithium-resistant adolescents has been noted (Himmelhoch and Garfinkel, 1986). There is no proven serum therapeutic level for carbamazepine and moderate to severe blood dyscrasias have been noted in up to 2.1% of psychiatric patients treated with carbamazepine (Tohen et al., 1995). Dermatologic complications can also be problematic and can be heralded by a delayed-onset rash. There are few available data of the efficacy of the newer generation of anticonvulsants, such as lamotrigine and gabapentin, in adolescent mania.

121


A variety of strategies can be used for the ultra-rapid or ultradian cycling young person. Four out of five adolescents with chaotic ultradian biphasic mood cycling responded to a ‘‘long night’’ treatment paradigm, where they were asked to go to bed in a darkened environment from 7 pm to 7 am each night for 4 weeks (Kusumakar et al., 1999). This technique not only helped the young people stabilize their chaotic moods, but also improved their sleep patterns. Lamotrigine, which should be used with great caution in young people, has also been used successfully in monotherapy in eight adolescents with refractory rapid cycling bipolar II disorder, and in the presence of concomitant obsessive– compulsive symptoms (Kusumakar and Latham, 1997; Kusumakar et al., 1999). Five out of eight of these young people showed more than 50% improvement not only in their mood dysfunction but also with their obsessive–compulsive symptoms. In a more recent open study in six adolescent girls, with ultradian rapid cycling bipolar I and II disorder and moderate to severe obesity developed while on previous mood stabilizer treatment, were treated with topiramate augmentation of a primary mood stabilizer treatment. Three of these young women attained significantly greater mood stability, while four of them lost more than 5% weight within 16 weeks (Kusumakar et al., 1999). For a patient on maintenance treatment, the emergence of severe insomnia or hypomanic symptoms can herald a full-blown mania, and the use of benzodiazepines both to help with sleep and manic symptoms is a reasonable intervention. There is no evidence, either from published literature in adult bipolar disorder and epilepsy, that serum medication levels, blood counts, and liver functions require to be conducted frequently. Once two consecutive serum levels have been confirmed to be in the ‘‘target range’’, then serum levels need to be repeated at 4 weeks after the intitiation of treatment, and once every 6 months thereafter. Serum levels and/or investigations may be repeated more frequently if clinically indicated (Kusumakar et al., 1997b). Bipolar depression

Dysthymia or many episodes of major depression are common in young people before they ever manifest a threshold level hypomania or mania. Hence, many young people who are initially diagnosed as having unipolar depression or dysthymia later meet criteria for a bipolar disorder. Indicators of risk for the development of future bipolar disorder are as follows: (1) psychotic depression, (2) a history of bipolar disorder in the parental or sibling generation, (3) pharmacologic hypomania or mania, (4) depression with reverse vegetative features or marked psychomotor retardation, and (5) depression with subthreshold biphasic mood dysregulation.

122

V. Kusumakar et al.

Evidence for the value of treatment with serotonin-specific reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine for depression in adolescence is beginning to emerge (Emslie et al., 1997; Keller et al., 1998). Yatham et al. (1997) reviewed the use of antidepressants in adults with bipolar depression and concluded that antidepressants are efficacious, but can lead to an increased risk of switch into hypomania or mania. These rates of switch are increased with TCAs rather than with SSRIs. The more recent concern in young people is that antidepressant treatment may induce marked biphasic mood instability of a subthreshold nature and rapid cycling. The debate of whether to start treatment with a mood stabilizer or an SSRI antidepressant, or whether to use antidepressants only under the cover of a mood stabilizer, in depressed young people who are also at high risk for bipolar disorder is complicated by the fact that, even in adult samples, there is a paucity of studies in bipolar depression. There are no published studies of IPT or cognitive–behavioral therapy in bipolar depression in young people, although current studies are underway with IPT (Santor et al., personal communication). Although lithium has some antidepressant properties, it is widely accepted that lithium, like DVP and carbamazepine, has limited efficacy in acute bipolar depression, although they are all likely have some efficacy in preventing depressive symptoms during prophylactic treatment (Yatham et al., 1997). The same therapeutic doses and serum levels as in mania should be used in bipolar depression. In an open study of lamotrigine augmentation of divalproex treatment in bipolar depression, Kusumakar et al. (1997b) reported that this combination was effective even in adolescents within this sample. Lamotrigine has to be used with great caution, however, as in younger adolescents there is a danger of a rash progressing to Steven–Johnson’s syndrome, the risk of which is increased with rapid uptitration of the dose or combination with medications such as divalproex, which nearly doubles the serum levels of lamotrigine. In young people, there are few experimental data that would support the recommendation of combining lithium with either divalproex or carbamazepine, although clinically these combinations are used to treat patients who show little or limited response to mood stabilizer monotherapy. SSRI antidepressants may be used in adolescent bipolar depression in the acute phase but under the cover of a mood stabilizer. It is best to reduce and gradually discontinue the antidepressants in 6–12 weeks after euthymia has been achieved, but there will always be patients who require antidepressants with mood stabilizers over the longer term. In an open study, Papatheodoru and Kutcher (1995) found light therapy (twice daily at 10 000 lux for 2 weeks) added to ongoing thymoleptic therapy effectively treated bipolar depressive symp-

123


toms. This treatment seems most useful if applied early on in the onset of the depressive episode (Kutcher, personal communication). ECT is known to be effective in adolescent bipolar illness (Kutcher and Robertson, 1994). There is considerable negative mythology about ECT, particularly in adolescents, leading to this treatment being not considered even where there are obvious clinical indications for its use and despite the fact that the efficacy and relative safety of ECT have been reasonably established in adolescent depression (Kutcher and Marton, 1996). ECT in adults with bipolar illness is one of the most effective treatments in both the depressive and manic phases of bipolar illness (Bratfos and Haug, 1965; Yatham et al., 1997). Hence, ECT should be considered as a treatment option in adolescents with refractory or chronic bipolar depression, bipolar depression with chronic and significant suicidal or homicidal risk, and where there is a clinical picture of severe psychomotor retardation or agitation. Prerequisites to using ECT in young people are informed consent from the patient and family, an independent psychiatric evaluation, and a thorough medical examination. Bilateral brief pulse ECT is likely to be more efficacious than unilateral ECT. It is not uncommon to administer two treatments per week. Young people may need in excess of 6–12 treatments, and it is not uncommon for hypomanic symptoms to emerge after the first few treatments before the patient achieves euthymia. Treatment in female-specific issues

Isojarvi et al. (1993, 1996) reported that young females receiving valproic acid for epilepsy were significantly more likely to develop obesity and polycystic ovary syndrome. The relationship warrants further study, so young female patients should be monitored carefully. Extensive endocrinal investigations and endocrinology consults should be reserved for young women who have, following induction of treatment with valproate, developed markedly irregular periods, dysmenorrhea, secondary hirsutism, or other emergent symptoms of an endocrine disorder (O’Donovan et al., 1999). Pregnancy itself may be associated with greater periods of euthymia when compared with illness course prepregnancy (Sharma and Persad, 1995) and the postpartum period carries with it an increased risk both for initial episodes of bipolar disorder and for recurrences of mood disorder. Females in the childbearing age should be advised against pregnancy when on mood stabilizer medication, except under exceptional circumstances, because of the teratogenic risks posed. Any decision to continue or discontinue thymoleptic medication during pregnancy should be made only after a thorough assessment of the comparative risk of a mood disorder episode and the teratogenic effects

124

V. Kusumakar et al.

of medications. Potential parents should be fully advised about all risks, and should be supported humanely with their decisions, as any decision in the circumstances carries risk. Hence, a safety net of support from family, friends, and professionals is essential. It is now accepted that the risk of Ebstein’s cardiac anomaly posed by lithium is much lower than initially reported, although the teratogenic risks of neural tube defects associated with anticonvulsant use (divalproex and carbamazepine) is likely to be higher (Altshuler et al., 1996). The risks are most significant in the first trimester of pregnancy, during which period ECT is likely the most effective and relatively safe treatment (Goldberg and DiMascio, 1978). Usage of haloperidol for mania and SSRIs for depression in the first trimester of pregnancy has not been associated with an increase in teratogenic risk. If the patient remains on a mood stabilizer during pregnancy, close monitoring of fetal development using timely ultrasound and amniocentesis is warranted. Diagnosis of fetal abnormalities in the first trimester can lead to the consideration of the option of a medical termination of pregnancy, in appropriate circumstances. It is often necessary to increase the dose of mood stabilizer to maintain the serum levels achieved before pregnancy because of increased body fluid volume and changes in protein binding. Common practice is to reduce and stop the mood stabilizer gradually about a week prior to the expected date of delivery to prevent any toxicity to the baby. There is a significant risk for postpartum depression, mania, or psychosis in the immediate postpartum period with up to 50% of women having a recurrence or exacerbation during this time. Mood stabilizer treatment is strongly recommended within 48–72 hours of childbirth as mood stabilizers can reduce the risk of relapse during this period from more than 50% to less than 10% (Cohen et al., 1995). There is also a need to pay particular attention to sleep deprivation, which can in itself trigger a mood disorder episode. With the free passage of lithium into breast milk and the potential risk for neonatal toxicity, breast-feeding is generally contraindicated during lithium treatment (Tunnessen and Hertz, 1972). Newborn serum levels of valproate and carbamazepine resulting from breast-feeding may be relatively low (Wisner and Perel, 1998), but there is little published work regarding the long-term behavioral toxic effects of psychotropic medications ingested during the neonatal period. Prudent clinical advice should suggest alternatives to breast-feeding if thymoleptics are indicated.

125


Treatment of bipolar disorder in the presence of comorbid symptom clusters or syndromes

Comorbid problems in juvenile bipolar disorder include ADHD and other disruptive behavior disorders, and alcohol/substance abuse difficulties. Generalized anxiety, social phobia, panic, and obsessive–compulsive symptoms are being increasingly recognized as coexisting with juvenile bipolar disorder. These coexisting syndromes often do not meet criteria for a separate comorbid disorder, but nevertheless have major adverse effects on scholastic or work performance, medication efficacy, and interpersonal and other social functioning. There are no systematic studies of the treatment of comorbid symptom clusters or syndromes, despite the fact that up to 50% of young people with bipolar disorder may have significant comorbid symptoms. Adjunctive treatments, biologic and psychosocial, are often necessary in helping young people deal with comorbid difficulties. These treatments should be seen as an adjunct to, rather than replacement of, mood stabilizer(s). Used judiciously and with appropriate thymoleptic ‘‘cover’’, methylphenidate and dexedrine can be useful to treat symptoms of ADHD. Unfortunately, the response to these medications has been reported to be both helpful (Max et al., 1995) and unhelpful (KoehlerTroy et al., 1986). Although there is little published evidence currently to support its use, bupropion is being increasingly utilized as an adjunct to a mood stabilizer in the presence of attention-deficit symptoms, excessive nicotine intake, or the presence of depression in young people with BMD. SSRIs may benefit some anxiety symptoms, but there is concern that these compounds may provoke biphasic mood instability and increased cycle frequency. Benzodiazepines, if used with care and close monitoring, have a useful place in the treatment of anxiety symptoms if behavioral treatment methods have not yielded results. In a small data set, Kusumakar and Yatham (1999) found evidence that lamotrigine, used with great caution, may be helpful in treating subthreshold obsessive–compulsive symptoms in the presence of BMD in some adolescents. Alcohol and substance abuse obviously need to be treated vigorously. Use of psychoeducation, detoxification, and other appropriate interventions are recommended. In a 6-week trial in adolescents with substance abuse, Geller et al. (1998) reported on the efficacy of lithium in this population. This result contradicts earlier reports that lithium failure could be predicted by the presence of comorbid substance abuse, but longer-term studies are required to answer questions of efficacy of mood stabilizers on BMD with substance abuse.

126

V. Kusumakar et al.

Maintenance treatment in juvenile bipolar disorder

As a vast majority of young people with BMD will experience recurrences and relapses, the need for maintenance treatment is apparent. This course of illness often has profound effects on functioning in a variety of domains and even on personality development in an interpersonal context. Young people and families may undergo years of suffering before accepting the need for a trial of maintenance treatment to prevent further episodes. Treatment nonadherence is a major problem during maintenance treatment and side effects, particularly weight gain and cognitive dulling, together with subsequent effects on symptoms and functioning, are the major causes of treatment discontinuation. Unfortunately, there are few published data from double-blind placebo-controlled trials of the value in young people of mood stabilizers in maintenance treatment and the issue of whether intermittent lithium treatment is helpful or leads to treatment refractoriness. It has been recommended that adolescents be kept on mood stabilizer treatment throughout the teenage years (Strober et al., 1990, 1995). In an open study supportive of maintenance lithium treatment for adolescents with bipolar disorder, 63% remained well on lithium compared with only 8% who discontinued lithium. Serum levels of 0.8–1.1 mmols/l are recommended for maintenance lithium treatment. In a case-controlled open study by Kusumakar et al. (1997c), of 38 early-onset and 38 adult-onset bipolar subjects, matched for gender and duration of illness, and who were compliant with maintenance treatment over 3 years with lithium or DVP, it was found that adolescents responded significantly better to divalproex. Sixty percent of young people treated with valproate were rated as exhibiting adequate episode suppression compared with 27% in the lithium-treated group. Valproic acid serum levels were over 500 mmols/l and lithium levels were 0.8–1.1 mmols/l. It should be noted that over 60% of the young people in this study suffered from rapid cycling or mixed states – usual predictors of lithium non-response. Over 80% of both early-onset groups continued to exhibit subthreshold symptoms and considerable dysfunction at the end of 3 years even in responders. These findings further emphasize the need to recognize the recurrent, relapsing, and even chronic nature of juvenile bipolar disorder, and the need for more efficacious treatments for prophylaxis not only in terms of symptoms, but also to help with functioning. There are no available data yet on the value of the newer anticonvulsants (such as lamotrigine and gabapentin) or ECT in the maintenance phase of treatment in juvenile bipolar disorder. The value of adjunctive psychosocial interventions, including psychoeducation, psychotherapy (individually, in

127


groups, or in a family context), and scholastic and social support cannot be overemphasized. The treatment team needs to use the treatment paradigm of chronic illness (such as diabetes) and must be available to the young person and family throughout the different phases of the illness.

REFE R EN C ES Akiskal H (1996). The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 16:4S–14S. Albus M, Hubmann W, Wahlheim C, Sobizack N, Franz U, Mohr F (1996). Contrasts in neuropsychological test profile between patients with first-episode schizophrenia and firstepisode affective disorders. Acta Psychiatr Scand 94:87–93. Alda M (1997). Bipolar disorder: from families to genes. Can J Psychiatry 42:378–87. Altshuler L, Cohen L, Szuba M, Burt V, Gitlin M, Mintz J (1996). Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 153:592–606. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Awad I, Johnson P, Spetzler R, Hodak J (1986). Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. II. Postmortem pathological correlations. Stroke 17:1090–7. Bertelsen A, Harvald B, Hauge M (1977). A Danish twin study of manic-depressive disorders. Br J Psychiatry 130:330–51. Biederman J, Wozniak J, Kiely K et al. (1995). CBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD. J Am Acad Child Adolesc Psychiatry 34:464–71. Bird D, Kutcher S, Robertson H (1998). Mathematics deficits in bipolar youth. American Psychiatric Association Annual Meeting. Toronto, Ontario: American Psychiatric Association, pp. 133– 4. Blackburn I, Loudon J, Ashworth C (1977). A new scale for measuring mania. Psychol Med 7:453–8. Bland R (1997). Epidemiology of affective disorders: A review. Can J Psychiatry 42:367–77. Botteron KN, Vannier MW, Geller B, Todd RD, Lee BC (1995). Preliminary study of magnetic resonance imaging characteristics in 8- to 16-year-olds with mania. J Am Acad Child Adolesc Psychiatry 34:742–9. Bowden C, Brugger A, Swann A et al. (1994). Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 271:918–24. Bowring M, Kovacs M (1992). Difficulties in diagnosing manic disorders among children and adolescents. J Am Acad Child Adolesc Psychiatry 31:611–14. Braffman B, Zimmerman R, Trojanowski J, Gonatas N, Hickey W, Schlaepfer W (1988). Brain MR: pathologic correlation with gross and histopathology. 2. Hyperintense white-matter foci

128

V. Kusumakar et al.

in the elderly. Am J Roentgenol 151:559–66. Bratfos O, Haug J (1965). Electroconvulsive therapy and antidepressant drugs in manic-depressive disease. Treatment results at discharge and 3 months later. Acta Psychiatr Scand 41:558–96. Carlson G (1984). Classification issues of bipolar disorders in childhood. Psychiatry Dev 2:273–85. Carlson GA (1996). Compared to attention deficit hyperactivity disorder . . . Am J Psychiatry 153:1128–30. Carlson GA, Fennig S, Bromet EJ (1994). The confusion between bipolar disorder and schizophrenia in youth: where does it stand in the 1990s? J Am Acad Child Adolesc Psychiatry 33:453–60. Cochran S (1984). Preventing medical noncompliance in the outpatient treatment of bipolar affective disorders. J Consult Clin Psychol 52:873–8. Coffman JA, Bornstein RA, Olson SC, Schwarzkopf SB, Nasrallah HA (1990). Cognitive impairment and cerebral structure by MRI in bipolar disorder. Biol Psychiatry 27:1188–96. Cohen L, Sichel D, Robertson L, Heckscher E, Rosenbaum J (1995). Postpartum prophylaxis for women with bipolar disorder. Am J Psychiatry 152:1641–2. Cooper T, Bergner P, Simpson G (1973). The 24-hour serum lithium level as a prognosticator of dosage requirements. Am J Psychiatry 130:601–3. Drevets WC, Ongur D, Price JL (1998). Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry 3:220–6,190–1. Drevets WC, Price JL, Simpson JR Jr et al. (1997). Subgenual prefrontal cortex abnormalities in mood disorders (see comments). Nature 386:824–7. Duffy A, Alda M, Kutcher S et al. (1998). Psychiatric symptoms and syndromes among adolescent children of parents with lithium responsive or nonresponsive bipolar disorder. Am J Psychiatry 155:431–3. Duffy A, Grof P, Kutcher S et al. (in press). Measures of attention and hyperactivity in affectively ill offspring of bipolar parents. Emslie G, Rush A, Weinberg W et al. (1997). A double blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–7. Faraone SV, Biederman J, Mennin D, Wozniak J, Spencer T (1997). Attention-deficit hyperactivity disorder with bipolar disorder: a familial subtype? (See comments). J Am Acad Child Adolesc Psychiatry 36:1378–87, 1387–90. Fetner H, Geller B (1992). Lithium and tricyclic antidepressants. Psychiatr Clin North Am 15:223–4. Flor-Henry P (1986). Observations, reflections and speculations on the cerebral determinants of mood and on the bilaterally asymmetrical distributions of the major neurotransmitter systems. Acta Neurol Scand Suppl 109:75–89. Frank E, Hlastala S, Ritenour A et al. (1997). Inducing lifestyle regularity in recovering bipolar disorder patients: results from the maintenance therapies in bipolar disorder protocol. Biol Psychiatry 41:1165–73. Friedman L, Findling RL, Kenny JT et al. (1999). An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects. Biol Psychiatry 46:78–88. Geller B, Cooper T, Sun K et al. (1998). Double blind and placebo-controlled study of lithium for

129


adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 37:171–8. Geller B, Fox L, Clark K (1994). Rate and predictors of prepubertal bipolarity during follow-up of 6- to 12-year-old depressed children. J Am Acad Child Adolesc Psychiatry 33:461–8. Geller B, Fox L, Fletcher M (1993). Effect of tricyclic antidepressants on switching to mania and on the onset of bipolarity in depressed 6- to 12-year-olds. J Am Acad Child Adolesc Psychiatry 32:43–50. Geller B, Sun K, Zimmerman B, Luby J, Frazier J, Williams M (1995). Complex and rapid cycling in bipolar children and adolescents: a preliminary study. J Affect Disord 34:259–98. Goldberg H, DiMascio A (1978). Psychotropic drugs in pregnancy. In M Lipton, A DiMascio, K Killam (Eds.), Psychopharmacology: A Generation of Progress. New York: Raven Press, pp. 1047– 55. Golombeck H, Kutcher S (1990). Feeling states during adolescence. Psychiatr Clin North Am 13:443–54. Grafton S, Sumi S, Stimac G, Alvord E, Shaw C, Nochlin D (1991). Comparison of postmortem magnetic resonance imaging and neuropathologic findings in the cerebral white matter. Arch Neurol 48:293–8. Grigoroiu-Serbanescu M, Nothen M, Propping P et al. (1995). Clinical evidence for genomic imprinting in bipolar I disorder. Acta Psychiatr Scand 92:365–70. Grigoroiu-Serbanescu M, Wickramaratne P, Hodge S, Milea S, Mihailescu R (1997). Genetic anticipation and imprinting in bipolar I illness. Br J Psychiatry 170:162–6. Harrington R, Campbell F, Shoebridge P, Whittaker J (1998). Meta-analysis of CBT for depression in adolescents. J Am Acad Child Adolesc Psychiatry 37:1005–7. Harvey NS, Peet M (1991). Lithium maintenance. 2. Effects of personality and attitude on health information acquisition and compliance. Br J Psychiatry 158:200–4. Hauser P, Dauphinais ID, Berrettini W, DeLisi LE, Gelernter J, Post RM (1989). Corpus callosum dimensions measured by magnetic resonance imaging in bipolar affective disorder and schizophrenia. Biol Psychiatry 26:659–68. Himmelhoch JM, Garfinkel ME (1986). Sources of lithium resistance in mixed mania. Psychopharmacol Bull 22:613–20. Huxley NA, Parikh SV, Baldessarini RJ (2000). Effectiveness of psychosocial treatments in bipolar disorder. State of the evidence. Harvard Rev Psychiatry 8:126–40. Isojarvi J, Laatikainen T, Knip M, Pakarinen A, Juntunen K, Myllyla V (1996). Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 39:579–84. Isojarvi J, Laatikainen T, Pakarinen A, Juntunen K, Myllyla V (1993). Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–8. Joyce PR (1984). Age of onset in bipolar affective disorder and misdiagnosis as schizophrenia. Psychol Med 14:145–9. Kaufman J, Birmaher B, Brent D et al. (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–8. Keller M, Gelenberg A, Hirschfeld R et al. (1998). The treatment of chronic depression, part 2: a

130

V. Kusumakar et al.

double blind, randomized trial of sertraline and imipramine. J Clin Psychiatry 59:598–607. Kerbeshian J, Burd L, Klug MG (1995). Comorbid Tourette’s disorder and bipolar disorder: an etiologic perspective. Am J Psychiatry 152:1646–51. Kirkpatrick J, Hayman L (1987). White-matter lesions in MR imaging of clinically healthy brains of elderly subjects: possible pathologic basis. Radiology 162:509–11. Knott V, Waters B, Lapierre Y, Gray R (1985). Neurophysiological correlates of sibling pairs discordant for bipolar affective disorder. Am J Psychiatry 142:248–50. Koehler-Troy C, Strober M, Malenbaum R (1986). Methylphenidate-induced mania in a prepubertal child. J Clin Psychiatry 47:566–7. Kusumakar V, Yatham LN (1997). An open study of lamotrigine in refractory bipolar depression. Psychiatry Res 72:145–8. Kusumakar V, Yatham LN (1999). Lamotrigine in adolescent rapid cycling bipolar disorder with co-existing obsessional compulsive symptoms. Annual Meeting of the Canadian Psychiatric Association. Toronto, Canada. Kusumakar V, Yatham LN, Haslam DR et al. (1997a). The foundations of effective management of bipolar disorder. Can J Psychiatry 42(Suppl 2):69–73. Kusumakar V, Yatham LN, Haslam DR et al. (1997b). Treatment of mania, mixed state, and rapid cycling. Can J Psychiatry 42(Suppl 2):79–86. Kusumakar V, Yatham LN, O’Donovan C, Kutcher SP (1999). Topiramate in the treatment of ultra-rapid and ultradian cycling bipolar disorder in women. World Psychiatric Congress. Hamburg, Germany. Kusumakar V, Yatham LN, Sacamano J (1997c). Divalproex sodium and lithium in the prophylaxis of adolescent bipolar disorder: a case controlled study. Meeting of the Child Mood Disorders Consortium of North America. Halifax, Canada. Kutcher S (1993). Rapid cycling and mixed mania in adolescent bipolar illness. Am Acad Child Adolesc Psychiatry. San Antonio, TX. Kutcher S (1994). Bipolar disorder in adolescence. Mania through the life cycle. American Psychological Association. Philadelphia, PA. Kutcher S, Marton P (1996). Treatment of adolescent depression. In K Schulman, M Tohen, S Kutcher (Eds.), Mood Disorders Across the Lifespan. New York: John Wiley, pp. 101–26. Kutcher S, Robertson H (1994). ECT treatment in adolescents: a review of the Sunnybrook experience, 13th Annual Child and Adolescent Depression Consortium Meeting. Providence, RI. Kutcher S, Marton P, Korenblum M (1989). Relationship between psychiatric illness and conduct disorder in adolescents. Can J Psychiatry 34:526–9. Kutcher S, Robertson H, Bird D (In press). A consumer study of factors relevant to clinical outcome and current well being in adolescent onset bipolar I disorder. J Am Acad Child Adolesc Psychiatry. Lewinsohn P, Klein D, Seeley J (1995). Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 34:454–63. Lombroso P, Pauls D, Leckman J (1994). Genetic mechanisms in childhood psychiatric disorders. J Am Acad Child Adolesc Psychiatry 33:921–38.

131


Loranger A, Levine P (1978). Age at onset of bipolar affective illness. Arch Gen Psychiatry 35:1345–8. MacInnis M, McMahon F, Chase G, Simpson S, Ross J (1993). Anticipation in bipolar affective disorder. Am J Hum Genet 31:686–9. Maier W, Merikangas K (1996). Co-occurrence and contransmission of affective disorders and alcoholism in families. Br J Psychiatry 30(Suppl):93–100. Marshall V, Bradley W, Marshall C, Bhoopat T, Rhodes R (1988). Deep white matter infarction: correlation of MR imaging and histopathologic findings. Radiology 167:517–22. Max JE, Richards L, Hamdan-Allen G (1995). Case study: antimanic effectiveness of dextroamphetamine in a brain-injured adolescent. J Am Acad Child Adolesc Psychiatry 34:472–6. McElroy S, Keck P, Stanton S, Tugrul K, Bennett J, Strakowski S (1996). A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 57:142–6. McGlashan T (1988). Adolescent versus adult onset of mania. Am J Psychiatry 145:221–3. McMahon F, DePaulo J (1996). Genetics and age at onset. In K Schulman, M Tohen, S Kutcher (Eds.), Mood Disorders Across the Life Span. New York: John Wiley, pp. 35–48. Mendlewicz J, Lindbald K, Souery D et al. (1997). Expanded trinucleotide CAG repeats in families with bipolar affective disorder. Biol Psychiatry 42:1115–22. Miklowitz D, Frank E, George E (1996). New psychosocial treatments for the outpatient management of bipolar disorder. Psychopharmacol Bull 32:613–21. Muffson L, Weissman M, Moreau D, Garfinkel R (1999). Efficacy of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry 56:573–9. O’Donovan C, Graves J, Kusumakar V (1999). Prevalence rates of self-reported menstrual abnormalities and clinical hyperandrogenism of women taking divalproex for bipolar mood disorder. In J Soares and S Gershon, S (Eds.), Vol 1. Proceedings of International Conference on Bipolar Disorder. Pittsburgh, PA: Munksgaard, pp. 45. Ongur D, Drevets W, Price J (1998). Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95:13290–5. Overall J, Gorham D (1962). The brief psychiatric rating scale. Psychol Rep 10:799–812. Papatheodoru G, Kutcher S (1993). Divalproex sodium treatment in late adolescent and young adult acute mania. Psychopharmacol Bull 29:213–19. Papatheodoru G, Kutcher S (1995). The effect of adjunctive light therapy on ameliorating breakthrough depressive symptoms in adolescent-onset bipolar disorder. J Psychiatry Neurosci 20:226–32. Papatheodoru G, Kutcher S (1996). Treatment of bipolar disorder in children and adolescents. In K Schulman, M Tohen, S Kutcher (Eds.), Mood Disorders Across the Life Span. New York: John Wiley, pp. 159–86. Peet M, Harvey N (1991). Lithium maintenance. 1. A standard education programme for patients. Br J Psychiatry 158:197–200. Quackenbush D, Kutcher S, Robertson H, Boulos C, Chaban P (1996). Premorbid and postmorbid school functioning in bipolar adolescents: description and suggested academic interventions. Can J Psychiatry 41:16–22.

132

V. Kusumakar et al.

Reddy Y, Girimaji S, Srinath S (1997). Clinical profile of mania in children and adolescents from the Indian subcontinent. Can J Psychiatry 42:841–6. Reus V, Freimer N (1997). Understanding the genetic basis of mood disorders: where do we stand? Am J Hum Genet 60:1283–8. Robertson H, Bird D, Kutcher S (1998). Bipolar and unipolar youth at school: academic and psychosocial difficulties. In M Schwab-Stone (Ed.), 45th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Anaheim, CA, pp. 100. Rutter M (1997). Implications of genetic research for child psychiatry. Can J Psychiatry 42:569–76. Ryan N, Puig-Antich J, Ambrosini P et al. (1987). The clinical picture of major depression in children and adolescents. Arch Gen Psychiatry 44:854–61. Santor D, Kusumakar V (1999). Interpersonal therapy and sertraline in depressed adolescents: a case controlled study. Annual Meeting of the Atlantic Provinces Psychiatric Associations. Whitepoint, Nova Scotia. Sax K, Strakowski S, Keck P et al. (1997). Comparison of patients with early-, typical-, and late-onset affective psychosis. Am J Psychiatry 154:1299–301. Sax K, Zimmerman M, DelBello M, Hawkins J, Keck P, Strakowski S (1998). Prefrontal cortical volume and attentional performance in bipolar disorder. Biol Psychiatry 43:16S. Segal J, Berk M, Brook S (1998). Risperidone compared with both lithium and haloperidol in mania: a double blind randomized controlled trial. Clin Neuropharmacol 21:176–80. Sharma V, Persad E (1995). Effect of pregnancy on three patients with bipolar disorder. Ann Clin Psychiatry 7:39–42. Silva R, Campbell M, Golden R, Small A, Pataki C, Rosenberg C (1992). Side effects associated with lithium and placebo administration in aggressive children. Psychopharmacol Bull 28:319– 26. Soares JC, Mann JJ (1997). The anatomy of mood disorders – review of structural neuroimaging studies. Biol Psychiatry 41:86–106. Strakowski S, McElroy S, Keck P, West S (1996). The effects of antecedent substance abuse on the development of first-episode psychotic mania. J Psychiatr Res 30:59–68. Strober M, Carlson G (1982). Bipolar illness in adolescents with major depression: clinical, genetic, and psychopharmacologic predictors in a three- to four-year prospective follow-up investigation. Arch Gen Psychiatry 39:549–55. Strober M, Morrell W, Burroughs J, Lampert C, Danforth H, Freeman R (1988). A family study of bipolar I disorder in adolescence. Early onset of symptoms linked to increased familial loading and lithium resistance. J Affect Disord 15:255–68. Strober M, Morrell W, Lampert C, Burroughs J (1990). Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: a naturalistic study. Am J Psychiatry 147:457–61. Strober M, Schmidt-Lackner S, Freeman R, Bower S, Lampert C, DeAntonio M (1995). Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. J Am Acad Child Adolesc Psychiatry 34:724–31. Todd R, Geller B, Neuman R, Fox L, Hickok J (1996). Increased prevalence of alcoholism in relatives of depressed and bipolar children. J Am Acad Child Adolesc Psychiatry 35:716–24.

133


Tohen M, Castillo J, Baldessarini R, Zarate C, Kando J (1995). Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228 patients at risk. Am J Psychiatry 152:413–18. Tohen M, Sanger T, McElroy S et al. (1999). Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 156:702–9. Tunnessen W, Hertz C (1972). Toxic effects of lithium in newborn infants: a commentary. J Pediatr 81:804–7. Vitiello B, Behar D, Malone R, Delaney M, Ryan P, Simpson G (1988). Pharmacokinetics of lithium carbonate in children. J Clin Psychopharmacol 8:355–9. Weller EB, Weller RA, Fristad MA (1995). Bipolar disorder in children: misdiagnosis, underdiagnosis, and future directions. J Am Acad Child Adolesc Psychiatry 34:709–14. Werry J, McClellan J, Chard L (1991). Childhood and adolescent schizophrenic, bipolar, and schizoaffective disorders: a clinical and outcome study. J Am Acad Child Adolesc Psychiatry 30:457–65. West S, Strakowski S, Sax K, McElroy S, Keck P, McConville B (1996). Phenomenology and comorbidity of adolescents hospitalized for the treatment of acute mania. Biol Psychiatry 39:458–60. Wisner K, Perel J (1998). Serum levels of valproate and carbamazepine in breastfeeding motherinfant pairs. J Clin Psychopharmacol 18:167–9. Woods BT, Yurgelun-Todd D, Mikulis D, Pillay SS (1995). Age-related MRI abnormalities in bipolar illness: a clinical study. Biol Psychiatry 38:846–7. Wozniak J, Biederman J, Kiely K et al. (1995). Mania-like symptoms suggestive of childhoodonset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 34:867–76. Yatham LN, Kusumakar V, Parikh SV et al. (1997). Bipolar depression: treatment options. Can J Psychiatry 42(Suppl 2):87–91. Zarate C, Tohen M (1996). Epidemiology of mood disorders throughout the life cycle. In K Schulman, M Tohen, S Kutcher (Eds.), Mood Disorders Across the Life Span. New York: John Wiley, pp. 17–34.

6 Schizophrenia and related psychoses Keith Marriage British Columbia Children’s Hospital, Vancouver, British Columbia, Canada

Overview The onset of a schizophrenic illness during childhood or adolescence often seems disastrous for the patient and the family. Management of the acute phase of the psychosis presents a true psychiatric emergency, usually requiring the services of a multidisciplinary team on an inpatient unit. A developmentally appropriate therapeutic milieu, i.e., one providing a school-based and structured program in the company of peers, is preferred to placing the patient on an adult inpatient service. Optimal management requires the successful differentiation of schizophrenia from a number of other psychotic and nonpsychotic disorders with similar presentations, but this may be extremely difficult in the acute situation, and it is important to reassess the initial diagnostic formulation in light of the course of the illness and treatment response. Some of the diagnostic difficulties arise from the current noseology. First, schizophrenia is spoken of as a unitary disorder, when it is more likely to be a conglomerate of various phenomenologically related syndromes, each having a different and complex etiologic pathway. Secondly, diagnostic criteria developed for adults have been applied across the life cycle, with only minor allowances made for developmental influences on the presentation of the important symptoms. Thirdly, there continues to be debate and uncertainty about the delineation of early-onset schizophrenia, schizotypal personality disorder, and the higher functioning pervasive developmental disorders (PDDs). Final clarification of these issues awaits an understanding of etiologies. Recent developments in the study of schizophrenia in adults have emphasized that, in addition to the previously appreciated problems with social adaptation, occupational functioning, and mood difficulties, the majority of these patients suffer from neurocognitive deficits which tend to persist after the resolution of the acute psychotic symptoms. These deficits likely contribute to negative symptoms and the declining course that the individuals with this disorder typically follow. 134

135


The classic subdivisions of schizophrenia were based on observation of the most prominent symptoms, i.e., hebephrenic, paranoid, catatonic, and simple. However, these subtypes do not breed true within a kinship, nor will a particular patient necessarily show similar symptom patterns in successive episodes of psychosis. A more recent approach to classification is to characterize an episode of psychosis along three-dimensional axes, i.e., positive symptoms, negative symptoms, and symptoms of disorganization. Positive symptoms include hallucinations, delusions, and disorders of thought form, i.e., new experiences and behaviors added to the patient’s premorbid functioning. Negative symptoms represent a loss of previous abilities, i.e., reduced cognition, motivation, emotion, and communication. Symptomatology on these three axes may vary from time to time during a particular psychotic episode, and may respond differentially to different neuroleptic medications. Description of the disorder The onset of schizophrenia varies, and may often begin with a prodromal phase during which there is gradual deterioration in academic, social, and interpersonal functioning, accompanied by suspiciousness and withdrawal. After weeks or months, acute psychotic symptoms of hallucinations, delusions, disorders of thought form, disorganized or catatonic behavior, and flat or inappropriate affect follow. In some cases, negative symptoms – flattening of affect, avolition, alogia, anhedonia, and problems with sustaining attention – may precede the acute positive symptoms and dominate the clinical picture. In other instances, the onset of hallucinations and delusions may appear suddenly, in an apparently previously well-functioning adolescent. For children and adolescents, a DSM-IV diagnosis (American Psychiatric Association, 1994) of schizophrenia requires 4 weeks of acute or positive symptoms and a total of 6 months of deterioration or failure to make expected progress in interpersonal, academic, or occupational achievement. In addition, mood disorders, schizoaffective disorder, and substance abuse as the cause of symptoms must be excluded. Deterioration in adaptive functioning usually persists to some degree after the resolution of the acute symptoms, but this is by no means universal, and the course of the illness and susceptibility to future relapses are difficult to predict for any particular individual. Schizophrenic illness occurring before adulthood may be subdivided into very early-onset schizophrenia (VEOS), commencing before 13 years of age, and early-onset schizophrenia (EOS) occurring in adolescence (Werry, 1996).

136

K. Marriage

The earlier the onset, the more likely will be the finding of premorbid personality abnormalities, ranging across the spectrum from odd and eccentric, through antisocial or histrionic, to the anxious and fearful. Premorbid learning and language disabilities and difficulties with motor coordination are also more frequent in the younger patient population (Alaghband-Rad et al., 1995). These findings have given rise to the proposal that these younger patients have received a larger ‘‘dose’’ of causative factors, whether genetic or environmental, and have been subtly disabled even prior to the onset of their psychosis. These premorbid problems may cause difficulty in ascertaining the exact onset of the prodromal phase of the illness. In adolescent-onset schizophrenia, up to 50% of the patients will have apparently normal premorbid functioning. Epidemiologically, this EOS group has a male to female ratio closer to 1: 1, whereas for VEOS there is a male predominance of approximately 2: 1 (Werry, 1992). Psychosis in intellectually disabled children and adolescents

Schizophrenic illness has been found to occur in approximately 3% of the intellectually disabled population (Reid, 1993; Fraser and Nolan, 1994), reflecting their greater vulnerability to all types of psychiatric disorder. The differential diagnosis of psychosis in this group can be complicated by the patient’s restricted or absent communication skills, their reduced understanding of elapsed time when reporting symptoms, and behavioral oddities which may be part of the usual premorbid functioning. In a study of 30 subjects with intellectual disability, i.e., IQ of less than 70, presenting with psychotic illness before age 18, Friedlander (personal communication) discovered that one-third were suffering from schizophrenia, one-fifth had a psychotic mood disorder, and 50% had a psychotic-appearing illness of an uncertain type. Of the latter group, those with nonverbal skills mostly had a history of abuse and deprivation, and were likely to be suffering from some type of dissociative disorder or posttraumatic stress disorder. Thus, the range of psychotic conditions in the intellectually disabled roughly parallels that found in children and adolescents with normal intellect. Differential diagnosis There are a large number of psychotic and nonpsychotic disorders that may present with symptoms that overlap with schizophrenia. Successful differential diagnosis is essential if the various available psychosocial and psychopharmacologic treatments are to be applied in an effective manner.

137


Mood disorders

Psychotic depression usually presents in adolescence with delusions or hallucinations whose content is depressed, nihilistic, persecutory, or guilty. Depressed affect is often evident on cross-sectional mental status, and there is a history of mood deterioration preceding psychotic symptoms, and often of mood disorders, in the family. However, a firm differentiation between schizophrenia and a psychotic mood disorder, especially mixed bipolar disorder, may not be possible during the acute phase. Both may present with hallucinations, delusions, agitation, and disordered thought form. Substance abuse and/or histrionic, narcissistic, or borderline personality traits may further complicate the picture. A number of months of tracking the patient’s course, ideally at a time when they do not have access to street drugs, may be necessary to reach a final diagnostic decision. Schizoaffective disorder, a presentation intermediate between a psychotic mood disorder and schizophrenia (DSM-IV), is poorly characterized in this age group. Follow-up may reveal the gradual separation from this group of some patients whose course is more consistently schizophrenic or bipolar. Substance abuse

Up to 50% of patients presenting with first-onset schizophrenia will have a history of substance abuse, and they are seldom able to report accurately on the frequency or type of drugs they have been using. Some may have been using central nervous system (CNS) depressants, especially marijuana and alcohol, to self-medicate anxiety, which has been part of the prodrome of their psychosis. However, it may be difficult to differentiate immediately patients who have negative symptoms due only to the abuse of depressant substances, or hallucinations and delusions due to stimulants or hallucinogens, from those who have precipitated or exacerbated a predetermined schizophrenic illness. Delusions or hallucination due to acute drug intoxication or withdrawal are usually accompanied by a disturbed and fluctuating conscious state, a finding which is not usually present in schizophrenia or affective psychosis. Drugassociated positive symptoms usually resolve within days, although disturbances in mood post alcohol or stimulant abuse may persist for months. An acute brain syndrome due to inhalation of toxic substances, i.e., glue, paint thinner, or petroleum products, is usually accompanied by the smell of the volatile substance on the patient’s breath. Brain damage, along with damage to the liver, kidneys, and hematopoietic system may persist after the volatile substance has been cleared via the lungs. Such abuse is more common in certain socioeconomic and ethnic groups, and knowledge of the local

138

K. Marriage

demographic pattern of abuse of the substance is useful in making a differential diagnosis in the subacute stage. Posttraumatic stress disorder/dissociative disorder

Children and adolescents who have been subject to severe or repeated psychological trauma can present with auditory and visual hallucinations, fluctuations in affect and consciousness, and deterioration in adaptive functioning. Hallucinations associated with a trauma are characterized by the presence of nightmares, trance-like states, and quick resolution of psychotic symptoms through psychotherapeutic interventions and/or the alleviation of psychosocial stresses or change in the environment. These children may also engage in impulsive aggression and self-injurious behavior, but they continue to be emotionally and socially connected to the people around them, and have a history of normal early development. Thought form disorder and negative symptoms are not usually found in this group, as they are in children with schizophrenia (Kaufman et al., 1997). Borderline personality disorder/traits

The validity of assigning a borderline personality disorder diagnosis to younger adolescents is, at present, in question. However, a number of adolescent females present to inpatient services with all the symptomatic hallmarks of borderline personality disorder, i.e., dysregulation in sense of self, emotions, interpersonal relationships, behavior, and cognition (Linehan, 1993). These individuals behave in a dramatic, unpredictable manner and can produce turmoil within the ward milieu. They may experience brief psychotic episodes, especially under the influence of street drugs or as an unexpected reaction to anxiolytic medication. Although they may report transient hallucinations, true delusional thinking and persisting thought form disorder is unusual in this group, and they retain the capability of intense emotional connection to those around them, rather than the disconnection that is seen in schizophrenia. A brief period of observation will usually assist with the differential diagnosis. In borderline patients, hospitalization of more than a few days may produce deterioration in both the functioning of the patient and in the ward milieu. Schizotypal personality disorder and autistic spectrum disorders

Children and adolescents who are odd, eccentric, and suspicious, and who have limited social relationships outside the family, may be seen from a developmental perspective as suffering from a higher functioning autism, Asperger’s syndrome, or a PDD not otherwise specified. However, from the perspective of

139


adult psychiatry, they might be seen as suffering from a schizotypal personality disorder or as demonstrating a prodrome of undifferentiated schizophrenia. Although the PDDs may be associated with brief psychotic episodes when the individual is under unusual stress, persisting hallucinations or delusions are not present. The content of the preoccupations of some Asperger’s patients may seem bizarre and delusional, but will often prove on further elucidation to have been appropriated from a book, video game, or television program. The difficulties of these types of patients tend to be longstanding and stable, and any deterioration in functioning is due to their inability to deal successfully with the increasing demands that society places on them as they grow up. Schizophrenia, bipolar disorder, or other psychoses may, however, develop in some young people suffering from PDDs. The boundary between schizotypal personality disorders and schizophrenia may be blurred, especially in youths with a gradual onset of positive symptoms. In a group of nonpsychotic, psychiatrically ill adolescents, Altman et al. (1997) found auditory hallucinations to have a strong relationship to the dissociative process, whereas subclinical delusions were most strongly correlated with schizotypal thought processes. Obsessive–compulsive disorder

While the vast majority of children and adolescents suffering from obsessive– compulsive disorder (OCD) recognize their obsessive thoughts and resulting compulsive behaviors as being unreasonable and unwanted, in some severe cases the patients come to believe in the authenticity of their ideas. In this situation, it may be very difficult to distinguish an obsession, particularly a bizarre one, from a delusion. It is also quite common to see OCD symptoms as part of the overall symptom picture in schizophrenia and severe or psychotic depression. Epilepsy

The onset of frontal or temporal lobe complex partial seizures may produce alterations in consciousness, episodes of circumscribed amnesia, irritability and other alterations in temperament, complex involuntary behaviors or ‘‘automatisms,’’ and hallucinations in various sensory modalities. If a focal seizure does not progress to produce a generalized tonic clonic fit, epilepsy may not be suspected. Hallucinations involving two or more senses simultaneously (e.g., the teenage girl who complained of seeing and smelling dead bodies) suggests partial complex seizures. If epilepsy is suspected, an EEG in waking and sleep may confirm the

140

K. Marriage

diagnosis, but continuous monitoring with video recording to provide a tracing during the actual occurrence of the symptoms may be required. A negative EEG, especially if an episode of the symptoms does not occur during the tracing, does not completely rule out epilepsy, and the clinician may decide on a trial of anticonvulsants on the basis of a highly suspicious history. Accurate differential diagnosis is important, because neuroleptics, at least in theory, may aggravate a seizure disorder, while anticonvulsant treatment has not shown to be effective in psychosis. Medical and surgical disorders

There are a number of medical and surgical conditions which can give rise to acute or subacute disorders of cerebral functioning, at times mimicking the positive or negative symptoms of schizophrenia. These include severe disturbances of any of the main organ systems, e.g., hepatic, renal, or respiratory insufficiency, endocrine disturbances, or inflammatory or infective processes directly affecting the CNS. Seizures, or the effects of a number of prescription medications, in therapeutic, intentional, or unintentional overdose may also produce delirium. Disorientation, confusion, and fluctuating conscious states, the hallmarks of an acute brain syndrome (delirium), are rare in the nonorganic or ‘‘functional’’ psychoses. However, these symptoms may be produced as side effects of the medications commonly used in treatment. Careful recording of hour by hour functioning and symptoms such as formication can be helpful in diagnosis. Chronic progressive loss of cerebral function, i.e., a dementia, is very rare in childhood and adolescence, but may be produced by various genetically determined errors of metabolism, e.g., lysosymal storage disease, or by solvent abuse, or a slow virus infection. Some of these disorders are readily diagnosed from a careful medical history and physical examination, together with the special investigations suggested by any positive findings. Routine screening investigations may reveal other disorders, although the hit rate from such tests is low in patients whose history and physical examination is negative (Adams et al., 1996). Diagnostic process The present cornerstone of diagnosis is careful psychiatric history, including detailed information about the onset and quality of positive and negative symptoms, past developmental and medical history, and a family medical and psychiatric history. Collateral information from various family members,

141


teachers, and others is often invaluable. The mental status, to give a crosssectional view of symptoms, should be recorded, but it is often difficult to differentiate between schizophrenia and psychoses associated with mood disorders in the acute phase of the illness. A history of substance abuse should also be pursued with the patient and any of their friends who are available as the best, although usually not completely reliable, informants. Careful physical examination and blood work to investigate electrolytes, complete blood count, and thyroid functioning may be considered, while any historical indications of possible neurologic disorder may suggest EEG and neuroimaging. Pediatric neurologic evaluation should be sought on all children and adolescents presenting for the first time with psychosis (American Academy of Child and Adolescent Psychiatry, 1997). However, the ‘‘organic workup’’ functions more to exclude the rare treatable cause of psychosis than to contribute to the management of the majority of cases, for whom an etiology susceptible to medical or surgical intervention is unlikely to be found. The patient’s response to admission to the structured setting of the ward, and perhaps treatment with short-acting anxiolytics to assist in regulating sleep, may prove informative. It is important to view such symptoms as delusions and hallucinations from a developmental perspective, taking into account the patient’s psychologic maturity, ethnic, and religious background. The content of both hallucinations and delusions tends to mature with the child, with increasing complexity and gradual approximation to the adult forms occurring with maturation (Volkmar, 1996). Disorders of thought form are difficult to ascertain reliably before 7 years of age, but in older children more severe illogical thinking and loose associations will be noted than is the case in adolescent-onset schizophrenia. This may reflect psychoses interrupting the usual development of cognitive and linguistic skills. Attention and information processing studies demonstrate difficulties in VEOS similar to those described in adult schizophrenia (Caplan, 1994). Given the challenges posed by differential diagnoses, and the changing course of the various psychotic illnesses, structured interviews may be fruitfully employed to produce a semiquantitative profile of symptoms at presentation, and to follow these symptoms as the illness evolves. The Interview for Childhood Disorders and Schizophrenia (ICDS) has been evaluated as most useful for children, and the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS) for adolescents (Russell, 1992).

142

K. Marriage

Theories of etiology The causal factors of this group of syndromes are unknown, but a number of different models have been proposed. Current thinking favors various biologic hypotheses, with some synthesis between biochemical, genetic, neuropathologic, and developmental factors (Schultz et al., 1998). Neurodevelopmental theories

One conceptualization is that genetic and/or intrauterine factors interfere with the evolving microarchitecture of neuronal development during the second trimester. It is suggested that the deficiencies thereby created only become manifest later in the individual’s life, when neuronal pruning shuts down an earlier system that was subserving specific neuropsychologic functions (Weinburger, 1995; Lewis, 1997). It has been proposed by DeLisi (1997) that the underlying basis for the neuropathology of schizophrenia resides in the activation of a defective gene (or genes) that determines the rate of neuron growth. This process could cause subtle cortical maldevelopment prenatally and through early childhood, and might be activated again through adolescent pruning of neurons, and again during the gradual aging process in the brain throughout adulthood. Neurodegenerative theories

One of the earliest descriptions of schizophrenia labeled it premature dementia (dementia praecox), and contemporary adult studies have highlighted evidence early in the illness of such neuropsychologic deficits as poor executive functioning (problem solving), vigilance (staying alert and on task), short-term memory, and ability to acquire new information. These deficits vary in severity independent of positive symptoms, but co-relate with negative symptoms. There are current proponents of theories of viral or bacteriologic damage to the CNS, and others who suggest the influence of environmental toxins; immune mechanisms have also been proposed. There is at present, however, no firm evidence for any of these factors causing a selectively dementing syndrome resulting in the symptoms of schizophrenia. However, Findling et al. (1995) reviewed the limited number of relevant articles that reported structural neuroimaging or neuropsychologic data in adolescent patients with schizophrenia and concluded that these were marred by methodologic issues. They decided that, at present, firm conclusions could not be made regarding the presence or absence of neuropsychologic dysfunction or structural neuroimaging abnormalities in this population.

143


Genetics

The aggregation of cases in some kinships, and the relative risk to identical twins and first- and second-degree relatives, suggests that 3–5 genes, each with a number of possible polymorphisms, contribute to the development of schizophrenic illness. Genes for such diverse functions as neuronal growth factors and the dopamine 4 receptor have been proposed. It is likely that the next 5–10 years will produce some definitive information in this rapidly advancing field. There is evidence from adult studies, however, that later environmental factors such as substance abuse and expressed negative emotions in the family can influence the course, and perhaps the timing, of the onset of symptoms. It seems likely that an interplay of various factors contributes differently for individual patients. Psychopharmacologic treatment of schizophrenia in adults Since the mid-1950s, antipsychotic medications have been the cornerstone of the pharmacologic management of schizophrenia. It has become clear that these medications are useful in controlling the positive symptoms, and allow most patients to be maintained in the community rather than in hospital. However, first generation antipsychotics often referred to as ‘‘typical’’ antipsychotics had very limited efficacy for negative symptoms, and demonstrated a number of long-term side effects (e.g., tardive dyskinesia) that contributed substantially to the patient’s social and occupational disability. Also, approximately 20% of patients show a poor response of positive symptoms to these compounds. In the past 10 years, a group of second generation or ‘‘atypical’’ neuroleptics have emerged, the prototype of which has been clozapine. This medication has proved to have efficacy in controlling positive symptoms in one-third to one-half of the sufferers who had been previously refractory to ‘‘typical’’ antipsychotic therapy, and it has also been shown to benefit negative symptoms and significantly decrease the risk of tardive dyskinesia. Unlike the more traditional neuroleptics, whose main action was thought to be through their blockade of various dopamine receptors, especially D2, clozapine blocks both dopaminergic, especially D4, and serotonergic receptors, together with adrenergic, cholinergic, and histaminic receptors (see Table 6.1). The advent of clozapine has refocused interest on the relative affinities of neuroleptics for various neuronal receptors. These affinities have been studied both in vitro and in vivo using positron emission tomography and single positron emission computer tomography scanning. It has been found that

144

K. Marriage

Table 6.1. Relative affinities of some neuroleptics for CNS receptors Drug

D1

D2

D3

D4

H1

5-HT-2 Ach

.1

.2

Chlorpromazine Thioridazine Loxapine Haloperidol Clozapine Risperidone Olanzapine Seroquel

3 3 3 2 2 2 3 1

3 3 3 4 2 4 3 2

4 4 ? 4 2 4 3 —

3 2 4 4 3 4 3 —

3 3 3 1 4 4 4 3

4 3 4 3 3 5 4 2

4 4 3 1 3 5 4 3

2 1 1 1 2 4 1 2

3 4 2 1 3 ± 4 ?

Key: KD (Equilibrium dissociation constant) 10 000–100 000 = ± 1000–10 000 = 1 100–1000 = 2, 10–100 = 3, 1–10 = 4, 1–0.1 = 5. Adapted from Der (1997).

typical neuroleptics produce their antipsychotic effects when about 60% of the mesolimbic dopamine-2 binding sites are occupied, while extrapyramidal effects tend to occur at 80% occupancy of the nigrostriatal sites. In adults, 60% occupancy occurs at a daily haloperidol dosage of 4–6 mg, or 4–8 mg per day of risperidone. Higher doses are not likely to produce any greater antipsychotic efficacy, but will increase the incidence of side effects. Knowledge of neuroleptic affinity for other receptors helps to predict side effects. For instance, the low potency neuroleptics, such as chlorpromazine, as a group, tend to block A1 adrenergic receptors (sedation and hypotension) and histamine 1 receptors (sedation). Blockage of muscarinic acetylcholine receptors tends to cause dry mouth, blurred vision, constipation, and tachycardia. Blockade of serotonergic receptors, particularly 5-HT-2, may be implicated in the lower incidence of extrapyramidal side effects and the improved efficacy for negative symptoms found with clozapine and other atypical neuroleptics (see Table 6.2). Unfortunately, our current state of knowledge does not allow us to anticipate reliably the response of an individual patient to a particular typical or atypical neuroleptic. This is in part because there is enormous individual variation in susceptibility to side effects, e.g., teenage males, Orientals, Native Americans, and those with evidence of organic brain damage may be more likely to develop dystonias and extrapyramidal syndromes. Further, it is as yet unclear which receptor blockades are necessary for improvement of either negative or positive symptoms of schizophrenia. Receptor blockade is just the first step in a pathway involving various

145


Table 6.2. Possible therapeutic action and side effects resulting from neuroleptic blockade of some CNS receptors Receptor blocked

Therapeutic action

Side effects

Dopamine 1 Dopamine 2

Antipsychotic action? Antipsychotic action on mesolimbic tracts – reduces positive symptoms of psychosis

Dopamine 3

Antipsychotic action on negative symptoms? Antipsychotic action on positive symptoms? Decreases negative symptoms of schizophrenia? Decreases extrapyramidal effects of D2 blockade? —

— Nigrostriatal tract: extrapyramidal effects, tardive dyskinesia. Tuberoinfundibular area: hyperprolactinemia. Sexual problems. Prefrontal cortex: exacerbation of negative symptoms —

Dopamine 4 5-HT-2

H1 Ach

Adrenergic 1 Adrenergic 2

— Hypotension, weight gain, sedation, role in serotonin syndrome

Sedation, weight gain, confusion, postural hypotension? Reduces extrapyramidal effects of Dry mouth, blurred vision, memory disturbance, urinary D2 blockade retention; pyrexia, delirium at high doses — Postural hypotension, sedation, reflex tachycardia — Sexual dysfunction

Adapted from Der (1997).

intracellular mechanisms which mediate between the receptor and its final influences on cell metabolism at the ribosomal, mitochondrial, and nuclear DNA levels. Fortunately, ongoing studies of the effect of neuroreceptor manipulation on gene expression are being carried out. Clozapine has been followed by other ‘‘atypical’’ neuroleptics which have varying affinities for an array of CNS neuroreceptors. These have been marketed as exhibiting a lower incidence of acute extrapyramidal side effects, being less likely to cause tardive dyskinesia, and as having some efficacy in reducing negative symptoms. It is as yet unclear to what degree they will facilitate better outcome in long-term management, as clozapine has done.

146

K. Marriage

Psychopharmacologic therapy of child- and adolescent-onset schizophrenia Acute or initial presentation

Managing a child or adolescent who presents with a psychosis includes dealing with issues of safety while carrying out assessment and differential diagnosis. While neuroleptic medication provides a powerful tool for the alleviation of some of the more disturbing symptoms of acute psychosis, pharmacotherapy provides only one arm of a multidimensional treatment approach. First, patients require management in a setting which provides containment of potential impulsive aggression or absconding. This environment should provide adequate structure and an appropriately low level of stimulation. Secondly, a careful psychiatric and medical assessment must be carried out, with as little interference as possible from the side effects of medication. Thirdly, work must begin on forming a therapeutic alliance with the patients and their families to form a basis for their support during the difficult months to come. A detailed program of directed education toward the patient and their family as to the nature of the assessment process, the uncertainties surrounding the diagnosis and the prognosis, and limits to the effectiveness of pharmacotherapy should commence in parallel with history taking. Since a psychosis often interferes with the patient’s insight and may be associated with frightening hallucinations or paranoid ideas, it is often difficult to obtain the patient’s cooperation with treatment. Other family members, distressed as they may be by the experience of seeing a loved one decompensate into a psychosis, may also have difficulty understanding the need for hospitalization and treatment. It may then be necessary to commit the patient to involuntary treatment, according to whatever legal structure for this pertains in a particular jurisdiction. If at all feasible, committal should be done with the agreement and cooperation of the family. Although involuntary treatment is against recent trends to give autonomy to children and adolescents in decision-making with respect to their own medical needs, it provides the legal framework for what may be literally a life-saving intervention. Baseline data Systematic recording of baseline data will allow the clinician to follow symptom response to treatment and to monitor for the emergence of medicationrelated side effects. The Brief Psychiatric Rating Scale (BPRS) can be used weekly during the acute phase of treatment, and may be combined with the Positive And Negative Syndrome Scale (PANSS) completed initially on a

147


Table 6.3. Initial medication of the psychotic child or adolescent Presenting problem Psychotic, agitated, combative, or otherwise dangerous to self and others

Initial treatment

Chlorpromazine 300–600 mg/day in divided doses Antiparkinsonian drugs e.g., benztropine 2–4 mg/day in two doses Patient hallucinating, Loxapine 10–40 mg/day in delusional, some agitation, divided doses disorganized Chlorpromazine 25–50 mg q 1 hourly (as necessary) for agitation Antiparkinsonian agent Patient hallucinating, Loxapine 10–40 mg/day in delusional, disordered thought, divided doses but not dangerous to self or Or haloperidol 2–4 mg/day others Or risperidone 2–6 mg/day And antiparkinsonian agents

Goal response Reduction of agitation over 2–24 hours Regulation of sleep over 1–4 days Agitation and sleep controlled over 1–3 days Delusions, hallucinations diminish over 2–4 weeks

Thought form improves over 1–2 weeks Delusions, hallucinations diminish in 2–4 weeks

Note: doses are for adolescents, and will require titration on an individual basis, depending on such factors as weight and ethnicity. Children will require correspondingly lower doses.

2–4-weekly basis. Videotaping of mental status interviews during the acute phase can also be useful, both for following symptoms and later for motivating the patient in medication adherence. Monitoring of side effects should commence prior to the initiation of pharmacotherapy with an Extrapryramidal Symptom Rating Scale (ESRS), Abnormal Involuntary Movements Scale, and a Medication-Specific Side Effect Scale (MSSES). Choice of initial medication Given the array of low, medium, and high potency neuroleptics that are available, the clinician can, to some extent, match therapeutic and side effect profiles to meet the symptoms presented by the patient (see Table 6.3). If agitation, aggressive behavior, self-injurious behavior, or attempts to elope from the treatment setting are prominent, treatment with the low potency neuroleptics, e.g., chlorpromazine, may be used. Low potency neuroleptics tend to be more sedating, and to produce few dystonic and extrapyramidal side effects. Prophylactic use of antiparkinsonian agents should be considered in every case, since the occurrence of extrapyramidal side effects can be

148

K. Marriage

uncomfortable and even dangerous for the patient and may also hinder future medication compliance. An alternative strategy for aggressive and agitated patients is to combine a high potency neuroleptic such as haloperidol with a benzodiazepine such as lorazepam or clonazepam. However, a proportion of adolescents responds to benzodiazepine by becoming disinhibited rather than calmed. With patients exhibiting agitation and aggression, the immediate goal is to diminish these symptoms within the course of a few hours to 1–2 days while keeping oversedation and side effects to a minimum. Until this chemical restraint is successful, the child or adolescent may require one to one nursing and physical restraint in the form of a locked room, and a well-trained response team should be available to deal with aggression. Patients who are not agitated or combative, and whose most salient symptoms are delusions, hallucinations, or disordered thought form, may be treated with medium potency neuroleptics, e.g., loxipine, perphenazine, or judiciously low doses of a high potency neuroleptic such as haloperidol. These medications should be combined with an antiparkinsonian agent such as benzatropine or procyclidine, particularly for adolescent males who seem more prone to the dystonic and extrapyramidal side effects of neuroleptics. Hallucinations, delusions, and disordered thought form usually respond more slowly to neuroleptic treatment, with improvement over 1–2 weeks, and maximal response to optimal dosage requiring 6 weeks or more. The earliest change reported by patients is often that, while they are still experiencing hallucinations or delusions, they are less troubled by them and more able to concentrate on external aspects of their daily life. A combination of medium and low potency neuroleptics may be useful during the first week or two of acute management. A conservative dose of medium potency neuroleptic may be started with the aim of gradually alleviating hallucinations, delusions, and thought form disorder, while the low potency neuroleptic may be titrated on an hour to hour basis to manage symptoms of agitation and combativeness. As the agitation gradually settles, the dosage of low potency medication, calculated in chlorpromazine equivalents, may gradually be represcribed in the form of equivalent dose of the medium potency neuroleptic. The response of positive symptoms should be carefully followed, in an effort to strike a balance which prevents exacerbation of delusions or hallucinations, while keeping side effects to a minimum. The BPRS and nurses’ notes of shift to shift fluctuations in mental status will facilitate the micromanagement of the acute stage. Choice of the initial neuroleptic may also be influenced by the anticipation that a depot neuroleptic will be necessary for the ongoing management of the patient.

149


Table 6.4. Medications used to prevent or treat the common side effects of neuroleptics Medication A. Benztropine B. Procyclidine C. Amantadine D. Diphenhydramine

Starting dose 1 mg 2.5 mg 100 mg 25 mg

Total daily dose range 2–6 mg 5–20 mg 100–400 mg 100–200 mg

A, B, and C are not useful for akathisia, but D reduces akathisia. These doses are suggested for older adolescents, and will require titration to the individual patient. These medications have their own side effects, e.g., sedation and anticholinergic effects.

Side effects of neuroleptics

Minimizing and managing the multiple side effects of neuroleptic medication is an important aspect of both initial and long-term management of the psychotic patient. The most important and more predictable side effects are dystonias, extrapyramidal effects, and akathisia, and the clinician must remain vigilant for evidence of developing neuroleptic malignant syndrome or tardive dyskinesia (Table 6.4). Dystonias Dystonic side effects range from increased tone or brief spasm of any of the voluntary muscles, including those subserving swallowing and eye movements, to severe contractions producing torticollis, opisthothonos, laryngospasm, or oculogyric crisis. Even mild manifestations of dystonia may be very uncomfortable for the patient, and may interfere with long-term medication compliance. Dystonias usually respond well to antiparkinsonian agents, or to antihistamines, or low-dose benzodiazepines. Parkinsonian side effects Parkinsonian side effects include a stiff or shuffling gait, reduced body movements and facial expression, slurred monotone speech, hypersalivation, and restlessness. They generally respond well to antiparkinsonian medication which can be given prophylatically for both parkinsonian side effects and dystonia. Akathisia, a subjective or objective restlessness which may be mistaken for the increasing agitation of the exacerbation of a psychotic illness, does not usually respond to the standard antiparkinsonian medications and can be difficult to treat. Decreasing the dose of neuroleptic, where possible, may be helpful, as may be the use of clonazepam, propanolol, or diphenhydramine.

150

K. Marriage

Prophylactic antiparkinsonian medication is not necessarily continued for as long as the patient continues on a neuroleptic medication. For example, if the patient has tolerated a clinically effective dose of an antipsychotic throughout the first few weeks of treatment without any evidence of extrapyramidal side effects, a trial of gradual discontinuation of antiparkinsonian agent may be considered. If treatment is with a neuroleptic which has strong anticholinergic action, or with an atypical neuroleptic with low potential for extrapyramidal side effects, such a trial might also be considered. Decrease should be carried out over 10–14 days with gradual reduction by a quarter of the original dose every 4 days to avoid the rebound occurrence of extrapyramidal side effects or of cholinergic symptoms, i.e., nausea, sweating, diarrhea, or incontinence. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is fortunately rare, but may present as a life-threatening medical emergency. NMS consists of pyrexia with fluctuating conscious state, increased skeletal muscle tone and other extrapyramidal effects, and autonomic instability with fluctuating pulse and blood pressure. Total white cell count is usually elevated with neutrophilia, and creatinine phosphokinase of skeletal muscle origin may be elevated 5-fold or more. However, it is important to note the results of these investigations may be in normal range in the presence of the syndrome. Untreated, NMS can proceed to coma, renal shut down, and death. NMS usually occurs in the first 1–2 weeks of treatment with a neuroleptic, or after a change to a new neuroleptic. The combination of lithium with a neuroleptic, and especially lithium and risperidone, may increase patient’s vulnerability, as may pre-existing organic brain damage, e.g., epilepsy or intellectual deficiency. The most important intervention is to suspect NMS in its incipient stage when there is an increase in extrapyramidal side effects combined with mild fever and alterations in cardiovascular tone. All neuroleptic treatment should be withdrawn at once, adequate hydration of the patient ensured, pyrexia treated symptomatically, and consultation sought from a critical care physician. Various medications, e.g., dantrolene and bromocriptine, have been used to treat this disorder in adults, but there is no information about their efficacy in children and adolescents. Anticholinergic side effects Anticholinergic side effects include blurred vision, dry mouth, nausea, constipation, urinary hesitancy, decreased sweating, and impotence. If exacerbated by an antiparkinsonian agent with its own anticholinergic effects, these symptoms

151


may be severe, or delirium with pyrexia may result. These side effects may be managed by decreasing the dose of neuroleptic, if possible, reducing the dose of antiparkinsonian treatment, or switching to a neuroleptic with less anticholinergic effect. Weight gain This is a prominent side effect with all neuroleptics and one of the most distressing for the patients and families; it seems more marked with the atypical neuroleptics. The proposed mechanisms are D2 + 5-HT blockade, effects on prolactin and cortisol, or dry mouth from anticholinergic effects leading to increased drinking often of high calorie beverages. Weight gain tends to plateau after 2 years of treatment. Endocrinic side effects All neuroleptics that cause hyperprolactinemia do so by blocking the dopamine-mediated inhibition of prolactin release in the tuberoinfundibular area. Gynecomastia and amenorrhea may result, and rarely galactorrhea. Sexual dysfunction has been reported in adults. Decreased neuroleptic dosage and endocrinologic consultation may be necessary, if these symptoms appear. Other side effects Rarely, neuroleptics cause disturbances in hematopoiesis or severe dermatologic problems. Cholestatic jaundice, laryngeal edema, or anaphylaxis are other rare complications and treatment should be discontinued at once. Tardive dyskinesia Tardive dyskinesia is more common in middle-aged female patients who have had a number of years’ treatment with neuroleptics, but can, in fact, occur in children and adolescents at any time after the initiation of neuroleptic therapy (Kumra et al., 1998b). It most commonly presents as involuntary rhythmic chewing movements of the mouth and tongue, but may also affect the neck, trunk, and limbs. Treatment consists of decreasing the dosage of the neuroleptic where possible or, in extreme cases, substituting clozapine. ‘‘Atypical’’ neuroleptic use in children and adolescents

The designation ‘‘atypical’’ has been applied to clozapine and a number of newly introduced agents which are thought to have demonstrated a significantly lower incidence of extrapyramidal side effects at therapeutic doses, and to have superior efficacy in treating negative symptoms. Information about the

152

K. Marriage

use of these agents in children and adolescents is, to date, quite limited. An open trial of clozapine in adolescents with childhood schizophrenia (Frazier et al., 1994) reported a favorable response in more than half of the group which had been partially or totally refractory to conventional neuroleptics. Superiority over haloperidol for both positive and negative symptoms has also been demonstrated (Kumra et al., 1996). However, Kumra et al. (1998a) reported that 12 (44%) of 27 child and adolescent patients treated with clozapine discontinued therapy because of seizures (n = 3), hematologic abnormalities (n = 2), or treatment nonresponse (n = 7). Clozapine can induce potentially lethal neutropenia in about 1% of adult patients, and in perhaps as many as 3% of child and adolescent patients, and its administration requires continuing, weekly monitoring of white blood cell indices. While the limited data available suggest that it will be useful in treatment-refractory or -semirefractory child and adolescent patients, these hematologic difficulties preclude its use as a ‘‘first-line’’ agent. Risperidone, unlike clozapine, has a high affinity for the dopamine 2 receptor. It also binds strongly to and blocks 5-HT receptors, and this may be the basis of its tendency to show a lower incidence of extrapyramidal side effects. However, in practice, at the recommended dosage of 4–6 mg in adolescents, dystonias and extrapyramidal side effects may occur, and the margin between a therapeutically effective dose and that likely to produce these side effects may be narrow. Tardive dyskinesia has been described with risperidone, but despite this it has gained some popularity in North America as a first-line drug in a number of childhood conditions, including schizophrenia, Tourette’s syndrome, and the PDDs. Olanzapine, a potent 5-HT-2A/2C, dopamine D1D2D4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. It does not cause neutropenia, and may be a good candidate for both a first-line medication, and for the treatment of the cases which have not responded to the traditional neuroleptics. However, Kumra et al. (1998a) described an open label comparison of olanzapine and clozapine and found that only two (25%) of eight olanzapine-treated patients would be considered drug responders and one a partial responder after 8 weeks of treatment. Clozapine was superior, and these investigators suggested that it remained the ‘‘gold standard’’ treatment for childhood schizophrenia refractory to traditional neuroleptics. Significant weight gain, seen in many young people treated with ‘‘atypicals’’, may be most extensive with olanzapine. Since the recent changes in the US Federal Drug Administration policies, formal clinical trials of new neuroleptic medications will be mandated in

153


children and adolescents as well as in adults, so it should become possible over the next few years to obtain a clearer idea of the place of these new medications in the therapy of childhood schizophrenia. Potential problems in management of the acute phase

Negative symptoms may be prominent at first presentation or may become more obvious as positive symptoms subside in response to neuroleptic treatment. These may be resistant to treatment with a typical antipsychotic and, in fact, may be in part due to dopamine blockades in the frontal lobes caused by too high a dose of either ‘‘typical’’ or ‘‘atypical’’ antipsychotic. Decreased dosage of antipsychotic or increasing antiparkinsonian medication may improve the picture. It is important, but sometimes difficult, to differentiate negative symptoms from depression, which may occur in schizophrenia or which may represent the misdiagnosis of a psychotic depressive episode. Negative symptoms may respond to appropriate doses of an atypical neuroleptic, such as risperidone or olanzapine. Relapse during treatment of the acute phase may be the result of undermedication, due to an insufficient initial dose or to switching from one neuroleptic to another. Undermedication may also be the result of noncompliance by the patient and, in this situation, consideration of the use of a liquid preparation may be appropriate. A fairly common cause of relapsing in the early phase of recovery is that the patient, either on the ward or during day or overnight passes, has resumed use of street drugs. Marijuana or alcohol use, or use of ‘‘hard’’ street drugs, can exacerbate psychotic symptoms. Urine drug testing and discussion of the possibility with patient may be necessary. Adult data suggest that 20–30% of patients will fail to respond to adequate dosage of the initial antipsychotic medication. These rates may be even higher in the younger patient. At this point, it is appropriate to consider if the symptoms are iatrogenic, e.g., as side effects to neuroleptic or antiparkinsonian treatment, and if adequate neuroleptic dosage has been given for a significant length of time. If these possibilities have been ruled out, it is necessary to change the dose of the original neuroleptic, combining the first neuroleptic with another medication such as lithium, or substituting another neuroleptic from another chemical class. Failure to respond to adequate treatment with two successive neuroleptics should lead to the consideration of treatment with clozapine. Electroconvulsive therapy Electroconvulsive therapy (ECT) is seldom used for adolescents and, although there is a literature supporting its efficacy in refractory bipolar disorder and

154

K. Marriage

depression in this age group, the rate of positive response in schizophrenia is probably only of the order of 33% (Schneekloth et al., 1993; Cohen et al., 1997). Severe catatonic symptoms that are unresponsive to medication are the main indication for the use of ECT in this group of patients. Intermediate and long-term management Re-establishing the patient in the community and facilitating their optimal function there poses a whole new set of challenges to the managing physician. Psychopharmacologically, the aim is to improve the patient’s chances for rehabilitation by preventing relapse and controlling the positive and negative symptoms, while minimizing the side effects and encouraging adherence to the medication regimen. The initial building of a therapeutic alliance with the patient and the family must be continued in the setting of the community. One of the issues facing the physician once the patient begins to recover from the acute psychotic episode is the question of maintenance medication. There is ample evidence that adherence to maintenance neuroleptics reduces the incidence of relapse, at least over the first few years of treatment. Most of this information is from the adult literature, but is presumed to be equally applicable to children and adolescents. It is often a challenge to convince the patient, whose insight into their illness may continue to be limited, to adhere to a medication regimen which produces uncomfortable and even debilitating side effects on a day to day basis. The patient’s memory of dystonias and other symptoms during the acute phase of treatment may be particularly pertinent in this situation. While the family may be more receptive to education as to the benefits of long-term medication, many adolescents will wish to make their own, sometimes contrary, decisions about their lifestyle. A videotaped vignette of the acute stage of the psychosis can be part of the information used in the discussion, if family and patient agree. Another issue is the decision between using oral daily medication and depot injections on a 2–4 weekly basis. Each case will need to be decided on its merits, with reference to such factors as the patient’s degree of insight and willingness to cooperate, the home environment to which the patient is returning and the quality of the supervision there, the day program or school in which the patient will participate, and the local mental health resources. Patients who lack insight and understanding of their illness, who have demonstrated oppositionality on the ward, who are returning to an unstable and undersupervised living situation, and who are not taking part in a structured vocational or school program where they can be reliably observed on a day to day basis have a better chance

155


of avoiding relapse if they can be treated with a depot neuroleptic. It should be borne in mind that, in studies with adults, properly administered depot neuroleptics produce a lower relapse rate, even when compared with patients who have shown satisfactory adherence to daily oral medication treatment. Oral medication has the advantages of easier titration to deal with symptom fluctuation or the emergence of side effects. For some patients or their families, the idea of taking pills is more acceptable than receiving injections and may denote a more active part in the treatment partnership with the physician. In some cases, occasional combination of oral antipsychotics with ongoing injectables may be of value. If, after weighing the qualities of the patient and his or her social system, it is decided to proceed to depot neuroleptic treatment, the patient may be switched to an oral form of the chosen medication and the dosage titrated on the ward until response is satisfactory. Alternatively, the dose of the current oral neuroleptic may be converted to ‘‘chlorpromazine equivalents,’’ where this number will be used to estimate the required 2- or 3-weekly intramuscular dosage of depot neuroleptic. Gradual crossover, with the introduction of test doses and then increasing doses of depot neuroleptic, while decreasing the dose of oral treatment, may then be carried out. Once again, careful titration of dosage to produce optimal symptom control with minimal side effects, and the use of oral antiparkinsonian agents, is necessary. To make the transition from oral to depot neuroleptic, the oral dosage may be decreased stepwise over 10–14 days, with the first dose of a fraction of the estimated final depot neuroleptic being given about day 7, with increasing intramuscular doses at weekly intervals until the estimated final depot dose is reached. Once the patient is stabilized on depot neuroleptic for about 3–4 months, consideration may be given to a trial of very gradual withdrawal of antiparkinsonian agents, with decrements being made at each depot injection, i.e., every 2–4 weeks. The usual strategy in pharmacotherapy is to give the minimal dose of antipsychotic which will prevent symptoms, in an effort minimize side effects. Gradual reduction of antipsychotic medication should be instituted only after a prolonged period of remission from the initial psychotic episode, i.e., 12 months or more. This should be done with careful monitoring for symptom recurrence. It should be recognized that, even with optimal treatment, relapses may occur and it is important to instruct families and patients in recognizing the early symptoms of such an event. Parents, in particular, can be very perceptive in picking up early changes that signify recurrence. Relapses require

156

K. Marriage

vigorous treatment with dosages similar to those required to manage the initial psychosis. Most patients with schizoprenia will require antipsychotic treatment for life, but, in an environment of evolving antipsychotics and treatment strategies, it is not possible to estimate what pharmacotherapy might be brought to bear in the future of these young patients. While there are long-term risks to the ongoing use of these compounds, especially tardive dyskinesia, the potential damage to long-term development that may be the result of recurrent psychotic episodes or incomplete symptom resolution usually far outweighs this risk. Ongoing negotiation and counseling with the patient and family should assist in weighing the cost–benefit ratio of continuing treatment. It is important to conduct regular checks for the emergence of medication side effects. This should include enquiring about the specific symptoms, and physical examination for cog wheeling, tremor, or bradykinesia. With the exception of clozapine, routine blood work is unlikely to be helpful in the management of the medically asymptomatic patient. Rather, the patient and family should be given ongoing education as to the early signs of such rare adverse events as liver dysfunction or hematologic problems. A neuroleptic side effect rating scale, such as MSSES, may be completed at each visit, as may be the BPRS, in order to follow the progress of psychiatric symptoms. Reconsideration of the initial diagnosis should be carried out at intervals of 1–2 years, utilizing any further background information that may come to light together with an appraisal of the patient’s progress to date. In the past, there has been the tendency to overdiagnose schizophrenia and underdiagnose bipolar disorder, and review of clinical course is the best way to correct any such error, which may have treatment and prognostic implications. Environmental factors that impinge on the patient’s maintaining recovery should be carefully considered. These would include a high level of expressed emotion in the family, lack of adequate educational and vocational resources in the community, and the patient’s recreational drug use. These three together would represent the majority of external factors that lead to the patient’s decompensation. Conclusion The pharmacologic management of schizophrenia requires strategic planning while attending to the details of day to day micromanagement of symptoms and side effects. The campaign of interventions is frequently planned and commenced before the clinician can be certain of the diagnosis. Challenges for

157


the clinician include attempting to control the symptoms of a disorder whose etiology is unknown, and forming a therapeutic alliance with a patient whose illness often renders him or her suspicious, erratic, and emotionally unresponsive. This is as exacting a task as any in medicine.

REFE R EN C ES Adams M, Kutcher S, Antoniw E, Bird D. (1996). Diagnostic utility of endocrine and neuroimaging screening tests in first onset adolescent psychosis. J Am Acad Child Adolesc Psychiatry 35:67–73. Alaghband-Rad J, McKenna K, Gordon C et al. (1995). Childhood onset schizophrenia: the severity of the premorbid course. J Am Acad Child Adolesc Psychiatry 34:1273–83. Altman H, Collins M, Mundy P (1997). Subclinical hallucination and delusions in non-psychotic adolescents. J Child Psychol Psychiatry 38:413–20. American Academy of Child and Adolescent Psychiatry (1997). Practice parameters for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 36:S177–93. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Caplan R (1994). Thought disorder in childhood. J Am Acad Child Adolesc Psychiatry 33:605–15. Cohen D, Paillere-Martinot ML, Basquin M (1997). Use of electroconvulsant therapy in adolescents. Convuls Ther 13:25–31. DeLisi LE (1997). Is schizophrenia a lifetime disorder of brain plasticity, growth and aging? Schizophrenia Res 23:119–29. Der D (1997). Human neurotransmitter receptors and psychotropic drug profiles. For Your Inpharmation, Riverview Hospital Pharmacy Newsletter, Vol. 17, issue 9. Findling RL, Friedman L, Kenny JT et al. (1995). Adolescent schizophrenia: a methodologic review of the current neuroimaging and neuropsychologic literature. J Autism Dev Disord, 6:627–39. Fraser W, Nolan M (1994). Psychiatric disorders in mental retardation. In Mental Health in Mental Retardation (Ed.) N Bouraj. Cambridge University Press, Cambridge, pp. 79–92. Frazier J, Gordon CT, McKenna K et al. (1994). An open trial of clozapine with 11 adolescents with childhood onset schizophrenia. J Am Acad Child Adolesc Psychiatry 33:658–63. Kaufman J, Birmhaher B, Clayton S et al. (1997). Case study: trauma-related hallucinations. J Am Acad Child Adolesc Psychiatry 36:1602–5. Kumra S, Jacobsen LK, Lenane M et al. (1998a). Childhood-onset schizophrenia: an open-label study of olanzapine in adolescents. J Am Acad Child Adolesc Psychiatry 37:377–85. Kumra S, Jacobsen LK, Lenane M et al. (1998b). Case series: spectrum of neuroleptic-induced movement disorders and extrapyramidal side effects in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 37:221–7.

158

K. Marriage

Kumra S, Frazier J, Jacobsen LK et al. (1996). Childhood onset schizophrenia: a double blind clozapine haloperidol comparison. Arch General Psychiatry 53:1090–7. Linehan M (1993). Cognitive Behavioural Therapy of Borderline Personality Disorder. New York: Guilford Press. Lewis DA (1997). Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology, 6:385–98. Reid A (1993). Schizophrenia and paranoid syndromes in persons with mental retardation: assessment and diagnosis. In Mental Health Aspects of Mental Retardation (Ed.) RJ Fletcher, A Dosen. New York: Lexington Books. Russell AT (1992). Schizophrenia. In Assessment and Diagnosis of Children and Adolescent Psychiatric Disorders: Current Issues and Procedures (Ed.) SR Hooper, GW Hynd, RE Mattison. New Jersey: Lawrence Erlbaum, pp. 23–63. Schneekloth TD, Rummans TA, Logan KM (1993). Electroconvulsive therapy in adolescents. Convuls Ther 9:158–66. Schultz SC, Findling FL, Wise A et al. (1998). Child and adolescent schizophrenia. Psychiatr Clin North Am 94:43–56. Volkmar FR (1996). Childhood and adolescent psychosis: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 35:843–51. Weinberger DR (1995). Schizophrenia as a neurodevelopmental disorder: a review of the concept. In Schizophrenia (Eds.) S Hirsch, D Weinberger. Blackwood Press, London, pp. 293– 323. Werry JS (1996). Childhood schizophrenia. In Psychoses and Pervasive Developmental Disorders in Childhood and Adolescence (Ed.) FR Volkmar. Washington, DC: American Psychiatric Press Inc. Werry JS (1992). Child and adolescent (early onset) schizophrenia: a review in light of DSM-III-R. J Autism Dev Disord 22:601–24.

7 Obsessive–compulsive disorder Douglas A. Beer1, Mai Karitani2, Henrietta L. Leonard2, John S. March3, and Susan E. Swedo4 1

Brown University, Providence, Rhode Island, USA. 2Rhode Island Hospital, Providence, Rhode Island, USA. 3Duke University Medical Center, Durham, North Carolina, USA. 4National Institute of Mental Health, Bethesda, Maryland, USA.

Despite having been described consistently in the psychiatric literature for close to a century, as recently as 10 years ago, obsessive–compulsive disorder (OCD) was still thought to be a relatively rare condition without a clearly effective treatment. The infrequency of the diagnosis of OCD in clinical settings owed both to the secretive nature of the disorder as well as to under-recognition and misdiagnosis. Recent epidemiologic data suggest that as many as 1–2% of children and adolescents in the United States may meet criteria for OCD. As is the case with adults, children with OCD often suffer silently for many years before they receive assessment, accurate diagnosis, and treatment. With increasing professional and media interest in this disorder and greater sensitivity to its diagnosis, many patients are now being recognized. Additionally, thanks to advances in clinical research, patients with OCD can now expect to receive more effective treatments than were available in the past. In this chapter, we review the current state of knowledge regarding the phenomenology, diagnosis, etiology, and treatment of OCD specifically as related to children and adolescents.

Epidemiology Initial estimates of the incidence of childhood OCD were made from psychiatric clinic populations. Berman (1942) reported ‘‘obsessive–compulsive phenomena’’ in six (0.2%) of 2800 patients. Similarly, Hollingsworth and colleagues (1980) found 17 cases of OCD (0.2%) in 8367 child and adolescent inpatient and outpatient records. The first epidemiologic study of psychiatric disorders in young people, the Isle of Wight study, reported ‘‘mixed obsessional/anxiety disorders’’ in seven (0.3%) of 2199 of the 10- and 11-year-old children surveyed (Rutter et al., 1970). More recently, however, Flament and colleagues (1988) found a weighted point prevalence rate of 1% and a lifetime prevalence of 1.9% 159

160

D.A. Beer et al.

in a study that surveyed over 5000 high school students in New Jersey. These findings are compatible with the estimated 1–2% 6–month, and 2–3% lifetime, prevalence for adults (Karno et al., 1988) and the finding that at least one-third to one-half of adult OCD patients report the onset of illness in childhood (Black, 1978; Rasmussen and Eisen, 1994). While similar data regarding young children are unavailable, it appears that, as in adults, OCD in children and adolescents is much more common than previously thought. Phenomenology Symptoms

To meet the criteria for OCD laid out in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994), one must have either recurrent obsessions or compulsions that are either significantly time-consuming (i.e., P 1 hour per day), cause marked distress, or result in significant impairment in routine social, occupational, or academic functioning. The current diagnostic criteria also require that affected individuals with OCD must at some point recognize that their obsessions or compulsions are excessive or unreasonable. Owing to the possibility that they will not possess the necessary cognitive maturity and insight required in making this judgment, children are exempted from this particular requirement. DSM-IV includes a ‘‘With Poor Insight’’ specifier for use with individuals who generally do not view their obsessions or compulsions as unreasonable or excessive, though this is more commonly applied to adults. Additionally, the specific content of the obsessions or compulsions cannot be accounted for by another axis I diagnosis, such as in the case of preoccupations about food resulting from an eating disorder, guilty ruminations from major depressive disorder, or hair pulling in trichotillomania. An individual typically attempts to ignore, suppress, or neutralize intrusive obsessive thoughts, though their effort may vary greatly across time and context. Generally, compulsions are carried out to prevent or quell anxiety, to ward off some anticipated catastrophe, and/or according to a fixed rule. The most commonly reported obsessions in children and adolescents in both clinical and community samples center on germs and contamination or fears about harm or danger to oneself or loved ones. Obsessions focused on moral scrupulosity and symmetry are also common. The most common compulsions seen include excessive washing or cleaning, repeating, checking, touching, counting, ordering/arranging, and hoarding (Flament et al., 1988; Swedo et al., 1989b). The great majority of children and adolescents with OCD, like adults,

161


report both obsessions and compulsions (Flament et al., 1988; Swedo et al., 1989b) with ‘‘pure ritualizers’’ being more common among children than ‘‘pure obsessives.’’ There does not appear to be a clear relationship between age and the number or content of obsessive–compulsive symptoms (Rettew et al., 1992). Additionally, specific subtypes of OCD have yet to be identified based solely on symptom content. Indeed, 90% of children studied at the National Institute of Mental Health (NIMH) study reported that their obsessions and compulsions changed in both content and severity over time (Rapoport, 1989; Swedo et al., 1989b). More recently, efforts have been directed at distinguishing OCD comorbid with tics from that which is not. Such studies suggest that OCD associated with tics may be more familial, may be more common in boys and those with early onset to their illness, and may require a unique pharmacological treatment approach compared with OCD without tics (Holzer et al., 1994; McDougle et al., 1994). Course

Despite an apparent core set of common specific symptoms, systematic studies have found considerable heterogeneity among pediatric OCD patients; for example, onset may be abrupt or insidious and may or may not be related to a clear precipitant. Pediatric OCD may follow a waxing and waning course – as has been consistently described in studies of adult OCD probands – or may be characterized by dramatic exacerbations and remissions (Swedo et al., 1989b; Riddle et al., 1990b). Despite changes in severity over time, the great majority of patients report a chronic course of illness with few complete remissions (Rasmussen and Eisen, 1994). Berg and colleagues (1989a), in a 2-year follow-up of a community sample, found that only two (13%) of 16 adolescents originally diagnosed with OCD were symptom free and 14 (88%) of 16 still had significant obsessive–compulsive symptoms; five (31%) of 16 still met full criteria for the disorder. Similarly, a systematic, prospective follow-up of 54 children and adolescents at 2–7 years (mean 3.4 ± 1.0 years) found that 43% still met diagnostic criteria for OCD and only 6% were considered to be in remission (Leonard et al., 1993). Nevertheless, 81% of subjects in this sample were considered at least somewhat improved with respect to OCD status. Importantly, these subjects were all initially treated with clomipramine, 96% received additional psychopharmacologic treatment in the interim, and one-third received some form of behavioral therapy.

162

D.A. Beer et al.

Despite these mixed results, significant advances in our understanding of OCD and its treatment have been made over the last decade such that the prognosis for most pediatric OCD patients appears considerably more promising than earlier studies suggested. Age and gender effects

There is some disagreement regarding gender distribution of children and adolescents with OCD. While there is a preponderance of males in most studies of children and adolescents with OCD, two epidemiologic studies of OCD in adolescents and two studies of referred children and adolescents with OCD found an approximately equal male to female ratio (Hanna, 1995). The differences may be explained by the fact that in the prepubertal years there is a higher male–female ratio, whereas postpubertally this ratio is equalized or reversed. Several studies suggest that boys have an earlier age at onset than girls (Flament et al., 1985; Last and Strauss, 1989; Swedo et al., 1989b) and that younger boys have more severe symptoms than younger girls (Flament et al., 1985). These data suggest the possibility of a bimodal distribution with preadolescent- and adolescent-onset groups. Additionally, in the early-onset OCD group, boys appear more likely to present with comorbid tics and/or disruptive behavior disorders. Thus, the differences in gender ratio between the studies may reflect ascertainment bias in some clinically referred samples. Recent studies have also suggested that earlier onset of illness may be associated with increased genetic loading and a greater likelihood of personal and familial tic disorders (Lenane et al., 1990; Pauls et al., 1995). Comorbidity

Phenomenologic studies of pediatric populations, in both clinical and community samples, indicate that OCD rarely exists without associated psychopathology. Such studies have consistently found elevated lifetime and concurrent rates of other anxiety, mood, and tic disorders. Disruptive behavior disorders and specific developmental disorders also appear to be common. Of the 70 consecutive children studied at the NIMH, only 18 (26%) had no other current or lifetime axis I diagnosis (Swedo et al., 1989b). The most common concurrent diagnoses in this group were major depression (26%), specific developmental disability (24%), simple phobia (17%), overanxious disorder (16%), adjustment disorder with depressed mood (13%), oppositional disorder (11%), and attention-deficit disorder (DSM-IIIR; American Psychiatric Association, 1987) (10%). Additionally, 20% of the sample had motor tics – especially male subjects with early onset – despite Tourette’s syndrome (TS) being an exclusionary diagnosis.

163


Similar results were reported by Hanna (1995) who found lifetime rates of depression, anxiety, disruptive behavior, and tic disorders ranged from 26% to 32% in children and adolescents with OCD. Perhaps the most considerable and consistent findings relate to the cooccurrence of OCD with tics and TS. Studies of OCD patients and TS patients alike have found that about one-third to one-half of subjects will meet criteria for both disorders (Pauls et al., 1986; Leonard et al., 1992). In their study, Leonard and colleagues (1992) found that 32 (59%) of 54 of children with OCD had a lifetime history of a tic disorder at follow-up. Eight of those 32 (15% of the total sample) met full criteria for TS despite TS having been a diagnosis of exclusion at the outset. Other reports have indicated that OCD patients who also have tics have a greater incidence of symmetry, exactness, and aggressive obsessions as well as touching, rubbing, staring, and blinking rituals compared with those subjects without tics (Holzer et al., 1994; Leckman et al., 1997). Diagnosis Children will often go to great lengths to conceal or disguise their rituals (Swedo and Rapoport, 1989). Embarrassment, parental minimization, and a lack of knowledge about OCD and the availability of effective treatment may all contribute to such secrecy. Optimally, children will inform us about their cognitions and emotions; however, in those children who do not have insight into the excessiveness of their obsessions or compulsions, or who would seek to keep their symptoms a secret, collateral information from parents and teachers may provide necessary clarification regarding particular symptoms. Behaviors which may indicate the presence of OCD include lengthy bedtime rituals or exaggerated requests for reassurance, particularly if centered on a fear of harm coming to self or others. Additional warning signs for OCD may include lengthy unproductive hours spent on homework, particularly if there is evidence of considerable erasing or retracing over letters or words. Unexplained high utility bills, a dramatic increase in laundry, or toilets stopped up from too much paper may alert parents to a child’s obsession about germs and contamination. Hoarding, beyond the typical childhood collecting, of seemingly useless objects (e.g., scraps of paper or street garbage) may be another cue to the presence of OCD. While less severely ill patients may prove difficult to recognize, particularly those adept at hiding their symptoms, severely incapacitated children and adolescents with hallmark OCD symptoms may be more readily diagnosed. In addition to complete developmental, personal and family medical and

164

D.A. Beer et al.

psychiatric histories, and a current assessment of social, academic, and family functioning, a comprehensive evaluation (American Academy of Child Adolescent Psychiatry, 1997) should seek to determine the full range of current and past symptoms. Clinicians should also seek out evidence of comorbidity that may complicate treatment. Detailed information regarding the onset and course may be helpful in identifying putative subtypes. A careful differential diagnosis is warranted in light of the many different disorders that may bear a striking phenomenologic resemblance to OCD. Body dysmorphic disorder (BDD), hypochondriasis, eating disorders, trichotillomania, and other impulse control disorders (e.g., severe skin picking or nail biting) are also characterized by persistent concerns and/or repetitive behaviors. These disorders can usually be distinguished from OCD by the content of the concerns expressed – e.g., worry about the appearance of a body part in BDD or the focus on food and body image in eating disorders. Despite clinicians’ abilities to distinguish OCD from these disorders, it is important to remember that they may frequently coexist (Phillips et al., 1995; Soriano et al., 1996; Thornton and Russell, 1997). Just as obsessions can be difficult to distinguish from the mental phenomena associated with many other disorders, there are many behavioral patterns that may be the source of diagnostic confusion when it comes to identifying compulsions. Simple tics are usually easy to identify as rapid, recurrent movements, or vocalizations. Differentiating tics from compulsions may be made more difficult by the finding that the vast majority of TS patients report ‘‘premonitory urges’’ prior to their tics (Leckman et al., 1993). The difference between tics and compulsions can be particularly difficult to ascertain when the tics are especially complex or involve touching, tapping, or spitting. Repetitive formalized behaviors, such as stereotypies seen in children and adolescents with autistic disorder or other pervasive developmental disorders (PDDs), mental retardation, or brain injury, or even in normal children (Castellanos et al., 1996), may superficially resemble OCD rituals. In the PDDs, the behaviors are generally simple, may be poorly organized, and are not clearly performed according to a specific rule or in a purposeful effort to neutralize obsession-related anxiety. As such, these repetitive behaviors also seem reassuring and lack the ego-dystonicity which is characteristic of the compulsions of OCD. Other features of PDD, such as peculiar speech patterns and/or severely impaired interpersonal relationships, are not typically seen in OCD. A review of the literature reveals that several authors, working with seemingly different populations, have described groups of children with aversion to

165


novelty, deficits in reciprocal social interaction, and affective lability. ‘‘Borderline syndrome of childhood’’ (Petti and Vela, 1990), ‘‘schizoid personality’’ (Wolff and Barlow, 1979), ‘‘multiplex developmental disorder’’ (Klin et al., 1995), and ‘‘obsessive difficult temperament’’ (Garland and Weiss, 1996) may share these core features. Such children, perhaps in an effort to avoid overwhelming anxiety caused by novel situations, may be extremely insistent on things being done in a highly predictable way. It is easy to see how the terms ‘‘obsessive’’ and/or ‘‘compulsive’’ might be used to describe such children, but the relationship between these putative diagnoses and OCD remains largely unexplored. Finally, the relationship between obsessive–compulsive personality disorder (OCPD) and OCD remains unclear ( Joffe et al., 1988) for children, as well as for adults. Indeed, the question of the validity of applying axis II personality disorder diagnoses to young children remains controversial. Swedo and colleagues (1989b) suggested that obsessive–compulsive personality traits might arise as a defense mechanism in the course of OCD. Interestingly, Ricciardi et al. (1992) reported that OCPD in adults might attenuate with treatment directed at comorbid OCD. Both lines of evidence raise questions regarding whether, and to what extent, OCPD represents a state or a trait in OCD patients. In either case, the rigidity, perfectionism, and hoarding of OCPD are usually ego-syntonic and not as content specific as the classic symptoms of OCD. The Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) is a widely used, reliable, and valid instrument (Goodman, 1989a,b) which has been specifically adapted for use with children (CY-BOCS) (Scahill, 1997b). The CY-BOCS includes a symptom checklist that is particularly useful in a clinical interview to elicit OCD symptoms, including more ‘‘minor’’ and more secretive ones which might otherwise go unnoticed or undisclosed. The CY-BOCS may also help clinicians to obtain a baseline symptom severity measure and to track changes over time. Etiology The etiology of OCD is unknown, but recent research has shifted the focus from psychologic to neurobiologic models. Freud held that obsessions and their attendant compulsions were the result of the ego struggling against unacceptable hostile impulses toward the parents. While such a conceptualization may provide a useful theoretical framework, application of psychodynamic principles to the treatment of OCD has not generally been found to be helpful

166

D.A. Beer et al.

in reducing obsessive–compulsive symptoms themselves in patients with OCD. Alternatively, behavioral theorists have posited that OCD results from a pattern in which escape and avoidance behaviors arise in response to normal but intrusive, anxiety-provoking thoughts. These behaviors are positively reinforced by their ability to reduce anxiety temporarily and, over time, they consolidate into compulsive rituals. Learning theory continues to provide a critical grounding for the behaviorally oriented therapeutic approaches that have become a mainstay of OCD treatment. In exposure/response prevention, for example, stimulating patient anxiety through exposure to a specific stimulus is coupled with preventing patients from performing their compulsive (escape and avoidance) rituals. While this predictably increases short-term anxiety, it leads to a predictable, gradual decline in anxiety. As they repeat this process, patients learn that they can experience anxiety–relief without resorting to the performance of compulsive rituals. In the context of somewhat limited results obtained with the use of traditional psychodynamic therapies, along with the dramatic advances in psychopharmacology and neurobiologic research, it is no surprise that the brain has supplanted the psyche as the reference for more recent etiologic theories of OCD. OCD has been associated with many illnesses and injuries affecting various parts of the brain. Head injury, brain tumors, carbon monoxide poisoning, and other brain insults resulting in basal ganglia damage have been reported to be related to the onset of OCD symptomatology (Insel, 1992). Basal ganglia diseases, such as postencephalitic Parkinson’s disease (von Economo, 1931) and Huntington’s chorea (Cummings and Cunningham, 1992), have also been associated with an increased rate of OCD. Alternatively, dysfunction in the temporal lobes (Kroll and Drummond, 1993), frontal lobes (Ames et al., 1994), and hypothalamus (Pitman, 1982) have all been associated with some cases of obsessive–compulsive symptoms. During the past two decades, multiple lines of evidence have been elaborated that implicate dysfunction in a cortico-striato-thalamocortical loop as underlying OCD (Modell et al., 1989; Insel, 1992; Rauch and Jenike, 1993). Additionally, neurotransmitter dysregulation, genetic susceptibility, and environmental triggers appear to have roles in the pathogenesis of this illness. The demonstration that serotonin reuptake inhibitors (SRIs) are specifically efficacious in the treatment of OCD led to the ‘‘serotonin hypothesis’’ of OCD (Greist et al., 1995b). The SRIs, and serotonin itself, appear to exert their influence on neural function through a complex interplay of receptor-coupled intracellular signal transduction pathways. In particular, cyclic adenosine monophosphate (cAMP) pathways are upregulated in response to long-term SRI/(SSRI) selective

167


serotonin reuptake inhibitors treatment (Duman, 1998). However, the specific site and mechanism of SRIs’ therapeutic action remain unclear in light of the increasingly evident complexity of serotonin receptors, and their associated intracellular mechanisms. Additionally, in light of the complex interrelation between different neurotransmitter systems, it appears quite unlikely that dysfunction of serotonergic systems alone can account for OCD. Indeed, there is preliminary evidence to suggest that other neurotrans-mitters (e.g., dopamine, glutamate) may also play a role in the pathogenesis of OCD (Goodman et al., 1990; Rosenberg et al., 2000). Additional evidence supporting a neurobiologic etiology of OCD includes a plethora of neuroanatomic, neurophysiologic, and neuroimmunologic findings. Morphometric magnetic resonance imaging studies, some of which include adult patients with childhood-onset OCD, tend to demonstrate caudate abnormalities, though methodologic differences between the studies have led to inconsistent findings (Luxenberg et al., 1988; Rauch and Baxter, 1998). Swedo et al. (1989c, 1992) studied 18 patients with childhood-onset OCD compared with matched controls and found positron emission tomography abnormalities in both frontal lobes and caudate metabolic rates. This is consistent with findings from similar studies in adults (Baxter et al., 1998; Benkelfat et al., 1990). Additionally, whereas symptom provocation tends to increase metabolism in the frontal and striatal areas (Rauch et al., 1994), effective treatment of OCD symptoms, whether achieved by pharmacologic or psychotherapeutic means, is associated with reductions in metabolic activity in these regions (Swedo et al., 1992; Schwartz et al., 1996). Studies of neuropsychologic functioning in both adult and pediatric OCD patients have identified impairments on measures of executive, memory, and visuospatial functioning which are also consistent with the cortico-striatal neurobiologic model of OCD (Cox et al., 1989). It has been theorized that many of the core symptoms of OCD – pathologic doubt, checking, compulsive ritualizing, etc. – may be related to an inability to adequately filter and appropriately identify fear stimuli and other environmental cues (Otto, 1992). This inability, in turn, appears to be related to deficits in executive function and working memory. As noted in the section on comorbidity above, intriguing links have also been found between TS, tic disorders, and OCD. Patients with TS frequently have obsessive–compulsive features, and OCD patients have an increased incidence of tic disorders (Pauls et al., 1986; Leonard et al., 1992). Support for a link between OCD and TS has been strengthened by findings of an increased rate of tic disorders in the first-degree relatives of OCD probands regardless of

168

D.A. Beer et al.

probands’ tic status and of an increased rate of OCD in TS probands regardless of the probands’ OCD status. Pauls et al. (1995) found that children with onset of OCD between 5 and 9 years of age had a much higher rate of family members with tics, suggesting an increased genetic loading in the families of patients with early-onset OCD. Interestingly, female relatives were more likely to have OCD without tics and male relatives were more likely to have TS. On the basis of such findings, Pauls and colleagues (1991, 1995) hypothesized that some cases of TS and OCD may be alternate expressions of a single gene that appears to display variable penetrance and gender-affected expression. Additional evidence for a genetic basis of OCD comes from systematic family studies. Such studies have frequently found elevated rates of OCD in firstdegree relatives of childhood-onset OCD probands. For example, Lenane and colleagues (1990) found that 20% of personally interviewed first-degree relatives of children and adolescents with OCD also met lifetime history criteria for OCD themselves. Importantly, the primary OCD symptom in the affected family member was usually different from that of the proband, suggesting against a modeling theory for OCD and against familial symptom subtypes. Some of the most exciting developments in pediatric OCD stem from initial findings of an increased rate of OCD in children with Sydenham’s chorea (SC) (Swedo et al., 1989a, 1994). SC is the neurologic variant of rheumatic fever and is characterized by an autoimmune response in the region of the basal ganglia caused by misdirected antibodies from a group A beta-hemolytic streptococcal (GABHS) infection (Swedo et al., 1989a, 1993). Recently, a subgroup of children with pediatric onset of OCD and/or tic disorder symptoms after GABHS infection (Swedo, 1994; Allen et al., 1995) has been identified. This group has been described by the acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). PANDAS patients are characterized by an abrupt prepubertal onset of their symptoms, after a GABHS, and by a course of illness that is characterized by periods of remissions and dramatic acute worsening of symptoms (Swedo et al., 1998). PANDAS likely represents a different genetic vulnerability from later-onset OCD. These children often have neurologic signs such as choreaform movements and tics. Children with PANDAS appear to have an underlying pathophysiology similar to that seen in SC, although they do not have SC (Swedo et al., 1998). A child presenting with an acute onset of OCD with or without tics, or a significant rapid deterioration, requires a thorough assessment and evaluation of recent or concomitant medical illnesses, which may include seemingly benign upper respiratory tract infections. Laboratory analyses such

169


as a throat culture, ASO (antistreptolysin O) titre, and an antiDNase B titre may be helpful in diagnosing PANDAS. It is critical to delineate this prepubertal pediatric subtype, as these patients require a different assessment and perhaps a different treatment than patients with nonPANDAS OCD or tic disorder. Investigational trials of immunomodulatory treatments and antibiotic prophylaxis of PANDAS are underway at NIMH. Thus, evidence suggests that early onset (prepubertal) may represent a meaningful OCD subtype characterized by a predominance of males, an increased rate of comorbid tic and disruptive behavior disorders, an increased relative risk for OCD, and/or tics. Interestingly, Ackerman and colleagues (1994) found age of onset of OCD to be a predictor of response to clomipramine in adults, again providing indirect evidence that early onset may represent a more severe form of the illness, perhaps with a unique underlying pathogenesis.

Treatment General comments

The specific nature of OCD and its impact varies significantly between affected individual children and adolescents. The specific treatment plan for a given child should take into consideration the unique psychopathologic and psychosocial features that may influence compliance and treatment response. Whenever possible, both the patient and their family should participate in the development of treatment plans. While individual judgment will always be of paramount importance, clinicians now have access to two valuable resources, which provide guidelines for the treatment of children and adolescents with OCD. The American Academy of Child and Adolescent Psychiatry’s (1998) Work Group on Quality Issues has developed practice parameters for the assessment and treatment of children and adolescents with OCD. The parameters are the result of a detailed review of the literature and expert consultation on the diagnosis and treatment of child and adolescent OCD. The Expert Consensus Guideline Series: Treatment of Obsessive-Compulsive Disorder (March et al., 1997) represents a detailed aggregation of the opinions of 69 OCD experts and addresses a broad range of practical clinical issues in the treatment of OCD in both adult and pediatric populations. Pharmacotherapy of OCD should always be considered in conjunction with other interventions, particularly individual psychologic treatments.

170

D.A. Beer et al.

Psychodynamic psychotherapy

In what way specific OCD symptoms represent specific intrapsychic conflicts is widely debated. Esman (1989) eloquently described how OCD could be understood as having both biologic and psychodynamic components. Jenike (1998) concluded that the ‘‘traditional psychodynamic psychotherapy is not an effective treatment for patients with OCD as defined in DSM-III-R (American Psychiatric Association, 1987), as there are no reports in the psychiatric literature of patients who stopped ritualizing when treated with this method alone’’. Psychotherapy (apart from cognitive–behavioral therapy [CBT]) may play an important adjunctive role, however, by addressing the impact of the illness on the patients’ self-esteem, peer and family relationships, and by improving compliance with the behavioral or pharmacologic treatments that deal more directly with OCD symptomatology. Additionally, psychodynamic psychotherapy may be an effective approach to the treatment of comorbid conditions such as depression or personality disorders (American Academy of Child and Adolescent Psychiatry, 1998). Individual and family therapy

Since family functioning affects and is affected by OCD, family members often need assistance and direction in how to participate effectively in a comprehensive treatment plan. Thus, a thorough family assessment is necessary as part of the initial diagnostic evaluation of every child or adolescent with OCD. Family involvement may help identify target symptoms that might otherwise remain hidden from the clinician’s view and offers the possibility of providing a valuable psychoeducational framework which helps both parents and child understand OCD as a disorder with neurobiologic underpinnings and a wellestablished therapeutic agenda. Additionally, early family involvement may be crucial in helping to identify counterproductive family dynamics such as overinvolvement of family members in the performance of a child’s rituals or blaming the child for the intentional production of OCD symptoms. The goal of this process is to assist the family so that it is better able to participate in the treatment plan of the identified OCD patient in a more positive and constructive manner. Behavioral treatment

CBT, particularly that which incorporates exposure and response prevention (E/RP), has been well developed and studied in adults with OCD (Baer, 1992; Greist, 1992). Available reports suggest that techniques employed with adults (Marks, 1987) are also generally applicable to, and can be modified for, children

171


(Berg et al., 1989b; March, 1995). In adults diagnosed with OCD, E/RP is considered the behavior treatment of choice (Dar and Greist, 1992) and many have suggested that CBT is the current psychotherapeutic approach of choice for children and adolescents with the disorder (March et al., 1997). CBT appears to be used clinically with much success, although it has not been systematically studied in children and adolescents with OCD and support for its efficacy in this group is based predominantly on open trials. March (1995) reviewed 32 investigations, most of them single case reports, all but one of which showed benefits for CBT interventions. In light of the emerging clinical and empirical evidence that CBT alone, or in combination with pharmacotherapy, is an important, safe, acceptable, and effective treatment for OCD in children and adolescents, a trial of CBT should be proposed and discussed with the child and family. As long as the patient is motivated and able to understand directions, then he or she is appropriate for behavior treatment. In fact, despite the apparent efficacy of CBT, lack of access to qualified practitioners may be the single biggest hurdle to its effective implementation, as there appears to be a shortage of mental health practitioners experienced in the behavioral treatment of OCD (March et al., 1994). Additionally, some clinicians may have misconceptions regarding CBT and E/RP in children and adolescents with OCD, including those about time, effort, expense, and associated patient anxiety. Recently, March and colleagues (1998) have developed a protocol-driven treatment manual (‘‘How I Ran OCD Off My Land’’) based on a framework of cognitive interventions and E/RP. The protocol was designed to facilitate patient and parental compliance, to be exportable to other clinicians, and to be amenable to empirical evaluation (March et al., 1998). As there are multiple methodologic limitations (i.e., outcomes by self-report, lack of any specific behavioral protocol) to studies of CBT for child and adolescent OCD, only limited conclusions can be drawn from these reports. Future research in this area will need to utilize controlled trials with standardized diagnostic definitions, baseline observations, established treatment time course, and objective rating scales to compare medications, behavior therapy, and combination treatment. Additionally, follow-up studies are needed to assess more adequately the long-term efficacy of CBT in children with OCD (March, 1995). For the present time, the empirical evidence for the efficacy of CBT in child subjects with OCD remains limited, especially when contrasted to the literature on pharmacotherapy (Rapoport et al., 1992).

172

D.A. Beer et al.

Pharmacologic treatment

Clomipramine The SRIs such as clomipramine, fluoxetine, sertraline, and fluvoxamine have demonstrated efficacy and superiority over drugs with less direct serotonergic activity in controlled trials of adults with OCD (Greist et al., 1995b; March et al., 1995). The similarities between adult and pediatric OCD suggested early on that SRIs might also be effective for children and adolescents with the disorder. Clomipramine (Ananfranilo“), a tricyclic antidepressant (TCA) and potent serotonin reuptake inhibitor, was the first drug to be studied extensively in the treatment of pediatric OCD. In the first of these studies, 23 pediatric OCD patients participated in a 10-week, double-blind, placebo-controlled crossover trial (Flament et al., 1985) in which clomipramine dosages were titrated to a target of 3 mg/kg/day (mean final dose of 141 mg/day). In the 19 patients who completed the trial, clomipramine was significantly better than placebo in decreasing obsessive–compulsive symptoms at week 5, and improvement in symptoms could usually be seen as early as week 3. Similarly, DeVeaugh-Geiss and colleagues (1992) reported that, in an 8-week, multicenter, double-blind parallel comparison, those receiving clomipramine (n = 31) experienced a mean 37% reduction in symptoms compared with 8% in the placebo group (n = 29). The results of this study led to the United States Food and Drug Administration’s (FDA) approval of a specific indication of clomipramine for the treatment of OCD in children and adolescents aged 10 years and older. Still, it should be remembered that, on average, subjects remained mildly to moderately ill at the conclusion of the study indicating, once more, that complete remissions in OCD may be rare. To assess the specific superiority of the SRI, a double-blind, crossover comparison of clomipramine and desipramine (a selective noradrenergic blocker) was performed in 48 children and adolescents with OCD (Leonard et al., 1989). Clomipramine was clearly superior to desipramine (both targeted to 3 mg/kg/day, not to exceed 5 mg/kg/day) in ameliorating OCD symptoms at week 5. The most common side effects of clomipramine reported by children and adolescents include, in order of decreasing frequency: dry mouth, somnolence, dizziness, fatigue, tremor, headache, constipation, anorexia, abdominal pain, dyspepsia, and insomnia. The side effects appear comparable to, but generally milder than, those seen in adults (Leonard et al., 1989; DeVeaugh-Geiss et al., 1992) and both the initial studies and clinical experience indicate that clomipramine is generally well tolerated in this age group. Additionally, long-term clomipramine maintenance has not revealed any unexpected adverse reactions (Leonard et al., 1991; DeVeaugh-Geiss et al., 1992).

173


Importantly, clomipramine, like other TCAs, should be prescribed with great caution to those at high risk for suicide as it carries the risk of cardiac EKG interval prolongation and may, therefore, cause potentially fatal heartblock when taken in an overdose. Although there are no reported cases of clomipramine-associated deaths in children, and no defined indications for longitudinal EKG monitoring or plasma level monitoring, Leonard and colleagues (1995) suggested that baseline and periodic EKG monitoring is advisable during clomipramine treatment. SSRIs The SSRIs – fluoxetine (Prozac“), sertraline (Zoloft“), paroxetine (Paxil“), citalopram (Celebrex“), and fluvoxamine (Luvox“) are currently available in the US – have a limited effect on other monoamines (Warrington, 1992). As a class, the SSRIs have distinct advantages over TCAs in terms of their side effect profile and their broad therapeutic index. Initial meta-analysis (Greist et al., 1995b) had indicated that clomipramine was somewhat more effective for the treatment of adult OCD than any of the SSRIs. Additionally, despite having more anticholinergic side effects than the SSRIs, the dropout rate was similar in those treated with clomipramine when compared with the SSRI groups. Recent reanalysis of the data suggests that such results may have been confounded by treatment order effects: the SSRI trials may have included previous nonresponders to clomipramine whereas nonresponse to an SSRI was not an issue for participants in the earlier clomipramine trials. Additionally, the few head-to-head comparisons of SSRIs with clomipramine, while methodologically limited by small sample size, have found them to be equally efficacious. Pigott et al. (1990) reported no difference between fluoxetine and clomipramine in a 10-week crossover (with a 4-week washout phase between medications) in 11 patients. Likewise, no difference in efficacy was found in two 10-week double-blind comparisons of fluvoxamine and clomipramine (Freeman et al., 1994; Koran et al., 1996). Whether clomipramine is superior to the SSRIs is difficult to ascertain. In light of the potential side effects associated with clomipramine use, the Expert Consensus Guidelines suggest that clomipramine be reserved for those patients who have failed to respond to 2–3 adequate trials of an SSRI in combination with CBT. Data from studies of children and adolescents are more scant, though initial studies indicate that the SSRIs are also effective and safe in, and well tolerated by, children and adolescents with OCD. Geller and colleagues (1995) reported that open treatment with fluoxetine was effective in the treatment of OCD in 6–12-year-old children and that the therapeutic effect can be sustained over time (mean follow-up of 19 months). Dosages used in the Geller study averaged

174

D.A. Beer et al.

1 mg/kg/day and effective dosages were as low as 5 mg/day; such results may relate to differences in pharmacodynamics and/or pharmacokinetics between children and adults. In the only published controlled trial of fluoxetine for the treatment of children and adolescents with OCD, Riddle et al. (1992) concluded that fluoxetine appeared to be safe, effective, and well tolerated at a fixed dose of 20 mg/day. Sertraline, paroxetine, citalopram, and fluvoxamine all have demonstrated efficacy in controlled trials in adult OCD samples (Greist et al., 1995a; Zohar and Judge, 1996; Goodman et al., 1996, respectively). An open trial of fluvoxamine in adolescents with OCD or depression reported that it was effective for the treatment of both conditions and that side effects were again similar to those seen in adults (Apter et al., 1993). Multicenter controlled trials of fluvoxamine (Riddle et al., 1996) and sertraline (March et al., 1997) have been completed and both drugs now have an FDA-approved indication for the treatment of pediatric OCD: fluvoxamine for those children 8 years and older and sertraline for those 6 years and older. The most common SSRI side effects include complaints of nausea, headache, nervousness, insomnia, diarrhea, drowsiness, and sexual dysfunction. More rarely, agitation or hypomania may occur. Generally, side effects reported by adolescents appear to be similar to those reported by adults (Riddle et al., 1990a, 1992; Stokes, 1993). SSRIs have been reported occasionally to precipitate or exacerbate tics which is, of course, an important consideration given the frequency with which tics and OCD are comorbid. Nevertheless, it has also been shown that most patients with comorbid tics and OCD benefit from SSRI treatment, usually without experiencing a worsening of their tics (Scahill et al., 1997a). The advantages of the few anticholinergic side effects and limited cardiovascular toxicities of the SSRIs are particularly relevant for the pediatric population (Leonard et al., 1995). The specific choice of medication should involve consideration of the risk-to-benefit ratio, side effect profile, route of metabolism and potential interaction with concomitant medications, comorbid diagnoses, and individual experience with prior pharmacotherapy (DeVane and Sallee, 1996; Leonard et al., 1997). Although little is known specifically about the pharmacokinetics of SSRIs in children, the relative half-life – i.e., long (fluoxetine) vs. short (fluvoxamine, sertraline, or paroxetine) – should be considered. For example, fluoxetine steady state is not achieved for 2–3 weeks in adults and interactions with other drugs have been reported as long as 6 weeks following discontinuation. On the other hand, withdrawal syndromes have been described for SRIs/

175


SSRIs. Symptoms described in case reports in adults vary widely, but often include dizziness, paresthesias, sleep disturbance, anxiety/agitation, nausea, and headaches. Reviews of the literature and of adverse incident reports indicate paroxetine may be the most likely, and fluoxetine the least likely, of the SSRIs to be associated with such withdrawal symptoms (Stahl et al., 1997; Zajecka et al., 1997). Differences in the incidence of withdrawal symptoms may be attributable to paroxetine’s relatively short half-life, greater serotonergic specificity, greater anticholinergic effect, and/or lack of an active metabolite. Generally, such symptoms are mild and short lived, though they may be distressing and the anxiety/agitation may be a source for diagnostic confusion. Restarting the SSRI and tapering more slowly may be an effective strategy for dealing with such withdrawal symptoms (Zajecka et al., 1997). The SSRIs are all metabolized via the cytochrome P450 pathway and may inhibit to varying degrees other drugs metabolized by the same pathway. For example, both paroxetine and fluvoxamine inhibit the isoenzyme CYP2D6 and may potentially lead to elevated levels of coadministered secondary or tertiary TCAs (e.g., clomipramine) which are also metabolized via this pathway. Additionally, the SSRIs are all highly bound to plasma protein and may therefore displace, or be displaced by, other drugs that are highly protein bound. Although there are few reports of clinically significant interactions between the SSRIs and other drugs in children, clinicians should also inquire about all over-the-counter, recreational, and prescription drugs. Potentially harmful interactions with SSRIs include, for example, prolongation of the QT interval with coadministration of TCAs, the antihistamines terfenadine (Seldane“) or astemizole (Hismanal“), the gastrointestinal prokinetic agent cisapride (Propulsid“) or the D2-receptor blocker pimozide (Orap“) (Leonard et al., 1995). There is no indication that clinicians must monitor EKGs when SSRIs are prescribed alone. While a complete review of this topic is beyond the scope of this chapter, the list of such potential interactions is extensive and expanding all the time; interested readers are referred to any of the several excellent reviews (Mitchell, 1997; Jefferson, 1998). Finally, a serotonin syndrome has been described primarily in the context of SSRI coadministration with other serotonergically active drugs (e.g., monoamine oxidase inhibitors), although there are also case reports of over-thecounter cold and cough medicines contributing to the syndrome. Common symptoms of this potentially fatal syndrome include autonomic nervous system dysfunction (fever, diaphoresis, tachycardia, hypertension, diarrhea), cognitive disturbance (confusion, disorientation, coma), and changes in neuromuscular activity (myoclonus, ataxia, hyper-reflexia) (Sternbach, 1991).

176

D.A. Beer et al.

Additionally, serotonin syndrome has twice been reported following sertraline overdose in children (Kaminski et al., 1994; Pao and Tipnis, 1997). Generally, this syndrome can be treated by discontinuation of the offending medication(s) and by provision of supportive care, though some have suggested that antiserotonergic agents (e.g., cyproheptadine) may be useful as well. The relationship between serotonin syndrome and neuroleptic malignant syndrome has been debated, but at this point they are generally felt to be distinct entities. Dosage and duration of treatment Clinicians should be aware that many patients do not have symptom relief until 6–10 weeks, and that, during early treatment (first 1–10 days) with SRIs, some patients may actually develop a worsening of their OCD symptoms or experience particularly annoying side effects (i.e., insomnia, increased psychomotor activity). Thus, the patient and family should be educated and encouraged to report worsening or problematic side effects to their clinician. Initial worsening in the first week usually is not a reason in and of itself to discontinue the medication, although it reinforces the dictum ‘‘start low and go slow.’’ Typically, the exacerbation subsides and a positive clinical response ensues. Unfortunately, at this point, systematic dose-response data exist only for adult OCD patients. In both Tollefson and colleagues’ (1994) study of fluoxetine (20–60 mg/day) and the study of sertraline (50–200 mg/day) by Greist et al. (1995a), lower and middle-range fixed doses were associated with reduced dropout rates and similar efficacy to higher dosages. It may be, then, that duration of treatment is equally if not more important than dose. As such, it makes sense to start with a low dose and, allowing for steady state to be reached, adjust the dose slowly upward as tolerated over a 10–12 week period before considering changing agents or undertaking augmentation regimens. If there is no clinical response after 12 weeks, switching to another SSRI is a reasonable step prior to augmentation. Failure to respond to one SSRI may not predict failure with another drug of the same class (Greist et al., 1995b; Rasmussen and Eisen, 1997). However, there is preliminary evidence to suggest that many adult patients who are intolerant of the side effects of fluoxetine may have the same trouble with sertraline (Zarate et al., 1996). Whether these findings apply to children and adolescents with OCD remains to be determined. It is also important to remember that many patients will experience some continued OCD symptoms that vary in severity over time. Although periodic decreasing of dosage should be considered, long-term maintenance may be required for some patients. Leonard and colleagues (1991) conducted a double-

177


blind desipramine substitution study of long-term clomipramine-maintained patients, and found that eight of the nine desipramine-substitution patients, but only two of the 11 nonsubstitution patients, relapsed within 2 months. Greater improvement and lower relapse rates in patients treated with both medications and CBT have led to the suggestion that CBT may decrease the need for long-term medication management (March et al., 1994, 1995).

Augmentation strategies

At this time, there are no systematic studies to support switching medications vs. adding an augmenting agent in nonresponsive OCD patients. However, given the limited data on the efficacy of the various augmentation strategies, it appears reasonable first to pursue sequential trials of the SRI/SSRIs. Generally, augmentation strategies are started when there is a partial response to an SSRI, whereas an alternative SSRI is tried when there has been no response. While various augmenting agents have been studied in adults with OCD, only clonazepam, haloperidol, and risperidone have been proven effective in controlled trials (Pigott and Rubenstein, 1992; McDougle et al., 1994; Leonard et al., 1998; McDougle et al., 2000) and there are no controlled trials of augmentating agents in children. Clonazepam may be considered, although concerns have been raised regarding the potential for paradoxical disinhibition and adverse effects on learning. As described above, it is common to see pediatric OCD patients who have personal or family histories of tics or TS. In this particular circumstance, patients’ OCD symptoms may be less likely to respond to SRI/SSRI monotherapy and may be particularly likely to benefit from the addition of haloperidol or risperidone. Obviously, significant caution is warranted when prescribing a neuroleptic because of the risk of tardive dyskinesia. While they have not been systematically studied as augmentation agents in the treatment of OCD itself, the alpha-2 agonists clonidine and guanfacine, and the neuroleptic pimozide, have been effective in the treatment of tics and may be combined with an SRI/SSRI. Again, because the combination of pimoxide with an SRI/SSRI may lead to QT interval prolongation, extra caution and close monitoring of cardiac status seem warranted in such a circumstance. Other agents that have appeared useful as augmenting agents in the treatment of depression, such as pindolol and buspirone, have not been shown to have the same beneficial effects in the treatment of OCD. A more systematic study of the use of augmentation medications in children and adolescents is indicated.

178

D.A. Beer et al.

Selection of treatment

Systematic comparisons of medication vs. behavioral therapy in children and adolescents with OCD are limited. Few clinical guidelines exist to indicate initial treatment; thus, clinicians must carefully evaluate available behavioral treatments, patient cooperation, and specific symptom patterns. Several authors have suggested that medication and behavior therapy actually complement each other (Baer and Minichiello, 1990; March et al., 1997). Potential advantages of behavioral therapy alone may include avoidance of adverse medication side effects. March et al. (1994) hypothesized that booster behavior therapy may prevent relapse when medications are discontinued. Even medication-responsive patients, including those for whom ongoing pharmacotherapy proves necessary, may exhibit both short- and long-term improvement when provided with concurrent CBT (March, 1995). In conclusion, CBT and pharmacotherapy appear to work well together, and many children with OCD require or would benefit from both CBT and pharmacotherapy (Piacentini et al., 1992). Summary It is estimated that perhaps as many as 1 million children and adolescents in the United States may have OCD. Childhood OCD presents in a form essentially identical to that seen in adults, and one-third of adult cases have had their onset in childhood. Boys seem to have an earlier age of onset of OCD (prepubertal). Washing, repeating, checking, touching, counting, arranging, hoarding, and scrupulosity are the most commonly seen rituals. Almost all patients report a change in their principal symptom over time. Increasing evidence supports a neurobiologic theory for the etiology of OCD, specifically a frontal lobe–basal ganglia dysfunction. Recent studies suggest that the early onset (prepubertal) of OCD and/or tic disorders characterized by abrupt onset and acute exacerbations may represent a subtype of pediatric OCD with increased family loading. Identification of such a subtype of pediatric-onset OCD may lead to new assessment and treatment interventions. Childhood OCD appears to have a similar treatment response to that seen in adults with the illness. Behavioral therapy has not been systematically studied in children and adolescents, but reports suggest that exposure and response prevention techniques are useful. In children and adolescents, clomipramine is superior to placebo and to desipramine in a double-blind crossover comparison. Sertraline and fluvoxamine have specific indications for the treatment of

179


pediatric OCD. Fluoxetine and paroxetine have been reported to be safe and well tolerated in the pediatric population, although systemic studies are ongoing. Nevertheless, follow-up studies indicate that at least 50% of pediatric OCD cases are still symptomatic as adults (Thomsen, 1995). These findings suggest that, although the majority of OCD patients can expect improvement with the new treatments available, there remains a small group of patients who continue to have a chronic and debilitating course. There are a number of important research issues for childhood-onset OCD. For example, it is not known which children will respond preferentially to behavioral or pharmacologic treatments. The identification of children at risk for OCD, through genetic or biologic studies, is a research priority. It is hoped that new treatment modalities and combinations of available treatments will improve the long-term outcome.

REFE R EN C ES Ackerman DL, Greenland S, Bystritsky A et al. (1994). Predictors of treatment response in obsessive-compulsive disorder: multivariate analyses from a multicenter trial of clomipramine. J Clin Psychopharmacol 14:247–54. Allen AJ, Leonard HL, Swedo SE (1995). Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. Am Acad Child Adolesc Psychiatry 34:307– 11. American Academy of Child and Adolescent Psychiatry (1997). Practice parameters for the Psychiatric Assessment of Children and Adolescents. J Am Acad Child Adolesc Psychiatry 36:4S–20S. American Academy of Child and Adolescent Psychiatry (1998). Practice parameters for the psychiatric assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 37(Suppl):27S–45S. American Psychiatric Association (1997). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. Washington, DC: American Psychiatric Press. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, Washington, DC: American Psychiatric Press. Ames D, Cummings JL, Wirshig WC et al. (1994). Repetitive and compulsive behavior in frontal lobe degenerations. J Neuropsychiatry Clin Neurosci 6:100–13. Apter A, Ratzioni G, King R (1993). Fluvoxamine open-label treatment of adolescent inpatients with obsessive–compulsive disorder or depression. J Am Acad Child Adolesc Psychiatry 33:342–8. Baer L (1992). Behavior therapy for obsessive-compulsive disorder and trichotillomania: implications for Tourette’s syndrome. Adv Neurol 58:333–40. Baer L, Minichiello WE (1990). Behavior therapy for obsessive-compulsive disorder. In Obsessive

180

D.A. Beer et al.

Compulsive Disorders: Theory and Management, Eds. M Jenike, L Baer, W Minichiello, pp. 203–32. Chicago: Year Book Medical Publishers. Baxter L, Schwartz J, Mazzioatta J et al. (1998). Cerebral glucose metabolic rates in non-depressed patients with obsessive-compulsive disorder. Am J Psychiatry 145:1560–3. Benkelfat C, Nordahl TE, Semple WE et al. (1990). Local cerebral glucose metabolic rates in obsessive-compulsive disorder: patients treated with clomipramine. Arch Gen Psychiatry 47:840–8. Berg CZ, Rapoport JL, Whitaker A et al. (1989a). Childhood obsessive compulsive disorder: a two-year prospective follow-up of a community sample. J Am Acad Child Adolesc Psychiatry 28:528–33. Berg CZ, Rapoport JL, Wolff RP (1989b). Behavioral treatment for obsessive-compulsive disorder in childhood. In Obsessive-Compulsive Disorder in Children and Adolescents, Ed JL Rapoport, pp. 169–85. Washington, DC: American Psychiatric Press. Berman L (1942). Obsessive-compulsive neurosis in children. J Nerv Ment Dis 95:26–39. Black A (1978). The natural history of obsessional neurosis. In Obsessional States, Ed. HR Beech, London, Methuen. Castellanos FX, Ritchie GF, Marsh WL et al. (1996). DSM-IV stereotypic movement disorder: persistence of stereotypies of infancy in intellectually normal adolescents and adults. J Clin Psychiatry 57:116–22. Cox CS, Fedio P, Rapoport JL (1989). Neuropsychological testing of obsessive compulsive adolescents. In Obsessive-Compulsive Disorder in Children and Adolescents, Ed. Rapoport JL, pp. 73–86, Washington, DC: American Psychiatric Press. Cummings JL, Cunningham K (1992). Obsessive-compulsive disorder in Huntington’s disease. Biol Psychiatry 31:263–70. Dar R, Greist J (1992). Behavior therapy for obsessive compulsive disorder. Psychiatr Clin North Am 15:885–94. DeVane CL, Sallee FR (1996). Serotonin selective reuptake inhibitors in child and adolescent psychopharmacology: a review of published experience. J Clin Psychiatry 57:55–66. DeVeaugh-Geiss GJ, Moroz G, Biederman J et al. (1992). Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder. A multicenter trial. J Am Acad Child Adolesc Psychiatry 31:45–9. Duman RS (1998). Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 44:324–35. Esman A (1989). Psychoanalysis and general psychiatry: obsessive-compulsive disorder as a paradigm. Am Psychoanalyt Assoc 37:319–16. Flament MF, Rapoport JL, Berg C et al. (1985). Clomipramine treatment of childhood obsessivecompulsive disorder. Arch Gen Psychiatry 42:977–83. Flament MF, Whitaker A, Rapoport JL et al. (1988). Obsessive compulsive disorder in adolescence: an epidemiological study. J Am Acad Child Adolesc Psychiatry 27:764–71. Freeman CPL, Trimble MR, Deakin JFW et al. (1994). Fluvoxamine versus clomipramine in the treatment of obsessive compulsive disorder: a multicenter, randomized, double-blind, parallel group comparison. J Clin Psychiatry 55:301–5.

181


Garland EJ, Weiss M (1996). Case study: obsessive difficult temperament and its response to serotonergic medication. J Am Acad Child Adolesc Psychiatry 35:916–20. Geller DA, Biederman J, Reed ED et al. (1995). Similarities in response to fluoxetine in the treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 34:36–44. Goodman WK, Kozak MJ, Liebowitz M et al. (1996). Treatment of obsessive-compulsive disorder with fluvoxamine: a multicentre, double-blind, placebo controlled trial. Int Clin Psychopharmacol 11:21–9. Goodman WK, McDougle CJ, Price LH et al. (1990). Beyond the serotonin hypothesis: a role for dopamine in some forms of obsessive compulsive disorder? J Clin Psychiatry 51(Suppl):36–43. Goodman WK, Price LH, Rasmussen SA et al. (1989a). The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 46:1006–101. Goodman WK, Price LH, Rasmussen SA et al. (1989b). The Yale-Brown Obsessive Compulsive Scale II. Validity. Arch Gen Psychiatry 46:1012–16. Greist JH (1992). An integrated approach to treatment of obsessive compulsive disorder. J Clin Psychiatry 53(Suppl):38–41. Greist JH, Chouinard G, DuBoff E et al. (1995a). Double-blind comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder. Arch Gen Psychiatry 52:289–95. Greist JH, Jefferson JW, Kobak KA et al. (1995b). Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder: a meta-analysis. Arch Gen Psychiatry 52:53–60. Hanna GL (1995). Demographic and clinical features of obsessive-compulsive disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 34:19–27. Hollingsworth C, Tanguay P, Grossman L et al. (1980). Long-term outcome of obsessive compulsive disorder in childhood. J Am Acad Child Psychiatry 19:134–44. Holzer JC, Goodman WK, McDougle CJ et al. (1994). Obsessive-compulsive disorder with and without a chronic tic disorder: a comparison of symptoms in 70 patients. Br J Psychiatry 164:469–73. Insel TR (1992). Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 49:739–44. Jefferson JW (1998). Drug interactions – friend or foe? J Clin Psychiatry 59(Suppl 4):37–47. Jenike MA (1998). Psychotherapy of obsessive-compulsive personality disorder. In ObsessiveCompulsive Disorder: Practical Management (Ed. MA Jenike). Chicago, IL: Mosby-Year Book. Joffe RT, Swinson RP, Regan JJ (1988). Personality features of obsessive-compulsive disorder. Am J Psychiatry 145:1127–9. Kaminski CA, Robbins MC, Weibley RE (1994). Sertraline intoxication in a child. Ann Emerg Med 23:1371–4. Karno B, Golding J, Sorenson S et al. (1988). The epidemiology of obsessive compulsive disorder in five U.S. communities. Arch Gen Psychiatry 45:1094–9. Klin A, Mayes LC, Volkmar FR et al. (1995). Multiplex developmental disorder. J Dev Behav Ped 16:S7–11.

182

D.A. Beer et al.

Koran LM, McElroy SL, Davidson DR et al. (1996). Fluvoxamine versus clomipramine for obsessive-compulsive disorder: a double-blind comparison. J Clin Psychopharmacol 16:121–9. Kroll L, Drummond LM (1993). Temporal lobe epilepsy and obsessive-compulsive symptoms. J Nerv Ment Dis 181:457–8. Last CG, Strauss CC (1989). Obsessive-compulsive disorder in childhood. J Anxiety Disord 3:295–302. Leckman JF, Grice DE, Boardman J et al. (1997). Symptoms of obsessive-compulsive disorder. Am J Psychiatry 154:911–17. Leckman JF, Walker DE, Cohen DJ (1993). Premonitory urges in Tourette’s syndrome. Am J Psychiatry 150:98–102. Lenane M, Swedo S, Leonard H et al. (1990). Psychiatric disorders in first degree relatives of children and adolescents with obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry 29:407–12. Leonard HL, Lenane MC, Swedo SE et al. (1992). Tics and Tourette’s syndrome: a two to seven year follow-up study of 54 obsessive-compulsive children. Am J Psychiatry 149:1244–51. Leonard HL, March J, Rickler KC et al. (1997). Pharmacology of the selective serotonin reuptake inhibitors in children and adolescents. J Am Acad Child Adolesc Psychiatry 36:725–36. Leonard HL, Swedo SE, Lenane MC et al. (1991). A double-blind desipramine substitution during long-term treatment in children and adolescents with obsessive-compulsive disorder. Arch Gen Psychiatry 48:922–6. Leonard H, Swedo S, Lenane M et al. (1993). A 2- to 7-year follow-up study of 54 obsessivecompulsive disorder children and adolescents. Arch Gen Psychiatry 50:429–39. Leonard HL, Swedo SE, March J et al. (1995). Obsessive-compulsive disorder. In Treatment of Psychiatric Disorders, 2nd edn, Ed. G Gabbard, pp. 301–13. Washington, DC: American Psychiatric Press. Leonard HL, Swedo SE, Rapoport JL et al. (1989). Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. Arch Gen Psychiatry 46:1088– 92. Leonard HL, Topol D, Bukstein O et al. (1998). Clonazepam as an augmenting agent in the treatment of childhood onset obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry 33:792–4. Luxenberg JS, Swedo SE, Flament MF et al. (1988). Neuroanatomical abnormalities in obsessivecompulsive disorder detected with quantitative X-ray computed tomography. Am J Psychiatry 145:1089–93. March JS (1995). Cognitive-behavioral psychotherapy for children and adolescents with OCD: a review and recommendations for treatment. J Am Acad Child Adolesc Psychiatry 34:7–18. March JS, Biederman J, Wolkow R et al. (1998). Sertraline in children and adolescents with obsessive compulsive disorder: a multicenter randomized controlled study. JAMA 280: 1752–6. March JS, Frances A, Kahn D et al. (1997). Expert Consensus Guidelines: treatment of obsessivecompulsive disorder. J Clin Psychiatry 58(Suppl 4):1–72. March JS, Leonard HL, Swedo SE (1995). Pharmacotherapy of obsessive-compulsive disorder.

183


Child Adolesc Psychiatr Clin North Am 4:217–36. March JS, Mulle K, Herbel B (1994). Behavioral psychotherapy for children and adolescents with obsessive-compulsive disorder: an open trial of a new protocol-driven treatment package. J Am Acad Child Adolesc Psychiatry 33:333–41. Marks I (1987). Behavioural psychotherapy in general psychiatry. Helping patients help themselves. Br J Psychiatry 150:593–7. McDougle CJ, Goodman WK, Leckman JF et al. (1994). Haloperidol addition in fluvoxamine refractory obsessive compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 51:302–8. McDougle CJ, Naylor ST, Cohen DJ et al. (2000). A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57:794–801. Mitchell PB (1997). Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Saf 17:390–406. Modell JG, Mountz JM, Curtis GC et al. (1989). Neurophysiologic dysfunction in basal ganglia/ limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neurosci 1:27–39. Otto MW (1992). Normal and abnormal informational processing: a neuropsychological perspective on obsessive-compulsive disorder. Psychiatr Clin North Am 15:825–48. Pao M, Tipnis T (1997). Serotonin syndrome following sertraline overdose in a 5-year-old girl. Arch Pediatr Adolesc Med 151:1064–7. Pauls DL, Alsobrook JP, Goodman WK et al. (1995). A family study of obsessive-compulsive disorder. Am J Psychiatry 152:76–84. Pauls DL, Raymond CL, Stevenson JM et al. (1991). A family study of Gilles de la Tourette syndrome. Am J Hum Genet 48:154–63. Pauls DL, Towbin KE, Leckman JF et al. (1986). Gilles de la Tourette syndrome and obsessive compulsive disorder: evidence supporting a genetic relationship. Arch Gen Psychiatry 43:1180– 2. Petti TA, Vela RM (1990). Borderline disorders of childhood: a review. J Am Acad Child Adolesc Psychiatry 29:327–33. Phillips KA, Atala KD, Albertini RS (1995). Case study: body dysmorphic disorder in adolescents. J Am Acad Child Adolesc Psychiatry 34:1216–20. Piacentini J, Jaffer M, Gitow A et al. (1992). Psychopharmacologic treatment of child and adolescent obsessive compulsive disorder. Psychiatr Clin North Am 15:87–107. Pigott TA, Rubenstein C (1992). A controlled trial of clonazepam augmentation in OCD patients treated with clomipramine or fluoxetine. Presented at the 145th Annual Meeting of the American Psychiatric Association, Washington, DC. Pigott TA, Pato MT, Bernstein SE et al. (1990). Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder: behavioral and biological results. Arch Gen Psychiatry 47:926–32. Pitman RK (1982). Neurological etiology of obsessive-compulsive disorders? Am J Psychiatry 139:139–40.

184

D.A. Beer et al.

Rapoport JL (1989). Obsessive Compulsive Disorder in Children and Adolescents. Washington, DC: American Psychiatric Press. Rapoport JL, Swedo SE, Leonard HL (1992). Childhood obsessive compulsive disorder. J Clin Psychiatry 53(Suppl):6–11. Rasmussen SA, Eisen JL (1994). The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 55(Suppl):5–10. Rasmussen SA, Eisen JL (1997). Treatment strategies for chronic and refractory obsessivecompulsive disorder. J Clin Psychiatry 58(Suppl 13):9–13. Rauch SL, Baxter LR (1998). Neuroimaging in obsessive compulsive disorder and related disorders. In Obsessive-Compulsive Disorder: Practical Management. Eds. MA Jenike, L Baer, WE Minichiello. Boston: Mosby. Rauch SL, Jenike MA (1993). Neurobiological models of obsessive-compulsive disorder. Psychosomatics 34:20–32. Rauch SL, Jenike MA, Alpert NM et al. (1994). Regional cerebral blood flow during symptom provocation in obsessive-compulsive disorder using 15O-labeled CO2 and positron emission tomography. Arch Gen Psychiatry 51:62–70. Rettew DC, Swedo SE, Leonard HL et al. (1992). Obsessions and compulsions across time in 79 children and adolescents with obsessive compulsive disorder. J Am Acad Child Adolesc Psychiatry 29:766–72. Ricciardi JN, Jenike MA, Fischer SL et al. (1992). Changes in DSM-III-R axis II diagnosis following treatment of obsessive-compulsive disorder. Am J Psychiatry 148:829–31. Riddle MA, Hardin MT, King R et al. (1990a). Fluoxetine treatment of children and adolescents with Tourette’s and obsessive compulsive disorders: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry 29:45–8. Riddle MA, Scahill L, King R et al. (1990b). Obsessive compulsive disorder in children and adolescents: phenomenology and family history. J Am Acad Child Adolesc Psychiatry 29:766–72. Riddle MA, Scahill L, King RA et al. (1992). Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 31:1062–9. Riddle MA, Walkup JT, Claghorn J et al. (1996). Fluvoxamine for OCD in children and adolescents: a controlled trial. Poster presented at the Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Philadelphia, PA. Rosenberg DR, MacMaster FP, Keshavan MS et al. (2000). Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry 39:1096–103. Rutter M, Tizard J, Whitmore K (1970). Education, Health and Behavior. London: Longmans. Scahill L, Riddle MA, King RA et al. (1997a) Fluoxetine has no marked effect on tic symptoms in patients with Tourette’s syndrome: a double-blind placebo-controlled study. J Child Adolesc Psychopharmacol 7:75–85. Scahill L, Riddle MA, McSwiggan-Hardin M et al. (1997b). The Children’s Yale-Brown Obsessive Compulsive Scale: preliminary report of reliability and validity. J Am Acad Child Adolesc Psychiatry 36:844–53.

185


Schwartz JM, Stoessel PW, Baxter LR et al. (1996). Systematic changes in cerebral glucose metabolic rate after successful behavior modification. Arch Gen Psychiatry 53:109–13. Soriano JL, O’Sullivan RL, Baer L et al. (1996). Trichotillomania and self-esteem: a survey of 62 female hair-pullers. J Clin Psychiatry 57:77–82. Stahl MM, Lindquist M, Pettersson M et al. (1997). Withdrawal reactions with selective serotonin reuptake inhibitors as reported to the WHO system. Eur J Clin Pharmacol 53:163–9. Sternbach H (1991). Serotonin syndrome. Am J Psychiatry 148:705–13. Stokes PE (1993). Fluoxetine: a five year review. Clin Ther 15:216–43. Swedo SE (1994). Sydenham’s chorea. A model for childhood autoimmune neuropsychiatric disorders. J Am Med Assoc 272:1788–91. Swedo SE, Rapoport JL (1989). Phenomenology and differential diagnosis of obsessive compulsive disorder in children and adolescents. In Obsessive Compulsive Disorder in Children and Adolescents, Ed. JL Rapoport, pp. 13–32. Washington, DC: American Psychiatric Press. Swedo SE, Leonard HL, Garvey M et al. (1998). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155:264–71. Swedo SE, Leonard HL, Kiessling LS (1994). Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood: commentaries. Pediatrics 93:323–6. Swedo SE, Leonard HL, Schapiro MB et al. (1993). Sydenham’s chorea: physical and psychological symptoms of St. Vitus’s dance. Pediatrics 91:706–13. Swedo SE, Pietrini P, Leonard HL et al. (1992). Cerebral glucose metabolism in childhood-onset obsessive compulsive disorder. Revisualization during pharmacotherapy. Arch Gen Psychiatry 49:690–4. Swedo SE, Rapoport JL, Cheslow DL et al. (1989a). High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. Am J Psychiatry 146:246–9. Swedo SE, Rapoport JL, Leonard HL et al. (1989b). Obsessive-compulsive disorder in children and adolescents: clinical phenomenology of 70 consecutive cases. Arch Gen Psychiatry 46:335– 44. Swedo SE, Shapiro ME, Grady CL et al. (1989c). Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry 46:518–23. Thomsen PH (1995). Obsessive-compulsive disorder in children and adolescents: predictors in childhood of long-term phenomenological course. Acta Psychiatr Scand 92:255–9. Thornton C, Russell J (1997). Obsessive compulsive comorbidity in the dieting disorders. Int J Eat Disord 21:83–7. Tollefson GD, Rampey AH Jr, Potvin JH et al. (1994). A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 51:559–67. von Economo C (1931). Encephalitis lethargica: its sequellae and treatment. Translated by Neuman KO. New York: Oxford University Press. Warrington SJ (1992). Clinical implications of the pharmacology of serotonin reuptake inhibitors. Int Clin Psychopharm 7:13–19. Wolff S, Barlow A (1979). Schizoid personality in childhood: a comparative study of schizoid, autistic and normal children. J Child Psychol Psychiatry 20:29–46.

186

D.A. Beer et al.

Zajecka J, Tracy KA, Mitchell S (1997). Discontinuation symptoms following treatment with serotonin reuptake inhibitors: a literature review. J Clin Psychiatry 58:291–7. Zarate CA, Kando JC, Tohen M et al. (1996). Does intolerance or lack of response to fluoxetine predict the same will happen with sertraline? J Clin Psychiatry 57:67–71. Zohar J, Judge R (1996). Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. OCD Paroxetine Study Investigators. Br J Psychiatry 169:468–74.

8 Anxiety disorders E. Jane Garland Outpatient Psychiatry, Vancouver, British Columbia, Canada

Overview Introduction

The pharmacologic treatment of child and adolescent anxiety disorders has evolved considerably in the past decade. Changes in the diagnostic system have brought childhood anxiety disorders into line with adult disorders, and this trend has been accompanied by a further extension of adult psychopharmacologic approaches to children. The importance of constitutional and persistent anxiety diathesis has been confirmed in genetic and longitudinal studies. Anxiety disorders of childhood are now recognized as chronic, disabling conditions requiring early and effective interventions. Extension of effective pharmacologic treatments from adult psychiatry has continued to guide child and adolescent psychopharmacologists, as systematic studies are still lacking in childhood anxiety disorders. At present, recommendations regarding pharmacotherapy in children are based on the accumulated best evidence from adult studies, a few controlled studies in children and adolescents, open trials, case studies, and clinical experience. There are recent practical developments in the psychopharmacologic treatment of anxiety disorders. Panic disorder is now known to respond to a number of pharmacologic interventions. It has also been shown that the chronic, disabling disorders of generalized anxiety and social phobia are responsive to the newer serotonergic agents. Since anxiety disorders tend to be chronic and relapsing, long-term or intermittent pharmacotherapy is often required. This leads to a clinical decision-making process which involves the patient and family in weighing the costs, benefits, and timing of pharmacotherapy as well as the adjunctive role of cognitive–behavioral therapy (CBT) and other nonpharmacologic coping strategies in managing anxiety and reducing the longterm disabling consequences of anxiety disorders. 187

188

E. J. Garland

Changes in diagnosis

Research on anxiety disorders in both children and adults has been compounded by rapid changes in the diagnostic system from DSM-III to DSM-IV (American Psychiatric Association, 1994). These changes have related to an unacceptably low reliability for anxiety disorders in structured interviews compared with other disorders such as mood disorders (Di Nardo et al., 1993), as well as problems of comorbidity and hierarchy of diagnoses. Diagnoses in childhood have changed significantly with the advent of DSM-IV to reflect the continuity of anxiety disorders throughout the lifespan, with varying developmental manifestations, as outlined in Table 8.1. Two childhood diagnoses, avoidant and overanxious disorders, have been eliminated with DSM-IV. Avoidant disorder of childhood has been subsumed under social phobia, and overanxious disorder (OAD) under generalized anxiety disorder (GAD) (American Psychiatric Association, 1994). Selective mutism is a diagnosis in childhood currently not classified under the anxiety disorders despite strong evidence that it is a variant of social phobia (Dummit et al., 1997). While there are both heuristic and practical advantages to rationalizing childhood diagnoses of OAD, avoidant disorder, separation anxiety disorder (SAD), and selective mutism with adult diagnoses, the disadvantage is that a decade of systematic research on anxiety disorders in childhood was put at risk by the disappearance of the very categories which had been used to study these disorders prospectively or pharmacologically (Bernstein et al., 1996; Werry, 1991). The only remaining specific anxiety disorder of childhood is SAD, although this may be an early manifestation of panic disorder. There is a similarity between separation anxiety and the fear of being away from home without the company of a ‘‘safe person’’ typical of agoraphobia. However, there is also evidence that SAD predicts a variety of adult anxiety disorders, and may be less specific (Lipsitz et al., 1994). As symptoms of separation anxiety may occur in the context of panic disorder, agoraphobia, social phobia, and generalized anxiety, the future of SAD as a specific childhood diagnosis remains uncertain. School refusal, a common manifestation of separation anxiety, has been a subject of many pharmacologic studies (Bernstein et al., 2000, 1990). Trends in the classification of anxiety

In adult anxiety disorders, response to psychopharmacologic agents and resultant assumptions about underlying neurobiology have shaped the current diagnostic system. A major diagnostic distinction between panic-based anxiety disorders and GAD was proposed 30 years ago (Klein, 1964), in that panic was observed to respond selectively to the catecholaminergic imipramine, while

189

Anxiety disorders

generalized anxiety responded to the GABA (gamma-aminobutyric acid) ergic benzodiazepines. Some genetic studies have supported this ‘‘pharmacologic dissection’’ of anxiety disorders, demonstrating strong heritability of the panic diathesis compared with low heritability for GAD (Torgerson, 1983). The description of panic disorder greatly advanced the field of anxiety disorders, and identification of a panic component to agoraphobia and social phobia encouraged the trials of pharmacotherapy directed at reducing panic attacks. Several developments have blurred the boundaries between panic disorder and generalized anxiety. Benzodiazepines such as alprazolam (Lydiard et al., 1992; Ballenger et al., 1988) and clonazepam (Pollack et al., 1993; Kutcher and Mackenzie, 1988) were found to be effective in reducing panic attacks. A more profound change occurred with the advent of specific serotonin reuptake inhibitors (SSRIs) which are much better tolerated than tricyclic antidepressants (TCAs) and have proven to have broad modulating effects on panic attacks (Boyer, 1995), social phobia ( Jefferson, 1995), obsessive–compulsive disorder (OCD) (March et al., 1995), and even generalized anxiety (Rocca et al., 1997). The specific pharmacologic dissection which began a revolution in the conceptualization of anxiety disorders has become replaced by a network of interrelated neurochemical pathways which may be influenced in a variety of ways. Furthermore, recent genetic studies have provided evidence for the heritability of GAD (Kendler et al., 1992). Panic attacks may play a pivotal role in initiating other symptom patterns including generalized anxiety.

Prevalence and epidemiology of child and adolescent anxiety disorders

The prevalence of anxiety disorders in children and adolescents varies greatly depending on the population studied, the instruments used, and the diagnostic criteria applied. Nonreferred youth have a rate of clinically significant anxiety disorders, excluding specific phobia, which is best estimated at 8–9%. One year prevalence rates in 11 year olds were found to be 3.5% SAD, 2.9% OAD, 2.4% simple phobia, and 1% social phobia (Anderson et al., 1987), and 3.5% SAD and 2.4% OAD (Bowen et al., 1990) in early adolescents. In adolescents, a 3.7% rate of GAD and a 0.6% rate of panic disorder have been found (Whitaker et al., 1990), while other community studies have reported an even higher rate of 6–7% for OAD in adolescents (Kashani and Orvaschel, 1988; McGee et al., 1980). In adult populations, rates of anxiety disorders are similar, with 4–6% meeting lifetime criteria for GAD, and about 0.8% meeting criteria for panic disorder (Kessler et al., 1994; Robins and Regier, 1991). The consistent rates for individual disorders such as GAD and panic disorder from childhood to

Not present Overanxious Disorder ( 18 years)

Social Phobia*

Avoidant Disorder of Childhood

Separation Anxiety Disorder *(18 year)

Acute Stress Disorder Generalized Anxiety Disorder*

Obsessive–Compulsive Disorder Post-Traumatic Stress Disorder

Specific Phobia

Response to a stressor involves intense fear, helplessness, or horror; subsequent hyperarousal and/or numbing, avoidance or intrusion of memories; acute and chronic forms Occurs within 4 weeks, lasts 2 days–4 weeks 6 months of excessive, difficult-to-control worry or apprehension. Children need only one of: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, or insomnia Distress when separated from attachment figures, or away from home, excessive worry about losing or harm to major attachment figures, reluctance or refusal to go to school, refusal to sleep apart, nightmares of separation, somatic complaints when

Acute, spontaneous four symptom panic attacks, 4/4 weeks, or impaired after 1 or more Specify degree of avoidance Fear of symptom such as dizziness or nausea leads to avoidance of being alone where escape is problematic Must be persistent, excessive, and unrealistic fear; subtypes include animals, natural environment, blood-injection-injury, situational In children may include crying, avoidance, tantrums, and selective mutism in social situations

Panic Disorder without Agoraphobia Panic Disorder with Agoraphobia* Agoraphobia without history of Panic Disorder*

Comments on diagnostic criteria

DSM-IV

Simple Phobia

DSM-III-R: Childhood anxiety disorders

Table 8.1. Childhood anxiety disorders: changes in diagnostic categories

* commonly leads to school refusal

Elective Mutism

Anxiety Disorder NOS

Anxiety Disorder due to Specified Medical Condition Substance-Induced Anxiety Disorder

Selective Mutism

anticipating separation; at least 4 weeks; specify early onset 6 years Not specifically classified as anxiety disorder; give concurrent diagnosis of Social Phobia if present Hyperthyroidism is a potential cause in adolescence Medications such as beta stimulators or cannabis-associated anxiety are common causes Often have multiple symptoms at a subclinical level from several anxiety disorders, but sufficiently impaired to diagnose a disorder

192

E. J. Garland

adulthood support the continuity of these chronic or recurrent disorders. The overall gender ratio for anxiety disorders is approximately equal. Rates of subclinical anxiety symptoms are also high in community populations using semistructured interviews (Muris et al., 1998), with 30% reporting some overanxious disorder symptoms (Bell-Dolan et al., 1990). A rate of 11% for recent four symptom panic attacks was reported in 11 year olds (Hayward et al., 1989). The threshold for diagnosing a disorder is established with a time criterion, for example, 6 months for SAD and GAD, or an impairment criterion such as persistent fear in panic disorder or interference with psychosocial functioning in OCD. What is striking, however, in the follow-up of subclinical anxiety, is that it is also persistent, recurrent, and can be associated with impairment. For example, a follow-up study found that first grade anxiety is predictive of lower academic functioning 5 years later (Ialongo et al., 1995). The age of onset of many adult anxiety disorders appears to be in childhood or adolescence. The mean age of onset of GAD was 10 years in an adolescent study (Keller et al., 1992), and adult studies show a typical duration at assessment of 20 years (Brown and Barlow, 1994). While changes in diagnostic criteria, especially in childhood, have obscured our knowledge of comorbidity, natural history, and treatment responsiveness, it appears that the DSM-IV criteria for GAD capture many of the features of the former OAD in children. However, in addition to the core symptoms of uncontrollable worry, difficulty with subjective reporting is recognized, and children only require one of the associated symptoms (American Psychiatric Association, 1994, p. 436). While there was controversy about the occurrence of panic disorder in children (Nelles and Barlow, 1988), childhood panic disorder is now well recognized, but there is an association between onset and pubertal stage (Hayward et al., 1992). Overall, panic symptoms are similar to those described by adults with a slightly greater rate of nausea and lower rate of reported depersonalization in children (Biederman et al., 1997). Children have a similar level of disability, with two-thirds agoraphobic and two-thirds depressed. Presentations in childhood and adolescence often involve somatic symptoms, behavioral symptoms, avoidance symptoms, and complications such as separation anxiety and agoraphobia (Moreau and Follett, 1993). Comorbidity is common in anxiety disorders with the nonhierarchical system of DSM-IIIR and DSM-IV. For GAD in adults, comorbidity is 60% and lifetime comorbidity is 90% (Robins and Regier, 1991), most commonly with mood disorder, panic disorder, and current agoraphobia. Comorbidity in children is at least 50% for GAD, especially with social phobia, panic disorder, agoraphobia, and depression (Last et al., 1997; Kendall et al., 1992). The high

193

Anxiety disorders

rate of comorbidity with dysthymia and major depression in DSM-IV field trials has led to proposals for a category of mixed anxiety–depression (Zinbarg et al., 1994). Axis II comorbidity is also significant, ranging from 30% to 60% (Schweizer, 1995). This may in part represent the impact of chronic anxiety on personality development. The diagnostic criteria for social phobia include children previously diagnosed as having avoidant disorder (Francis et al., 1992). Some recent studies have placed the rate of current social phobia at 7–8% and, lifetime, as high as 15% (Magee et al., 1996), and there has been discussion about the appropriate threshold for clinical diagnosis (Davidson et al., 1994; Stein et al., 1994). A distinction is being made between individuals with only a fear of speaking or writing in public, and those with ‘‘generalized social phobia’’, having broad difficulties meeting new people, attending social events, or talking to people in authority (Kessler et al., 1998; Heimberg et al., 1993). Generalized social phobia is more clearly heritable at twice the population rate (Stein et al., 1998), is more disabling, and is thought to relate most closely to avoidant disorder and lifelong ‘‘shyness’’ (Safren et al., 1997; Schneier et al., 1994). Selective mutism, characterized by refusal to speak to nonfamily members, is thought to be a symptom primarily of social phobia (Black and Uhde, 1992), representing an extreme on a spectrum of social anxiety and avoidance (Dummit et al., 1997). The evaluation of selective mutism, however, requires consideration of factors such as ruling out language disorders or other developmental disorders, and careful evaluation for other anxiety or psychiatric disorders (Dow et al., 1995). Specific phobia is reported to occur in 7–22% of nonclinical populations, but the degree of impairment is often not clarified in epidemiologic studies (Magee et al., 1996). Many phobias reflect extremes of relatively common fears which may have adaptive evolutionary origins (Stein and Bouwer, 1997), including developmental phobias such as fear of large animals, fear of spiders or snakes, and blood-injection-injury phobia which leads to a vasovagal or fainting response. ‘‘Natural environmental’’ phobias include immobilization or freezing in response to heights, and fear of storms or water, and may also theoretically have a survival value. New ‘‘situational’’ phobias may develop through modeling by a parent or sibling, when a panic attack occurs in a specific situation, or through sensitization after a traumatic event such as a vicious dog attack or being stuck in an elevator. Multiple phobias are more common in an individual with other anxiety disorders. Specific phobias in the absence of comorbidity are rarely impairing, although they may lead to occupational or behavioral restriction. Post-traumatic stress disorder (PTSD) describes disabling anxiety responses to an extreme traumatic stressor involving actual or threatened personal injury,

194

E. J. Garland

or ‘‘threats to one’s integrity’’, but may also include indirect exposure through witnessing or learning about such events occurring to close family members or associates. Horror, fear, and helplessness at the time are followed by persistent re-experiencing through intrusive recollection, hyperarousal, numbing of responsiveness, and avoidance behavior (American Psychiatric Association, 1994, pp. 424–31). In fact, potentially traumatizing events such as abuse, accidents, and witnessing violence are not uncommon in children’s lives. The prevalence of exposure to traumatic events of a magnitude to satisfy the DSM-IIIR criterion was 40% in a community sample of children up to age 18, while about 6% met lifetime criteria for actual PTSD (Giaconia et al., 1995); subclinical symptoms were common. Individuals may be more or less prone to these traumatizing effects depending on vulnerability to anxiety, physiologic reactivity, and prior life experiences (Pfefferbaum, 1997; Tyano et al., 1996). Current hypothesized central nervous system mechanisms for anxiety Review of neurobiology of anxiety disorder

The neurobiology of anxiety has been examined using pharmacologic challenges and brain imaging techniques. Noradrenergic, serotonergic, and GABAergic systems are implicated. Recently, neuropeptides and neurohormones have been demonstrated to produce physiologic anxiety in experimental models. Studies in humans and other primates demonstrate a genetic influence on temperamental profiles predisposing to anxiety and on the vulnerability to panic attacks. Provocation studies of panic attacks and anxiety support this biologic vulnerability. However, repeated observations indicate that cognitive responses, rather than the intensity of measurable physiologic reactions, mediate the distress associated with provoked panic attacks. Stimulation of the locus ceruleus, the center of noradrenergic activity in the brainstem, in primates provokes anxiety reactions resembling panic attacks (Charney et al., 1995; Robbins and Everitt, 1995). A presumption of adrenergic hyperactivity in panic disorder is supported by the role of noradrenergic tricyclics in treatment, the improvement in symptoms with beta blockade, and adrenergic challenge studies triggering panic attacks in panic-prone patients with isoproterenol and yohimbine. Panic disorder patients are observed to have greater cognitive sensitivity to somatic sensations with these stimuli even when they do not show more physiologic sensitivity than nonpanickers ( Johnson and Lydiard, 1995). Patients may also show blunted heart rate response to isoproterenol, suggesting chronic central hyperactivity of this system leading to peripheral downregulation. There is additional evidence (Kagan et al., 1987) of

195

Anxiety disorders

noradrenergic hyperactivity in behavioral inhibition to the unfamiliar, a constitutional precursor to later anxiety disorders. In adults with panic disorder and GAD, blunted growth hormone release with clonidine stimulation is noted, suggesting downregulation of hypothalamic alpha-2 adrenergic postsynaptic receptors which mediate growth hormone release (Charney et al., 1995). The only study of clonidine challenge in children, however, has failed to replicate this (Sallee et al., 1998), indicating that the adrenergic hyperactivity present in children prone to anxiety disorder may not yet be associated with downregulation. Serotonergic neurons originate in the dorsal raphe nucleus in the brainstem and have broad modulatory effects on anxiety, mood, and hypothalamic functions via projections to the midbrain, amygdala, and frontal cortex (Graeff et al., 1996). This is a complex system with multiple pre-and postsynaptic receptor subtypes, often with opposing effects. Infusion of the direct serotonin agonist methchlorophenylpiperazine (mCPP) is a trigger of equal levels of anxiety and panic reactions in both panic patients and controls, but, at lower doses, panic patients show more sensitivity, suggesting that abnormalities do exist in serotonin receptors in these patients ( Johnson and Lydiard, 1995). This is consistent with clinical observations of a transient increase in panic anxiety during the initiation of SSRI treatment in panic patients. Serotonin stimulation has also been shown to increase anticipatory anxiety, and its broad role is supported by the therapeutic effects of SSRIs in reducing panic attack frequency, social phobia, obsessive–compulsive symptoms, and possibly generalized anxiety. Other neurohormones are involved in anxiety responses, and autoregulatory loops relate hypothalamic hormones with the locus ceruleus. For example, corticotropin-releasing factor (CRF) stimulates locus ceruleus activity, and, with chronic hyperactivity, may lead to later downregulation. CRF also coordinates endocrine physiologic and behavioral responses to stress, and may be chronically overproduced after early life stresses in animals and humans (Bremner et al., 1997). In animals, CRF produces anxiogenic effects when infused in the locus ceruleus or amygdala, and CRF has also been shown to be anxiogenic in humans ( Johnson and Lydiard, 1995). Benzodiazepines appear to reduce CRF release, suggesting a mechanism for their effects in reducing not only generalized and anticipatory anxiety but also panic attacks, by reducing central noradrenergic hypersensitivity. The role of GABAergic systems in anxiety is evidenced by the anxioloytic effects of benzodiazepines which are GABA agonists, and the anxiogenic effect of inverse agonists even in normals. It appears that GABA has a very

196

E. J. Garland

generalized inhibitory effect rather than specific panicolysis. Studies on panic patients are in fact quite limited, but decreased sensitivity to GABA agonists and increased sensitivity to antagonists have been noted ( Johnson and Lydiard, 1995). Research on the role of neuropeptides such as pentagastrin and cholecystokinin (CCK) underscores the potential modulatory effects within a complex web of neurotransmitter regulation of anxiety. These neuropeptides have widespread distribution in the brain in both subcortical and cortical areas. Research has demonstrated the panicogenic effects of CCK-4 in healthy volunteers, and blockade of this effect by pretreatment with CCK antagonists. Panic patients show more sensitivity to these agents than normal controls. Since the most direct effects of CCK are dyspnea and increased ventilation (Bradwejn et al., 1998), an indirect panicogenic effect has been proposed, mediated through respiratory sensitivity in panic patients. Pentagastrin is another neuropeptide whose final tetrapeptide is identical to CCK-4, and it has similar panicogenic effects as well as producing symptoms of social anxiety (Brawman-Mintzer et al., 1997). Neuropeptide Y, widely distributed in the central nervous system (CNS), is an endogenous anxiolytic agent which is of interest in the development of new therapeutic agents. Its anxiolytic effects may be mediated through specific receptors in the amygdala (Kunovac and Stahl, 1995). Chemoreceptor and respiratory sensitivity may play a role in panicogenesis, as noted in the panic responses to CCK. This sensitivity is relatively specific to panic patients compared with those with GAD (Papp et al., 1993), and may mediate the panic response to CO2 and lactate infusions, as well as producing an oversensitive suffocation alarm and hyperventilation responses to minor changes in CO2 associated with sleep or exercise. Cognitive factors contribute to this sensitivity, as sham control of CO2 inhalations alters subjective symptoms, and physiologic changes, but not panic responses, occur during sleep inhalation of CO2. Structural abnormalities of the brain have not been found in studies of anxiety disordered patients on computed tomography scans. However, there is some evidence of more right temporal lobe abnormalities in magnetic resonance imaging of lactate-sensitive panic patients compared with controls, abnormalities which are also associated with a higher rate of EEG changes (Dantendorfer et al., 1994). The advent of dynamic imaging such as positron emission tomography has allowed examination of blood flow changes in over 20, often conflicting, studies (Reiman, 1997). The most robust findings involve panic disorder patients. For example, right/left asymmetry in parahippocampal blood flow has been reported in lactate-sensitive panic patients, and several

197

Anxiety disorders

studies indicate increased right frontal blood flow in panic patients at rest, with a tendency to decrease during panic attacks (Fredrikson et al., 1997). Temperament, neuroevolutionary factors, and the neurobiology of environmental effects

Temperament research focuses on behavioral patterns which are presumed to reflect neurobiologic makeup. In most cases, correlations between behavioral constructs and underlying neurobiology have been lacking. However, one temperamental pattern, ‘‘behavioral inhibition to the unfamiliar’’, has not only been shown to correlate with later anxiety disorders, but has also been associated with familial risk and neuroendocrine markers of altered noradrenergic reactivity. The behavioral inhibition pattern is present in about 10– 15% of children. In follow-up research, stable behavioral inhibition is associated with anxiety disorders at a rate of 66% vs. 20% of control children (Hirschfeld et al., 1992). A familial association is indicated by a 35% rate of anxiety disorders in the parents of stable inhibited children. The presence of stable behavioral inhibition plus multiple anxiety disorders in parents identified a group at very high risk of multiple anxiety disorders in children (Biederman et al., 1991). The neuroendocrine correlates of this temperamental trait include autonomic changes associated with a low threshold for arousal to unfamiliar events (Kagan et al., 1987). The response involves both behavioral retreat and avoidance, and autonomic changes which implicate the limbic system. Baseline sympathetic activation is implied by the high baseline heart rate with decreased variability seen in these children from infancy. Acceleration of heart rate in response to mild stress and greater postural blood pressure changes provide further evidence of over-reactivity of the sympathetic system. This pattern of response is also seen in ‘‘high reactive’’ primates and other mammals. The heritability of this trait in animals and the stable occurrence in populations indicate that this behavioral pattern is under genetic control. Animals with this pattern have more pronounced responses to separation and present behaviors analogous to human anxiety syndromes. The association of behavioral inhibition primarily with noradrenergic reactivity does not allow for the role of serotonin and other modulators in the constitutional vulnerability to anxiety. Other behavioral traits may shed some light on these relationships. First, evidence suggests that the serotonergic system is involved in ‘‘freezing’’ reactions and harm avoidance (Stein and Bouwer, 1997; Cloninger et al., 1996). Secondly, the construct of anxiety sensitivity provides a model for incorporating the cognitive elaboration on somatic sensations which could involve a variety of neurotransmitters and

198

E. J. Garland

peptides, and may relate to observed frontal changes on neuroimaging. Anxiety sensitivity, described in adults (Reiss et al., 1986) and in children (Silverman et al., 1991), is a trait construct describing the propensity to react to biologic provocations with psychologic anxiety or panic because of the tendency to predict negative consequences when somatic sensations are experienced. Anxiety sensitivity appears to be an important factor determining the development of clinical panic disorder after an individual has had a spontaneous panic attack (Donnell and McNally, 1990). Given the stable occurrence of traits like behavioral inhibition to the unfamiliar in the human, primate, and other animal populations, it is presumed that they have adaptive value in evolutionary terms (Stein and Bouwer, 1997). Behavioral inhibition provides the advantage of being cautious about unknown stimuli or avoiding a predator by freezing. Separation anxiety with associated protest in a toddler can result in parental rescue. The serotonergic system may also play a role in adaptive responses to threats. In invertebrates, learned avoidance responses to noxious stimuli involve serotonergic receptors. More complex anxious reactions in social phobia include blushing and gaze aversion, which is a social communication pattern akin to animal appeasement displays which are associated with serotonergic activity ( Jefferson, 1995). These adaptive systems require a network of controls to ensure an optimal responsiveness without over-reacting to background noise. Regulation of these neural networks will be subject to genetic variation and modified by learning through specific events, modeling, and reinforcement. Environmental experiences also have potentially persistent neurobiologic effects. Evidence for this includes the production of phenocopies of highly reactive or behaviorally inhibited primates achieved using a specific rearing paradigm (Coplan et al., 1995), and the evidence of enduring effects of early trauma in persistent abnormalities of cortisol regulation (Bremner et al., 1997). Overview of pharmacotherapy for anxiety disorders in adults General

Medications targeting anxiety disorders affect the classical neurochemical systems mentioned above, GABAergic, serotonergic, and noradrenergic. Combined pharmacotherapy may be used to target acute anxiety while also modulating underlying anxiety levels, as in benzodiazepine coverage during initiation of serotonergic medications. In theory, targeting several anxiety-modulating systems simultaneously may be optimal for more severe anxiety disorders. The

199

Anxiety disorders

tricyclic and monoamine oxidase inhibitor (MAOI) medications known to be effective for panic anxiety or social phobia have the advantage of multiple targets, but at the cost of side effects which are often intolerable for long-term use. Given the early onset, chronicity, and recurrence rate of most anxiety disorders, long-term maintenance or intermittent therapy is required and issues of medication tolerability are crucial. Lack of acceptability to patients of medication side effects has likely contributed to the undertreatment of anxiety disorders. A summary of medications found efficacious in adult anxiety disorders is provided in Table 8.2. Specific disorders

Panic disorder While imipramine was the first agent shown to be effective for panic disorder (Boyer, 1995; Mavissakalian and Perel, 1995; Clark et al., 1994; Klein, 1964), clomipramine (Modigh et al., 1992), phenelzine (Buigues and Vallejo, 1987), benzodiazepines including clonazepam (Pollack et al., 1993) and alprazolam (Boyer, 1995; Lydiard et al., 1992; Ballenger et al., 1988), and the SSRIs paroxetine (Ballenger et al., 1998; Oehrberg et al., 1995), fluoxetine (Schneier et al., 1990; Gorman et al., 1987), fluvoxamine (Black et al., 1993a; Hoehn-Saric et al., 1993; Den Boer and Westenberg, 1988), and sertraline (Chouinard et al., 1990) have also proven effective in placebo-controlled trials. Although medications have been found effective in improving symptoms in at least two-thirds of patients in follow-up studies over several years, persistent symptoms and relapses are common. Fewer than 15% of patients are symptom free even with treatment (Pollack and Smoller, 1995; Pollack et al., 1993; Noyes and Garvey, 1989). Problems of withdrawal anxiety or recurrence of anxiety leads to difficulty discontinuing medications (Rickels et al., 1993b). Intolerance of nuisance side effects due to anxiety sensitivity and initial exacerbation of panic symptoms are also significant limiting factors, best managed by low initial dose and short-term use of benzodiazepine while initiating other medications (Schatzberg and Ballenger, 1991). Patient tolerance of SSRIs appears to be somewhat better than TCAs (Noyes et al., 1989). The long-term outcome may be somewhat better with CBT than with medication, although comparative studies in the same population are lacking, and patient preference is often for the medication rather than for the CBT which requires exposure to anxious sensations (Otto and Whittal, 1995). Certain anxiety-related symptoms such as agoraphobia may require higher doses of medication and associated behavior therapy to achieve resolution of impaired function. Recent controlled studies of paroxetine found that differences from placebo in panic disorder could only be

PC PC X X

Panic Disorder Generalized Anxiety Social Phobia PTSD

PC = placebo-controlled research supports DC = drug-control supports UC = uncontrolled research supports X = shown ineffective DK = no information or inconclusive

Benzodiazepines

Disorder PC DC PC PC

SSRI PC PC X PC

TCA

Table 8.2. Summary of medications for adult anxiety disorders

PC DK PC PC

MAOI X PC X UC

Buspirone DK PC UC DK

SNRI (Venlafaxine)

201

Anxiety disorders

found at 40 mg daily (Ballenger et al., 1998) or even higher (Oehrberg et al., 1995). Social phobia Pharmacologic agents effective in social phobia include MAOIs and SSRIs ( Jefferson, 1995). The MAOIs phenelzine, moclobemide (Versiani et al., 1997), and bufaramine (van Vliet et al., 1992) were efficacious in controlled trials. Of the SSRIs, fluvoxamine (van Vliet et al., 1994), sertraline (Keck and McElroy, 1997), and paroxetine (Baldwin et al., 1999) have been found effective in placebo-controlled trials, while fluoxetine (van Ameringen et al., 1993) has been found effective in open trials. Notably, effective doses may be as high as 60 mg daily, leading to the hypothesis that marked serotonin overactivity in social phobia may necessitate higher doses for downregulation of receptors. This is consistent with a model of harm avoidance and introversion associated with serotonergic overactivity, for which there is evidence in serotonergic challenge studies (Tancer et al., 1994). Buspirone, on the other hand, was not found helpful in a placebo-controlled trial after positive results in open trials (van Vliet et al., 1997). The serotonin–noradrenaline reuptake inhibitor (SNRI) venlafaxine has also been reported helpful in SSRI nonresponders (Altamura et al., 1999). GAD Pharmacotherapy for GAD in adults has received increased attention due to the advent of efficacious nonbenzodiazepine medication. Previously, concerns about the adverse cognitive effects of benzodiazepines, the discontinuation difficulties, the possibility of long-term drug dependency, and withdrawal symptoms had led to therapeutic pessimism. While imipramine was also shown to be efficacious for acute treatment, side effects limited long-term acceptability compared with benzodiazepines (Hoehn-Saric et al., 1988). Buspirone was demonstrated to achieve partial acute remission of symptoms, especially in benzodiazepine-naive patients. Nevertheless, two-thirds of cases recur by 1 year, and maintenance or recurrent treatment is likely to be necessary. There is research showing continued efficacy of maintenance therapy with benzodiazepines (Rickels et al., 1988; Schweizer, 1996; Rickels et al., 1993a), and buspirone (Rakel, 1990). Given the early onset of the disorder, this may mean decades of treatment starting in childhood or teen years. Recently, the acute efficacy of paroxetine over 2–4 weeks in a comparison study with imipramine and a benzodiazepine, even in the absence of depression, has increased interest in the SSRI pharmacotherapy of GAD (Rocca et al., 1997). It is notable that both of the antidepressants were more effective for the

202

E. J. Garland

psychic symptoms compared with the benzodiazepine, which was more rapidly effective for somatic symptoms. The antidepressant SNRI venlafaxine, in its sustained release form, has recently proven effective in GAD both in the short term (Rickels et al., 2000) and over a 6-month period (Gelenberg et al., 2000), and was superior to buspirone (Davidson et al., 1999). Medication choice is guided by comorbidity, with benzodiazepines achieving rapid onset of relief in two-thirds of patients within 1 week, and also being efficacious for panic, while buspirone is slower to onset and is not effective in panic or social phobia. Buspirone has not been found helpful in facilitating long-term benzodiazepine discontinuation, but pretreatment may facilitate resolution of short-term benzodiazepine use. As a pharmacotherapeutic strategy, however, the SSRIs have the advantage of broad spectrum of action, given the 60% current comorbidity with depressive disorders, panic disorder, and social phobia (Wittchen et al., 1994). Venlafaxine, indicated for both GAD and major depression, should also be considered, as it outperformed fluoxetine in combined anxiety and depression (Silverstone and Ravindran, 1999). It should also be noted that, although more demanding for the patient, over the long term, CBT is as effective as medication and has also been found helpful in facilitating the tapering and discontinuation of medication (Otto et al., 1992). PTSD There is evidence in placebo-controlled trials for efficacy of traditional MAOIs (Kosten et al., 1991), TCAs (Kosten et al., 1991; Davidson et al., 1990), and the SSRI fluoxetine (van der Kolk et al., 1994), while other SSRIs (Marshall et al., 1998) and moclobemide (Neal et al., 1997) show promise in open trials (Davidson, 1997). However, in PTSD, the placebo response is high, residual symptoms are typical, and the target symptoms most affected are depressive and anxiety symptoms rather than psychic numbing or avoidance (Davidson et al., 1997). Overall, the effect size of antidepressants is moderate (Penava et al., 1997; Shalev et al., 1996), some studies have not shown efficacy greater than placebo (Baker et al., 1995; Reist et al., 1989), and response may be better in those patients with comorbid depressive disorders (Dow and Kline, 1997). It has been noted that medications with serotonergic effects are more effective than nonserotonergic TCAs (Dow and Kline, 1997; Reist et al., 1989). Furthermore, side effects have limited study completion, so that intent-to-treat analyses are less impressive, suggesting that actual clinical effectiveness in this population is lower than efficacy in the controlled studies (Marshall et al., 1995). Benzodiazepines have not been shown useful (Braun et al., 1990) and problems of rebound anxiety have been noted (Risse et al., 1990). Comorbid diagnoses of

203

Anxiety disorders

depression, panic, or generalized anxiety should be taken into account in choosing pharmacotherapy, while symptoms such as avoidance need to be targeted by a multimodal treatment approach (Sutherland and Davidson, 1994). Open studies of the anticonvulsants valproate and carbamazepine (Keck et al., 1992) and of buspirone and clonidine (Sutherland and Davidson, 1994) have also been reported. Review of child and adolescent psychopharmacology Overview

Generally, medications used in adult anxiety disorders have also been used in children, but controlled research is limited in children for several reasons. First is the problem of changing diagnosis discussed above. As a result, the largest controlled studies, primarily of school refusal, lack diagnostic specificity. Secondly, a very high placebo response rate is evident in controlled studies. Other limitations include small sample sizes, ethical issues in conducting placebo controlled studies in minors, and lack of funding. At this point, drug efficacy in young people has been demonstrated for social phobia and adolescent panic disorder, as well as for OCD and major depression. Pharmacotherapeutic approaches to other anxiety disorders in children are derived from open trials and adult research. The primary medications which have been used are the TCAs (imipramine and clomipramine), benzodiazepines (especially alprazolam and clonazepam), and SSRIs. Each of these groups of medications will be commented on specifically, including evidence for efficacy and tolerability, and dosing schedule. Indications and dosing are summarized in Table 8.3. Other agents are briefly reviewed. Disorder-specific management is described subsequently. Medications used in childhood anxiety disorders

SSRIs Evidence of efficacy The mechanism of SSRI action is presumed to relate to serotonin reuptake inhibition, which over a period of weeks causes adaptation in postsynaptic receptors. Shown effective in a controlled study of selective mutism (Black and Uhde, 1994), panic disorder in adults (Sheevan and Harnett-Sheehan, 1996), and in OCD in adults ( Jenike et al., 1990a,b) and children (Apter et al., 1994; Riddle et al., 1992), SSRIs have gained favor in children due to their relative lack of serious, especially cardiac, side effects and relative safety in overdose (Leonard et al., 1997). Increasingly, they are also used clinically for GAD with persistent

15 mg b.i.d. 37.5–150 mg daily 60 mg 200 g b.i.d.

10 mg b.i.d.

50 g h.s.

Propranolol

Clonidine

Weekly 1–2 weeks

2.5–5 mg b.i.d. 37.5 mg XR

Buspirone Venlafaxine

75–150 mg; higher for CMI in OCD (up to 5 mg/kg)

Up to 40 mg fluoxetine or paroxetine; 200 mg sertraline, fluvoxamine

150 mg t.i.d.

5 mg fluoxetine Titrate dose each 5–10 mg paroxetine 1–2 weeks 25 mg sertraline 25–50 mg fluvoxamine 10 mg–25 mg starting Titrate every 1–2 weeks

SSRI: fluoxetine paroxetine fluvoxamine sertraline TCA: imipramine (IMI) clomipramine (CMI) Moclobemide

Up to 2–4 mg daily

Range

75 mg b.i.d. trial dose 150 mg b.i.d. first week

Alprazolam 0.125–0.25 mg t.i.d.-q.i.d. clonazepam 0.25–1 mg b.i.d.

Benzodiazepines: alprazolam clonazepam

Titration

Starting dose

Medication

Table 8.3. Dosing for medications used in childhood anxiety disorders Cautions

No studies in adolescents except in ADHD Onset over 4–6 weeks

Sexual side effects in adolescents; withdrawal syndrome with short-acting SSRIs Withdrawal syndrome

Short-term use preferred; taper by 25% per week

Comments

Behavioral activation; nausea; hypertension Performance anxiety; Bronchospasm, PTSD hypotension PTSD Rebound hyperDo not abruptly tension; arrhythmias, discontinue depression

GAD GAD

Panic disorder; early a.m. alprazolam for school refusal

If 2 mg daily, disinhibition more likely; withdrawal if use greater than 2 weeks Panic disorder; Akathisia, initial social phobia; exacerbation of GAD OCD anxiety; mania; behavioral activation Second line: panic Cardiac effects, disorder, GAD, sleep overdose, disorders, comorbid anticholinergic, anxiety/ADHD (IMI); postural hypotension OCD (CMI) Social phobia

Disorder

205

Anxiety disorders

sleep disturbance and impaired function. A mixed group of children including those with OAD and avoidant disorder did improve in an open trial of fluoxetine at doses of 10–60 mg per day (Birmaher et al., 1994). Safety and tolerability The safety and tolerability of SSRIs in children have been established by recent studies in depression and OCD (Alderman et al., 1998; Emslie et al., 1997). In a pharmacokinetic and tolerability study of sertraline in 56 children and adolescents, the pharmacokinetic profile was similar to adults, serum level was not predictive of adverse events, and adverse effects were mild even with forced titration to 200 mg daily at a rate of 50 mg per week (Alderman et al., 1998). In this 6-week study, however, 84% did have some side effects at the dose of 200 mg: 21% nausea, 21% headache, 21% insomnia, and 15% somnolence. Only 5% of patients withdrew because of adverse events, however, so that these effects were mild or transient enough to be tolerated. One of the side effects of SSRIs which has been noted in children is behavioral activation (Riddle et al., 1991) which must be distinguished from the precipitation of mania which may occur with any antidepressant agent. If an individual is at risk of mania due to family history of bipolar disorder, a shorter-acting agent should be initiated rather than fluoxetine. These causes of increased agitation need to be distinguished from transient worsening of panic symptoms during medication initiation, which may occur with TCAs as well, and which is best managed by low and slow dosing. Anorgasmia occurs in 30–40% of patients remaining on SSRIs for several months, and this may be especially upsetting to anxious adolescents who worry about permanent effects. Long-term SSRI use is likely to occur in anxiety disorders especially OCD, GAD, and panic. Long-term effects on major organ systems have not been noted in adults or children. However, an ‘‘amotivational’’ syndrome may develop which appears to be idiosyncratic (Hoehn-Saric et al., 1991, 1990). The apathy resembles a frontal lobe syndrome, and the primary approach to this is dose reduction. Since there is a hypothesis that this may relate to the indirect dopamine-blocking action of serotonergic agents, another clinical strategy to manage this has been the use of dopaminergic agents such as stimulants or bupropion. Indirect dopamine-blocking effects of SSRIs are also assumed to be responsible for the uncommon but potentially serious extrapyramidal side effects reported with paroxetine, fluoxetine, and sertraline. These include bruxism, dystonias, and akathisia which have been reported in both adults and children (Leo, 1996). While tardive dyskinesia has not been reported, this is

206

E. J. Garland

theoretically possible, so that significant extrapyramidal side effects in an individual could be considered a relative contraindication to long-term treatment with that agent. This effect appears to be idiosyncratic and may not occur with each SSRI in an individual. Another infrequent effect which has been reported in an adolescent is reversible memory impairment (Bradley, 1993). Finally, another long-term concern is the occurrence of a withdrawal syndrome with the shorter-acting SSRIs including paroxetine (Barr et al., 1994) and fluvoxamine (Black et al., 1993b). Symptoms of nausea, vomiting, ‘‘lightening pains’’, tremor, and other flu-like symptoms are noted. This can be prevented by slow tapering, no faster than one-half or even one-quarter of the dose per week in patients on long-term treatment. Despite the lack of evidence of increased toxicity in children, and the evidence that doses are similar to those in adults, some issues regarding pharmacokinetics and metabolism in children need to be noted (Leonard et al., 1997). Hepatically metabolized drugs like SSRIs are much more quickly cleared in infancy and childhood. This begins to decrease in prepuberty, reaching the adult rate in adolescence. Individual genetic variations in the p450 enzymes will affect metabolism. Changes in protein binding and fat stores with age may affect drug distribution; fluoxetine, for example, is fat soluble and slowly eliminated. The practical significance of these age-related changes in metabolism is not clear, especially given the lack of clear relationship between serum levels and efficacy or adverse effects. It has been noted that paroxetine and fluoxetine inhibit their own metabolism, so effects are expected to be nonlinear for these medications compared with fluvoxamine and sertraline. Active metabolites occur only with fluoxetine. Drug interactions with SSRIs are significant and complex, involving both competition for hepatic metabolism and protein binding (Leonard et al., 1997). Several medications used in childhood psychiatric disorders compete for 2D6 p450 enzyme, including other SSRIs, TCAs, beta blockers, thioridazine, perphenazine, and haloperidol. In addition, benzodiazepines, fluvoxamine, fluoxetine, and sertraline compete at 3A4. All SSRIs but fluoxetine displace valproate and phenytoin from protein binding. Serious interactions can occur with the antihistamines terfenadine and astemizole. Sumatriptan, for acute treatment of migraines, is relatively contraindicated due to potential serotonin syndrome. Furthermore, there are potential interactions with herbal remedies with serotonergic effects such as St. John’s Wort, and recreational drugs such as marijuana (Stoll et al., 1991).

207

Anxiety disorders

Dose and course of treatment recommendations Medication should be initiated at low doses in those with a history of panic, such as 25 mg sertraline and 10 mg or less of fluoxetine, with dose increased weekly as tolerated to the target range of 50–100 mg of sertraline, 100 mg fluvoxamine, 20–40 mg of fluoxetine, and 20-40 mg of paroxetine, keeping in mind the adult dosing studies which have supported an even higher dose in panic disorder, social phobia, and OCD. Tolerability data in children support a wide dose range (Alderman et al., 1998; Birmaher et al., 1994). Patients and families need to be warned about the common side effects of nausea, headache, and either somnolence or activation, and the likelihood that these will improve in the first week in most cases. Time of dosing may be adjusted according to the individual response of being either sedated or stimulated. Short-term use of benzodiazepines such as alprazolam or clonazepam should be considered in patients with panic disorder while initiating SSRIs. Although no clear guidelines regarding duration of treatment exist, the chronicity of symptoms and adult longitudinal studies suggest that treatment should continue for at least 6 months, with an approach of dose tapering (e.g., 25% every 1–2 weeks) to reduce withdrawal syndrome and to determine if symptoms break through before stopping the medication. Benzodiazepines Efficacy Benzodiazepines operate by general CNS inhibitory effect through indirect activation of the benzodiazepine–GABA receptor complex. Benzodiazepines were among the first agents used to treat childhood anxiety, including open trials of chlordiazepoxide which indicated positive response in school refusal (Kraft, 1965; D’Amato, 1962). Recent studies have used the high potency agents alprazolam, which is short acting, or clonazepam which is intermediate acting. Children metabolize benzodiazepines faster than adults (Coffey, 1990) and hence drug accumulation is unlikely with these agents. An open trial with alprazolam 0.25–1.5 mg daily indicated improvement in clinician ratings in 12 children and adolescents with OAD and avoidant disorder (Simeon and Ferguson, 1987). A subsequent placebo-controlled trial by the same researchers in 30 patients with OAD and avoidant disorder, using a mean dose of 1.75 mg, found a strong treatment effect for both drug and placebo, but no significant advantage of drug over placebo (Simeon et al., 1992a). More recently, alprazolam has been compared with imipramine in school refusal, with a nonsignificant trend to superiority shown for both drugs in a placebo-controlled trial (Bernstein et al., 1990), after an open trial by the

208

E. J. Garland

same authors found that two-thirds improved with either medication. Clonazepam improved anxiety symptoms in two children with SAD and one with OAD and panic-like symptoms at doses of 0.5–3 mg per day (Biederman, 1987). In a double-blind, crossover, placebo-controlled trial of clonazepam, 14 of 15 children with SAD improved in a 4-week trial, but the drug condition was not superior to placebo on Clinical Global Impressions (CGI) or Brief Psychiatric Rating Scale (BPRS) (Graae et al., 1994). While there may be a sample size problem, all of these studies underscore the high likelihood of improvement with placebo and hence the risk of attributing improvement to medication in clinical practice. The only positive controlled study of benzodiazepines is of clonazepam in adolescent panic disorder. After an open trial demonstrated positive response to clonazepam 1–2 mg daily as measured by Hamilton Anxiety Rating and reduction of panic attack frequency, a double-blind trial confirmed this effect in 12 patients (Kutcher et al., 1992). Tolerability and side effects The commonest side effect is drowsiness, with disinhibition or irritability being less common, reported with chlordiazepoxide in up to 10% of children (Kraft, 1965) and with the newer agent clonazepam in some teens at doses of 2 mg or higher for panic disorder (Reiter and Kutcher, 1991). The only data available on cognitive effects in anxious children indicated that there is no cognitive deterioration and perhaps a slight improvement on alprazolam (Simeon et al., 1992a; Simeon and Ferguson, 1987). While dependency problems and withdrawal symptoms including seizures due to abrupt discontinuation are theoretically possible, these have not been reported in studies of anxious children. Dose and course of treatment Clonazepam may be used for the short-term treatment of adolescent panic disorder with a dose starting at 0.5 mg b.i.d. and increasing to 1 mg b.i.d. This may be continued for several months if required and well tolerated, with the alternative being to initiate an SSRI. Alprazolam at a dose of 0.125–0.25 mg is usually reserved for exposure to stressful stimuli, such as school attendance in the morning. Tapering medication is important, especially in children who have a developmentally lower seizure threshold. TCA Efficacy With broad effects on serotonergic, noradrenergic, and histaminic receptors,

209

Anxiety disorders

this class of medications has been primarily used for school refusal and panic disorder in children. An early placebo-controlled study demonstrated efficacy of imipramine compared with placebo in returning children to school; both medications were combined with a behavioral psychotherapy program (Gittelman-Klein and Klein, 1971). This led to common prescription of imipramine for separation anxiety and school refusal. However, these results were not replicated by the same authors (Klein et al., 1992), in that 50% responded to either placebo or imipramine over 6 weeks at doses around 150 mg, although it is notable that this group had already been selected by failure to respond to behavioral treatment. With a relatively low dose of clomipramine, a difference between drug and placebo was not demonstrated in school phobic children (Berney, 1981), and, in a controlled comparison of imipramine, alprazolam, and placebo, both medications showed a trend to improvement in anxiety scores but this did not reach significance (Bernstein et al., 1990). Recently, however, imipramine combined with CBT did prove superior to placebo combined with CBT in school-refusing children (Bernstein et al., 2000). Case studies suggest that imipramine may be effective in panic disorder (Garland and Smith, 1991; Black and Robbins, 1990; Garland and Smith, 1990), but the only clear evidence of efficacy for a TCA in children is for clomipramine in OCD (DeVeaugh-Geiss et al., 1992). In summary, while there is some evidence for the effectiveness of imipramine for panic disorder or related symptoms of separation anxiety or school refusal, recent controlled research has not confirmed this. Side effects and tolerability TCAs are associated with unpleasant effects such as anticholinergic symptoms including dry mouth, blurred vision, and constipation. With longer-term use, weight gain may be a problem especially in teens. Cardiovascular effects include postural hypotension, and increases in heart rate and blood pressure. TCAs are also associated with serious cardiac toxicity (Wilens et al., 1993) including arrhythmias due to impaired conduction. Due to increased metabolism to the desmethyl forms of imipramine and clomipramine, thought to be more cardiotoxic, children are particularly susceptible (Wilens et al., 1996, 1995). Behavioral toxicity including agitation may occur with TCAs due to anticholinergic or activating noradrenergic effects. Current role of TCAs In children who have not tolerated SSRIs, TCAs may be used in panic, sleep disturbance, or separation anxiety. Clinically, imipramine or clomipramine may be also tried for anxious children with sleep disturbances, or clomipramine

210

E. J. Garland

for children with GAD with many obsessive features. There is evidence for the short-term effectiveness of imipramine in GAD in adults (Rickels et al., 1993a; Hoehn-Saric et al., 1988). Tolerability at low doses, especially for children under 12, may be acceptable. Sedative effects may be beneficial for children with sleep disturbance, while anticholinergic effects may benefit some children with irritable bowel or other gastrointestinal symptoms. An additional role for TCAs is with comorbid anxiety and attention-deficit/hyperactivity disorder (ADHD) (Ambrosini et al., 1993) which may respond better to TCAs than to stimulants (Pliszka, 1989; Garfinkel et al., 1983). Dose and course of treatment If a TCA is chosen for treatment, a cardiogram should be done at baseline and with each dose increase of 50 mg. Dose responses in individuals vary widely, likely due to metabolic differences, poor correlation between dose and plasma level, and the poor correlation between plasma level and cardiotoxic effect. Changes in heart rate and blood pressure, including postural hypotension, should be monitored. Significant changes in heart rate ( 15 beats per minute) indicate an individual in whom cardiovascular function and ECG should be more closely monitored and this may include cardiac consultation with stress testing. Based on earlier studies indicating efficacy, effective doses range from 50 to 150 mg daily or from 2.5 to 5 mg/kg. Duration will depend on target symptoms, but commonly will be 4–6 months with gradual dose tapering to determine whether symptoms break through. During medication discontinuation or changes, withdrawal effects due to cholinergic rebound and drug interactions need to be considered. Concerns include the serotonin syndrome when combined with SSRIs which also raise TCA serum levels, and interactions with MAOIs. A washout period for TCAs of a week is sufficient as this represents more than 5 half-lives in children. When switching to TCAs from SSRIs, the long half-life of fluoxetine with active drug present for up to 5 weeks needs to be considered. However, to prevent disabling symptom exacerbation in severely affected individuals, overlapping medications with cautious dose substitution during a switch can be considered. Buspirone Efficacy Buspirone is effective in adult GAD, but not panic or social phobia (van Vliet et al., 1997). Buspirone has been examined in open trials of children and adolescents with OAD or GAD (Kutcher et al., 1992; Kranzler, 1988). An open trial demonstrated moderate response to 4 weeks of buspirone titrated to 20 mg

211

Anxiety disorders

daily in 13 children with mixed anxiety disorders (Simeon et al., 1992b), but controlled research is lacking. Side effects and tolerability Among the advantages of buspirone are few negative cognitive effects and no demonstrated abuse potential (Balster, 1990). The most common side effects are nausea, dizziness, and headache (Simeon et al., 1992b), but these do not appear to limit continued treatment in most patients. Somnolence does not occur at a rate greater than placebo (Newton et al., 1982). Drug interactions are few, as buspirone does not appear to affect the metabolism of other drugs, but, in theory, interaction with other serotonergic medications and MAOIs can occur. Dosing Initial dose in children is 5 mg daily, 10 mg in adolescents, increasing over a week to t.i.d. Side effects limiting rapidity of titration include nausea and dizziness. Frequent dosing of this hepatically metabolized drug is needed, because of the variable half-life which may be as low as a few hours. Target dose is 20 mg or 30 mg for a trial of 4–6 weeks, although doses as high as 60 mg or more have been used in some children and adolescents (Kutcher et al., 1995). As a result of the subtlety and gradual onset of response, specific individualized target symptoms should be monitored, such as somatic complaints or amount of time spent worrying. If response occurs, a course of 4–6 months followed by trial tapering can be considered. Moclobemide The reversible MAOI moclobemide has also been found effective in adult studies of social phobia (Versiani et al., 1997), but has not been researched in adolescents despite its clinical use. The classic MAOI phenelzine has been found effective for selective mutism in childhood case studies (Black and Uhde, 1992; Golwyn and Weinstock, 1990). The only data on tolerability of moclobemide in young people comes from uncontrolled research on ADHD (Preist et al., 1995; Trott et al., 1991). Moclobemide has a favorable side effect profile, with symptoms not significantly greater than placebo. Dose is initiated at 75–150 mg b.i.d. and increased to a target of at least 300–450 mg daily. However, there are potential interactions with other serotonergic agents to produce serotonin syndrome and, at higher doses, especially greater than 600 mg daily, potential tyramine reactions.

212

E. J. Garland

Venlafaxine

The SNRI venlafaxine is effective and well tolerated in its extended release (XR) form in adult studies of depression and GAD. It was also well tolerated in a small placebo-controlled trial of depressed children and adolescents (Mandoki et al., 1997), although efficacy was not demonstrated – probably because of the small sample size, low dose, and short duration. It was well tolerated and clinically effective for behavioral symptoms in a small open trial of autistic spectrum children (Hollander et al., 2000). Behavioral activation and nausea were seen in an earlier study of ADHD children (Olvera et al., 1996), which did not use the better-tolerated XR form now available. The emerging consensus is that this medication will be useful in anxiety, depression, and, possibly, ADHD in children (Weller et al., 2000). Dose range is 37.5–150 mg of the XR form once daily, except in adolescents with severe depression in whom adult doses of up to 300 mg may be required. Miscellaneous agents

Propranolol Propranolol is a beta blocker which is lipophilic and hence is distributed in the CNS. It reduces blood pressure, heart rate, and other peripheral symptoms of sympathetic activity which are associated with hyperarousal and anxiety disorders. At a dose of 10–40 mg, propranolol acutely reduces somatic symptoms of performance anxiety in musicians and students (Drew et al., 1985). In an open trial in children with panic-like hyperventilation syndrome, symptoms did improve at a dose of 30–60 mg daily in 13 of 14 children in a 4-week trial; discontinuation led to return of the symptoms ( Joorabchi, 1977). Hyperarousal symptoms in 11 children with acute PTSD improved with propranolol titrated to a maximum of 2.5 mg/kg/day in a 4-week open trial (Famularo et al., 1988). The value of this medication is significantly limited by side effects such as bronchoconstriction in susceptible children, hypotension, bradycardia, and sedation. Clonidine Clonidine is an alpha-adrenergic agonist at presynaptic receptors, which has the net effect of reducing central noradrenergic activity. It is considered for conditions involving hyperarousal, especially PTSD (Pfefferbaum, 1997). Clonidine at doses of 100–200 g daily produced improvement in an open trial in seven severely abused or neglected preschool children who had not responded to multimodal inpatient treatment (Harmon and Riggs, 1996). Target symptoms included aggression, impulsivity, general anxiety, oppositionality, and sleep.

213

Anxiety disorders

Clonidine side effects include excessive sedation, cardiac conduction problems, and potential rebound hypertension. Concerns about clonidine toxicity, especially in combination with other medications, have been raised recently (Cantwell, 1997). In addition, irritable and depressive reactions are among the side effects noted in research in patients with tic disorder and ADHD (Hunt, 1987) and in patients with autistic spectrum disorders. Depressive reactions, consistent with the theoretical effects of decreased central noradrenergic activity, may develop after 2 or 3 months of clonidine treatment. Summary: effectiveness of pharmacotherapy for specific anxiety disorders in children and adolescents

Panic/agoraphobia including SAD and school refusal The only medication for which efficacy has been demonstrated in a controlled trial is clonazepam 1–2 mg daily in divided doses for panic disorder in adolescents, with the main limitation being disinhibition and irritability at higher doses (Kutcher et al., 1992). Case studies and open trials support the use of imipramine and alprazolam; imipramine plus CBT is effective for school refusal. The well-demonstrated effectiveness of SSRIs in adults, and the evidence of tolerability in children, has led this class of medications to be increasingly prescribed for children and adolescents with panic disorder. Social phobia/selective mutism Fluoxetine has been demonstrated to be efficacious in selective mutism (Black and Udhe, 1994), which is consistent with the efficacy of SSRIs for social phobia in adults ( Jefferson, 1995). It is notable that behavioral and practical counseling strategies will be necessary to reverse the behavioral aspects, as in other phobias. Medication duration is likely to be for several years. For individuals not tolerating or not responding to SSRIs, moclobemide is also an alternative in adolescents, based on adult efficacy and adolescent tolerability. GAD As a result of the chronicity of illness, long-term treatment is likely if a child with GAD appears to respond to a therapeutic agent. Hence, the clinical indications for pharmacotherapy in GAD must be considered carefully given the high placebo response and lack of evidence of efficacy in children to date. Alprazolam has a trend to effectiveness for a broad range of anxious symptoms (Simeon et al., 1992a, 1987). Open studies in children also support the effectiveness of buspirone (Simeon et al., 1992b; Kranzler, 1988) and fluoxetine (Birmaher et al., 1994) in children with OAD and avoidant disorder. Since

214

E. J. Garland

comorbidity is at least 50% in children with GAD, especially social phobia, specific phobia, panic disorder, and major depressive disorder (Last et al., 1997; Kendall et al., 1992), SSRIs may be indicated for other reasons. With sleep problems, sedative SSRIs such as fluvoxamine or paroxetine may be preferred. Based on adult studies, venlafaxine XR is an alternative for GAD with or without comorbid depression. TCAs such as clomipramine and amitryptyline in low doses (10–50 mg) have also been used for sleep disturbance and somatic complaints, but controlled research is lacking. PTSD In PTSD, medication should be targeted to specific associated symptom patterns such as panic or depression. SSRIs can be considered in children based on their moderate effectiveness in adults. Based on small case series in children, an alternative is to consider clonidine (Harmon and Riggs, 1996) or propranolol (Famularo et al., 1988) for symptomatic treatment for hyperarousal. Potentially serious side effects need to be considered for both of these medications. Specific phobia Pharmacotherapy for specific phobia is limited to treatment of comorbid panic attacks or other anxiety disorders. Pretreatment with benzodiazepines such as alprazolam may facilitate exposure practice. Clinical guidelines for psychopharmacologic treatment Assessment

In adult studies of anxiety, help-seeking focuses on either psychologic distress or somatic symptoms. In children, less able to describe the cognitive features, presentations are often with gastrointestinal, respiratory, cardiac, muscular tension, and neurologic symptoms. Behavioral presentations include avoidance, oppositional defiance, tantrums associated with panic reactions, bedtime resistance, or sleep disturbance. Anxiety disorders may present as ‘‘pseudoADHD’’ with irritability, poor concentration, and restlessness. Assessment will involve documentation of symptoms and behavioral description from parents, as well as a direct report from the child regarding subjective state, worries, and somatic complaints. Note is taken of acute and chronic stressors (e.g., death of relative, change of school, learning disability, chronic marital conflict), family psychiatric history, and developmental and temperamental history. There must be systematic probing for comorbid disorders especially depression, OCD, and other anxiety disorders. Previous

215

Anxiety disorders

episodes of anxiety symptoms and mode of resolution should be noted. Physical status, current medication, over-the-counter drugs, herbal remedies, and use of caffeine-containing beverages are carefully reviewed. In adolescents, it is important to do a thorough and confidential history for substance use. Family functioning and expectations for child’s coping are noted as these have an impact on the impairment associated with symptoms (Kortlander et al., 1997). Expectations for treatment and attitudes toward medication should be explored. Finally, concurrent untreated anxiety disorders in the parents should be explored as a target for potential intervention. Given the common and transient nature of anxiety symptoms, the focus in the assessment should be on the degree of impairment – that is, the degree to which symptoms are interfering with normal developmental tasks, physical health, interpersonal relations, and academic functioning. Psychosocial impairment includes school avoidance, isolation from peers, and social or performance anxiety which limits participation in sports teams or group activities. Somatic symptoms may lead to learned reactions such as muscle tension headaches or stomach aches in response to stressors, as well as a general erosion of confidence resulting in vulnerability to depression. Suicidal risk needs to be assessed, especially in panic patients in whom acute suicidal ideation may occur during panic episodes. The risks of medication availability need to be noted, especially TCAs, or the combining of sedatives with alcohol. Rating scales are of value in documenting the severity of anxiety symptoms and treatment response, not as diagnostic instruments. In children, the Revised Children’s Manifest Anxiety Scale (RCMAS) (Reynolds and Richmond, 1978) is the most commonly used, and focuses on several kinds of cognitive worry as well as somatic symptoms. The State-Trait Anxiety Inventory (Spielberger, 1973) makes an effort to distinguish stable anxious trait from acute state anxiety, although the reliability of these constructs in children is not great. The Multidimensional Anxiety Scale for Children (MASC) (March et al., 1997) is a recent addition which addresses clusters of symptoms which correspond to clinical diagnoses, specifically physical symptoms, social anxiety, harm avoidance and separation anxiety. With any of these scales, parent–child agreement is poor to fair. For adolescents, adult clinician rating scales such as the Hamilton Anxiety Scale can be useful (Hamilton, 1959). Finally, a side effect scale at baseline and during treatment is helpful to document physical and psychologic symptoms which may be both symptoms of anxiety and side effects of medication, such as nausea or dizziness, or symptoms like irritability and fatigue. A general or medication-specific scale may be used (Kutcher, 1997, pp. 379–97).

216

E. J. Garland

Treatment model

The recommended approach is to present pharmacotherapy as one of a number of tools to manage anxiety disorders. The overall goal of intervention is to provide patients with a range of strategies to manage current and future anxiety episodes. Medication may reduce physical anxiety, reset the panic alarm, and reduce the cognitive worry associated with anxiety sensitivity. However, relying on medication alone to manage anxiety symptoms is fraught with problems for several reasons. First, symptoms are rarely completely eliminated by medication; for example, successful clonazepam treatment of panic attacks in adolescents reduced the frequency of attacks from three to one per week (Kutcher and Mackenzie, 1988). Even in open studies with a positive result, subjective improvement is less than clinician-rated improvement (Birmaher et al., 1994). Secondly, symptoms will no doubt recur in future either on or off medication, and the patient needs to have some way of managing them effectively. Thirdly, due to anxiety sensitivity, anxious patients often do not tolerate even normal levels of anxiety. Through a coping rather than a cure model, residual anxiety can be described as essential to provide opportunities to practice cognitive and behavioral strategies.

(1)

(2)

(3)

Prepharmacologic interventions Psychoeducation consists of educating children and their families regarding the nature of anxiety, the role of an ‘‘overactive alarm system’’ in producing physical symptoms, and the natural worry and feeling of impending doom that these symptoms produce. The roles of conditioned avoidance and anticipatory anxiety with self-triggering of panic need to be understood by the patient and family members so that more adaptive responses can be learned. The adaptive nature of normal levels of anxiety is contrasted with the exhausting and paralyzing effects of excessive anxiety. Basic behavioral strategies include predictable routines, forbidding avoidance behavior, reinforcing exposure to anxiety-provoking situations, and consistent parenting expectations to increase predictability of the environment and reduce conflict. Gradual introduction of children with cautious temperament into new situations may reduce the risk of acute anxiety. ‘‘Nondrug biologic interventions’’ include those strategies which stabilize autonomic activity and circadian rhythms. These include sleep hygiene, a regular schedule, physical exercise, and self-soothing skills such as abdominal breathing, progressive muscular relaxation, visualization techniques, and effective self-talk. These are among the life skills which anxiety-prone individuals would benefit from mastering in order to manage their vulnerability.

217

Anxiety disorders

(4)

Specific cognitive–behavioral strategies have been adapted for children in order to reduce anticipatory anxiety, catastrophic responses to physiologic sensations, and avoidance behaviors (Garland and Clark, 1995; Kendall, 1993). These may be provided on an individual or group basis, and as an adjunct to pharmacotherapy.

When to use medications

With transient, situational, or developmental anxieties, education is the first intervention. This serves as an attentional-placebo, and allows for spontaneous resolution. If medication is initiated too quickly, this may lead to the assumption that improvement is pharmacologic, leading to potentially unnecessary continuing treatment. In most cases, symptoms will resolve or improve significantly in 4–6 weeks. However, with acute panic attacks, if psychoeducation and environmental changes do not eliminate attacks within a week, short-term pharmacotherapy should be considered to prevent avoidance which often develops rapidly. With GAD, which is by definition chronic, nondrug interventions may be tried for longer, but if persistent sleep disturbance or impairments in concentration, socialization, and general functioning occur, pharmacotherapy should be considered. Choosing and titrating medication

For most anxiety disorders, one of several agents may be chosen, guided by comorbid disorders, age, response to test dose of medication, chronicity of symptoms, and likelihood of ongoing pharmacotherapy. In most cases, a low initial dose of medication should be prescribed due to the short-term exacerbation of anxiety with agents such as SSRIs, and the poor tolerance for minor side effects for all agents due to anxiety sensitivity. In initiating pharmacotherapy for childhood anxiety disorders, it is helpful and accurate to present this to the child and parent as a ‘‘trial,’’ rather than encouraging unrealistic expectations that medication will rapidly eliminate all symptoms. Children and adolescents with anxiety may be quite reluctant to try medication because of fear of side effects or due to concerns that they will be committed to stay on it, but they will usually accept the idea of being a ‘‘scientist’’ and participating in the evaluation of this treatment in their case. Use of clinician- and self-rating scales assists in this process. If the family wishes, a clinical placebo-controlled trial can be arranged for the individual case, by having the pharmacy crush tablets or inert fillers and place in capsules for a 4-week trial of each. When there is a lack of evidence for efficacy for a particular medication, it is important to obtain at the minimum verbal informed consent,

218

E. J. Garland

letting the family know what research and what clinical experience is available, details regarding tolerability, side effects, and potential idiosyncratic responses, as well as how long the medication has been used in children. The time frame of side effects and response should be detailed, target symptoms identified, a titration plan outlined, and treatment alternatives or potential subsequent trials should be identified. Telephone contact between appointments is offered to address concerns of anxious parents and children. Duration and tapering

Very significant changes in children’s behavior may result from the resolution of anxiety symptoms, including a change from a very inhibited, cautious child to a more outgoing or risk-taking person without necessarily representing a true pharmacologic disinhibition. Many anxious children will have immature socialization strategies due to the chronic inhibition of interactions, and once they are more confident will demonstrate these gaps. Assistance with social skills may need to be introduced. Once symptoms have resolved, a period of 4–6 months is recommended for stabilization in chronic conditions like social phobia or GAD. The exception would be for benzodiazepines where an effort should be made to taper by 4–6 weeks, and sooner if another medication such as an SSRI has already been started. After about 6 months, medication tapering can be considered to determine if symptoms remain in remission. However, in children and adolescents, the time of year needs to be considered, so that medication is often tapered in the summer when academic achievement will not be placed at risk. Similarly, dose increases may be considered at times of high risk such as return to school in the fall or after a winter break. At the time of tapering, increased coaching on cognitive and behavioral self-management strategies should be provided. In order to avoid withdrawal symptoms from long-term treatment, the dose of SSRIs or TCAs should be reduced no faster than 25% per week, and even slower for chronic benzodiazepine use. If symptom relapse occurs with tapering, medication should be continued and reviewed after another 6 months. There are risks in allowing a full relapse to occur in that this may reduce the child’s confidence, reactivate avoidance habits, and have a detrimental impact on school and social functioning, such as losing a school term or missing an opportunity on a sports team. Often, mid and late adolescents who have had chronic anxiety requiring pharmacotherapy become increasingly motivated to manage their symptoms, and will participate actively in learning coping strategies to assist them in reducing or eliminating medication. They often have the self-awareness and

219

Anxiety disorders

cognitive capacity to be successful in using cognitive and behavioral strategies. However, close follow-up is important to ensure that they are in fact managing, as they may be reluctant to admit recurrent symptoms and the need to restart medication. Conclusions Anxiety disorders are increasingly recognized as an important cause of chronic disability in children and adolescents. The continuity of diagnosis between childhood and adulthood is being demonstrated. Pharmacotherapy is being initiated earlier in life, despite a relative lack of controlled research demonstrating efficacy, in the hope of reducing the impairment, comorbidity, and complications associated with anxiety disorders. SSRIs have become common clinical interventions for panic disorder, social phobia, and, more recently, GAD, while benzodiazepines and buspirone have more specific roles for panic and GAD, respectively. Even when medication is effective, residual symptoms remain, and multimodal treatment with an emphasis on cognitive and behavioral strategies is recommended. Research now underway should provide clearer evidence of short-term efficacy and long-term reduction in impairment and complications in children and adolescents with anxiety disorders.

REFE R EN C ES Alderman J, Wolkow R, Chung M, Johnston HF (1998). Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetic, tolerability and efficacy. J Am Acad Child Adolesc Psychiatry 37:386–94. Altamura AC, Pioli, R, Vitto M, Mannu P (1999). Venlafaxine in social phobia: a study in selective serotonin reuptake inhibitor non-responders. Int Clin Psychopharmacol 14:239–45. Ambrosini PJ, Bianchi MD, Rabinovich H, Elia J (1993). Antidepressant treatments in children and adolescents. II. Anxiety, physical, and behavioral disorders. J Am Acad Child Adolesc Psychiatry 32:483–93. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Anderson J, Williams S, McGee et al. (1987). DSM-III disorders in pre-adolescent children. Arch Gen Psychiatry 44:69–76. Apter A, Ratzoni G, Kinge RA et al. (1994). Fluvoxamine open-label treatment of adolescent inpatients with obsessive-compulsive disorder or depression. J Am Acad Child Adolesc Psychiatry 33:342–8. Baker DG, Diamond BI, Gillette G et al. (1995). A double-blind, randomized, placebo-controlled,

220

E. J. Garland

multi-center study of brofaramine in the treatment of posttraumatic stress disorder. Psychopharmacology 122:386–9. Baldwin D, Bobes J, Stein DJ et al. (1999). Paroxetine in social phobia/social anxiety disorder. Randomized, double-blind placebo-controlled study. Br J Psychiatry 175:120–6. Ballenger JC, Burrows G, DuPont R et al. (1988). Alprazolam in panic disorder and agoraphobia: results from a multi-center trial. I: Efficacy in short term treatment. Arch Gen Psychiatry 45:413–22. Ballenger JC, Wheadon DE, Steiner MBW, Gergel IP. (1998). Double-blind, fixed-dose, placebocontrolled study of paroxetine in the treatment of panic disorder. Am J Psychiatry 155:36–42. Balster R (1990). Abuse potential of buspirone and related drugs. J Clin Psychopharmacol 10:S31–7. Barr LC, Goodman WK, Price L (1994). Physical symptoms associated with paroxetine discontinuation. Am J Psychiatry 151:289. Bell-Dolan DJ, Last CG, Strauss CC (1990). Symptoms of anxiety disorders in normal children. J Am Acad Child Adolesc Psychiatry 29:759–65. Berney T (1981). School phobia: a therapeutic trial with clomipramine and short term outcome. Br J Psychiatry 138:110–18. Bernstein G, Borschardt CM, Perwien AR (1996). Anxiety disorders in children and adolescents: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 35:1110–19. Bernstein GA, Borschardt CM, Perwin AR et al. (2000). Imipramine plus cognitive-behavioral therapy in the treatment of school refusal. J Am Acad Child Adolesc Psychiatry 39:276–83. Bernstein GA, Garfinkel BD, Borchardt CM (1990). Comparative studies of pharmacotherapy for school refusal. J Am Acad Child Adolesc Psychiatry 29:773–81. Biederman J (1987). Clonazepam in the treatment of prepubertal children with panic-like symptoms. J Clin Psychiatry 48:38–41. Biederman J, Faraone SV, Marrs A et al. (1997). Panic disorder and agoraphobia in consecutively referred children and adolescents. J Am Acad Child Adolesc Psychiatry 36:214–23. Biederman J, Rosenbaum JF, Bolduc EA, Faraone SV, Hirschfield DR (1991). A high risk study of young children of parents with panic disorder and agoraphobia with and without comorbid depression. Psychiatry Res 37:333–48. Birmaher B, Waterman GS, Ryan N et al. (1994). Fluoxetine for childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 33:993–9. Black B, Robbins DR (1990). Panic disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 29:36–44. Black B, Uhde TW (1992). Elective mutism as a variant of social phobia. J Am Acad Child Adolesc Psychiatry 31:1090–4. Black B, Uhde TW (1994). Treatment of elective mutism with fluoxetine: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 33:1000–6. Black DW, Wesner R, Bowers W, Gabel J (1993a). A comparison of fluvoxamine, cognitive therapy and placebo in the treatment of panic disorder. Arch Gen Psychiatry 50:44–50. Black DW, Wesner R, Gabel J (1993b). Abrupt discontinuation of fluvoxamine in patients with panic disorder. J Clin Psychiatry 54:146–9. Bowen RC, Offord DR, Boyle MH (1990). The prevalence of overanxious disorder and separation

221

Anxiety disorders

anxiety disorder: results from the Ontario Child Health Study. J Am Acad Child Adolesc Psychiatry 29:753–8. Boyer W (1995). Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks; a meta-analysis. Int Clin Psychopharmacol 10:45–9. Bradley SJ (1993). Fluoxetine and memory impairment. J Am Acad Child Adolesc Psychiatry 32:1078–9. Bradwejn J, LeGrand J-M, Koszycki D, Bates JHT, Bourin M (1998). Effects of cholecystokinin tetrapeptide on respiratory function in healthy volunteers. Am J Psychiatry 155:280–2. Braun P, Greenberg D, Dasberg H, Lerer B (1990). Core symptoms of post-traumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry 51:236–8. Brawman-Mintzer O, Lydiard RB, Bradwejn JVG et al. (1997). Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder. Am J Psychiatry 154:700–2. Bremner JD, Licinio J, Darnell A et al. (1997). Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154:624–9. Brown TA, Barlow DHLMR (1994). The empirical basis of generalized anxiety disorder. Am J Psychiatry 151:1272–80. Buigues J, Vallejo J (1987). Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. J Clin Psychiatry 48:55–9. Cantwell DP (1997). Case study: adverse response to clonidine. J Am Acad Child Adolesc Psychiatry 36:539–44. Charney DS, Bremner JD, Redmond DE (1995). Noradrenergic neural substrates for anxiety and fear: clinical associations based on preclinical research. In FE Bloom, DJ Kupfer (Eds.), Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 387–95. Chouinard GGW, Goodman W, Greist J et al. (1990). Results of a double-blind placebo controlled trial of a new serotonin uptake inhibitor, sertraline, in the treatment of obsessivecompulsive disorder. Psychopharmacol Bull 26:279–84. Clark DM, Salkovskis PM, Hackmann A et al. (1994). A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder. Br J Psychiatry 164:759–69. Cloninger CR, Adolfsson R, Svrakic NM (1996). Mapping genes for human personality. Nature Genet 12:3–4. Coffey B (1990). Anxiolytics for children and adolescents: traditional and new drugs. J Child Adolesc Psychopharmacol 1:57–83. Coplan JD, Rosenblum LA, Gorman JM (1995). Primate models of anxiety: longitudinal perspectives. Psychiatr Clin North Am 18:727–43. D’Amato G (1962). Chlordiazepoxide in management of school refusal. Dis Nerv System 23:292–5. Dantendorfer K, Amering M, Berger P et al. (1994). High frequency of MRI brain abnormalities in panic disorder. Psychopharmacol Bull 30:97. Davidson J, Kudler H, Smith R et al. (1990). Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry 47:259–66. Davidson JR (1997). Biological therapies for posttraumatic stress disorders: an overview. J Clin Psychiatry 58 (Suppl) 9:29–32. Davidson JR, DuPont RL, Hedges D, Haskins JT (1999). Efficacy, safety, and tolerability of

222

E. J. Garland

venlafaxine extended-release and buspirone in outpatients with generalized anxiety disorders. J Clin Psychiatry 60:528–35. Davidson JR, Malik ML, Sutherland SN (1997). Response characteristics to antidepressants and placebo in post-traumatic stress disorder. Int Clin Psychopharmacol 12:291–6. Davidson JRT, Hughes DC, George LK, Blazer DG (1994). The boundaries of social phobia. Arch Gen Psychiatry 51:975–83. Den Boer JA, Westenberg HG (1988). Effect of a serotonin and noradrenaline uptake inhibitor in panic disorder: a double-blind comparative study with fluvoxamine and maprotiline. Int Clin Psychopharmacol 3:59–74. DeVeaugh-Geiss J, Moroz G, Biederman J et al. (1992). Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder: a multicenter trial. J Am Acad Child Adolesc Psychiatry 31:45–9. Di Nardo PA, Moras K, Barlow DH et al. (1993). Reliability of DSMIII-R anxiety disorder categories using the Anxiety Disorders Interview Schedule-Revised (ADIS-R). Arch Gen Psychiatry 50:251–6. Donnell CD, McNally R (1990). Anxiety sensitivity and panic attacks in a nonclinical population. Behav Res Ther 28:83–5. Dow B, Kline N (1997). Antidepressant treatment of posttraumatic stress disorder and major depression in veterans. Ann Clin Psychiatry 9:1–5. Dow SP, Sonies BC, Scheib D, Moss SE, Leonard HL (1995). Practical guidelines for the assessment and treatment of selective mutism. J Am Acad Child Adolesc Psychiatry 34:836–46. Drew PJT, Barnes JN, Evans SJW (1985). Effect of acute beta-adrenoreceptor blockage on examination performance. Br J Clin Pharmacol 19:783–6. Dummit ES, Klein RG, Tancer NK, Asche B, Martin J, Fairbanks J (1997). Systematic assessment of 50 children with selective mutism. Am J Psychiatry 36:653–60. Emslie GJ, Rush AJ, Weinberg AW et al. (1997). A double-blind, randomized placebo-controlled trial of fluoxetine in depressed children and adolescents. Arch Gen Psychiatry 54:1031–7. Famularo R, Kinscherff R, Fenton T (1988). Propranolol treatment for childhood post-traumatic stress disorder, acute type. Am J Dis Child 142:1244–7. Francis G, Last CG, Strauss CC (1992). Avoidant disorder and social phobia in children and adolescents. J Am Acad Child Adolesc Psychiatry 31:1086–9. Fredrikson M, Fischer H, Wik G (1997). Cerebral blood flow during anxiety provocation. J Clin Psychiatry 58(Suppl 16):16–21. Garfinkel BD, Wender P, Sloman L et al. (1983). Tricyclic antidepressant and methylphenidate treatment of attention deficit disorder in children. J Am Acad Child Adolesc Psychiatry 22:343–8. Garland EJ, Clark SL (1995). Taming Worry Dragons. Vancouver: Mood and Anxiety Disorders Clinic, British Columbia’s Children’s Hospital. Garland EJ, Smith DH (1990). Panic disorder on a child psychiatric consultation service. J Am Acad Child Adolesc Psychiatry 29:785–788. Garland EJ, Smith DH (1991). Simultaneous prepubertal onset of panic disorder, night terrors, and somnambulism. J Am Acad Child Adolesc Psychiatry 30:553–5. Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E (2000). Efficacy of

223

Anxiety disorders

venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6 month randomized controlled trial. JAMA 283:3082–8. Giaconia RM, Reinherz HZ, Silverman AB, Pakiz B, Frost AK, Cohen E (1995). Traumas and posttraumatic stress disorder in a community population of older adolescents. J Am Acad Child Adolesc Psychiatry 34:1369–80. Gittelman-Klein R, Klein DF (1971). Controlled imipramine treatment of school phobia. Arch Gen Psychiatry 25:204–7. Golwyn DH, Weinstock RC (1990). Phenelzine treatment of elective mutism: a case report. J Clin Psychiatry 51:384–5. Gorman JM, Liebowitz MR, Fyer AJ, Goetz D, Campeas RB (1987). An open trial of fluoxetine in the treatment of panic attacks. J Clin Psychopharmacol 7:329–32. Graae F, Milner J, Rizzotto L, Klein RG (1994). Clonazepam in childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 33:372–6. Graeff FG, Guimaraes FS, De Andre TG, Deakin JF (1996). Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 54:124–41. Hamilton M (1959). The assessment of anxiety states by rating. Br J Med Psychol 32:50–5. Harmon RJ, Riggs PD (1996). Clonidine for posttraumatic stress disorder in preschool children. J Am Acad Child Adolesc Psychiatry 35:1247–9. Hayward C, Killen JD, Hammer LD et al. (1992). Pubertal stage and panic attack history in sixth and seventh grade girls. Am J Psychiatry 149:1239–43. Hayward C, Killen JD, Taylor CB (1989). Panic attacks in young adolescents. Am J Psychiatry 146:1061–2. Heimberg RG, Holt CSD, Schneier FR, Liebowitz MR (1993). The issue of subtypes in the diagnosis of social phobia. J Anxiety Disord 7:249–69. Hirschfeld DR, Rosenbaum JF, Biederman J et al. (1992). Stable behavioral inhibition and its association with anxiety disorder. J Am Acad Child Adolesc Psychiatry 31:103–11. Hoehn-Saric R, Harris GJ, Pearlson GD, Cox CS, Machlin SR, Camargo EE (1991). A fluoxetine induced frontal lobe syndrome in an obsessive compulsive patient. J Clin Psychiatry 52:131–3. Hoehn-Saric R, Lipsey JR, McLeod DR (1990). Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol 10:343–5. Hoehn-Saric R, McLeod DR, Hipsley PA (1993). Effect of fluvoxamine on panic disorder. J Clin Psychopharmacol 13:321–6. Hoehn-Saric R, McLeod DR, Zimmerli WD (1988). Differential effects of alprazolam and imipramine in generalized anxiety disorder: somatic versus psychic symptoms. J Clin Psychiatry 49:293–301. Hollander E, Kaplan A, Cartwright C, Reichman D (2000). Venlafaxin in children, adolescents, and young adults with autism spectrum disorders: an open retrospective clinical report. J Child Neurol 15:132–5. Hunt RD (1987). Treatment effects of oral and transdermal clonidine in relation to methyphenidate – an open pilot study in ADHD. Psychopharmacol Bull 23:111–14. Ialongo N, Edelsohn GW-LL, Crockett LKS (1995). The significance of self-reported anxious symptoms in first grade children. J Child Psychol Psychiatry 22:441–5.

224

E. J. Garland

Jefferson JW (1995). Social phobia: a pharmacological treatment overview. J Clin Psychiatry 56:18–24. Jenike MA, Baer L, Summergrad P, Minichiello WE, Holland A, Seymour R (1990a). Sertraline in obsessive-compulsive disorder: a double-blind comparison with placebo. Am J Psychiatry 147:923–8. Jenike MA, Hyman S, Baer L et al. (1990b). A controlled trial of fluvoxamine in obsessive compulsive disorder: implications for a serotonergic theory. Am J Psychiatry 147:1209–15. Johnson MR, Lydiard RB (1995). The neurobiology of anxiety disorders. Psychiatr Clin North Am 18:681–725. Joorabchi B (1977). Expressions of the hyperventilation syndrome in children. Clin Pediatr 16:1110–15. Kagan J, Reznik JS, Snidman N (1987). The physiology and psychology of behavioral inhibition in children. Child Dev 58:1459–73. Kashani JH, Orvaschel H (1988). Anxiety disorders in midadolescence: a community sample. Am J Psychiatry 145:960–4. Keck PE, McElroy SL (1997). New uses for antidepressants: social phobia. J Clin Psychiatry 58:37–8. Keck PE Jr, McElroy SL, Freidman LM (1992). Valproate and carbamazepine in the treatment of panic and posttraumatic stress disorders, withdrawal states and behavioral dyscontrol syndromes. J Clin Psychopharmacol 12(Suppl 1):S36–41. Keller MB, Lavori PW, Wunder J, Beardslee WR, Schwartz CE, Roth J (1992). Chronic course of anxiety disorders in children and adolescents. J Am Acad Child Adolesc Psychiatry 31:595–9. Kendall PC (1993). Cognitive-behavioral therapies with youth: guiding therapy, current status, and emerging developments. J Consult Clin Psychol 61:235–47. Kendall PC, Kortlander E, Chansky TE, Brady EU (1992). Comorbidity of anxiety and depression in youth: treatment implications. J Consult Clin Psychol 60:869–80. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ (1992). Generalized anxiety disorder in women: a population-based twin study. Arch Gen Psychiatry 49:267–72. Kessler RC, McGonagle KA, Zhao S et al. (1994). Lifetime and 12 month prevalence of DSMIII-R psychiatric disorders in the United States. Arch Gen Psychiatry 51:8–19. Kessler RC, Stein MB, Berglund P (1998). Social phobia subtypes in the National Comorbidity Study. Am J Psychiatry 155:613–19. Klein DF (1964). Delineation of two drug-responsive anxiety syndromes. Psychopharmacology (Berlin) 3:397–408. Klein RG, Kopelwicz HS, Kanner A (1992). Imipramine treatment of children with separation anxiety disorder. J Am Acad Child Adolesc Psychiatry 31:21–8. Kortlander E, Kendall PC, Panichelli-Mindel SM (1997). Maternal expectations and attributions about coping in anxious children. J Anxiety Disord 11:297–315. Kosten TR, Frank JB, Dan E, McDougle CJ, Giller ELJ (1991). Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine. J Nerv Ment Dis 179:366–70. Kraft I (1965). A clinical study of chlordiazepoxide used in psychiatric disorders of children. Int J Neuropsychiatry 1:433–7.

225

Anxiety disorders

Kranzler H (1988). Use of buspirone in an adolescent with overanxious disorder. J Am Acad Child Adolesc Psychiatry 27:789–90. Kunovac JL, Stahl SM (1995). Future directions in anxiolytic pharmacotherapy. Psychiatr Clin North Am 18:895–909. Kutcher SP (1997). Child and Adolescent Psychopharmacology. Philadelphia, PA: WB Saunders. Kutcher SP, Mackenzie S (1988). Successful clonazepam treatment of adolescents with panic disorder. J Clin Psychopharmacol 8:299–301. Kutcher SP, Reiter S, Gardner D (1995). Pharmacotherapy: approaches and applications. In March JS (Ed.), Anxiety Disorders in Children and Adolescents. New York: Guilford Press, pp. 341–85. Kutcher SP, Reiter S, Gardner DM, Klein RG (1992). The pharmacotherapy of anxiety disorders in children and adolescents. Psychiatr Clin North Am 15:41–67. Last CG, Hansen C, Franco N (1997). Anxious children in adulthood: a prospective study of adjustment. J Am Acad Child Adolesc Psychiatry 36:645–52. Leo RJ (1996). Movement disorders associated with the serotonin selective reuptake inhibitors. J Clin Psychiatry 57:449–54. Leonard H, March J, Rickler KC, Allen AJ (1997). Pharmacology of the selective serotonin reuptake inhibitors in children and adolescents. J Am Acad Child Adolesc Psychiatry 36:725–36. Lipsitz JD, Martin LY, Mannuza S, Chapman TF, Liebowitz MR, Klein DF (1994). Childhood separation anxiety disorder in patients with adult anxiety disorders. Am J Psychiatry 151:927–9. Lydiard RB, Lesser IM, Ballenger JC et al. (1992). Fixed dose study of alprazolam 2 mg, alprazolam 6 mg and placebo in panic disorder. J Clin Psychopharmacol 12:96–103. Magee WJ, Eaton WW, Wittchen H-U, McGonagle KA, Kessler RC (1996). Agoraphobia, simple phobia and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry 53:159–68. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL (1997). Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull 33:149–54. March JS, Leonard HL, Swedo SE (1995). Pharmacotherapy of obsessive-compulsive disorder. Child Adolesc Psychiat Clin North Am 4:217–36. March JS, Parker JD, Sullivan K, Stallings P, Conners, CK (1997). The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry 36:554–65. Marshall RD, Printz D, Cardenas D, Abbate L, Liebowitz MR (1995). Adverse events in PTSD patients taking fluoxetine. Am J Psychiatry 152:1238–9. Marshall RD, Schneier FR, Fallon BA et al. (1998). An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder. J Clin Psychopharmacol 18:10–18. Mavissakalian MR, Perel JM (1995). Imipramine treatment of panic disorder with agoraphobia: dose ranging and plasma level-response relationships. Am J Psychiatry 152:673–82. McGee R, Feehan M, Williams S et al. (1980). DSM-III disorder in a large sample of adolescents. J Am Acad Child Adolesc Psychiatry 29:611–19. Modigh K, Westberg P, Eriksson E (1992). Superiority of clomipramine over imipramine in the treatment of panic disorder. A placebo controlled trial. J Clin Psychopharmacol 12:251–61.

226

E. J. Garland

Moreau D, Follett C (1993). Panic disorder in children and adolescents. Child Adolesc Psychiatr Clin North Am 2:581–602. Muris P, Meesters C, Merckelbach H, Sermon A, Zwakhalen S (1998). Worry in normal children. J Am Acad Child Adolesc Psychiatry 37:703–10. Neal LA, Shapland W, Fox C (1997). An open trial of moclobemide in the treatment of post-traumatic stress disorder. Int Clin Psychopharmacol 12:231–7. Nelles WB, Barlow DH (1988). Do children panic? Clin Psychol Rev 8:359–72. Newton R, Casten G, Alms DR (1982). The side effect profile of buspirone in comparison to active control and placebo. J Clin Psychiatry 43:100–2. Noyes R, Garvey MJ (1989). Follow-up study of patients with panic attacks treated with tricyclic antidepressants. J Affect Disord 16:249–57. Noyes R, Garvey MJ, Cook BI, Samuelson L (1989). Problems with tricyclic antidepressant use in patients with panic disorder or agoraphobia: results of a naturalistic follow-up study. J Clin Psychiatry 50:163–9. Oehrberg S, Christiansen PE, Behnke K et al. (1995). Paroxetine in the treatment of panic disorder: a randomized, double-blind, placebo-controlled study. Br J Psychiatry 167:374–9. Olvera RL, Pliszka RSR, Luh J, Tatum R (1996). An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol 6:241–50. Otto MW, Whittal ML (1995). Cognitive-behavior therapy and the longitudinal course of panic disorder. Psychiatr Clin North Am 18:803–20. Otto MW, Pollack MH, Meltzer-Brody S et al. (1992). Cognitive-behavioral therapy for benzodiazepine discontinuation in panic disorder patients. Psychopharmacol Bull 28:123–30. Papp LA, Klein DF, Gorman JM (1993). Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry 150:1149–57. Penava SJ, Otto MW, Pollack MH, Rosenbaum JF (1997). Current status of pharmacotherapy for PTSD: an effect size analysis of controlled studies. Depress Anxiety 4:240–2. Pfefferbaum B (1997). Post-traumatic stress disorder in children: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 36:1503–11. Pliszka SR (1989). Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 28:882–7. Pollack MH, Smoller JW (1995). The longitudinal course and outcome of panic disorder. Psychiatr Clin North Am 18:785–801. Pollack MH, Otto MW, Tesar GE et al. (1993). Long-term outcome after acute treatment with clonazepam and alprazolam of panic disorder. J Clin Psychopharmacol 13:257–63. Preist RG, Gimbrett R, Roberts N, Steinart J (1995). Reversible and selective inhibitors of monoamine oxidase in mental and other disorders. Acta Psychiatr Scand Supplementum 386:40–3. Rakel RE (1990). Long term buspirone therapy for chronic anxiety: a multicenter study to determine safety. South Med J 83:194–8. Reiman EM (1997). The application of positron emission tomography to the study of normal and pathological emotions. J Clin Psychiatry 58(Suppl 16):4–12. Reiss S, Peterson R, Gursky D, McNally RJ (1986). Anxiety, anxiety sensitivity, and the prediction

227

Anxiety disorders

of fearfulness. Behav Res Ther 24:1–8. Reist C, Kauffman CD, Haier RJ et al. (1989). A controlled trial of desipramine in 18 men with posttraumatic stress disorder. Am J Psychiatry 146:513–6. Reiter S, Kutcher S (1991). Disinhibition and anger outbursts in adolescents treated with clonazepam. J Clin Psychopharmacol 11:268. Reynolds CR, Richmond BO (1978). What I think and feel: a revised measure of children’s manifest anxiety. J Abnorm Child Psychol 6:787–92. Rickels K, Downing R, Schweizer E et al. (1993a). Antidepressants for the treatment of generalized anxiety disorder: a placebo-controlled comparison of imipramine, trazodone and diazepam. Arch Gen Psychiatry 50:884–95. Rickels K, Pollack MM, Sheehan DV, Haskins JT (2000). Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry 157:968–74. Rickels K, Schweizer E, Csanalosi I et al. (1988). Long-term treatment of anxiety and the risk of withdrawal. Prospective comparison of clorazepate and buspirone. Arch Gen Psychiatry 45:444– 50. Rickels K, Schwiezer E, Weis S (1993b). Maintenance drug treatment for panic disorder. II Short and long term outcome after drug taper. Arch Gen Psychiatry 50:61–8. Riddle MA, King RA, Hardin MT et al. (1991). Behavioral side effects of fluoxetine in children and adolescents. Journal of Child and Adolescent Psychopharmacology 1:193–8. Riddle MA, Scahill L, King RA et al. (1992). Double-blind, cross-over trial of fluoxetine and placebo in children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 31:1062–9. Risse SC, Whitters A, Burke J, Chen S, Scurfield RM, Raskind MA (1990). Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder. J Clin Psychiatry 51:206–9. Robbins T, Everitt BJ (1995). Central norepinephrine neurons and behavior. In FE Bloom, DJ Kupfer (Eds.), Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp. 363–72. Robins LN, Regier DA (Eds.) (1991). Psychiatric Disorders in America: The Epidemiological Catchment Area Study. New York: The Free Press. Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L (1997). Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatr Scand 95:444–50. Safren SA, Heimberg RG, Brown EJ, Holle C (1997). Quality of life in social phobia. Anxiety 4:126–33. Sallee FR, Richman H, Sethuraman G, Dougherty D, Sine L, Altman-Hamamdzic S (1998). Clonidine challenge in childhood anxiety disorder. J Am Acad Child Adolesc Psychiatry 37:655– 62. Schatzberg AF, Ballenger JC (1991). Decisions for the clinician in the treatment of panic disorder: when to treat, which treatment to use, and how long to treat. J Clin Psychiatry 52(Suppl 2):26–31. Schneier FR, Heckelman LR, Garfinkel R et al. (1994). Functional impairment in social phobia. J Clin Psychiatry 55:322–31.

228

E. J. Garland

Schneier FR, Liebowitz MR, Davies SO et al. (1990). Fluoxetine in panic disorder. J Clin Psychopharmacol 10:119–21. Schweizer E (1995). Generalized anxiety disorder: longitudinal course and pharmacologic treatment. Psychiatr Clin North Am 18:843–57. Schweizer ERK (1996). The long-term management of generalized anxiety disorder: issues and dilemmas. J Clin Psychiatry 57(Suppl 7):9–12. Shalev AY, Bonne O, Eth S (1996). Treatment of posttraumatic stress disorder: a review. Psychosom Med 58:165–82. Sheevan DV, Harnett-Sheehan K (1996). The role of SSRIs in panic disorder. J Clin Psychiatry 57(Suppl 10):51–8. Silverman WK, Gleisig W, Rabian B, Peterson RA (1991). The Childhood Anxiety Sensitivity Index. J Clin Child Psychol 20:162–8. Silverstone PH, Ravindran A (1999). Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. J Clin Psychiatry 60:22–8. Simeon JG, Ferguson HB (1987). Alprazolam effects in children with anxiety disorders. Can J Psychiatry 32:570–4. Simeon JG, Ferguson HB, Knott V et al. (1992a). Clinical, cognitive, and neurophysiological effects of alprazolam in children and adolescents with overanxious and avoidant disorders. J Am Acad Child Adolesc Psychiatry 31:29–33. Simeon JG, Knott VJ, Thatte S, Dubois CD, Wiggins DM, Geraets I (1992b). Pharmacotherapy of childhood anxiety disorders. Clin Neuropharmacol 15(Suppl 1 Part A):229–30. Spielberger CD (1973). Manual for the State-Trait Anxiety Inventory for Children. Palo Alto, CA: Consulting Psychologists’ Press. Stein DJ, Bouwer C (1997). A neuro-evolutionary approach to the anxiety disorders. J Anxiety Disord 11:409–29. Stein MB, Chartier MJ, Hazen AL et al. (1998). A direct-interview family study of generalized social phobia. Am J Psychiatry 155:90–7. Stein MB, Walker JR, Forde DR (1994). Setting diagnostic thresholds for social phobia: considerations from a community survey of social anxiety. Am J Psychiatry 151:408–12. Stoll AL, Cole JO, Lukas SE (1991). A case of mania as a result of fluoxetine-marijuana interaction. J Clin Psychiatry 52:280–1. Sutherland SM, Davidson JR (1994). Pharmacotherapy for post-traumatic stress disorder. Psychiatr Clin North Am 17:409–23. Tancer ME, Mailman RB, Stein MB, Mason GA, Carson SW, Golden RN (1994). Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety 1:216–23. Torgerson S (1983). Genetic factors in anxiety disorders. Arch Gen Psychiatry 40:1085–9. Trott GE, Friese HJ, Menzel M, Nissen G (1991). Use of moclobemide in children with attention deficit hyperactivity disorder. Jugendpsychiatrie 19:248–53. Tyano S, Iancu I, Solomon Z et al. (1996). Seven-year follow-up of child survivors of a bus accident. J Am Acad Child Adolesc Psychiatry 35:365–73. van Ameringen M, Mancini C, Streiner DL (1993). Fluoxetine efficacy in social phobia. J Clin Psychiatry 54:27–32.

229

Anxiety disorders

van der Kolk BA, Dreyfuss D, Michaels M et al. (1994). Fluoxetine in post-traumatic stress disorder. J Clin Psychiatry 55:517–22. van Vliet IM, Den Boer JA, Westenberg HG (1992). Psychopharmacological treatment of social phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor. Eur Neuropsychopharmacol 2:21–9. van Vliet IM, Den Boer JA, Westenberg HG (1994). Psychopharmacological treatment of social phobia: a double-blind placebo-controlled study with fluvoxamine. Psychopharmacology (Berlin) 115:128–34. van Vliet IM, Den Boer JA, Westenberg HG, Pian KL (1997). Clinical effects of buspirone in social phobia: a double-blind placebo-controlled study. J Clin Psychiatry 58:164–8. Versiani M, Amrein R, Montgomery SA (1997). Social phobia: long-term treatment outcome and prediction of response – a moclobemide study. Int Clin Psychopharmacol 12:239–54. Weller EB, Weller RA, Davis GP (2000). Use of venlafaxine in children and adolescents: a review of current literature. Depress Anxiety 12(Suppl 1):85–9. Werry JS (1991). Overanxious disorder: a review of its taxonomic properties. J Am Acad Child Adolesc Psychiatry 30:533–44. Whitaker A, Johnson J, Shaffer D (1990). Uncommon troubles in young people: prevalence estimates of selected psychiatric disorders in a nonreferred adolescent population. Arch Gen Psychiatry 47:487–96. Wilens TE, Biederman J, Baldessarini RJ et al. (1996). Cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents. J Am Acad Child Adolesc Psychiatry 35:1491–501. Wilens TE, Biederman J, Mick E, Spencer TJ (1995). A systematic assessment of tricyclic antidepressants in the treatment of adult attention-deficit hyperactivity disorder. J Nerv Ment Dis 183: 48–50. Wilens TE, Biederman J, Spencer TJ, Geist DE (1993). A retrospective study of serum levels and electrocardiographic effects of nortriptyline in children and adolescents. J Am Acad Child Adolesc Psychiatry 32:270–7. Wittchen HU, Zhao S, Kessler RC, Eaves WW (1994). DSMIII-R generalized anxiety disorder in the National Comorbidity Study. Arch Gen Psychiatry 51:355–64. Zinbarg RE, Barlow DH, Liebowitz M et al. (1994). The DSMIV field trial for mixed anxietydepression. Am J Psychiatry 151:1153–62.

9 Attention-deficit/hyperactivity disorder Thomas Spencer, Joseph Biederman, and Timothy Wilens Massachusetts General Hospital, Boston, Massachusetts, USA

Introduction Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder. DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV) recognizes three subtypes of ADHD: a predominantly inattentive subtype, a predominantly hyperactive–impulsive subtype, and a combined subtype (American Psychiatric Association, 1994). These categories acknowledge clinical heterogeneity and reflect a change in emphasis from earlier definitions that stressed motoric symptoms to current nosology in which inattention is emphasized. ADHD is one of the major clinical and public health problems because of its associated morbidity and disability in children, adolescents, and adults. Its impact on society is enormous in terms of financial cost, stress to families, impact on academic and vocational activities, as well as negative effects on self-esteem. Data from cross-sectional, retrospective, and follow-up studies indicate that children with ADHD are at risk for developing other psychiatric difficulties in childhood, adolescence, and adulthood including antisocial behaviors, substance use disorders, and mood and anxiety symptoms and disorders.

The pathophysiology of ADHD ADHD is a heterogeneous disorder of unknown etiology. An emerging neuropsychologic and neuroimaging literature suggests that abnormalities in frontal networks or fronto-striatal dysfunction is the disorder’s underlying neural substrate, and that catecholamine dysregulation is its underlying patho-physiologic substrate. The pattern of neuropsychologic deficits found in ADHD children implicates executive functions and working memory; this pattern is similar to that which has been found among adults with frontal lobe damage, which suggests that the frontal cortex or regions projecting to the frontal cortex are dysfunctional in at least some ADHD children. Recent studies using magnetic resonance imaging of the brain indicate that 230

231

Attention-deficit/hyperactivity disorder

there are subtle anomalies in caudate and corpus callosum size and shape or possible reductions in right frontal area in ADHD (Castellanos et al., 1996). These data are consistent with a positron emission tomography study which identified abnormalities of cerebral metabolism in the prefrontal and premotor areas of the frontal lobe in ADHD adults who had ADHD children (Zametkin et al., 1990). Thus, the emerging neuroimaging literature points to abnormalities in frontal networks in ADHD (fronto-striatal dysfunction) and it is these networks that control attention and motor intentional behavior. Zametkin postulated that ‘‘inhibitory influences of frontal cortical activity, predominantly noradrenergic acting on lower (striatal) structures that are driven by . . . dopamine agonists . . .’’ (Zametkin and Rapoport, 1987) may be implicated in the pathophysiology of ADHD. The fronto-subcortical pathways are rich in catecholamines and catecholamines are also implicated in ADHD because of the mechanism of action of stimulants. Yet, human studies of the catecholamine hypothesis of ADHD have produced conflicting results, perhaps due to the insensitivity of peripheral measures. Data from family genetic, twin, and adoption studies as well as segregation analysis suggest a genetic origin for some forms of the disorder (Biederman et al., 1992). Although their results are still tentative, molecular genetic studies suggest that three genes may increase the susceptibility to ADHD: the D4 dopamine receptor gene, the dopamine transporter gene, and the D2 dopamine receptor gene (Faraone et al., 1999). Studies of environmental adversity have implicated pregnancy and delivery complications, marital distress, family dysfunction, and low social class (Biederman et al., 1994; Milberger et al., 1997b). Recently, the Council of Scientific Affairs of the American Medical Association reviewed issues of diagnosis, optimal treatment, and care of ADHD patients to deal with public and professional concern regarding the possible inappropriate prescription of ADHD medications (Goldman et al., 1998). This distinguished panel of authors outlined several factors related to existing controversies. (1) Like most psychiatric disorders, the diagnostic criteria for ADHD are by history and behavioral assessment and there are no pathognomonic laboratory or radiologic tests; (2) ADHD is a chronic disorder that requires extended treatment; and (3) treatment includes potentially abusable medications. After a review of the voluminous literature, they concluded that ADHD is one of the best researched disorders in medicine; in fact, the overall data on its validity are far more compelling than for many medical conditions. They also concluded that there was little evidence of widespread overdiagnosis or misdiagnosis of ADHD or of widespread overprescription of stimulants by physicians.

232

T. Spencer et al.

Comorbidity and ADHD Conduct disorder

Conduct disorder (CD) is the most well-established comorbid condition of childhood ADHD, and has been widely reported in epidemiologic (Anderson et al., 1987; Bird et al., 1988; McGee et al., 1985), clinical (Barkley et al., 1989; Quay et al., 1987), follow-up (Gittelman et al., 1985; Loney et al., 1981a; Weiss and Hechtman, 1986), and family genetic studies (Biederman et al., 1992). The presence of CD is important to consider and identify since it has been associated with poor prognosis (Loney et al., 1981b; McGee et al., 1984; Milich and Loney, 1979) and a high risk of developing addictions (Biederman et al., 1995d; Gittelman et al., 1985). Mood, anxiety, and learning disorders

In addition to the well-documented comorbidity with CD, recent studies have also documented high rates of mood disorders in epidemiological samples of ADHD children (Anderson et al., 1987; Bird et al., 1988; McGee et al., 1985) and clinical studies of ADHD children, adolescents, and adults (Biederman et al., 1991, 1993c, 1995b; Jensen et al., 1993). Conversely, high rates of ADHD have been found in mood disordered children, adolescents (Alessi and Magen, 1988; Angold and Costello, 1993; Biederman et al. 1995a,d; Geller et al., 1995; Wozniak et al., 1995), and adults (Alpert et al., 1996; Sachs et al., 1993). Similarly, investigators have noted high rates of anxiety in children with ADHD (Lahey et al., 1987, 1988) and high rates of ADHD in children with anxiety (Last et al., 1987). Studies have also clearly documented high levels of comorbidity with both reading and arithmetic disability in ADHD children (Biederman et al., 1991; Semrud-Clikeman et al., 1992) and, conversely, high rates of ADHD in samples of learning disordered children (Cantwell, 1985; Silver and Brunstetter, 1986). Pharmacotherapy Stimulants

Stimulants are sympathomimetic drugs structurally similar to endogenous catecholamines (e.g., dopamine and noradrenaline). The most commonly used compounds in this class include methylphenidate (Ritalin), D-amphetamine (Dexedrine), D, L-amphetamine (Adderall), and magnesium pemoline (Cylert). These drugs are thought to act in both the central and peripheral nervous systems by preventing the reuptake of catecholamines into presynaptic nerve

233


endings, thereby preventing their degradation by monoamine oxidase. In addition, amphetamine compounds appear to cause retrograde release of catecholamines through the transporter as well as numerous intracellular actions on the vesicular storage of catecholamines (Wilens and Spencer, 1988). Methylphenidate as a secondary amine gives rise to four optical isomers: d-threo, l-threo, d-erythro, and l-erythro (Patrick et al., 1987). There is stereoselectivity in receptor site binding and its relationship to response. The standard preparation is comprised of the threoracemate as it appears to be the central nervous system (CNS) active form (Hubbard et al., 1989; Patrick et al., 1987). In addition, in rats, the d-methylphenidate isomer shows greater induction of locomotor activity and reuptake inhibition of labeled dopamine and noradrenaline than the l-isomer (Patrick et al., 1987). The amphetamine class of agents are among the oldest compounds available in the United States. Amphetamine was first synthesized in 1887 and found in the 1920s to be a potential alternative to ephedrine which had been running in short supply for the treatment of asthma (Alles, 1928). Amphetamine has pharmacologic activity on the catecholaminergic input to smooth muscles, metabolism, and the cardiovascular system and CNS (Hoffman and Lefkowitz, 1990). Both methylphenidate and amphetamines are classified by the Drug Enforcement Agency as schedule II agents, while pemoline is a class IV agent. Methylphenidate and D-amphetamine are both short-acting compounds, with an onset of action within 30–60 minutes and a peak clinical effect usually seen between 1 and 3 hours after administration. Therefore, multiple daily administrations are required for a consistent daytime response. Typically, these compounds have a rapid onset of action so that clinical response is evident soon after a therapeutic dose is obtained. Slow release preparations, with a peak clinical effect between 1 and 5 hours, are available for methylphenidate, D-amphetamine, and D, L-amphetamine, and can often allow for a single dose to be administered in the morning that will last for the entire school day. Magnesium pemoline is a longer-acting compound generally allowing for one or two daily doses. Contrary to previous indications (Conners and Taylor, 1980), a recent study has suggested that when the dose of pemoline (1–2 mg/kg) is calculated to achieve a reasonable plasma concentration (greater than 2 g/ml), clinically measurable effects are apparent within hours (Sallee et al., 1992). There are more than 170 controlled studies of stimulants with more than 6000 children, adolescents, and adults (Spencer et al., 1996b). These studies clearly document the efficacy on core features of ADHD (motoric overactivity, impulsivity, and inattentiveness) as well as associated symptoms including

1.0–2.0 1.0–3.0

2.0–5.0 (1.0–3.0 for NT)

Methylphenidate Magnesium pemoline

Antidepressants Tricyclics (TCAs) e.g., imipramine, desipramine, nortriptyline (NT)

0.2–0.6 mg/kg

0.5–1.0 mg/kg

0.3–1.5

Dextro, levoamphetamine

Monoamine oxidase inhibitors (MAOIs) e.g., phenelzine, tranylcypromine, selegiline

0.3–1.0

Stimulants Dextroamphetamine

Daily dose (mg/kg)

Table 9.1. Psychotropics used in ADHD

Twice or three times

Once or twice

Once or twice


Daily Dosage Schedule

Anticholinergic (dry mouth, constipation, blurred vision) Weight loss Cardiovascular (mild increase) diastolic blood pressure and ECG conduction parameters with daily doses 3.5 mg/kg. Treatment requires serum levels and ECG monitoring Severe dietary restrictions (high tyramine foods) Hypertensive crisis with dietetic transgression or with certain drugs Weight gain Drowsiness Changes in blood pressure Insomnia Liver toxicity (remote)

Insomnia, decreased appetite, weight loss Depression, psychosis (rare, with very high doses) Increase in heart rate and blood pressure (mild) Possible reduction in growth velocity with long-term use Withdrawal effects and rebound phenomena Same as other stimulants Abnormal liver function tests

Common adverse effects

Once or twice

3–10 g/kg

15–43 g/kg

2–8 mg/kg

Alpha-2 agonists Clonidine

Guanfacine

Beta agonist Propranolol Twice


1–3 mg/kg

Venlafaxine

Similar to clonidine Higher risk for bradycardia and hypotension (dose dependent) and rebound hypertension Bronchospasm (contraindicated in asthmatics) Rebound hypertension on abrupt withdrawal

Sedation (very frequent) Hypotension (rare) Dry mouth Confusion (with high dose) Depression Rebound hypertension Localized irritation with transdermal preparation Same as clonidine (less sedation)

Once (a.m. or p.m.) Irritability Insomnia Gastrointestinal symptoms Headaches Sexual dysfunction Three times Irritability Insomnia Drug-induced seizures (in doses 6 mg/kg) Contraindicated in bulimics Twice-three times Similar to SSRIs Irritability Insomnia Gastrointestinal symptoms Headaches Blood pressure changes

0.5–1.0 mg/kg 1.5–3.0 mg/kg 0.25–0.70 mg/kg 1.5–4.5 mg/kg 0.5–1.0 mg/kg 3–6 mg/kg

Selective serotonin reuptake inhibitors (SSRIs) e.g., Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram Bupropion

236

T. Spencer et al.

cognition, on-task behavior, academic performance, social function, defiance, and aggression. Consistent with the evolving definition of ADHD, stimulants also are effective in patients with ADHD in whom hyperactivity is not a significant clinical problem (Safer and Krager, 1988). Stimulants have been demonstrated to improve cognitive function as measured by tests of vigilance, impulsivity, reaction time, short-term memory, and learning of verbal and nonverbal material in children with ADHD (Barkley, 1977; Klein, 1987; Rapport et al., 1988). These stimulant-associated improvements have also been demonstrated in a simulated classroom paradigm (Barkley, 1991; Du Paul et al., 1994). Treatment with stimulants increases schoolbased productivity (Famularo and Fenton, 1987) and improves performance in academic testing (Abikoff et al., personal communication). However, despite these beneficial cognitive effects, some children with ADHD have additional learning disabilities that are not responsive to pharmacotherapy (Bergman et al., 1991; Faraone et al., 1993), but which may require educational remediation. While stimulants have traditionally been used for academic amelioration, they produce profound effects on social skills and apparent emotional maturity. In several studies, stimulants appeared to ‘‘normalize’’ behaviors of the ADHD child in initially deviant behaviors of impulsivity, noncompliance, disruption, and overall hyperactivity (Whalen, 1989). Observational studies have also demonstrated stimulant-enhanced social skills in school, within families, and with peers, including improved maternal–child and sibling interactions (Barkley and Cunningham, 1979). Studies also find that families of stimulant responsive children are more amenable to psychosocial interventions (Schachar et al., 1987). Investigations of peer relationships in ADHD children show that those treated with stimulants have increased abilities to perceive peer communications, self-perceptions, and situational cues. In addition, these children show improved modulation of the intensity of behavior, improved communication, and greater responsiveness with fewer negative interactions (Whalen et al., 1990). In adults with ADHD, occupational and marital dysfunction were noted to improve with stimulant treatment (Wender et al., 1985a). These findings support the importance of treating ADHD children, adolescents, and adults beyond school and work hours to include evenings, weekends, and vacations, should problems exist at these times. As is the case with cognitive learning disorders, some ADHD children demonstrate additional brain-based abnormal social behavior, so-called ‘‘social’’ learning disorders (Greene et al., 1996; Weintraub et al., 1981). These deficits may not respond to traditional ADHD therapy and may require psychosocial treatments such as provided by group therapies. While originally

237


it was thought that cognition and behavior were responsive to different doses of stimulants (Sprague and Sleator, 1977), recent studies indicate that both behavior and cognitive performance improve with stimulant treatment in a dose-dependent fashion (Douglas et al., 1988; Klein, 1987; Kupietz et al., 1988; Pelham et al., 1985; Rapport et al., 1985, 1989a,b; Tannock et al., 1989). Doses that improve behavior rarely constrict attention or cause ‘‘overfocusing’’ (Douglas et al., 1995; Solanto and Wender, 1989). While the vast majority of stimulant studies are in latency-age children, a more limited literature reveals a good response in both preschoolers, adolescents, and adults. Studies in preschoolers report improvement in structured tasks as well as mother–child interactions (Barkley, 1988; Barkley et al., 1984; Conners, 1975; Mayes et al., 1994; Schleifer et al., 1975). In adolescents, response has been reported as moderate to robust, with no abuse or tolerance noted (Brown and Sexson, 1988; Coons et al., 1987; Evans and Pelham, 1991; Klorman et al., 1987; Lerer and Lerer, 1977; MacKay et al., 1973; Safer and Allen, 1975; Varley, 1983). While earlier studies in ADHD adults reported mixed responses (ranging from 25% to 75%) (Gualtieri et al., 1985; Mattes et al., 1984; Wender et al., 1981, 1985a; Wood et al., 1976), a recent investigation documented robust response when an adequate dose was used. Previous studies had used a low average daily dose (0.6 mg/kg) that was not consistent with that used in most child studies (1.0 mg/kg). The author’s group reported a marked therapeutic response on methylphenidate vs. placebo (78% vs. 4%) that appeared to be dose dependent up to 1.0 mg/kg/day (Spencer et al., 1995). As in other adult ADHD studies, women responded as well as men did. Due to their short half-life, the short-acting stimulants (methylphenidate and dextroamphetamine) should be given in divided doses throughout the day, typically 4 hours apart. The total daily dose ranges from 0.3 mg/kg/day to 2 mg/kg/day (1.0 mg/kg/day for d-amphetamine). The starting dose is generally 2.5–5 mg/day, given in the morning, with the dose being increased if necessary every few days by 2.5–5 mg in a divided dose schedule. Due to the anorexogenic effects of the stimulants, it may be beneficial to administer the medicine after meals. The longer half-life agent, magnesium pemoline, is typically given once or twice daily (such as 8:00 a.m. and 2:00 p.m.) in doses ranging from 1 to 3 mg/kg/day. The typical starting dose of pemoline is 18.75–37.5 mg with increments in dose of 18.75 mg every few days thereafter until desired effects occur or side effects preclude further increments. Similarly, D, L-amphetamine with its longer half-life is typically given once or twice daily (such as 8:00 a.m. and 2:00 p.m.) in doses ranging from 1 to 1.5 mg/kg/day. The most commonly reported side effects of stimulants are appetite

238

T. Spencer et al.

suppression and sleep disturbances. The sleep disturbance that is most commonly reported is delay of sleep onset. This usually occurs when stimulants are administered in the late afternoon or early evening and may be alleviated by treatment with clonidine or other medications (Brown and Gammon, 1992; Prince et al., 1996). In addition, stimulants can induce anxiety (Gittelman and Koplewicz, 1986; Swanson et al., 1978) or depression (Barkley, 1977, 1990; Gittelman and Koplewicz, 1986; Wilens and Biederman, 1992) in some patients. Other infrequent side effects include headaches, abdominal discomfort, increased lethargy, and fatigue. Although the cardiovascular effects of stimulants may vary, mild increases in pulse and blood pressure of unclear clinical significance have been observed (Brown et al., 1984). Stimulant-associated toxic psychosis is rare, but resembles a toxic phenomenon (e.g., visual hallucinosis) and not a schizotypal-like exacerbation of psychotic symptoms. The development of psychotic symptoms in a child being treated with stimulants requires a careful re-evaluation to rule out the presence of a pre-existing psychotic disorder. Administration of magnesium pemoline has been associated with hypersensitivity reactions involving the liver accompanied by elevations in liver function studies (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) after several months of treatment (Shevell and Schreriber, 1997). Baseline liver function studies and repeat studies are recommended with the administration of this compound. There have been longstanding concerns about stimulant-associated growth deficits in children with ADHD. Despite reports of height deficits in preadolescence, adult height has been reported to be uncompromised (Gittelman et al., 1988; Hechtman, 1985), which was thought to be due to discontinuation of stimulant treatment; however, there are no studies of the effects of stimulants on growth in children treated continually from childhood through adolescence and young adulthood. It is possible that catch-up growth is related to ADHDassociated delayed maturation and not removal of stimulant treatment. To date, no consistent neurohormonal pathophysiology has been identified to explain stimulant-associated height deficits (Spencer et al., 1998). In addition, initial associations of height and weight deficits have not been replicated. ADHD itself is associated with dysregulation of several neurotransmitter systems, especially the catecholamines, that may alter neuroendocrine function and lead to growth delays. Preliminary work from the author’s group supports a disorder-based, dysmaturity hypothesis (Spencer et al., 1996a). In a large sample of ADHD children and controls, small but significant differences in height were identified. However, height deficits were evident in early- but not late-adolescent ADHD children and were unrelated to the use of psychotropic

239


medications. Over the long term, there was no evidence of weight deficits in ADHD children relative to controls, and no relationship between measures of malnutrition and short stature was identified. These findings suggest that ADHD may be associated with temporary deficits in growth-in-height through midadolescence that may normalize by late adolescence. This effect appears to be mediated by ADHD and not its treatment. Current data do not support the common practice of drug holidays in children without evidence of growth deficits. However, until more is known, it seems prudent, in children suspected of stimulant-associated growth deficits, to provide them with drug holidays or alternative treatments. This recommendation, however, should be carefully weighed against the risk of symptom exacerbation due to drug discontinuation. Early reports indicated that children with personal or family histories of tic disorders were at greater risk for developing a tic disorder when exposed to stimulants (Lowe et al., 1982). However, recent work has increasingly challenged this view (Comings and Comings, 1988; Gadow et al., 1992, 1995). For example, in a recent short-term, controlled study of 34 children with ADHD and tics using multiple informants and direct observation, Gadow et al. (1995) reported that methylphenidate effectively suppressed ADHD symptoms, with only a weak effect on the frequency of tics. The author’s group examined tic disorders in a large, controlled prospective study of ADHD boys (Spencer, unpublished data). It was found that ADHD boys had more tic disorders at baseline and follow-up than controls. However, tic disorders had little impact on the psychosocial functioning of ADHD boys and stimulant treatment was not associated with increased rates, severity, or persistence of the tic disorders. Nonetheless, the only other prospective longitudinal study reported that 30% of ADHD children with tics had to discontinue stimulant treatment due to worsening of their tics (Castellanos et al., 1997). Until more is known, it seems prudent to weigh the risks and benefits on individual cases with appropriate discussion with the patient and family about the benefits and pitfalls of the use of stimulants in individuals with ADHD and tics. Similar uncertainties remain about the abuse potential of stimulants in children with ADHD. Despite the concern that ADHD may increase the risk of drug abuse in adolescents and young adults (or his/her associates), there are no scientific data that stimulant-treated ADHD children abuse prescribed medication when appropriately administered and monitored. Moreover, recent work has shown that the most commonly abused substance in ADHD adolescents and adults is marijuana and not stimulants (Biederman et al., 1995d). Despite its clinical importance, interdose rebound has not been adequately examined in the literature. Poststimulant worsening of symptoms may be

240

T. Spencer et al.

particularly taxing in the evening when family life takes place. Treatment options include use of additional immediate-release stimulants, long-acting agents, such as time-release stimulant preparations, or alternative medications such as antidepressants. The interactions of the stimulants with other prescription and nonprescription medications are generally mild and not a source of concern (Wilens and Biederman, 1992). However, caution should be exercised when using stimulants and antidepressants of the monoamine oxidase inhibitor (MAOI) type because of the potential for hypertensive reactions with this combination. Antidepressants

Tricyclic antidepressants in ADHD Tricyclic antidepressants (TCAs) include the tertiary amines amitriptyline, imipramine, doxepin, and trimipramine, and the secondary amines desipramine, nortriptyline, and protriptyline. The mechanism of action appears to be due to the blocking effects of these drugs on the reuptake of brain neurotransmitters, especially noradrenaline and serotonin. However, these agents have variable effects on pre- and postsynaptic neurotransmitter systems, resulting in differing positive and adverse effect profiles. Unwanted side effects may emerge from blockade of histaminic receptors (sedation, weight gain), cholinergic receptors (dry mouth, constipation), alpha-adrenergic receptors (postural hypotension), and serotonin uptake (sexual dysfunction). Accordingly, more selective (noradrenergic) secondary amines have less side effects in sensitive, such as juvenile and geriatric, populations. To date, 31 studies (19 controlled; 12 open) have evaluated TCAs in children, adolescents (n = 1064), and adults (n = 78). Almost all published studies have reported at least moderate improvement. Most studies were short-term studies composed of latency-age boys. Eight of nine studies reported moderate to robust response for up to 2 years. Sustained improvement was associated with adequate dosing and dose adjustments of desipramine ( 4 mg/kg) (Biederman et al., 1986; Gastfriend et al., 1985) and nortriptyline (2.0 mg/kg) (Wilens et al., 1993). Studies examining TCA serum levels reported high interindividual variability in serum with little relationship between serum level and daily dose or response, with nortriptyline being the exception (Wilens et al., 1993). The author’s group reported results from a 6-week, controlled trial of desipramine (n = 62) in mostly stimulant-resistant ADHD children (Biederman et al., 1989). Efficacy was comparable to that of the stimulants, with a 68% response to desipramine and only a 10% placebo response. Further, neither comorbidity with CD, major depression, or an anxiety disorder, or a family

241


history of ADHD, predicted response to desipramine treatment (Biederman et al., 1993b). There was a substantial reduction in depressive symptoms in desipramine-treated patients (Biederman et al., 1989), suggesting that desipramine may be useful treatment in depressed, ADHD children. In another controlled study, the author and colleagues recently demonstrated the efficacy of nortriptyline in doses of up to 2 mg/kg daily in school-aged youths with ADHD (n = 35) (Prince et al., 2000). A novel design was used in this study; an open trial of medication was followed by a randomized discontinuation trial. In the open phase, 80% of youth responded by week 6. During the discontinuation phase, most subjects randomized to placebo lost the antiADHD effect and most receiving nortriptyline maintained a robust antiADHD effect. As with other TCA studies, there was a lag in response to medication administration and a lag in loss of response to medication discontinuation. While the full dose was achieved by week 2, the full effect evolved slowly over the ensuing 4 weeks. In this study, ADHD youths receiving nortriptyline were also found to have significant reductions in oppositionality and anxiety. Nortriptyline was well tolerated with some weight gain being considered a desirable adverse effect. Analysis of response profiles in the literature suggests that TCAs more consistently improve behavioral symptoms than they impact on cognitive function per se (Gualtieri and Evans, 1988; Quinn and Rapoport, 1975; Rapport et al., 1993; Werry, 1980). Of 13 studies that compared TCAs with stimulants, five studies each reported that stimulants were superior to TCAs (Garfinkel et al., 1983; Gittelman-Klein, 1974; Greenberg et al., 1975; Rapoport et al., 1974) or equal to TCAs (Gross, 1973; Huessy and Wright, 1970; Kupietz and Balka, 1976; Rapport et al., 1993; Yepes et al., 1977), and three studies reported that TCAs were superior to stimulants (Watter and Dreyfus, 1973; Werry, 1980; Winsberg et al., 1972). Reports of sudden unexplained death in four ADHD children treated with desipramine have engendered concerns about the safety of the use of TCAs in children (Abramowicz, 1990). A recent conference sponsored by the National Institute of Health (NIH) examined the cardiovascular risk of psychotropics in children (Heart, Lung, and Blood Section of the National Institute of Health – Diane Atkins, M.D., Chair, Special Emphasis Panel on Cardiac Arrhythmia’s in Children, 29 August, 1996; Gutgesell et al., 1999). To put these concerns in context, Dr. Atkins noted that there was a rate of sudden death in children and adolescents of 1–4 per 100 000 per year that was unrelated to the presence of a psychiatric disorder or medication use. Three-quarters of these deaths are thought to be due to pre-existing cardiac conditions such as hypertrophic

242

T. Spencer et al.

cardiomyopathy or anomalies of the coronary arteries. Since some of the lesions are small, accurate diagnosis requires meticulous autopsies by cardiac pathologists. A recent report estimated that the magnitude of desipramine-associated risk of sudden death in children may not be much larger than the baseline risk of sudden death in this age group (Biederman et al., 1995c). The NIH conference participants concluded that the causal link between DMI and these deaths remains uncertain. In most studies, TCA treatment has been associated with asymptomatic, minor, but statistically significant increases in heart rate and ECG measures of cardiac conduction times consistent with the adult literature (Biederman et al., 1993a). As a result of these concerns, EKGs are obtained before and during treatment with TCAs. Abnormal EKGs, or symptoms pertaining to the cardiovascular system, would indicate revaluation of the risks and benefits of treatment with the TCAs. Consultation with a pediatric cardiologist may be necessary to establish guidelines for the safe use of TCAs in children with an unusual cardiac risk. Non-TCA antidepressants Bupropion Bupropion hydrochloride is a novel-structured antidepressant of the aminoketone class related to the phenylisopropylamines but pharmacologically distinct from known antidepressants (Casat et al., 1989). Bupropion appears to possess both indirect dopamine agonist and noradrenergic effects. Bupropion has been shown to be effective for ADHD in children, in a large, controlled multisite study (n = 72) (Casat et al., 1987, 1989; Conners et al., 1996) and in a comparison with methylphenidate (n = 15) (Barrickman et al., 1995). In an open study of ADHD adults, sustained improvement was documented at 1 year (Wender and Reimherr, 1990). In that study, dosing for ADHD, an average of 360 mg of bupropion for 6–8 weeks, appeared to be similar to that recommended for depression. While bupropion is metabolized at a similar rate as the TCAs, with a half-life of 14 hours, it is taken in divided doses to minimize the slightly increased risk (0.4%) for drug-induced seizures relative to other antidepressants. However, this risk has been linked to high doses, a previous history of seizures, and bulimia. Thus, by avoiding these risk factors, and by dividing the daily dose or using the long-acting preparation (bupropion SR), the risk of seizures may be comparable to other antidepressants. While the medication is generally well tolerated, other potential side effects include edema, rashes, nocturia, irritability, anorexia, and insomnia.

243


MAOIs The MAOIs inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase (MAO-A and B), both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes noradrenaline adrenaline, and serotonin, and MAO-B preferentially metabolizes phenylethylamine, an endogenous amphetamine-like substance, and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective. In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the ‘‘cheese effect’’ than the reversible MAOIs (e.g., moclobemide). Preliminary studies suggest that MAOIs are effective in juvenile and adult ADHD. In a recent open study ( Jankovic, 1993), selegiline (l-deprenyl, a specific MAOI-B at low dose) was evaluated in 29 children with both ADHD and tics. Ninety percent of the children demonstrated significant improvement in their ADHD symptoms at a mean dose of 8 mg/day. Feigin et al. (1996) conducted a controlled crossover trial of selegiline (10 mg) in 24 children with ADHD and Tourette’s syndrome. A carry-over effect confounded the analysis of the crossover study; however, selegiline was associated with a robust ADHD response in the first period of the study. In both studies, selegiline was well tolerated. In a 12-week double-blind, crossover trial, using two MAOIs in 14 hyperactive children, Zametkin et al. (1985) reported significant and rapid reduction in ADHD symptoms with minimal adverse effects. These investigators used clorygline (a specific MAOI-A) and tranylcypromine sulfate (a mixed MAOI-A/B). In open studies in adult ADHD, moderate improvements were reported in studies with pargyline and selegiline (selective MAOI-Bs) with associated adverse effects (Wender et al., 1983, 1985b). Of interest, the authors reported a delayed onset of action, and a postdosing stimulant-like quality of the MAOIs on ADHD symptoms lasting up to 6 hours (Wender et al., 1983). Ernst (1996) reported findings in a study of low (20 mg) and high (60 mg) dose selegiline in adults with familial ADHD (n = 36). Active drug did not separate from placebo, although a high placebo response may have confounded the findings. High dose was more effective than low-dose selegiline. While low-dose selegiline is more selective for MAOI-B, high dose produces a mixed MAOI-A and B effect, suggesting that the MAOI-A effects of selegiline may be more helpful in the treatment of ADHD. A major limitation to the use of MAOIs is the potential for hypertensive crisis (treatable with phentolamine) associated with dietetic transgressions (tyramine-containing foods, i.e., most cheeses) and drug interactions (pressor

244

T. Spencer et al.

amines, most cold medicines, amphetamines). A serotonergic syndrome may occur when MAOIs are combined with predominantly serotonergic drugs (e.g., serotonin-specific reuptake inhibitors [SSRIs]). Additional adverse effects include orthostatic hypotension, weight gain, drowsiness, and dizziness. There is no information on long-term adverse effects of MAOIs in children. Extrapolating from the adult literature, these may include hypomania, hallucinations, confusion, and hepatotoxicity (rare). Pediatric dose ranges have not been established. While dietetic restrictions and potential drug–drug interactions complicate the use of MAOIs in this clinical population, they may, nonetheless, be important to consider in treatment-refractory ADHD individuals. The ongoing development of reversible and transdermal preparations may lead to MAOIs with a more favorable safety profile. SSRIs Currently available SSRIs include fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram. Emerging evidence suggests that these medications are the most effective for childhood depression and obsessive–compulsive disorder (along with clomipramine) and are promising agents for childhood anxiety. SSRIs have not been systematically evaluated in the treatment of ADHD. Although a small open study (Barrickman et al., 1991) suggested that fluoxetine may be beneficial in the treatment of ADHD children, a consensus of ADHD experts at a National Institute of Mental Health (US) conference did not support the usefulness of these compounds in the treatment of core ADHD symptoms (National Institute of Mental Health Alternative Pharmacology of ADHD conference, 1996). Nevertheless, because of the high rates of comorbidity in ADHD, these compounds are frequently combined with effective antiADHD agents (see below). As a result of their pharmacologic profile, these medications have fewer anticholinergic, sedative, cardiovascular (blood pressure and ECG changes), and weight-affecting adverse side effects than the TCAs. Unlike TCAs, SSRIs are structurally dissimilar to each other. Further, these agents vary in their pharmacokinetics and side effect profiles. Antidepressants and many other psychotropics are metabolized in the liver by the cytochrome P450 system (Nemeroff et al., 1996). The coadministration of TCAs (and similar compounds) and SSRIs may result in increased levels of the TCAs, and thus great caution should be exercised when using TCAs and the SSRIs. However, the SSRIs vary in their propensity to inhibit the P450 system.

245


Venlafaxine Venlafaxine (Effexor) is chemically unrelated to other antidepressants. It has both SSRI and TCA properties (noradrenergic and serotonergic). Venlafaxine is an established antidepressant in adults and controlled studies are underway in the treatment of juvenile mood disorders. There are four open studies of venlafaxine in ADHD adults (n = 61) reporting an overall response of 77% in completers with a 21% rate of dropout due to side effects (Adler et al., 1995; Findling et al., 1996; Hornig, 1998; Reimherr et al., 1995). In addition, an open study of 16 ADHD children reported a 50% response rate in completers with a 25% rate of drop out due to side effects, most prominently increased hyperactivity (Luh et al., 1996). Venlafaxine has a medium half-life of approximately 5 hours (O-desmethylvenlafaxine is approximately 11 hours) with an increased clearance in children and adolescents (Devinan, 1995). The usual dose range is 2.0–5.0 mg/kg daily given in three divided doses or twice a day in an extended release preparation. Tolerance is improved by slow upward titration. Venlafaxine lacks significant activity at muscarinic/cholinergic, alpha-adrenergic, and histaminergic sites and thus has less side effects (sedation, anticholinergic) than other antidepressants. However, when using venlafaxine, unlike the SSRIs, there is a need to monitor for potential cardiac effects such as diastolic hypertension. Antipsychotics

In an early literature, a number of controlled studies evaluated the efficacy and safety of typical antipsychotics for ADHD. Much of this literature is dated and confounded by diagnostic uncertainty. A mixed to moderate efficacy was reported, primarily to behavioral symptoms. While there was no evidence of antipsychotic-associated impaired cognitive performance in these studies, there was no evidence of the cognitive enhancement obtained with the stimulants. Their spectrum of both short- (extrapyramidal reactions) and long-term (tardive dyskinesia) adverse effects greatly limits their usefulness in the treatment of ADHD. Other drugs

Alpha, noradrenergic agonists Clonidine is an alpha-2, noradrenergic agonist. There have been four pediatric studies – two controlled (Gunning, 1992; Hunt et al., 1985), one open (Hunt, 1987), and one retrospective review (Steingard et al., 1993) – reporting beneficial effects of clonidine in the treatment of ADHD in children and adolescents (n = 122) with ADHD with daily doses of up to 4–5 g/kg (average 0.2

246

T. Spencer et al.

mg/day). All studies reported positive behavioral response, with 50–70% of subjects having at least a moderate response. There appears to be less of an effect on cognition. There has been recent concern about the cardiovascular safety of clonidine, based on four cases of death which have occurred in children who had received clonidine plus other medications including methylphenidate. Three cases were captured by the US Food and Drugs Administration (FDA) (Fenichel, 1995) and one through other sources (Cantwell et al., 1997). In the review of these cases, converging evidence from independent investigation (Popper, 1995), the FDA (Fenichel, 1995), and the Heart, Lung, and Blood Section of the National Institute of Health (Gutgesell, 1999) indicated that many mitigating and extenuating circumstances were operative, making causality in these cases uninterpretable (Wilens and Spencer, 1999). For example, one case appeared to be an overdose of fluoxetine and promethazine. Moreover, in studies monitoring adverse effects of clonidine, no clinically meaningful ECG changes have been identified. Due to its propensity for less sedation and longer duration of action than clonidine, there has been an increased interest in guanfacine. There have been two open studies (n = 28) of the more selective alpha-2a agonist, guanfacine, in children and adolescents with ADHD. Beneficial effects on hyperactive behaviors and attentional abilities have been reported (Horrigan and Barnhill, 1995; Hunt et al., 1995). Beta, noradrenergic antagonists Propranolol is a nonselective beta-adrenergic antagonist – it blocks both beta-1 and beta-2 receptors. It is unclear whether the benefits obtained from propranolol are primarily due to peripheral or central effects of the drug. A small open study of propranolol for ADHD adults with temper outbursts found some improvement at daily doses of up to 640 mg/day (Mattes, 1986). Another report indicated that beta blockers may be helpful in combination with the stimulants (Ratey et al., 1991). Pindolol is a centrally acting beta-adrenergic antagonist. A controlled comparison study of pindolol with methylphenidate in 52 children has been reported (Buitelaar et al., 1996). Similar to clonidine, pindolol appears to be effective with symptoms of behavioral dyscontrol and hyperactivity, with less apparent cognitive benefit. However, prominent adverse effects such as nightmares and paraesthesias led to discontinuation of the drug in all test subjects. In contrast to pindolol, nadolol is a peripherally acting beta-adrenergic antagonist. An open study of nadolol in aggressive children with CNS deficits and ADHD symptoms reported effective diminution of

247


aggression with little apparent effect on ADHD symptoms (Connor et al., 1997). Nadolol was well tolerated with few side effects. Other compounds Buspirone is a nonbenzodiazepine anxiolytic that has recently been tested as an antiADHD treatment for children. Buspirone has a high affinity to 5-HT-1A receptors, both pre- and postsynaptic, as well as a modest effect on the dopaminergic system and alpha-adrenergic activity. Buspirone’s major metabolite, 1,2-pyrimidinyl piperazine, has a high affinity for alpha-2 receptors and is present in higher concentrations in the CNS than the parent compound. A recent open study reported findings of 6 weeks of monobuspirone treatment (0.5 mg/kg/day) of 12 ADHD children (Malhotra and Santosh, 1998). ADHD symptoms as well as disruptive behavior and psychosocial function (Clinical Global Assessment Scale) significantly improved on medicine and re-emerged after medicine withdrawal in all subjects. Buspirone was associated with mild side effects (dizziness) only during the first week. These preliminary findings provide support for ongoing controlled trials of buspirone. There is little in the English literature, but a larger world literature, on the use of carbemazepine, a traditional anticonvulsant, for the treatment of ADHD. A recent meta-analysis provided preliminary evidence that carbemazepine may be promising as an alternative treatment (Silva et al., 1996). The overall response rate in open (n = 7) and controlled (n = 3) studies was robust (70%) in contrast to a relatively low placebo rate (26%). However, due to diagnostic complexities and the lack of standardized rating scales, firm conclusions await further systematic studies. For instance, since carbemazepine is a well-established mood stabilizer, it remains unclear whether the behavioral benefits reported are due to treatment of mood or ADHD in these studies. The most common side effects reported were sedation and rashes. In addition, carbemazepine is associated with rare but more serious effects such as hematologic changes and liver abnormalities. In addition, carbamazepine is associated with a number of potential drug–drug interactions by several mechanisms including induction of the P4502D6 system, decreasing the serum concentration of other drugs, and susceptibility to increased carbamazepine levels when given with 3A4 inhibitors. Impact of psychiatric comorbidity in the pharmacotherapy of ADHD Since ADHD is a risk factor for several comorbidities, their existence frequently complicates considerations of pharmacotherapy. ADHD is often accompanied

248

T. Spencer et al.

by aggressive behavior and CD. A number of controlled studies reported improvement in ADHD and aggressive symptoms in ADHD subjects treated with stimulants (Amery et al., 1984; Barkley et al., 1989; Cunningham et al., 1991; Gadow et al., 1990; Hinshaw et al., 1989, 1992; Kaplan et al., 1990; Klorman et al., 1988, 1989, 1994; Livingston et al., 1992; Murphy et al., 1992; Pelham et al., 1990; Pliszka, 1989; Taylor et al., 1987; Whalen et al., 1987; Winsberg et al., 1972, 1974). Other comorbidities may not be as responsive to stimulants. For example, stimulants can induce anxiety (Barkley, 1977; Swanson et al., 1978) or depression (Barkley, 1977, 1990; Gittelman and Koplewicz, 1986; Wilens and Biederman, 1992) in some patients. In addition, the presence of comorbid mood and anxiety disorders appears to worsen significantly the response of ADHD symptoms to stimulant treatment. In 75% (six of eight) of studies in ADHD individuals with comorbid anxiety or depression (n = 260 children), investigators reported a lesser response to stimulants of ADHD symptoms (Du Paul et al., 1994; Gittelman and Koplewicz, 1986; Tannock et al., 1995; Pliszka, 1989; Taylor et al., 1987; Voelker et al., 1983). In contrast, in a controlled trial of desipramine, neither comorbidity with conduct disorder, depression, nor anxiety yielded differential responses to desipramine treatment (Biederman et al., 1993b). Moreover, desipramine-treated ADHD patients showed a substantial reduction in depressive symptoms compared with placebo-treated patients (Biederman et al., 1989). These results provide support for the suggestion that a TCA may be superior to a stimulant in cases of ADHD when depression or anxiety are prominent comorbidities. Alternatively, the safety and efficacy of combined SSRI and stimulant pharmacotherapy have been addressed in two open studies (see below). Despite increasing recognition of the co-occurrence of ADHD and bipolarity (West et al., 1995; Wozniak et al., 1995), little is known about the pharmacotherapy of the combined condition. In order to evaluate pharmacologic approaches for ADHD children who have manic symptoms, the author and colleagues conducted an extensive chart review of 38 children and adolescents over multiple visits to assess improvement and prescription patterns (Biederman et al., 1999). The mean duration of manic symptoms prior to treatment at the author’s center was 3.2 years and the mean age at onset of mania was 5.4 years. As previously reported (Biederman et al., 1995a), manic symptoms improved in 34% of the 38 subjects analyzed after treatment with mood stabilizers. The mean follow-up was 617 days. These subjects contributed a total of 330 visits (255 before initial reduction of manic symptoms and 75 following initial improvement in manic symptoms). Despite a variety of

249


treatments, ADHD symptoms did not improve unless manic symptoms improved. Stimulants were minimally effective in treating ADHD even following mood stabilization. Although TCAs significantly increased the probability of ADHD improvement following mood stabilization, there was also a significant association between treatment with TCAs and relapse of manic symptoms. These results support the hypothesis that mood stabilization is a prerequisite for the successful pharmacologic treatment of ADHD in children with both ADHD and manic-like symptoms. Although TCAs can be helpful in the management of ADHD children with manic-like symptoms, these drugs should be used with caution since they can also have a destabilizing effect on manic symptoms (Wozniak and Biederman, 1996). As detailed above, stimulants are poor treatments for mood disorders and most antidepressants that treat ADHD are not effective for childhood depression. Similarly, treatments for mania do not treat ADHD and vice versa. The question may arise: if an ADHD individual has a mood disorder, why treat the ADHD? After all, ADHD is considered a more benign condition. Additional treatment for ADHD may be needed to address academic, occupational, cognitive, or social dysfunction specific to ADHD symptoms. For example, persistent ADHD may interfere with the psychosocial and educational treatments targeted to the mood disorders themselves, as well as understanding the importance of treatment compliance. Combined pharmacotherapy Although in clinical practice ADHD patients commonly receive more than one psychotropic, little is known about combined pharmacotherapy in ADHD. In contrast to polypharmacy, rational combined pharmacologic approaches can be used for the treatment of comorbid ADHD, as augmentation strategies for patients with insufficient response to a single agent, and for the management of treatment-emergent adverse effects. Examples of the rational use of combined treatment include the use of an antidepressant plus a stimulant for ADHD and comorbid depression, the use of clonidine to ameliorate stimulant-induced insomnia, and the use of a mood stabilizer plus an antiADHD agent to treat ADHD comorbid with bipolar disorder (Wilens et al., 1994). The safety and efficacy of combined TCA pharmacotherapy has been systematically evaluated in two studies. Rapport et al. (1993) evaluated the separate and combined effects of methylphenidate and desipramine in 16 hospitalized children. These investigators found that methylphenidate alone improved vigilance, both methylphenidate and desipramine alone produced

250

T. Spencer et al.

positive effects on short-term memory and visual problem solving, and their combination produced positive effects on learning of higher order relationships. The authors speculated that performance on different cognitive measures may be modulated by separate neurotransmitter systems and that the combination produced a useful synergism. Of note, the subjects in this study were children with ADHD and comorbid major depression (11 of 16), dysthymia (four of 16), and anxiety (six of 16). These investigators (Pataki et al., 1993) also reported that, although this combined pharmacotherapy was associated with more side effects than monotherapy, there was no evidence that the combined use of both drugs was associated with unique or serious side effects. Cohen et al. (1999) examined the effect of stimulants on the pharmacokinetics of desipramine in a large (n = 142) sample of children from the author’s Pediatric Psychopharmacology Clinic. In examining 403 serum concentrations, they found that pharmacokinetic parameters were similar for both the desipramine and desipramine + stimulant groups including the mean weight-corrected dose (mg/kg), weight- and dose-normalized desipramine serum concentrations ([mcg/l]/mg/kg), and desipramine clearance ([l/kg]/ hr). The comparison between groups remained nonsignificant when stratified by age, gender, and type of stimulant. The authors concluded that there was an absence of a clinically significant pharmacokinetic interaction between desipramine and stimulants in children. The safety and efficacy of combined SSRI and stimulant pharmacotherapy has been addressed in two open studies. Gammon and Brown (1993) reported on the successful addition of fluoxetine to stimulants in the management of 32 patients with ADHD with comorbid depressive and anxiety disorders. These comorbid children had failed to respond to methylphenidate alone. After the addition of fluoxetine, improvement was noted in both ADHD and depressive symptoms. The combined treatment was well tolerated. Another report detailed the addition of methylphenidate to SSRI treatment (Findling, 1996). Twelve depressed children and adults with comorbid ADHD were treated with either fluoxetine or sertraline. While depressive symptoms remitted, ADHD symptoms persisted. Methylphenidate was added and successfully treated the ADHD symptoms. The combined treatment was well tolerated. With the exception of hypertension in one adult on methylphenidate monotherapy, there were no significant changes in cardiovascular parameters, increased side effects, or emergent aggressiveness or mania.

251


Future directions Noradrenergic-specific compounds

The experimental compound tomoxetine is highly noradrenergic with little effect on other transmitter systems, including no effects on cardiac conduction or repolarization. In a controlled trial in adults with ADHD, tomoxetine treatment was effective and well tolerated. Significant tomoxetine-associated improvement was noted on neuropsychologic measures of inhibitory capacity from the Stroop. These initial encouraging results, coupled with extensive safety data in adults, fueled efforts at developing this compound in the treatment of pediatric ADHD. One initial open study has documented strong clinical benefits with excellent tolerability in children with ADHD, including a safe cardiovascular profile (Spencer et al., in press). These results support the tolerability, safety, and efficacy of tomoxetine in children with ADHD and encourage further exploration of tomoxetine’s antiADHD properties in controlled investigations. Cholinergic drugs

In recent years, evidence has emerged that nicotinic dysregulation may contribute to the pathophysiology of ADHD. This is not surprising considering that nicotinic activation enhances dopaminergic neurotransmission (Dalack et al., 1998; Mereu et al., 1987; Westfall et al., 1983). Independent lines of investigation have documented that ADHD is associated with an increased risk and earlier age of onset of cigarette smoking (Milberger et al., 1997a; Pomerleau et al., 1996), that maternal smoking during pregnancy increases the risk for ADHD in the offspring, and that in utero exposure to nicotine in animals confers a heightened risk for an ADHD-like syndrome in the newborn (Fung, 1988; Fung and Lau, 1989; Johns et al., 1982; Milberger et al., 1996). In nonADHD subjects, central nicotinic activation has been shown to improve temporal memory (Meck and Church, 1987), attention ( Jones et al., 1992; Peeke and Peeke, 1984; Wesnes and Warburton, 1984), cognitive vigilance ( Jones et al., 1992; Parrott and Winder, 1989; Wesnes and Warburton, 1984), and executive function (Wesnes and Warburton, 1984). Support for a ‘‘nicotinic hypothesis’’ of ADHD can be derived from a recent study that evaluated the therapeutic effects of nicotine in the treatment of adults with ADHD (Levin et al., 1996). Although this controlled clinical trial in adults with ADHD documented that commercially available transdermal nicotine resulted in significant improvement of ADHD symptoms, working memory, and neuropsychologic functioning (Levin et al., 1996), the trial was very

252

T. Spencer et al.

short (2 days) and included only a handful of patients. More promising results supporting the usefulness of nicotinic drugs in ADHD derive from a recent controlled clinical trial of ABT-418 in adults with ADHD. ABT-418 is a CNS cholinergic nicotinic-activating agent with structural similarities to nicotine. Phase one studies of this compound in humans indicated its low abuse liability, as well as adequate safety and tolerability in elderly adults (Abbott laboratories, personal communication). This was a double-blind, placebo-controlled, randomized, crossover trial, comparing a transdermal patch of ABT-418 (75 mg daily) with placebo in adults with DSM-IV ADHD. A significantly higher proportion of ADHD adults was considered to have very much improved while receiving ABT-418 compared with placebo (40% vs. 13%; 2 = 5.3, p = 0.021). Although preliminary, these results suggest that nicotinic analogs may have activity in ADHD. Conclusions A large literature has documented the effectiveness of medication in the treatment of ADHD over the last six decades. Parallel to the evolution of the disorder from hyperactive to inattentive symptoms, the symptom targets for ADHD treatment have evolved from motoric to cognition, social skills, and family function, in after school as well as academic settings. While stimulants have been the most common, traditional treatments, there is a considerable literature indicating an important role for other psychopharmacologic agents including several antidepressants and alpha-adrenergic agents. Effective pharmacologic treatments for ADHD seem to share noradrenergic and dopaminergic mechanisms of action with intriguing evidence on newer cholinergic agents. There is increasing recognition that ADHD is a heterogeneous disorder with considerable and varied comorbidity. If not recognized and attended to, the combination of comorbid symptoms and ADHD may lead to high morbidity and disability with poor long-term prognosis. Current clinical experience suggests that multiple agents may be necessary in the successful treatment of some complex ADHD patients with partial responses or psychiatric comorbidity.

REFE REN C ES Abramowicz M (Ed.) (1990). Sudden death in children treated with a tricyclic antidepressant. Med Lett Drugs Ther 32:37–40.

253


Adler L, Resnick S, Kunz M, Devinsky O (1995). Open-label trial of venlafaxine in adults with attention deficit disorder. Psychopharmacol Bull 31:785–8. Alessi N, Magen J (1988). Comorbidity of other psychiatric disturbances in depressed, psychiatrically hospitalized children. Am J Psychiatry 145:1582–4. Alles GA (1928). The comparative physiological action of phenylethanolamine. J Pharmacol Exp Ther 32:121–8. Alpert J, Maddocks A, Nierenberg A et al. (1996). Attention deficit hyperactivity disorder in childhood among adults with major depression. Psychiatry Res 62:213–19. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Amery B, Minichiello M, Brown G (1984). Aggression in hyperactive boys: response to damphetamine. J Am Acad Child Adolesc Psychiatry 23:291–4. Anderson JC, Williams S, McGee R, Silva PA (1987). DSM-III disorders in preadolescent children: prevalence in a large sample from the general population. Arch Gen Psychiatry 44:69–76. Angold A, Costello EJ (1993). Depressive comorbidity in children and adolescents: Empirical, theoretical and methodological issues. Am J Psychiatry 150:1779–91. Barkley RA (1977). A review of stimulant drug research with hyperactive children. J Child Psychol Psychiat 18:137–65. Barkley RA (1988). The effects of methylphenidate on the interactions of preschool ADHD children with their mothers. J Am Acad Child Adolesc Psychiatry 27:336–41. Barkley RA (1990). Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York: Guilford Press. Barkley RA (1991). The ecological validity of laboratory and analogue assessment methods of ADHD symptoms. J Abnorm Child Psychol 19:149–78. Barkley RA, Cunningham C (1979). The effects of methylphenidate on the mother-child interactions of hyperactive children. Arch Gen Psychiatry 36:201–8. Barkley RA, Karlsson J, Strzelecki E, Murphy JV (1984). Effects of age and ritalin dosage on mother-child interactions of hyperactive children. J Consult Clin Psychol 52:750–8. Barkley RA, McMurray MB, Edelbrock CS, Robbins K (1989). The response of aggressive and nonaggressive ADHD children to two doses of methylphenidate. J Am Acad Child Adolesc Psychiatry 28:873–81. Barrickman L, Noyes R, Kuperman S, Schumacher E, Verda M (1991). Treatment of ADHD with fluoxetine: a preliminary trial. J Am Acad Child Adolesc Psychiatry 30:762–7. Barrickman L, Perry P, Allen A et al. (1995). Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 34:649–57. Bergman A, Winters L, Cornblatt B (1991). Methylphenidate: effects on sustained attention. In Greenhill L, Osman B (Eds.), Ritalin: Theory and Patient Management. New York: Mary Ann Liebert pp. 223–31. Biederman J, Baldessarini R, Goldblatt A, Lapey K, Doyle A, Hesslein P (1993a). A naturalistic study of 24-hour electrocardiographic recordings and echocardiographic findings in children and adolescents treated with desipramine. J Am Acad Child Adolesc Psychiatry 32:805–13. Biederman J, Baldessarini RJ, Wright V, Keenan K, Faraone S (1993b). A double-blind placebo

254

T. Spencer et al.

controlled study of desipramine in the treatment of attention deficit disorder. III. Lack of impact of comorbidity and family history factors on clinical response. J Am Acad Child Adolesc Psychiatry 32:199–204. Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz J (1989). A double-blind placebo controlled study of desipramine in the treatment of attention deficit disorder. I. Efficacy. J Am Acad Child Adolesc Psychiatry 28:777–84. Biederman J, Faraone SV, Keenan K et al. (1992). Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder (ADHD): patterns of comorbidity in probands and relatives in psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 49:728–38. Biederman J, Faraone S, Mick E, Lelon E (1995a). Psychiatric comorbidity among referred juveniles with major depression: fact or artifact? J Am Acad Child Adolesc Psychiatry 34:579–90. Biederman J, Faraone SV, Mick E et al. (1995b). High risk for attention deficit hyperactivity disorder among children of parents with childhood onset of the disorder: a pilot study. Am J Psychiatry 152:431–5. Biederman J, Faraone SV, Spencer T et al. (1993c). Patterns of psychiatric comorbidity, cognition and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry 150:1792–8. Biederman J, Gastfriend DR, Jellinek MS (1986). Desipramine in the treatment of children with attention deficit disorder. J Clin Psychopharmacol 6:359–63. Biederman J, Mick E, Prince J et al. (1999). Systematic chart review of the pharmacologic treatment of comorbid attention deficit hyperactivity disorder in youth with bipolar disorder. J Child Adolesc Psychopharmacol 9:247–56. Biederman J, Milberger S, Faraone S et al. (1994). Family environmental risk factors for attention deficit hyperactivity disorder: a test of Rutter’s indicators of adversity. Arch Gen Psychiatry 52:464–70. Biederman J, Newcorn J, Sprich S (1991). Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148:564–77. Biederman J, Thisted R, Greenhill L, Ryan N (1995c). Estimation of the association between desipramine and the risk for sudden death in 5- to14-year-old children. J Clin Psychiatry 56:87–93. Biederman J, Wilens T, Mick E, Milberger S, Spencer T, Faraone S (1995d). Psychoactive substance use disorder in adults with attention deficit hyperactivity disorder: effects of ADHD and psychiatric comorbidity. Am J Psychiatry 152:1652–8. Bird HR, Canino G, Rubio-Stipec M et al. (1988). Estimates of the prevalence of childhood maladjustment in a community survey in Puerto Rico. Arch Gen Psychiatry 45:1120–6. Brown TE, Gammon GD (1992). ADHD-associated difficulties falling asleep and awakening: clonidine and methylphenidate treatments. Scientific Proceedings of the Annual Meeting: American Academy of Child and Adolescent Psychiatry, Washington, DC. Brown RT, Sexson SB (1988). A controlled trial of methylphenidate in black adolescents. Clin Pediatr 27:74–81. Brown RT, Wynne ME, Slimmer LW (1984). Attention deficit disorder and the effect of methylphenidate on attention, behavioral, and cardiovascular functioning. J Clin Psychiatry

255


45:473–6. Buitelaar J, van de Gaag R, Swaab-Barneveld H, Kuiper M (1996). Pindolol and methylphenidate in children with attention deficit hyperactivity disorder. J Child Adolesc Psychiatry 36:587–95. Cantwell DP (1985). Hyperactive children have grown up: what have we learned about what happens to them? Arch Gen Psychiatry 42:1026–8. Cantwell D, Swanson J, Connor D (1997). Case study: adverse response to clonidine. J Am Acad Child Adolesc Psychiatry 36:539–44. Casat CD, Pleasants DZ, Schroeder DH, Parler DW (1989). Bupropion in children with attention deficit disorder. Psychopharmacology 25:198–201. Casat CD, Pleasants DZ, Van Wyck Fleet J (1987). A double-blind trial of bupropion in children with attention deficit disorder. Psychopharmacology 23:120–2. Castellanos F, Giedd J, Elia J et al. (1997). Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry 36:589–96. Castellanos F, Giedd J, Marsh W et al. (1996). Quantitative brain magnetic resonance imaging in attention deficit hyperactivity disorder. Arch Gen Psychiatry 53:607–16. Cohen L, Prince J, Biederman J (1999). Absence of effect of stimulants on the pharmacokinetics of desipramine in children. Pharmacotherapy 19:746–52. Comings DE, Comings BG (1988). Tourette’s syndrome and attention deficit disorder. In Cohen DJ, Bruun RD, Leckman JF (Eds.), Tourette’s Syndrome and Tic Disorders: Clinical Understanding and Treatment. New York: John Wiley and Sons, pp. 119–36. Conners C, Casat C, Gualtieri C et al. (1996). Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 35:1314–21. Conners CK (1975). Controlled trial of methylphenidate in preschool children with minimal brain dysfunction. Int J Ment Health 4:61–74. Conners CK, Taylor E (1980). Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction. Arch Gen Psychiatry 37:922–30. Connor D, Ozbayrak K, Benjamin S, Ma Y, Fletcher K (1997). A pilot study of nadolol for overt aggression in developmentally delayed individuals. J Am Acad Child Adolesc Psychiatry 36:826– 34. Coons HW, Klorman R, Borgstedt AD (1987). Effects of methylphenidate on adolescents with a childhood history of ADHD II. Information processing. J Am Acad Child Adolesc Psychiatry 26:368–74. Cunningham C, Siegel L, Offord D (1991). A dose-response analysis of the effects of methylphenidate on the peer interactions and simulated classroom performance of ADD children with and without conduct problems. J Child Psychol Psychiatry 32:439–52. Dalack G, Healy D, Meador-Woodruff J (1998). Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. Am J Psychiatry 155:1490–501. Devinan A (1995). Venlafaxine metabolism in children and adolescents. Scientific Proceedings of the Annual Meeting: American Academy of Child and Adolescent Psychiatry, New Orleans XI. Douglas V, Barr R, Amin K, O’Neill M, Britton B (1988). Dosage effects and individual responsivity to methylphenidate in attention deficit disorder. J Child Psychol Psychiatry 29:453–75.

256

T. Spencer et al.

Douglas V, Barr R, Desilets J, Sherman E (1995). Do high doses of stimulants impair flexible thinking in attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 34:877– 85. DuPaul G, Barkley R, McMurray M (1994). Response of children with ADHD to methylphenidate: interaction with internalizing symptoms. J Am Acad Child Adolesc Psychiatry 33:894–903. Ernst M (1996). MAOI treatment of adult ADHD. NIMH Conference on Alternative Pharmacology of ADHD, Washington, DC. Evans SW, Pelham WE (1991). Psychostimulant effects on academic and behavioral measures for ADHD junior high school students in a lecture format classroom. J Abnorm Child Psychol 19:537–52. Famularo R, Fenton T (1987). The effect of methylphenidate on school grades in children with attention deficit disorder without hyperactivity: a preliminary report. J Clin Psychiatry 48:112– 14. Faraone SV, Biederman J, Krifcher-Lehman B et al. (1993). Intellectual performance and school failure in children with attention deficit hyperactivity disorder and in their siblings. J Abnorm Psychol 102:616–23. Faraone SV, Biederman J, Weiffenbach B et al. (1999). Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am J Psychiatry 156:768–70. Feigin A, Kurlan R, McDermott M et al. (1996). A controlled trial of deprenyl in children with Tourette’s syndrome and attention deficit hyperactivity disorder. Neurology 46:965–8. Fenichel RF (1995). Combining methylphenidate and clonidine: The role of post-marketing surveillance. J Child Adolesc Psychopharmacol 5:155–6. Findling R (1996). Open-label treatment of comorbid depression and attentional disorder with co-administration of SRIs and psychostimulants in children, adolescents, and adults: a case series. J Child Adolesc Psychopharmacol 6:165–75. Findling R, Schwartz M, Flannery D, Manos M (1996). Venlafaxine in adults with ADHD: an open trial. J Clin Psychiatry 57:184–9. Fung YK (1988). Postnatal behavioural effects of maternal nicotine exposure in rats. J Pharm Pharmacol 40:870–2. Fung YK, Lau YS (1989). Effects of prenatal nicotine exposure on rat striatal dopaminergic and nicotinic systems. Pharmacol Biochem Behav 33:1–6. Gadow K, Nolan E, Sverd J (1992). Methylphenidate in hyperactive boys wtih comorbid tic disorder: II. Short-term behavioral effects in school settings. J Am Acad Child Adolesc Psychiatry 31:462–71. Gadow KD, Nolan EE, Sverd J, Sprafkin J, Paolicelli L (1990). Methylphenidate in aggressivehyperactive boys. I. Effects on peer aggression in public school settings. J Am Acad Child Adolesc Psychiatry 29:710–18. Gadow K, Sverd J, Sprafkin J, Nolan E, Ezor S (1995). Efficacy of methylphenidate for ADHD in children with tic disorder. Arch Gen Psychiatry 52:444–55. Gammon GD, Brown TE (1993). Fluoxetine and methylphenidate in combination for treatment of attention deficit disorder and comorbid depressive disorder. J Child Adolesc Psychopharmacol 3:1–10.

257


Garfinkel BD, Wender PH, Sloman L, O’Neill I (1983). Tricyclic antidepressant and methylphenidate treatment of attention deficit disorder in children. J Am Acad Child Adolesc Psychiatry 22:343–8. Gastfriend DR, Biederman J, Jellinek MS (1985). Desipramine in the treatment of attention deficit disorder in adolescents. Psychopharmacology 21:144–5. Geller B, Sun K, Zimmerman B, Luby J, Frazier J, Williams M (1995). Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disorders 34:259–68. Gittelman RA, Koplewicz HS (1986). Pharmacotherapy of childhood anxiety disorders. In Gittelman RA (Eds.), Anxiety Disorders of Childhood. New York: Guilford Press, pp. 188–203. Gittelman R, Landa B, Mattes J, Klein D (1988). Methylphenidate and growth in hyperactive children: a controlled withdrawal study. Arch Gen Psychiatry 45:1127–30. Gittelman R, Mannuzza S, Shenker R, Bonagura N (1985). Hyperactive boys almost grown up. I. Psychiatric status. Arch Gen Psychiatry 42:937–47. Gittelman-Klein R (1974). Pilot clinical trial of imipramine in hyperkinetic children. In Conners C (Ed.), Clinical Use of Stimulant Drugs in Children. The Hague, Netherlands: Excerpta Medica, pp. 192–201. Goldman L, Genel M, Bezman R, Slanetz P (1998). Diagnosis and treatment of attention-deficit/ hyperactivity disorder in children and adolescents. JAMA 279:1100–7. Greenberg L, Yellin A, Spring C, Metcalf M (1975). Clinical effects of imipramine and methylphenidate in hyperactive children. Int J Ment Health 4:144–56. Greene R, Biederman J, Faraone S, Ouellette C, Penn C, Griffin S (1996). Toward a new psychometric definition of social disability in children with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 35:571–8. Gross M (1973). Imipramine in the treatment of minimal brain dysfunction in children. Psychosomatics 14:283–5. Gualtieri CT, Evans RW (1988). Motor performance in hyperactive children treated with imipramine. Percept Mot Skills 66:763–9. Gualtieri CT, Ondrusek MG, Finley C (1985). Attention deficit disorders in adults. Clin Neuropharmacol 8:343–56. Gunning B (1992). A controlled trial of clonidine in hyperkinetic children. PhD Thesis: Department of Child and Adolescent Psychiatry, Academic Hospital Rotterdam – Sophia Children’s Hospital Rotterdam, The Netherlands. Gutgesell M, Atkins D, Barst R et al. (1999). Cardiovascular monitoring of children and adolescents receiving psychotropic drugs. Circulation 99:978–82. Hechtman L (1985). Adolescent outcome of hyperactive children treated with stimulants in childhood: a review. Psychopharmacology 21:178–91. Hinshaw S, Buhrmester D, Heller T (1989). Anger control in response to verbal provocation: effects of stimulant medication for boys with ADHD. J Abnorm Child Psychol 17:393–407. Hinshaw S, Heller T, McHale J (1992). Covert antisocial behavior in boys with attention-deficit hyperactivity disorder: external validation and effects of methylphenidate. J Consult Clin Psychol 60:274–81. Hoffman BB, Lefkowitz RJ (1990). Catecholamines and sympathomimetic drugs. In Gilman AG,

258

T. Spencer et al.

Rall TW, Nies AS, Taylor P (Eds.), The Pharmacological Basis of Therapeutics. New York: Pergamon Press, pp. 187–220. Hornig M (1998). Addressing comorbidity in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry 59(Suppl 7):69–75. Horrigan JP, Barnhill LJ (1995). Guanfacine for treatment of attention-deficit hyperactivity disorder in boys. J Child Adolesc Psychopharmacol 5:215–23. Hubbard JW, Srinivas NR, Quinn D, Midha KK (1989). Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit disorder. J Pharm Sci 78:944–7. Huessy H, Wright A (1970). The use of imipramine in children’s behavior disorders. Acta Paedopsychiatrie 37:194–9. Hunt RD (1987). Treatment effects of oral and transdermal clonidine in relation to methylphenidate: an open pilot study in ADD-H. Psychopharmacology 23:111–14. Hunt R, Arnsten A, Asbell M (1995). An open trial of guanfacine in the treatment of attentiondeficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 34:50–4. Hunt RD, Minderaa RB, Cohen DJ (1985). Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial. J Am Acad Child Psychiatry 24:617–29. Jankovic J (1993). Deprenyl in attention deficit associated with Tourette’s syndrome. Arch Neurol 50:286–8. Jensen P, Shervette R III, Xenakis S, Richter J (1993). Anxiety and depressive disorders in attention deficit disorder with hyperactivity: new findings. Am J Psychiatry 150:1203–9. Johns JM, Louis TM, Becker RF, Means LW (1982). Behavioral effects of prenatal exposure to nicotine in guinea pigs. Neurobehav Toxicol Teratol 4:365–9. Jones G, Sahakian B, Levy R, Warburton D, Gray J (1992). Effects of acute subcutaneous nicotine on attention, information and short-term memory in Alzheimer’s disease. Psychopharmacology 108:485–94. Kaplan SL, Busner J, Kupietz S, Wasserman E, Segal B (1990). Effects of methylphenidate on adolescents with aggressive conduct disorder and ADHD: a preliminary report. J Am Acad Child Adolesc Psychiatry 29:719–23. Klein RG (1987). Pharmacotherapy of childhood hyperactivity: an update. In Meltzer HY (Eds.), Psychopharmacology: The Third Generation of Progress. New York: Raven Press, pp. 1215–24. Klorman R, Brumaghim J, Fitzpatrick P, Borgstedt A, Strauss J (1994). Clinical and cognitive effects of methylphenidate on children with attention deficit disorder as a function of aggression/oppositionality and age. J Abnorm Psychol 103:206–21. Klorman R, Brumaghim JT, Salzman LF et al. (1988). Effects of methylphenidate on attentiondeficit hyperactivity disorder with and without aggressive/noncompliant features. J Abnorm Psychol 97:413–22. Klorman R, Brumaghim JT, Salzman LF et al. (1989). Comparative effects of methylphenidate on attention-deficit hyperactivity disorder with and without aggressive/noncompliant features. Psychopharmacology 25:109–13. Klorman R, Coons HW, Borgstedt AD (1987). Effects of methylphenidate on adolescents with a

259


childhood history of attention deficit disorder. I. Clinical findings [published erratum appears in J Am Acad Child Adolesc Psychiatry 1987 26:820]. J Am Acad Child Adolesc Psychiatry 26:363–7. Kupietz SS, Balka EB (1976). Alterations in the vigilance performance of children receiving amitriptyline and methylphenidate pharmacotherapy. Psychopharmacology 50:29–33. Kupietz SS, Winsberg BG, Richardson E, Maitinsky S, Mendell N (1988). Effects of methylphenidate dosage in hyperactive reading-disabled children. I. Behavior and cognitive performance effects. J Am Acad Child Adolesc Psychiatry 27:70–7. Lahey BB, Pelham WE, Schaughency EA et al. (1988). Dimensions and types of attention deficit disorder. J Am Acad Child Adolesc Psychiatry 27:330–5. Lahey BB, Schaughency EA, Hynd GW, Carlson CL, Nieves N (1987). Attention deficit disorder with and without hyperactivity: comparison of behavioral characteristics of clinic-referred children. J Am Acad Child Adolesc Psychiatry 26:718–23. Last CG, Strauss CC, Francis G (1987). Comorbidity among childhood anxiety disorders. J Nerv Ment Dis 175:726–30. Lerer RJ, Lerer MP (1977). Responses of adolescents with minimal brain dysfunction to methylphenidate. J Learning Disab 10:223–8. Levin E, Conners C, Sparrow E et al. (1996). Nicotine effects on adults with attention-deficit/ hyperactivity disorder. Psychopharmacology 123:55–63. Livingston R, Dykman R, Ackerman P (1992). Psychiatric comorbidity and response to two doses of methylphenidate in children with attention deficit disorder. J Child Adolesc Psychopharmacol 2:115–22. Loney J, Kramer J, Milich RS (1981a). The hyperactive child grows up: Predictors of symptoms, delinquency and achievement at follow-up. In Gadow KD, Loney J (Eds.), Psychosocial Aspects of Drug Treatment for Hyperactivity. Boulder, CO: Westview Press, pp. 381–416. Loney J, Whaley KMA, Ponto LB, Adney K (1981b). Predictors of adolescent height and weight in hyperkinetic boys treated with methylphenidate [proceedings]. Psychopharm Bull 17:132–4. Lowe TL, Cohen DJ, Detlor J (1982). Stimulant medications precipitate Tourette’s syndrome. JAMA 247:1168–9. Luh J, Pliszka S, Olvers R, Tatum R (1996). An open trial of venlafaxine in the treatment of attention deficit hyperactivity disorder: a pilot study. San Antonio: The University of Texas Health Science Center. MacKay MC, Beck L, Taylor R (1973). Methylphenidate for adolescents with minimal brain dysfunction. N Y State J Med 73:550–4. Malhotra S, Santosh PJ (1998). An open clinical trial of buspirone in children with attention deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 37:364–71. Mattes JA (1986). Propranolol for adults with temper outbursts and residual attention deficit disorder. J Clin Psychopharmacol 6:299–302. Mattes JA, Boswell L, Oliver H (1984). Methylphenidate effects on symptoms of attention deficit disorder in adults. Arch Gen Psychiatry 41:1059–63. Mayes S, Crites D, Bixler E, Humphrey F, Mattison R (1994). Methylphenidate and ADHD: influence of age, IQ and neurodevelopmental status. Dev Med Child Neurol 36:1099–107. McGee R, Williams S, Silva PA (1984). Behavioral and developmental characteristics of aggres-

260

T. Spencer et al.

sive, hyperactive and aggressive-hyperactive boys. J Am Acad Child Psychiatry 23:270–9. McGee R, Williams S, Silva PH (1985). Factor structure and correlates of ratings of inattention, hyperactivity, and antisocial behavior in a large sample of 9-year old children from the general population. J Consult Clin Psychol 53:480–90. Meck W, Church R (1987). Cholinergic modulation of the content of temporal memory. Behav Neurosci 101:457–64. Mereu G, Yoon K, Gessa G, Naes L, Westfall T (1987). Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. Eur J Pharmacol 141:395–9. Milberger S, Biederman J, Faraone SV, Chen L, Jones J (1996). Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry 153:1138–42. Milberger S, Biederman J, Faraone S, Chen L, Jones J (1997a). ADHD is associated with early initiation of cigarette smoking in children and adolescents. J Am Acad Child Adolesc Psychiatry 36:37–43. Milberger S, Biederman J, Faraone S, Guite J, Tsuang M (1997b). Pregnancy, delivery and infancy complications and ADHD: issues of gene-environment interactions. Biol Psychiatry 41:65–75. Milich R, Loney J (1979). The role of hyperactive and aggressive symptomatology in predicting adolescent outcome among hyperactive children. J Pediatr Psychol 4:93–112. Murphy D, Pelham W, Lang A (1992). Aggression in boys with attention deficit-hyperactivity disorder: methylphenidate effects on naturalistically observed aggression, response to provocation, and social information processing. J Abnorm Child Psychol 20:451–66. Nemeroff C, DeVane L, Pollock B (1996). Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153:311–20. Parrott AC, Winder G (1989). Nicotine chewing gum (2 mg, 4 mg) and cigarette smoking: comparative effects upon vigilance and heart rate. Psychopharmacology 97:257–61. Pataki C, Carlson G, Kelly K, Rapport M, Biancaniello T (1993). Side effects of methylphenidate and desipramine alone and in combination in children. Am J Psychiatry 32:1065–72. Patrick KS, Caldwell RW, Ferris RM, Breese GR (1987). Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 241:152–8. Peeke S, Peeke H (1984). Attention, memory, and cigarette smoking. Psychopharmacology 84:205– 16. Pelham WE, Bender ME, Caddell J, Booth S, Moorer SH (1985). Methylphenidate and children with attention deficit disorder. Arch Gen Psychiatry 42:948–52. Pelham WE, Greenslade K, Vodde-Hamilton M et al. (1990). Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. Pediatrics 86:226–37. Pliszka SR (1989). Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 28:882–7. Pomerleau O, Downey K, Stelson F, Pomerleau C (1996). Cigarette smoking in adult patients diagnosed with ADHD. J Subst Abuse 7:373–8. Popper CW (1995). Combining methylphenidate and clonidine: pharmacologic questions and

261


news reports about sudden death. J Child Adolesc Psychopharmacol 5:157–66. Prince J, Wilens T, Biederman J, Millstein R, Spencer T (2000). A controlled study of nortriptyline in children and adolescents with ADHD. J Child Adolesc Psychopharmacol 10:193–204. Prince J, Wilens T, Biederman J, Spencer T, Wozniak J (1996). Clonidine for ADHD related sleep disturbances: a systematic chart review of 62 cases. J Am Acad Child Adolesc Psychiatry 35:599–605. Quay HC, Routh DK, Shapiro SK (1987). Psychopathology of childhood: from description to validation. Annu Rev Psychol 38:491–532. Quinn PO, Rapoport JL (1975). One-year follow-up of hyperactive boys treated with imipramine or methylphenidate. Am J Psychiatry 132:241–5. Rapoport JL, Quinn P, Bradbard G, Riddle D, Brooks E (1974). Imipramine and methylphenidate treatment of hyperactive boys: a double-blind comparison. Arch Gen Psychiatry 30:789–93. Rapport M, Carlson G, Kelly K, Pataki C (1993). Methylphenidate and desipramine in hospitalized children: I. Separate and combined effects on cognitive function. J Am Acad Child Adolesc Psychiatry 32:333–42. Rapport MD, DuPaul GJ, Kelly KL (1989a). Attention deficit hyperactivity disorder and methylphenidate: the relationship between gross body weight and drug response in children. Psychopharmacology Bull 25:285–90. Rapport MD, Quinn SO, DuPaul GJ, Quinn EP, Kelly KL (1989b). Attention deficit disorder with hyperactivity and methylphenidate: the effects of dose and mastery level on children’s learning performance. J Abnorm Child Psychol 17:669–89. Rapport MD, Stoner G, DuPaul GJ, Birmingham BK, Tucher A (1985). Methylphenidate in hyperactive children: differential effects of dose on academic, learning, and social behavior. J Abnorm Child Psychol 13:227–43. Rapport MD, Stoner G, DuPaul GJ, Kelly KL, Tucker SB, Shroeler T (1988). Attention deficit disorder and methylphenidate: a multilevel analysis of dose-response effects on children’s impulsivity across settings. J Am Acad Child Adolesc Psychiatry 27:60–9. Ratey J, Greenberg M, Lindem K (1991). Combination of treatments for attention deficit disorders in adults. J Nerv Ment Dis 176:699–701. Reimherr F, Hedges D, Strong R, Wender P (1995). An open-trial of venlafaxine in adult patients with attention deficit hyperactivity disorder. Orlando: New Clinical Drug Evaluation Unit Program. Sachs GS, Conklin A, Lafer B, Thibault AB, Rosenbaum JF, Biederman J (1993). Psychopathology in children of late vs. early onset bipolar probands. Proceedings of the Annual Meeting of the American Academy of Child and Adolescent Psychiatry, San Antonio. Safer DJ, Allen RP (1975). Stimulant drug treatment of hyperactive adolescents. Dis Nerv System 454–7. Safer DJ, Krager JM (1988). A survey of medication treatment for hyperactive/inattentive students. JAMA 260:2256–8. Sallee F, Stiller R, Perel J (1992). Pharmacodynamics of pemoline in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 31:244–51. Schachar R, Hoppe C, Schell A (1987). Changes in family function and relationships in children

262

T. Spencer et al.

who respond to methylphenidate. J Am Acad Child Adolesc Psychiatry 26:728–32. Schleifer N, Weiss G, Cohen N, Elman M, Cvejic H, Kruger E (1975). Hyperactivity in pre-schoolers and the effect of methylphenidate. Am J Orthopsychiatry 45:38–50. Semrud-Clikeman MS, Biederman J, Sprich S, Krifcher B, Norman D, Faraone S (1992). Comorbidity between ADHD and learning disability: a review and report in a clinically referred sample. J Am Acad Child Adolesc Psychiatry 31:439–48. Shevell M, Schreriber R (1997). Peroline-associated hepatic failure: a critical analysis of the literature. Pediatr Neurol 14–16. Silva R, Munoz D, Alpert M (1996). Carbamazepine use in children and adolescents with features of attention-deficit hyperactivity disorder: a meta-analysis. J Am Acad Child Adolesc Psychiatry 35:352–8. Silver LB, Brunstetter RW (1986). Attention deficit disorder in adolescents. Hosp Comm Psychiatry 37:608–13. Solanto MV, Wender EH (1989). Does methylphenidate constrict cognitive functioning? J Am Acad Child Adolesc Psychiatry 28:897–902. Spencer T, Biederman J, Harding M, O’Donnell D, Faraone S, Wilens T (1996a). Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays? J Am Acad Child Adolesc Psychiatry 35:1460–9. Spencer T, Biederman J, Wilens T (1998). Growth deficits in ADHD children. Pediatrics 102(Suppl):501–6. Spencer T, Biederman J, Wilens T, Harding M, O’Donnell D, Griffen S (1996b). Pharmacotherapy of attention-deficit hyperactivity disorder across the lifecycle. J Am Acad Child Adolesc Psychiatry 35:409–32. Spencer T, Biederman J et al. (in press). An open-label, dose-ranging study of tomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. Spencer T, Wilens TE, Biederman J, Faraone SV, Ablon S, Lapey K (1995). A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention deficit hyperactivity. Arch Gen Psychiatry 52:434–43. Sprague RL, Sleator EK (1977). Methylphenidate in hyperkinetic children: Differences in dose effects on learning and social behavior. Science 198:1274–6. Steingard R, Biederman J, Spencer T, Wilens T, Gonzalez A (1993). Comparison of clonidine response in the treatment of attention deficit hyperactivity disorder with and without comorbid tic disorders. J Am Acad Child Adolesc Psychiatry 32:350–3. Swanson J, Kinsbourne M, Roberts W, Zucker K (1978). Time-response analysis of the effect of stimulant medication on the learning ability of children referred for hyperactivity. Pediatrics 61:21–4. Tannock R, Ickowicz A, Schachar R (1995). Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34:886–96. Tannock R, Schachar RJ, Carr RP, Logan GD (1989). Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children. Pediatrics 84:648–57. Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M (1987). Which boys

263


respond to stimulant medication? A controlled trial of methylphenidate in boys with disruptive behaviour. Psychol Med 17:121–43. Varley CK (1983). Effects of methylphenidate in adolescents with attention deficit disorder. J Am Acad Child Psychiatry 22:351–4. Voelker SL, Lachar D, Gdowski LL (1983). The personality inventory for children and response to methylphenidate: preliminary evidence for predictive validity. J Pediatr Psychol 8:161–9. Watter N, Dreyfuss FE (1973). Modifications of hyperkinetic behavior by nortriptyline. Va Med Monthly 100:123–6. Weintraub S, Mesulam MM, Kramer L (1981). Disturbances in prosody. Acta Neurol 38:742–4. Weiss G, Hechtman LT (1986). Hyperactive Children Grown Up. New York: Guilford Press. Wender PH, Reimherr FW (1990). Bupropion treatment of attention-deficit hyperactivity disorder in adults. Am J Psychiatry 147:1018–20. Wender PH, Reimherr FW, Wood DR (1981). Attention deficit disorder (‘‘minimal brain dysfunction’’) in adults: a replication study of diagnosis and drug treatment. Arch Gen Psychiatry 38:449–56. Wender PH, Reimherr FW, Wood DR, Ward M (1985a). A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults. Am J Psychiatry 142:547– 52. Wender PH, Wood DR, Reimherr FW (1985b). Pharmacological treatment of attention deficit disorder, residual type (ADDRT, ‘‘minimal brain dysfunction’’, ‘‘hyperactivity’’) in adults. Psychopharmacology 21:222–32. Wender PH, Wood DR, Reimherr FW, Ward M (1983). An open trial of pargyline in the treatment of attention deficit disorder, residual type. Psychiatry Res 9:329–36. Werry J (1980). Imipramine and methylphenidate in hyperactive children. J Child Psychol Psychiatry 21:27–35. Wesnes K, Warburton D (1984). The effects of cigarettes of varying yield on rapid information processing performance. Psychopharmacology 82:338–42. West S, McElroy S, Strakowski S, Keck P, McConville B (1995). Attention deficit hyperactivity disorder in adolescent mania. Am J Psychiatry 152:271–4. Westfall T, Grant H, Perry H (1983). Release of dopamine and 5-hydroxytryptamine from rat striatal slices following activation of nicotinic cholinergic receptors. Gen Pharmacol 14:321–5. Whalen C (1989). Does stimulant medication improve the peer status of hyperactive children? J Consult Clin Psychol 57:545–9. Whalen C, Henker B, Granger D (1990). Social judgement processes in hyperactive boys: effects of methylphenidate and comparisons with normal peers. J Abnorm Child Psychol 18:297–316. Whalen C, Henker B, Swanson J, Granger D, Kliewer W, Spencer J (1987). Natural social behaviors in hyperactive children: Dose effects of methylphenidate. J Consult Clin Psychol 55:187–93. Wilens T, Biederman J (1992). The stimulants. In Schaffer D (Eds.) Psychiatr Clin North Am. Philadelphia: Saunders, pp. 191–222. Wilens T, Spencer T (1988). Pharmacology of amphetamines. In Tarter R, Ammerman R, Ott P

264

T. Spencer et al.

(Eds.) Handbook of Substance Abuse: Neurobehavioral Pharmacology. New York: Plenum Press, pp. 501–13. Wilens T, Spencer T (1999). Combining methylphenidate and clonidine: a clinically sound medication option. J Am Acad Child Adolesc Psychiatry 38:614–22. Wilens TE, Biederman J, Geist DE, Steingard R, Spencer T (1993). Nortriptyline in the treatment of attention deficit hyperactivity disorder: a chart review of 58 cases. J Am Acad Child Adolesc Psychiatry 32:343–9. Wilens T, Spencer T, Biederman J, Wozniak J, Connor D (1994). Combined pharmacotherapy: An emerging trend in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry 34:110–12. Winsberg BG, Bialer I, Kupietz S, Tobias J (1972). Effects of imipramine and dextroamphetamine on behavior of neuropsychiatrically impaired children. Am J Psychiatry 128:1425–31. Winsberg BG, Press M, Bialer I, Kupietz S (1974). Dextroamphetamine and methylphenidate in the treatment of hyperactive/aggressive children. Pediatrics 53:236–41. Wood DR, Reimherr FW, Wender PH, Johnson GE (1976). Diagnosis and treatment of minimal brain dysfunction in adults: a preliminary report. Arch Gen Psychiatry 33:1453–60. Wozniak J, Biederman J (1996). A pharmacological approach to the quagmire of comorbidity in juvenile mania. J Am Acad Child Adolesc Psychiatry 35:826–8. Wozniak J, Biederman J, Kiely K et al. (1995). Mania-like symptoms suggestive of childhood onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 34:867–76. Yepes LE, Balka EB, Winsberg BG, Bialer I (1977). Amitriptyline and methylphenidate treatment of behaviorally disordered children. J Child Psychol Psychiat 18:39–52. Zametkin AJ, Nordahl TE, Gross M et al. (1990). Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med 323:1361–6. Zametkin AJ, Rapoport JL (1987). Noradrenergic hypothesis of attention deficit disorder with hyperactivity: a critical review. In Meltzer HY (Eds.), Psychopharmacology: The Third Generation of Progress. New York: Raven Press, pp. 837–42. Zametkin A, Rapoport JL, Murphy DL, Linnoila M, Ismond D (1985). Treatment of hyperactive children with monoamine oxidase inhibitors. I. Clinical efficacy. Arch Gen Psychiatry 42:962–6.

10 Pervasive development disorder Sandra N. Fisman Children’s Hospital of Western Ontario, London, Ontario, Canada

Introduction The pervasive developmental disorders (PDDs) are characterized by impairments in socialization, communication, and imagination, and the presence of repetitive and ritualistic behaviors (American Psychiatric Association, DSM-IV, 1994). While these deficit areas echo Kanner’s original description of ‘‘early infantile autism’’ (Kanner, 1943), considerable strides have been made over the past 50 years in the diagnostic clarification and categorization of these disorders. A substantial body of neurobiologic and psychologic research has emerged regarding these phenomenologically similar disorders (Cohen et al., 1994). The PDDs were first included as a separate category in the third edition of the American Psychiatric Association Diagnostic and Statistical Manual (American Psychiatric Association, DSM-III, 1980). Prior to this, the conceptualization of autism as a form of childhood psychosis (Creak, 1963) led to the lumping together of a heterogeneous group of children with impaired emotional relatedness, abnormal perceptual sensitivities, poorly modulated anxiety, and disordered language and sense of personal identity. This group included children with Kanner’s autism as well as those children with hallucinations, delusions, and formal thought disorder. Subsequent differentiation of these children by age of onset, clinical course, and family history (Kolvin, 1971) allowed for diagnostically separate entities. In DSM-III, autism was included under the umbrella of the PDD and criteria for the diagnosis of childhood schizophrenia were subsumed with the adult disorder (American Psychiatric Association, DSM-III, 1980). In this third edition of the diagnostic manual, age of onset prior to or after 30 months of age (i.e., infantile autism vs. childhoodonset PDD) and the absence of delusions and hallucinations were important defining characteristics for PDD. While the convincing differentiation of PDD and childhood schizophrenia 265

266

S.N. Fisman

has been invaluable in moving the field forward, there are similarities and differences in the phenomenology of these disorders. The PDDs do share some of the positive and negative symptoms of schizophrenia (Fisman and Steele, 1996). For both autistic disorder and Asperger’s disorder, two of the subcategories of the PDDs in the current DSM-IV classification (American Psychiatric Association, DSM-IV, 1994), the presence of negative or negative-like symptoms is most striking. The DSM-IV criteria for autistic disorder and Asperger’s disorder that are comparable to the positive and negative symptoms of schizophrenia as listed in the Positive and Negative Symptom Scale for Schizophrenia (PANSS; Kay et al., 1987) and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen and Olsen, 1982) are summarized in Tables 10.1 and 10.2. However, the positive symptoms of delusions and hallucinatory experiences, typically seen in schizophrenia, are not part of PDD. In addition, the delayed and deviant language typical of autistic disorder does not fall within the negative/positive symptom complex and nor do resistance to change and preoccupation with particular interests which are characteristic of both autistic disorder and Asperger’s disorder. Nevertheless, the symptom overlap, as well as the insidious nature of onset of childhood schizophrenia and the prevalence of premorbid neurodevelopmental difficulties, may suggest some shared neurobiologic underpinnings (Bettes and Walker, 1987) and may explain the symptom response, in both PDD and childhood schizophrenia, to similar psychopharmacologic agents (Fisman and Steele, 1996). The concept of an autistic spectrum influenced the diagnostic criteria for PDD in the third revised edition of the Diagnostic and Statistical Manual (American Psychiatric Association, DSM-IIIR, 1987). The notion of an autistic spectrum evolved from an epidemiologic study of mentally and physically handicapped children in the London area (Wing and Gould, 1979). The three clusters of difficulty found in language and socially impaired children in this study were referred to as ‘‘the autistic triad.’’ This triad included: absent or impaired two-way social interaction; abnormalities in communication including verbal and nonverbal language impairment; and restricted interests carried out in a repetitive or stereotyped manner. Children could possess difficulties in these three areas to varying degrees. Those who showed abnormalities in all three areas would be considered part of the autistic spectrum disorders (Wing, 1986; Wing, 1981). It was suggested that Asperger’s disorder was on one end of the continuum and low functioning autism on the other. Using this spectrum concept , DSM-IIIR (American Psychiatric Association, DSM-IIIR, 1987) provided only two diagnostic options: autistic disorder representing classic Kanner’s autism and the broad category of Pervasive Developmental Disorder Not

267


Table 10.1. Negative-type symptoms Schizophrenia (adapted from PANSS1)

PDD (adapted from DSM-IV2)

Blunted affect

Impairment in nonverbal communication

Poor rapport Emotional withdrawal

Lack of social or emotional reciprocity

Passive/apathetic Lack of spontaneous seeking to share Social withdrawal enjoyment, interest, or achievement with Lack of spontaneity and flow of conversation others Stereotypic thinking/speech

Stereotyped and repetitive use of language or idiosyncratic language

1

PANSS Positive and Negative Symptom Scale (Kay et al., 1987) DSM-IV (American Psychiatric Association, 1994)

2

Table 10.2. Positive symptoms Schizophrenia (adapted from PANSS1)

PDD (adapted from DSM-IV2)

Excitement Anxiety Conceptual disorganization Hostility Suspiciousness/persecution Hallucinations Delusions

Abnormalities in mood/affect Impulsivity, hyperactivity Odd responses to perceptual stimuli Aggression, temper tantrums Excessive fear in response to harmless stimuli

1

PANSS Positive and Negative Symptom Scale (Kay et al., 1987) DSM-IV (American Psychiatric Association, 1994)

2

Otherwise Specified (PDDNOS). The end result of this classification system was high sensitivity but low specificity for these disorders (Volkmar et al., 1992). Current diagnostic concepts

Subsequent to DSM-IIIR (American Psychiatric Association, 1987), evidence has accumulated for a categoric approach to diagnosis of the PDDs. This approach was reflected in the tenth edition of the International Classification of Diseases (World Health Organization, ICD-10, 1992) and subsequently in the

268

S.N. Fisman

Table 10.3. Diagnostic criteria for autistic disorder1 A. A total of six (or more) items from (1), (2), and (3) with at least two from (1) and one each from (2) and (3) (1) Qualitative impairment in social interaction, as manifested by at least two of the following: (a) Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction (b) Failure to develop peer relationships appropriate to developmental level (c) A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest) (d) A lack of social or emotional reciprocity (2) Qualitative impairments in communication as manifested by at least one of the following: (a) Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime) (b) In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others (c) Stereotyped and repetitive use of language or idiosyncratic language (d) Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level (3) Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following: (a) Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus (b) Apparently inflexible adherence to specific, nonfunctional routines or rituals (c) Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) (d) Persistent preoccupation with parts of objects B. Delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years: (1) social interaction, (2) language as used in social communication, or (3) symbolic or imaginative play C. The disturbance is not better accounted for by Rett’s disorder or childhood disintegrative disorder 1

Diagnostic and Statistical Manual–IV (DSM-IV); American Psychiatric Association, 1994

fourth edition of the Diagnostic and Statistical Manual (American Psychiatric Association, DSM-IV, 1994). Other conditions grouped with autistic disorder in the PDD class include Asperger’s disorder, Rett’s disorder, childhood disinteg-

269


Table 10.4. Diagnostic criteria for Asperger’s disorder1 A. Qualitative impairment in social interaction, as manifested by at least two of the following: (1) Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction (2) Failure to develop peer relationships appropriate to developmental level (3) A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest to other people) (4) A lack of social or emotional reciprocity B. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following: (1) Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus (2) Apparently inflexible adherence to specific, nonfunctional routines, or rituals (3) Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) (4) Persistent preoccupation with parts of objects C. The disturbance causes clinically significant impairment in social, occupational, or other important areas of functioning D. There is no clinically significant general delay in language (e.g., single words used by age 2 years, communicative phrases used by age 3 years) E. There is no clinically significant delay in cognitive development or in the development of age-appropriate self-help skills, adaptive behavior (other than in social interaction), and curiosity about the environment in childhood F. Criteria are not met for another specific pervasive developmental disorder or schizophrenia. 1

Diagnostic and Statistical Manual–IV (DSM-IV); American Psychiatric Association, 1994

rative disorder, and the maintenance (from DSM-IIIR) of the category of PDDNOS (including atypical autism). In the last case, criteria for one of the specific pervasive developmental categories are not met, but there is a severe and pervasive impairment in the development of two-way social interaction, or of verbal and nonverbal communication, or the presence of stereotyped behavior, interests, and activities. A brief description of each main PDD category follows; diagnostic criteria (American Psychiatric Association, DSM-IV, 1994) for autistic disorder and Asperger’s disorder are found in Tables 10.3 and 10.4.

270

S.N. Fisman

Autistic disorder

Autistic disorder is the paradigmatic PDD. A disturbance in social relatedness remains a major defining feature of the disorder. Classically, these children have a very early age of onset; difficulties are most often noted in the first year of life, but there may be a period of 1 or 2 years of apparently normal development prior to the onset of autistic symptomatology (Short and Schopler, 1988; Volkmar et al., 1985). Children with autism have profound problems with all aspects of communication (verbal and nonverbal) and language development is both delayed and deviant (Frith, 1991). Many autistic individuals remain nonverbal and, for those who develop speech, prolonged echolalia, pronoun reversal, unusual prosody, and extreme literalness are typical. High functioning individuals whose IQs are within the normal range have considerable difficulty with the nuances of social language and picking up of nonverbal cues. Autistic children display a range of unusual behaviors, which may be variable from child to child, but which are captured in the overall descriptors of resistance to change or insistence on sameness. Children may insist on a particular routine, become very difficult during transitions, and become preoccupied with objects or particular repetitive activities. Mental retardation is associated with autism in at least 70% of cases (Lord and Schopler, 1988) and is the single most powerful predictor of outcome (Ventner et al., 1992). Why autistic children are often cognitively delayed is unknown. However, it appears that a number of cognitive processes may be affected, resulting in an overall lower IQ (Sigman et al., 1995). Asperger’s disorder

Asperger was a Viennese pediatrician who described a group of children with social isolation, pedantic speech, one-sided conversation with others, and eccentric unusual interests that occupied a large part of their time (Asperger, 1991). The disorder was said to be more common in boys than girls and Asperger believed that intelligence in these children was above average. Although the differentiation of high functioning autism and Asperger’s disorder continues to be debated (Rutter and Schopler, 1992), there is support for the separate categorization of these two disorders (Szatmari et al., 1995). In contrast to autistic disorder, there are no clinically significant delays in language, cognitive development, or age-appropriate self-help and adaptive skills (other than social interaction) in children with Asperger’s disorder. There must be significant functional impairment (social, occupational, or other) (American Psychiatric Association, DSM-IV, 1994). Differentiation between the two dis-

271


orders has also been made in terms of neuropsychologic abnormalities with Asperger’s disorder often associated with the psychometric profile of a NonVerbal Learning Disability and underlying right hemispheric dysfunction (Rourke, 1989). Some investigators maintain that Asperger’s disorder is a mild variant of autism (Green, 1990) and that the differentiation should be made between higher functioning and lower functioning individuals, with the lower functioning autistics having more evidence of brain pathology and dysfunction, while higher functioning autism and Asperger’s disorder share similar underlying genetic abnormalities (DeLong and Dwyer, 1988). Also at issue is the change over time in clinical presentation of the high functioning group. Gillberg (1991) has suggested that, over time, high functioning autism comes to resemble Asperger’s disorder in terms of odd and eccentric interactions with others. Rett’s disorder and childhood disintegrative disorder

These disorders have been grouped with the PDDs because of the abnormalities of function that develop in the areas of social interaction, communication, and stereotyped behaviors. They both share a period of apparently normal development (for at least 5 months in the case of Rett’s disorder and at least 2 years with childhood disintegrative disorder). Both conditions are typically associated with severe mental retardation and may follow a deteriorating course. While all of the PDDs are more common in males, Rett’s disorder has only been reported in females. Characteristic of Rett’s disorder is the development of stereotyped hand movements resembling hand wringing or hand washing, deceleration of head growth, and deterioration in gait. Social interaction, lost early in the course, may develop later. PDDs: hypothesized central nervous system mechanisms Given the heterogeneity in the clinical presentation of the PDDs, it is not surprising that there is a diversity in hypothesized central nervous system (CNS) dysfunction for these disorders. Ideally, this diversity should reflect the diagnostic categories as have been outlined in DSM-IV, but, at the present time, it is the descriptive phenomenology that separates the disorders rather than precise knowledge of pathogenesis (Szatmari et al., 1995). An analogous situation would apply to epilepsy or cerebral palsy where there is something generally abnormal about the CNS, but the etiology and pathogenesis may vary from case to case (Gillberg, 1995). While specific abnormalities of brain function remain elusive, there have

272

S.N. Fisman

been advances in the study of neurocognitive performance, psycholinguistics, and increasingly sophisticated neuroimaging techniques. Hypothesized mechanisms of brain dysfunction will be reviewed under four headings: theoretical concepts, neurocognitive mechanisms, neuroanatomic features, and neurotransmitter changes. Research aimed at elucidating underlying causes and mechanisms for these disorders will assist in the development of rational interventions and, particularly, psychopharmacologic interventions. Theoretical concepts

Debate continues whether the behavioral inflexibility and disturbance in interpersonal interactions, so evident with the PDDs, result from a primary dysfunction that is cognitive or one that is affective (Brook and Bowler, 1992). Affective protagonists argue that these children lack the capacity to identify and recognize cues in the emotional realm and that communication deficits result from abnormal affective development (Hobson, 1988). Evidence of impairment in emotional perception has been contradictory, however (Ozonoff et al., 1991; Braverman et al., 1989). Additionally, research into the affective components of PDDs is difficult due to the nature of the disorders and that affect recognition is a qualitative experience and difficult to operationalize in a quantitative fashion (Hobson, 1991). The alternative cognitive view, which has been influential in recent years is that a failure in meta-representation precludes the development of a ‘‘theory of mind’’ – that is, the capacity to attribute thoughts, feelings, and desires to oneself and other people (Baron-Cohen et al., 1985). Theory of mind tasks are divided between first order (involving reasoning of the kind ‘‘he thinks that’’) and second order (‘‘he thinks that she thinks that’’). Developmentally normal children pass first order tasks by the age of 4 years and second order tasks by the age of 7. While Baron-Cohen (1989) found that autistic children who passed first order tasks were not able to pass second order tasks, studies of high functioning autistic individuals have not supported these conclusions (Dahlgren and Trillingsgaard, 1996; Bowler, 1992). There appears to be a developmental progression in ‘‘theory of mind’’ attributions in autistic children with a crucial role played by intellectual level, particularly verbal ability (Sparrevohn and Howie, 1995). Cognitive and affective mechanisms are not necessarily mutually exclusive; there may be an underlying common denominator affecting the development of linguistic and intellectual skills as well as social relatedness. Children with autism fail to attend jointly to others and to objects and events (Mundy, 1995). Index finger pointing, use of eye gaze to direct another’s attention, and the

273


child’s response to the attempts of others to share attention with them are typically absent. The capacity for development of joint attention is a necessary precursor for meta-representational thinking (Baron-Cohen, 1993). Deviance occurring early in meta-representational thinking as indicated by verbal ability would result in a spectrum of affective and cognitive symptoms, the severity of which may be determined by the extent of neurodevelopmental deficit. Neurocognitive deficits

The most consistent finding in neuropsychologic studies of high functioning autism and Asperger’s disorder is an abnormality of executive functioning leading to problems in planning and sequencing. The Wisconsin Card Sort Test (WCST) is a test of executive function localized to the prefrontal cortex. In autism, there is a preponderance of perseveration on the WCST and difficulty in shifting cognitive set (Ozonoff and McEvoy, 1994; Szatmari et al., 1990); other frontal executive measures have indicated poor planning and deficits in working memory (Ozonoff and McEvoy, 1994). It has been proposed that there is an interrelationship between operations governed by executive (anterior higher level) and more basic (posterior lower level) attentional systems (Bryson et al., 1990). Basic attentional processes appear to be involved in automatic response to modality-specific stimuli and especially in visual–spatial attention (Posner and Peterson, 1990). On the other hand, the shifting of attention and recruitment of relevant attentional systems for goal-directed behavior appears to be governed by higher order anterior executive functions. Additionally, the anterior system provides focus and direction for the operations of the posterior system. Underlying autistic disorders are abnormalities in the initial attentional processes controlled by posterior lower brain centers that ultimately regulate anterior higher brain center development. Several clinical groups, including schizophrenia, perform poorly on measures of executive function (Berman et al., 1988), but it is the difficulty in planning and shifting across stimulus dimensions that distinguishes autism from other disorders (Hughes and Russell, 1993). It is possible that dysfunction in attentional processes is shared by all the PDDs and that deficits in the development of posterior attentional systems might relate both to the maldevelopment of higher order executive frontal functions as well as motivational–affective systems. Spatial inattention in early development may also explain the repetitive repertoire of these children, their narrow response to external stimuli, and the difficulty they have in generalizing learning across different experiences (Smith and Bryson, 1994).

274

S.N. Fisman

Neuroanatomic changes

A number of neuroanatomic loci, as well as abnormalities in cerebral lateralization, have been described in PDD. These loci include the prefrontal cortex, temporal lobe, cerebellum, limbic system, and subcortical brain areas. The prefrontal cortex The prefrontal cortex plays an important role in planning, sequencing, and novel goal-directed behavior and speech. Complex connections exist between the prefrontal cortex and the temporal and parietal lobes as well as subcortical structures such as the basal ganglia (Horne, 1993). Abnormalities in development of the frontal cortex have been implicated in autism (Zilbovicius et al., 1995). Brains of autistic children have shown enlargement in all cortical areas except the frontal area (Piven et al., 1995). This may possibly be a compensatory mechanism resulting from input abnormalities to the frontal cortex during early development of the autistic child’s brain. The temporal lobe The temporal lobe serves functions such as control of language and memory. Important connections exist with the limbic system for integration of emotion and motivation and with the frontal lobe ensuring integration, sequencing, and planning of information processed by the temporal lobe. Temporal lobe hypoperfusion has been described in high functioning autism (perhaps Asperger’s syndrome) compared with normals (Gillberg, 1992) and lesions in the temporal lobe have been found in Asperger’s disorder ( Jones and Kerwin, 1990). Abnormalities in prefrontal cortical activity and the temporal lobe have also been found in schizophrenia (Frith et al., 1995) and it may be the dysregulation between the frontal cortex and the temporal lobe that explains the overlap in symptom profile in schizophrenia and Asperger’s disorder and the responsiveness in both disorders to the new generation of antipsychotic medications (Fisman et al., 1998). The cerebellum The cerebellum is generally linked with motor activity, and strong prefrontal– neocerebellar connections are associated with functions such as calculations and conscious control of fine motor movement and speech (Dow, 1974). Both neocerebeller hypo- and hyperplasia have been reported from magnetic resonance imaging studies in autism (Courchesne et al., 1994). However, in a carefully executed imaging study, Piven et al. (1997) found no evidence to

275


suggest a neuroanatomic abnormality in the neocerebellar vermis of autistic individuals. This is consistent with neuropathologic findings of a decreased number of Purkinje cells more marked in the cerebellar hemispheres and not confined to the vermis (Arin et al., 1991). Piven et al. (1997) suggest that any increase in volume of the cerebellum is similar to that of the temporal, parietal, and occipital lobes and that the primary deficit in autism is not localized, but more likely related to abnormal development of a neural network for complex information processing distributed throughout several brain regions. The limbic system and subcortical brains areas It has been suggested that subcortical structures including the diencephalon, with its intimate connections to the limbic area and reticular formation, are primarily affected in autism causing deficits in attention, abnormal affective responsiveness, and stimulus-bound behavior (Bauman, 1991; Ornitz, 1985). This provides the neuroanatomic substrate for the posterior attentional systems described under neurocognitive mechanisms. The thalamus is a diencephalic structure considered to act as a sensory or attentional filter to higher cortical areas. The thalamus’ filtering function is essential to preventing overload of higher brain systems through its selection of relevant stimuli and inhibition of irrelevant stimuli (O’Leary et al., 1994). The mediodorsal nucleus of the thalamus has strong connections with the prefrontal cortex; it may be that abnormal frontal cortical development in autism (Piven et al., 1995; Zilbovicius et al., 1995) is the result of a thalamic lesion leading to deviant neurodevelopment of cortical areas. Thalamo-cortical dysfunction expressed early in development may also explain findings of cerebral asymmetry and abnormalities in hemispheric lateralization described in autism (Cantor et al., 1986; Tanguay, 1974) and Asperger’s disorder (Semrud-Clikeman and Hynd, 1990). The thalamus may play a role in the control of synaptic proliferation and elimination (Rajakumar et al., 1998). Synaptic proliferation occurs within the first few years of childhood development with synaptic elimination and stabilization continuing throughout later childhood. The timing of normally developing specific behaviors corresponds with periods of rapid synaptogenesis, occurring in a sequential pattern in the cortex and ending in the frontal areas. Delayed synaptogenesis in the frontal cortex on positron emission tomography scanning in autistic children at 3–4 years of age is supportive of this hypothesis (Zilbovicius et al., 1995).

276

S.N. Fisman

Neurotransmitter changes

Serotonin The most consistent neurotransmitter abnormalities in the PDDs have been found in the serotonin (5-hydroxytrypamine [5-HT]) system (Martineau et al., 1992; Piven et al., 1991; Minderaa et al., 1989; Anderson et al., 1987) with elevated whole blood serotonin in 30–40% of autistic children being the most consistent biologic marker. Hyperserotonemia segregates within families: the presence of a hyperserotonemic child with autistic disorder was found to be related to a 2.5-fold increase in the likelihood of a hyperserotonemic relative (Leventhal et al., 1990). Autistic children with a sibling who also has autistic disorder have been reported to have a much higher rate of hyperserotonemia than autistic children without affected siblings (Piven et al., 1991). On the other hand, an acute depletion of the 5-HT precursor, tryptophan, can exacerbate many of the behavioral symptoms of autistic disorder (McDougle et al., 1996b). A dysfunction of central 5-HT synthesis may occur at different steps in brain metabolism (Eufemia et al., 1995); low brain tryptophan availability resulting from low serum tryptophan levels in relation to serum levels of large neutral amino acids could be one of the mechanisms in the alteration of serotonergic functions in autism. The role of serotonin in the filtering of sensory information, pain, perception, and motor functions (all of which may be impaired in these disorders) (Anderson, 1987; Young et al., 1982), suggests it may be involved in the etiopathogenesis of PDD. Drugs affecting the serotonin system which have been used in the PDDs include serotonin agonists (clomipramine, fluoxetine, fluvoxamine, sertraline, buspirone, and fenfluramine) as well as serotonin antagonists (risperidone, clozapine, and methysergide). Table 10.5 lists the mechanisms of action for these drugs and their clinical utility. While it seems puzzling that both 5-HT agonists and 5-HT antagonists have proven useful in treating these disorders, it may be that these agents share the functional similarity of downregulating postsynaptic 5-HT-2 receptors in chronic treatment (Zohar et al., 1988). Dopamine Clinical neurobiologic studies and the response to drugs with dopamine blocking action suggest that dopamine function is increased in some patients with PDD. Most studies of dopamine in autistic disorder have focused on the measurement of homovanillic acid (HVA), the main metabolite of dopamine. Research findings vary according to whether cerebrospinal fluid (CSF), blood, or urine is assayed (Narayan et al., 1993) as well as the severity of autistic

277


symptoms and neurologic impairment (Martineau et al., 1992). Increased HVA levels have been found in the urine samples of autistic children compared with nonautistics and controls (Barthelemy et al., 1988; Garreau et al., 1988) and in CSF in autistics vs. controls (Gillberg and Svennerholm, 1987; Gillberg et al., 1983). No significant differences in CSF HVA were found between autistic children and neurologically impaired controls (Narayan et al., 1993), but dopamine levels have been related to the severity of autistic behavior (Martineau et al., 1992), with more severely autistic children having lower dopamine levels. Differences in HVA levels may be more predictive of symptom profile than diagnostic category (Hameury et al., 1995) or essential pathoetiology. Controlled studies of dopamine antagonists have found these drugs effective in improving some of the behavioral symptoms in PDD including hyperactivity, aggression, temper tantrums, stereotypies, and lack of social relatedness. Dopamine antagonists include haloperidol, pimozide, risperidone, olanzapine, and clozapine. Amphetamine, an indirect dopamine agonist, and L-dopa, a dopamine precursor, may worsen pre-existing symptoms in autistic children, offsetting any improvement in play, responsivity, and energy level (Campbell et al., 1976). In support of this hypothesis, a study comparing amisulpride, a dopamine antagonist, with bromocriptine, a dopamine agonist, in children with autism, in a placebo washout-crossover design, found that amisulpride was associated with an improvement on the specific autistic scale of the Behavioral Summarized Evaluation (behavioral inhibition and withdrawal symptoms), while bromocriptine improved symptoms of hyperactivity and inattention on the Connors Parent Teacher Questionnaire (Dollfus and Petit, 1992). Drugs with dopamine antagonistic effect which have been used in the PDDs are those with dopamine-2 (D2) receptor blockade. Haloperidol and pimozide are high potency, ‘‘typical’’ neuroleptics with strong D2 blockade action, while the atypical neuroleptics such as risperidone have a weaker D2 blocking effect in addition to serotonin antagonism. Noradrenaline and adrenaline Noradrenaline and adrenaline levels (and their metabolites) have not been reported to show significant abnormalities in autistic disorder (Minderaa et al., 1994). However, drugs with a sympatholytic action may still have a limited role in the treatment of PDD. These include propranolol and nadolol, both postsynaptic beta-adrenergic blockers, and clonidine, an alpha-2 presynaptic noradrenergic agonist. The common impact of the two classes of drugs is to reduce CNS noradrenaline transmission. The resulting reduction in hyperarousal has

Potent inhibitor of 5-HT uptake Also affects noradrenaline and dopamine uptake

Potent and selective 5-HT uptake inhibitor

Potent and selective 5-HT uptake inhibitor Minimal affinity for 5-HT

Potent and selective 5-HT uptake inhibitor

Potent and selective 5-HT uptake inhibitor 5-HT-1A partial agonist with an affinity for dopamine receptors

5-HT antagonist and weaker dopamine blockade

Clomipramine

Fluoxetine

Fluvoxamine

Sertraline

Paroxetine Buspirone

Risperidone

Mechanism of action

Dosage range

Significant improvement in aggression, social 20–200 mg/day in divided doses relatedness, repetitive behavior (Preferable not to exceed 3–5 mg/kg/day) May cause increase in agitation/aggression Small risk of seizures Effective in reducing ritualistic behavior, 5–40 mg/day as a single morning dose aggression, and improving social function May cause restlessness, hyperactivity, agitation, decreased appetite, insomnia Moderate efficacy in reducing repetitive 50–200 mg/day in a single or divided dose behaviors, aggression, and improving social relatedness; generally well tolerated but may cause nausea and sedation Significant and sustained improvement in 20–25 mg/day in a single dose taken with transition anxiety and agitation food Well tolerated; low propensity for drug interactions No available evidence for use in PDD 25–80 mg in a single or divided dose Decreased anxiety and irritability 15–60 mg/day in three divided doses Well tolerated but occasional dyskinetic movements Effective in reducing aggression and agitation 0.25–4 mg/day in a single or divided dose and improving social awareness May cause reduction in repetitive behaviors Side effects include weight gain and transient drowsiness

Clinical use in PDD

Table 10.5. Drugs affecting the serotonin (5-HT) system of potential use in PDD

5-HT antagonist and weaker dopamine blockade

5-HT antagonist

Olanzapine

Methysergide

2.5–20 mg/day in a single dose Effective in reducing aggression, irritability, hyperactivity, anxiety, and in improving social relatedness No effect on repetitive behaviors Side effects include sedation and weight gain Effectiveness not demonstrated 2–4 mg/day Not clinically indicated for PDD

280

S.N. Fisman

been described as leading to an improvement in aggressive, hyperactive, and impulsive behaviors ( Jaselskis, 1992; Ratey et al., 1987). Neuropeptides Excessive brain opioid activity may account for some of the symptoms seen in autistic disorders including the social deficits and decreased pain sensitivity evident in some of these children (Panksepp and Sahley, 1987). Plasma and CSF levels of endorphins have been compared with levels in nonautistic subjects and results have varied from elevated (Leboyer et al., 1992, Marchetti et al., 1990), to decreased (Weizman et al., 1984; Sandman et al., 1980), and equal (Herman et al., 1988) plasma levels. Studies of neuropeptide CSF levels have been equally inconclusive (Nagamitsu et al., 1997; Ross et al., 1987; Gillberg et al., 1985). Results of studies using naltrexone, an opioid antagonist, have been equally variable (Herman et al., 1993; Borghese et al., 1991; Campbell et al., 1990). Other neuropeptides that have been studied in a preliminary fashion, and may hold promise following additional study, include the ACTH analog ORG2766, a synthetic analog of ACTH (4–9), which was shown to improve the play and social interaction between the child and experimenter in a controlled clinical trial. Stereotypic behavior was decreased, and adverse events were not noted (Buitelaar et al., 1998, 1990). Oxytocin, a 9-amino acid peptide, can induce prosocial behaviors in animals and may prove useful in autistic disorder (Insel, 1992). Overview of known psychopharmacologic treatment for an adult PDD Since the PDDs are early-onset developmental disorders more readily identifiable in childhood, there is a paucity of information available on the psychopharmacologic treatment of adults with PDD. In addition, most of the evidence for efficacy comes from case reports or open case series, although more recent double-blind, placebo-controlled studies have been undertaken (McDougle et al., 1996a; Fankhauser et al., 1992). The potent serotonin transport inhibitors have been most commonly used in autistic adults. Clomipramine, a tricyclic nonselective serotonin reuptake inhibitor (SRI) was used in 35 adults with PDD to determine its short-term efficacy and tolerability (Brodkin et al., 1997). The sample included 18 patients with autistic disorder, six with Asperger’s disorder, and 11 with PDDNOS diagnosed according to DSM-IV criteria. Eighteen of the 35 patients showed significant improvement, with decreased aggression and a decrease in repeti-

281


tive thoughts and behaviors; some aspects of social relatedness such as eye contact and verbal responsiveness were also reported to have improved. Improvement did not relate to the subcategory of PDD. While there were no adverse cardiovascular or extrapyramidal side effects, three of the patients, two with pre-existing seizure disorders, did have seizures during clomipramine therapy. Clomipramine dosage ranged from 75 to 250 mg daily and, although clomipramine levels were not obtained, there was no significant difference in clomipramine dose between responders and nonresponders. In an earlier case series, McDougle et al. (1992) described a significant decrease in aggression and repetitive behaviors and improvement in social relatedness in four out of five adults diagnosed with autism according to DSM-IIIR criteria and treated with clomipramine. Dosage range for clomipramine was similar: 75–250 mg/day with a mean dose of 185 mg/day. Other than dry mouth in two cases, the drug was well tolerated with no adverse effects. The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine, sertraline, and fluoxetine have been used in autistic adults with reasonable efficacy and tolerability. McDougle et al. (1996a) completed a double-blind, placebo-controlled study of 30 adults with autistic disorder over a 12-week period. Fiftythree percent of the fluvoxamine-treated group showed significant improvements in social relatedness (especially language usage) and decreases in repetitive behaviors and thoughts, maladaptive behavior, and aggression, while there were no changes in the placebo group. Fluvoxamine was well tolerated with mild sedation and nausea evident in only a few patients. Dosage was initiated at 50 mg and final doses ranged from 200 to 300 mg daily. In addition to the statistically significant changes in rating scales, meaningful changes in adaptive function and quality of life were noted in several patients. Given the high level of functional impairment experienced throughout the lives of the majority of autistic individuals (Wolf and Goldberg, 1980), a potential change in functionality with a psychotropic drug intervention is of great benefit to the individual, their families, and the community. Sertraline was administered to nine adults with mental retardation, five with comorbid autistic disorder, in an open trial (Hellings et al., 1996) targeting symptoms of self-injury and/or aggression. Total daily doses ranged from 25 to 150 mg with a starting dose of 25 mg to avoid side effects such as akithisia and irritability. Eight of the nine patients showed significant improvement in Clinical Global Impression (CGI) ratings. Only one patient (with Prader–Willi syndrome) deteriorated with an increase in agitation and self-picking. Otherwise, the sertraline was well tolerated with minimal side effects. In a larger open-label case series, fluoxetine was effective in reducing ritualistic behavior

282

S.N. Fisman

and aggression and in improving social function in children and adults (age range 7–28 years) with autism and mental retardation (Cook et al., 1992). Dosage ranged from 20 mg alternate days to 80 mg/day. Six of the 23 subjects with autistic disorder had significant side effects, including restlessness, hyperactivity, agitation, decreased appetite, or insomnia. Similar improvements in adults treated with fluoxetine have been reported in small number and single case studies (Mehlinger et al., 1990). Other serotonergic drugs which have been used in self-injurious and aggressive adults include the 5-HT-1A partial agonist buspirone and trazodone, a serotonin agonist. In an open-label study of buspirone in 14 developmentally disabled adults, three of whom were autistic, buspirone in doses of 15–45 mg/day improved self-injurious behavior, allowed reduction or discontinuation of concomitant neuroleptic, and improved functional adaptation for several of these individuals (Ratey et al., 1989). Ritanserin and nefazodone, both serotonin 5-HT2A antagonists, have not yet been used in PDD. Although there has been a long-standing clinical practice of using ‘‘typical’’ neuroleptics in developmentally handicapped individuals for behavior control, there are no documented trials using traditional compounds in adults. Case reports of the atypical neuroleptic, risperidone, which is a potent 5-HT-2 antagonist with a weaker, but still significant, D2 blocking effect ( Janssen et al., 1988) have been published following open-label use in adult males with PDD (McDougle et al., 1995; Purdon et al., 1994). Significant improvements were noted in social relatedness, repetitive thoughts, and behavior. Four adults with PDD were included in a small open-label trial of olanzapine monotherapy and a significant decrease in core and related PDD symptoms was found (Potenza et al., 1999). There are currently no data on the use of other newer generation atypical antipsychotics, such as clozapine, seroquel, sertindole, and ziprasidone, in adults with PDD. Of the sympatholytic agents, propranolol or nadolol have been reported to reduce aggression, impulsivity, and self-injurious behavior in eight autistic adults in an open-label study (Ratey et al., 1987) and in a single double-blind, placebo-controlled case study (Cohen et al., 1991). All, but one, of these patients were receiving concomitant neuroleptic or mood-stabilizing drugs. Ratey et al. (1987) also described an improvement in speech in four and improved socialization in six of the eight subjects. A similar ‘‘calming effect’’ has been noted for the beta blockers in mentally retarded individuals (Ratey et al., 1986). The authors postulate that these drugs lessen the ‘‘reflex’’ reaction to an otherwise arousing stimulus, with a learned component to the dampened response, so that, over time, the frequency of rage and anxiety reactions

283


diminishes. In a similar vein, transdermal clonidine was effective in reducing hyperarousal and improving social relationships in a double-blind, placebocrossover study with nine autistic males aged 5–33 years (Fankhauser et al., 1992). Dosages, calculated by weight, ranged from 0.15 to 0.3 mg per day. The most common side effects were drowsiness and fatigue in the first 2 weeks of treatment. Although there was a significant lowering of systolic blood pressure in the drug vs. placebo group, none of the subjects demonstrated clinical hypotensive symptoms during the study. Finally, in a double-blind, placebo-controlled study of 32 adults (23 with autism) who had self-injurious behavior, naltrexone failed to have significant therapeutic effects on self-injurious behavior or core symptoms of autism (Willemsen-Swinkels et al., 1995). Other studies that have reported therapeutic benefit in adults have been very small sample sizes or open-label designs. Review of child and adolescent psychopharmacologic treatment for PDD The empirical basis for the psychopharmacologic treatment of a number of childhood psychiatric disorders has been derived from studies in adult patients because of the lack of adequately controlled drug trials in children and adolescents. Examples include childhood-onset mood disorders, obsessive–compulsive disorder (OCD), and schizophrenia. As we have seen in the previous section, there is limited information to be extrapolated from the treatment of adults with PDD to children. Currently, the best guide for pharmacologic management of these disorders is empirical treatment of target symptoms (Table 10.6). Evidence for effective drug treatment of PDD symptoms with different classes of psychoactive agents will be reviewed as will the evidence for the tolerability of these agents in children and adolescents. Potent serotonin transport inhibitors

These drugs include the SSRIs, fluoxetine, sertraline, fluvoxamine, citalopram, and paroxetine, and the less selective but still potent SRI clomipramine, a tricyclic antidepressant (TCA). These medications are most effective when rituals or insistence on sameness interfere with function often to the point of manifest anxiety or aggression in response to interruption of these routines or rituals. They are also helpful with the onset of comorbid depression (Ghaziuddin et al., 1991) or OCD (Clomipramine Collaborative Study Group, 1991). Clomipramine has also been reported to reduce dyskinetic movements related to neuroleptic treatment (Brasic et al., 1994). In a double-blind crossover design comparison of clomipramine,

+ +

— ±

+ ±

+ ± +

++

++ +

+ ±

+ —

Fluvoxamine Sertraline Buspirone

Haloperidol

Risperidone Propranolol

Clonidine Naltrexone

Mood stabilizers Stimulants

Distractibility – inattentive

— +

— —

+ —

±

— — —

± —

— —

— —

+ —

±

+ + —

+ +

Withdrawal Social relatedness — —

± —

+ ±

+

+ + —

+ +

Mood Affect — —

— —

+ ±

±

+ + +

+ +

— —

± —

+ ±

+

+ ++ —

± +

Difficulty with transitions

Key: ++ Definite benefit; + Likely benefit; ± Some benefit; — No benefit

++ +

++

± ± —

± ±

Aggression

Clomipramine Fluoxetine

Hyperactivity Impulsivity

Psychoactive Agent

Distractibility – overfocused

Table 10.6. Targeting interfering symptoms

Irritability Temper tantrums + —

± ±

++ +

++

± ± +

± ±

Repetitive behaviors/rituals/ compulsions — —

— ±

+ —

++

++ ++ —

+ ++

± —

— ±

± +

±

+ + +

+ +

Self-injurious behaviors

May increase agitation and aggression Restlessness/agitation, insomnia, decreased appetite; length of time to judge efficacy Nausea, anorexia Not identified Limited effectiveness, can get extrapyramidal reactions Risk for extrapyramidal side effects and dyskinesias (tardive and withdrawal) Weight gain and dose-related drowsiness Small margin between efficacy and ‘‘cardioblocking’’ effect Sedation; tolerance to the therapeutic effect Questionable effectiveness; unpalatable taste if chewed Need for blood level monitoring May worsen stereotypies and cause behavioral disorganization

Main disadvantages of psychoactive agent

285


desipramine, and placebo with seven autistic children (mean age 9.6 ± 4.4 years), clomipramine was superior to desipramine, a relatively selective noradrenaline update inhibitor (Gordon et al., 1992). A statistically significant improvement was seen in the core symptoms of autism. Additionally, anger and obsessive–compulsive symptoms also improved with clomipramine treatment, while no change was seen with desipramine. Both drugs were rated as better than placebo, but similar to one another for reducing hyperactivity. Side effects included mild disturbances in sleep, dry mouth, and constipation; mild tremor was noted in one patient. Two patients discontinued desipramine after 3 weeks because of uncharacteristic severe irritability and temper outbursts. There were no serious cardiac or CNS effects reported. Dosage of clomipramine was 129 ± 39 mg/day and, of desipramine, 111 ± 40 mg/day. Agitation and aggression have been described with the use of clomipramine in autistic children and adolescents (Brasic et al., 1997; Fisman and Steele, 1996; Alarcon et al., 1991). The major mechanism of action of clomipramine may involve its active metabolite, desmethylclomipramine, which has a greater effect on noradrenergic than on serotonergic uptake (Schatzberg and Nemeroff, 1988). Agitation may relate to an initial rapid accumulation of serotonin in the synaptic cleft before downregulation of postsynaptic 5-HT-2 receptor sensitivity has occurred or to the nonadrenergic effect of desmethylclomipramine, especially in the subgroup of the population who are rapid metabolizers (Schatzberg and Nemeroff, 1998). Brasic et al. (1997) have suggested that neurobehavioral toxicity is dose related and recommend that children receive no more than 3–5 mg/kg per day. Sertraline has been used in an open-label study of children aged 6–12 years with autistic disorder, specifically targeting transition anxiety and agitation in these children. Eight of nine patients showed a clinically significant improvement at doses of 25–50 mg a day (Steingard et al., 1997). In six of the nine children, the beneficial effects of sertraline were sustained over the several months follow-up period. Sertraline was well tolerated and adverse effects were minimal (stomach aches in one child), except for behavioral worsening in two children when their doses were raised to 75 mg/day. Other than the open study by Cook et al. (1992) described in the previous section involving adults and some children, reports of fluoxetine use in children and adolescents have been restricted to case reports (Awad, 1996; Todd, 1991) with mixed results. There has been a reduction in ritualistic behavior or increased tolerance to change reported in some cases. As a result of the long half-life of fluoxetine (Green, 1995), it takes 4–5 weeks to reach steady state, requiring dosage increments at monthly intervals to avoid adverse side effects.

286

S.N. Fisman

This may also result in initial underdosing during the slow titration period and the need for patience in awaiting therapeutic benefit. There are no published reports of response to paroxetine in children or adolescents with PDD. Relative to fluoxetine, sertraline and citalopram, in particular, are less likely to interfere with the metabolism of other drugs such as risperidone and carbamazepine which are metabolized by cytochrome p4502D6. Sertraline, fluvoxamine, citalopram, and paroxetine also have the advantage of shorter half-lives than fluoxetine. Fluoxetine can be abruptly stopped because of its very long half-life, while the other SSRIs should be slowly tapered. Partial serotonin agonists

Buspirone, the 5-HT-1A partial agonist, has antianxiety and possible antidepressant effects. In addition to its 5-HT-1A agonist action, it also has affinity for dopamine receptors. A small case series reported that two of four autistic children aged 9–10 years showed a beneficial response to buspirone 5 mg three times daily for 4 weeks (Realmuto et al., 1989). Buitelaar et al. (1998) reported on an open-label study of buspirone, targeting anxiety and irritability in 22 patients aged 6–17 years with PDDNOS (DSM-IIIR criteria). They were treated with doses ranging from 15 to 45 mg per day and followed for 12 months. Nine subjects had a marked therapeutic response and seven a moderate response on the CGI scale after 6–8 weeks of treatment. Side effects were minimal except for one patient who developed buccolingual dyskinetic movements, reversible after 2 weeks with drug discontinuation. Fenfluramine is an indirect 5-HT agonist that releases 5-HT presynaptically and blocks its reuptake from 5-HT neurons. Although fenfluramine increases 5-HT neurotransmission acutely, continued administration results in brain depletion of 5-HT (Schuster et al., 1986). Initial enthusiastic reporting of cognitive and social improvements in three hyperserotonemic autistic boys with fenfluramine treatment was not borne out in subsequent double-blind, placebo-controlled studies (Elkman and Miranda-Linne, 1989; Campbell et al., 1988). In addition, untoward side effects including weight loss, excessive sedation, loose stools and irritability proved problematic. Although there was no effect on the core symptoms of autistic disorder, fidgitiness and social withdrawal were significantly improved in the fenfluramine-treated group, and these symptoms worsened after drug withdrawal. However, with the risks of long-term, possibly irreversible, changes in 5-HT neurons (Schuster et al., 1986) and the minimal benefit compared with placebo, fenfluramine is not recommended as a routine treatment in PDD.

287


Neuroleptics

Since they were among the earliest developed psychoactive drugs, the typical neuroleptics – especially haloperidol (Perry et al., 1989; Anderson et al., 1984; Cohen et al., 1980; Campbell et al., 1978) and others, including trifluperazine (Fish et al., 1966) and pimozide (Earnst et al., 1992; Naruse et al., 1982), to a more limited extent – have been studied in a mixture of open and controlled clinical trials. Haloperidol in doses ranging from the initiation dose of 0.5 mg/day to 4 mg/day was compared with placebo in children ranging in age from 2.0 to 7.6 years. Haloperidol was superior to placebo in reducing stereotypies and withdrawal especially for the older children and had a positive effect on mood, hyperactivity, and negativism. Haloperidol also improved discriminant learning, which was felt to be directly related to its effect on attention. The most frequently reported side effects were excessive sedation and irritability which were dosage related. It was subsequently demonstrated that lower doses of haloperidol reduced hyperactivity, temper tantrums, and stereotypies, and increased social relatedness, without untoward effects on learning (although without the facilitation of learning at higher doses) (Anderson and Campbell, 1989). The suggested dosage was 1.3 ± 0.7 mg/day ( Joshi et al., 1988). The main disadvantage of the typical neuroleptics, particularly the high potency drugs such as haloperidol with potent D2 blocking effect, is the risk for development of drug-induced extrapyramidal syndromes. Early-appearing extrapyramidal syndromes include acute dystonic reactions which may onset within hours to 5 days after initiation of neuroleptic therapy and parkinsonian symptoms including tremor, cogwheel rigidity, drooling, decrease in facial expression, and slowness in initiating movement and motor restlessness (akithisia). Late-appearing dyskinesias appear after months or years of neuroleptic treatment and may develop while a patient is actively receiving a neuroleptic (tardive dyskinesia) or when a neuroleptic is being decreased or withdrawn. Baldessarini (1990) has indicated that, in younger patients, tardive dyskinesia disappears over the course of a few weeks to 3 years following medication discontinuation. In disorders that are characterized by stereotypical movements, it may be difficult to differentiate these from tardive dyskinesia or withdrawal dyskinesias without baseline assessments of abnormal movements (Shay et al., 1993). In a longitudinal prospective study over 15 years, Campbell et al. (1997) have evaluated the evidence of tardive dyskinesia and withdrawal dyskinesias in 118 children receiving a mean dose of haloperidol of 1.75 mg/day. One-third of the group developed withdrawal dyskinesias; tardive dyskinesia was much less

288

S.N. Fisman

frequent. Occurrence rates of tardive dyskinesia and multiple episodes of withdrawal and tardive dyskinesias were higher among girls. Greater cumulative haloperidol dosage as well as greater exposure to the drug appeared to be risk factors. As a result of their lower propensity to induce extrapyramidal side effects (Chouinard and Arnott, 1993), the ‘‘atypical’’ antipsychotics are promising agents in the treatment of the PDDs. These medications are termed ‘‘atypical’’ due to their combined serotonin- and dopamine-blocking effects. At present, risperidone is the only one of these drugs with an evidence base for its potential effectiveness and relative safety. This evidence comes from initial case reports (Demb, 1996; Simeon et al., 1995) and seven open trials of risperidone in children and adolescents with PDD (Nicolson et al., 1998; Findling et al., 1997; Horrigan and Barnhill, 1997; McDougle et al., 1997; Perry et al., 1997; Fisman and Steele, 1996). Dosages range from 0.5 to 4 mg daily. Risperidone was found to reduce aggression and agitation effectively and to improve social awareness. In many cases, there was a lessening of repetitive and obsessional behaviors. These benefits were sustained with longer-term use of risperidone (Perry et al., 1997). The most problematic side effects were weight gain (which tended to be greatest in the initial phase of administration and then plateaued) and sedation. Other occasional side effects included nausea, enuresis, galactorrhea, agitation, insomnia, and dizziness. Orthostatic hypotension, tachycardia, elevated liver function tests, and a case of risperidone-related acute leukocytopenia have been reported (Kumra et al., 1997; Edelman, 1996). There may be a relationship between extent of weight gain and hepatotoxicity. Side effects, particularly the emergence of extrapyramidal syndrome, appear more likely beyond daily doses of 6 mg. Casaer et al. (1994) gave six autistic children (aged 3–7 years) a single oral dose of risperidone at 0.05 mg/kg (three subjects) or 0.03 mg/kg (three subjects) of body weight. Risperidone was rapidly absorbed 1 hour postdose. The active metabolite, 9-hydroxyrisperidone, reached a peak level close to that of risperidone in 1–4 hours. The elimination half-life of risperidone was 2 hours and its active moiety 11–16 hours, about 30–35% lower than those in adults. While pharmacokinetics suggest that once-daily dosing is adequate, clinical experience in children has indicated more even symptom control with a twice-daily dosage schedule. The more recent availability of a liquid preparation allows for the accurate use of microdosages. Zuddas et al. (1996) described three autistic children (two 8-year-old boys and a 12-year-old girl) treated with clozapine. Improvement was noted in fidgitiness, hyperactivity, relatedness, and negativism at 4 months and an

289


improvement in affect and communication skills at 8 months. The use of clozapine is limited by the 1% risk of agranulocytosis (Alivir et al., 1993) and 1–2% seizure risk (Haller and Binder, 1990). The risk of seizures is dose related and increases beyond this level when the dose goes above 300 mg/day. There is a report of the use of olanzepine in two boys, aged 9 and 10 years, one with a mixed developmental disorder and the other with PDD (Horrigan et al., 1997) and a small open-label prospective trial using olanzapine alone in eight subjects including four children and adolescents. In the latter study, olanzapine was well tolerated in doses ranging from 5 to 20 mg/day (Potenza et al., 1999). Weight gain and sedation were the most significant adverse effects. Clinical response was promising but further study is necessary. Thymoleptics

There is a limited role for the use of lithium and anticonvulsants (valproate and carbamazepine) in targeting aggression and irritability in PDD children. While a single trial of lithium (compared with chlorpromazine) (Campbell et al., 1972) failed to demonstrate symptom improvement in autistic disorder, the presence of cyclical irritability and a family history of mood disorder may predict positive response to lithium (Cook and Leventhal, 1995). Similarly, cyclical irritability, insomnia, and hyperactivity may respond to valproate in the presence of EEG abnormalities (Plioplys, 1994). Sympatholytic agents

Supporting evidence for use of beta-blocking agents in children with PDD is minimal and comes from the adult literature (Ratey et al., 1987) and some open studies targeting rage outbursts in mentally retarded children and adults (Williams et al., 1982). Contraindications to the use of beta-blocking agents include a history of asthma, diabetes mellitus, cardiovascular disease, and hypothyroidism. Laboratory tests should include a fasting blood sugar and an EKG is recommended. Careful monitoring of heart rate and blood pressure (sitting and standing) is necessary until the target dosage is well established and stabilized. Clinically significant changes in these parameters (heart rate less than 50 beats/min) and sitting blood pressure less than 80/50 mm Hg) indicate a need for downward adjustment of the dose. The suggested dosage range for younger children is 30–160 mg per day of propranolol in three divided doses and, for older children and adolescents, 100–300 mg is suggested, again in divided doses. An appropriate dosing strategy is to start with 10 mg three times daily, then to increase the dose by 30 mg daily every 3–4 days until a desired therapeutic effect is noted. Some clinicians recommend that ‘‘cardioblocking’’,

290

S.N. Fisman

i.e., a resting pulse rate of about 60 beats/minute, is indicative of an effective dose. However, this author recommends dosage titration by clinical response and limits to dose increments with evidence of ‘‘cardioblocking.’’ Clonidine was given to eight autistic boys (aged 5–13.4 years) targeting symptoms of inattention, impulsivity, and hyperactivity ( Jaselskis et al., 1992) in a double-blind, placebo-controlled crossover study. Clonidine or placebo dosage ranged from 0.15 to 0.2 mg/day three times daily for 6 weeks and, after a 1-week washout, the alternative treatment was administered for 6 weeks. Parent and teacher ratings of hyperactivity and irritability showed moderate improvement during clonidine treatment, not confirmed by clinician ratings in videotaped sessions. Sedation and lowered blood pressure were the most frequent side effects. Many of the patients developed tolerance to the therapeutic effects of clonidine. Thus, clonidine may have a limited role in PDD targeting aggression and hyperactivity. Stimulants

Some information suggests that stimulants (including dextroamphetamine and methylphenidate), as well as predominantly noradrenergic TCAs such as imipramine, may worsen stereotypies and cause behavioral disorganization and excitation in autistic children (Sporn and Pinsker, 1981; Campbell et al., 1976, 1971). There are other more recent reports of modest reductions in hyperactivity (Quintana et al., 1995; Birmaher et al., 1988; Strayhorn et al., 1988) using this class of compounds. When targeting inattention in children with PDD, a distinction should be made between random distractibility akin to the poorly sustained attention of children with attention-deficit/hyperactivity disorder and the child who is distracted by specific attention to a ritualistic activity or routine, when a caregiver or educator is attempting to maintain attention in a joint task. The latter ‘‘distractibility’’ is best managed with educational and behavioral strategies and pharmacologic interventions that target repetitive behaviors (Table 10.6). With random inattention, the cautious use of stimulants at the lower end of the dosage range (e.g., 0.3 mg/kg/dose for methylphenidate) is possible, provided the child is closely monitored for side effects (irritability, excitability, insomnia, anorexia, and an increase in rituals and stereotypies). Opioid antagonists

Modest clinical benefits have been described for naltrexone in autistic children at daily doses of 0.5–2 mg/kg with reduced restlessness and hyperactivity and improved attention (Koleman et al., 1995; Herman et al., 1993; Leboyer et al.,

291


1992; Scifio et al., 1991; Campbell et al., 1990). Variable effects have been reported on social communication and there does not appear to be a beneficial effect on learning (Koleman et al., 1997). In several uncontrolled trials, naltrexone has reduced self-injurious behaviors, stereotypies, and other compulsive behaviors. However, in an 8 week double-blind, placebo-controlled study (Campbell et al., 1993), naltrexone did not decrease self-injurious behavior and there was a rebound increase in symptoms toward the latter part of the placebo period. The variable findings may relate to the biochemical heterogeneity of PDD. Bouvard et al. (1995) have suggested that pretreatment elevations of arginine– vasopressin levels, 5-HT levels, and possibly elevated terminal beta-endorphin and noradrenaline levels, with normalization of these during naltrexone treatment, may be predictive of a positive response, implying a subgroup of responders. The small differences observed between drug and placebo may relate to the long half-life of naltrexone (24 hours) with some carryover into a placebo period with a crossover design. In these studies, naltrexone has been reported as being well tolerated with mild sedation being the main side effect and decreased appetite and ‘‘running nose’’ also noted. Liver function tests remained within normal limits. Principles of assessment and management The assessment of children and adolescents with PDD is an interdisciplinary process. The goal of assessment is to obtain a coherent view of the child so that a management plan can be developed that optimizes functionality of communication and social adaptive skills, and minimizes interfering behaviors. As a result of the complexity and chronicity of these disorders, the assessment process is the beginning of a partnership between the child’s caregivers (including parents), educators, and habilitation therapists (speech and occupational therapist) that allows treatment interventions to be maximized, monitored, and changed contingent on the child’s progress. Pharmacologic treatment must be seen in the context of an overall treatment plan. An overview of general assessment is outlined in Table 10.7. Given the differences in clinical presentations for the categories of PDDs and the IQ span within the autistic disorders, clinical judgement will guide the nature of assessment instruments used, particularly in the areas of cognitive and communications assessment. Modification of test instruments and procedures may be necessary to obtain information that is relevant to the child’s developmental needs. Wherever possible, parents should be encouraged to observe the

292

S.N. Fisman

Table 10.7. PDD: overview of assessment Psychiatric/medical assessment History of presenting difficulties ∑ communication/imagination/play ∑ social reciprocity ∑ behavior Developmental history ∑ pregnancy/delivery/neonatal period ∑ social–emotional development infant temperament/early attachment eye contact social smiling/anticipatory gestures stranger/separation anxiety development of relationships ∑ language development prelanguage skills intent to communicate expressive/receptive language milestones deviant language e.g., echolalia, pronoun reversal development of play skills ∑ motor development ∑ skill development General medical history and physical examination ∑ baseline physical parameters ∑ gross and fine motor coordination Family history ∑ developmental disabilities/psychiatric illness ∑ family coping/support ∑ sibling adjustment Observational interview of child ∑ mental status examination ∑ relatedness ∑ separation behavior Anciliary tests/information Preschool/school report Psychologic evaluation ∑ cognitive testing using a nonverbal measure if indicated e.g., Leiter International Performance Scale ∑ measure of adaptive behavior e.g., Vineland Adaptive Behavior Scale Speech/language evaluation Occupational therapy assessment when indicated for skill assessment

293


assessment of their child and siblings should be included in the interviews. Parental observation demystifies the procedures and provides common ground for subsequent discussion of observations (Morgan, 1988). Including siblings in the definition of family and providing them with age-appropriate information about their handicapped sibling, as well as defining their needs for support, will improve their outcome for adjustment (Fisman et al., 2000). Choice of pharmacologic agent

Initial medication choice is guided by targeting the most interfering symptom(s) for the child and caregivers (Table 10.6). While monotherapy is ideal, combination pharmacotherapies may be necessary to optimize response. This demands caution and cognisance of potential drug interactions. Since they target several symptoms, the neuroleptics are often the drugs of first choice. With the likelihood that psychoactive agents, especially when effective, will be used for lengthy periods of time, the atypical neuroleptics, especially risperidone, may be a preferable initial choice rather than the high potency agents such as haloperidol. Baseline evaluations

Medical A general physical examination with baseline height, weight, pulse, and blood pressure is recommended. Pretreatment baseline liver functions and a complete blood count are also suggested and the latter is essential if the use of clozapine is contemplated. A pretreatment EKG is necessary when using clomipramine in children and is suggested if higher doses of risperidone are contemplated (4–6 mg or greater). An EEG must be done prior to clozapine use in children to rule out EEG abnormalities. Neurologic As a result of the risks for development of abnormal movements with the neuroleptics, a baseline is necessary to rule out pre-existing stereotypies and dyskinetic movements. The Abnormal Involuntary Movement Scale (AIMS) (Green, 1995) is recommended at baseline and at 6–12 month intervals during treatment and treatment withdrawal to assess dyskinetic symptoms, and the Extrapyramidal Rating Scale (ESRS) (Chouinard et al., 1980) to assess extrapyramidal symptoms and involuntary movements at baseline and with follow-up visits.

294

S.N. Fisman

Psychiatric A baseline profile of symptoms that become the target for pharmacologic intervention can be established using a general scale such as the Aberrant Behavior Checklist (ABC) (Aman et al., 1985), and/or a more specific rating scale such as the Childhood Autism Rating Scale (CARS) (Schopler et al., 1988). A global rating scale such as the Childrens’ Global Assessment Scale (CGAS) (Shaffer et al., 1983) will provide a measure of impairment which can be periodically reviewed to monitor response. Finally, a 10 cm Visual Analog Scale (VAS) can be used to evaluate individual symptom severity and monitor symptom change. Initiating and monitoring treatment

Once informed consent is obtained from the legal guardian, and assent where appropriate from the child or adolescent, treatment is initiated. By beginning with a low-dose of medication that is generally below the therapeutic target dose, low dose responders can be identified and side effects minimized. Dosage increments are guided by the pharmacokinetics of an individual agent, with increments generally following the time it takes the drug to reach steady state. Target dosage is titrated with symptom response and limited by the development of side effects. In the early stages of treatment initiation, regular patient contact is necessary, often by phone, with office visits at 2–3 week intervals as symptom response is evaluated. During maintenance therapy, visits at 3–6 month intervals are adequate. The VAS and ESRS should be regularly evaluated at each visit, along with other baseline measures being repeated at 3–6 month intervals. Inadequate or poor clinical response

The clinician must ensure that an adequate trial (both dosage and duration) has occurred. Consideration may then be given to tapering and discontinuing the initial medication with a trial of an alternative agent. If there has been symptom response to the first medication, but interfering symptoms, which may be targeted with a second drug, continue to impair the child’s function, then a second agent may be introduced. With concurrent use of more than one agent, care must be taken to anticipate possible drug interactions and monitor side effects as well as being cognisant of interactions with nonpsychotropic drugs (Fisman et al., 1996). Long-term psychopharmacologic treatment

Given the chronicity of these disorders, there is often a need for long-term

295


maintenance treatment. The decision to undertake long-term pharmacologic treatment must take into account the risks and benefits for such treatment with caretakers being involved in the decision-making in an informed fashion. It is prudent to evaluate the child’s entire treatment program on an annual basis and a psychopharmacologic review should be part of this. When a decision is made to try a child off-medication, gradual withdrawal is strongly recommended for all agents other than fluoxetine (which can be abruptly stopped). The goal is to prevent rebound emergence of symptoms and withdrawal dyskinesias, particularly with high potency neuroleptics. Summary and conclusions The PDDs are a group of phenomenologically similar, but etiologically heterogeneous, complex disorders that are severely impairing for the individual and present a challenge to parent and teacher. As we gain more understanding of the biologic underpinnings of these disorders, and with an accumulation of evidence for drug effectiveness through methodologically sophisticated trials, pharmacologic interventions will become increasingly rational and important in the overall management of these handicapped individuals.

REFE R EN C ES Alarcon RD, Johnson BR, Lucas JP (1991). Paranoid and aggressive behavior in two obsessivecompulsive adolescents treated with clomipramine. J Am Acad Child Adolesc Psychiatry 30:999– 1002. Alivir JMJ, Lieberman JA, Safferman AZ et al. (1993). Clozapine induced agranulocytosis; incidence and risk factors in the United States. New Engl J Med 329:162–7. Aman MG, Singh NN, Stewart AW (1985). The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 5:485–91. American Psychiatric Association (1994). Diagnostic and Statistical Manual, 4th edn. Washington, DC: APA Press. American Psychiatric Association (1987). Diagnostic and Statistical Manual, 3rd edn revised. Washington, DC: APA Press. American Psychiatric Association (1980). Diagnostic and Statistical Manual, 3rd edn. Washington, DC: APA Press. Anderson GM (1987). Monoamines in autism: an update of neurochemical research on a pervasive developmental disorder. Med Biol 65:67–74. Anderson L, Campbell M (1989). The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord 19:227–39.

296

S.N. Fisman

Anderson L, Campbell M, Grega D et al. (1984). Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry 141:1195–202. Anderson GM, Freedman DX, Cohen DJ et al. (1987). Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 28:885–900. Andreasen NC, Olsen S (1982). Negative vs. positive schizophrenia: definition and validation. Arch Gen Psychiatry 39:789–94. Arin DM, Baumann ML, Kemper TL (1991). The distribution of Purkinje cell loss in the cerebellum in autism. Neurology 41(Suppl):307. Asperger H (1991). Autistic psychopathy in childhood (transl.) In Autism and Asperger Syndrome, (Ed.) U Frith, Cambridge: Cambridge University Press. Awad GA (1996). The use of selective serotonin reuptake inhibitors in young children with pervasive developmental disorders: some clinical observations. Can J Psychiatry 41:361–6. Baldessarini RJ (1990). Drugs and the treatment of psychiatric disorders. In The Pharmacological Basis of Therapeutics, (Eds.) Goodman and Gillman, 8th edn. New York: Pergamon Press, pp. 383–435. Baron-Cohen S (1993). From attention-goal psychology to belief-desire psychology: the development of a theory of mind, and its dysfunction. In Understanding Other Minds: Perspectives from Autism, (Eds.) S Baron-Cohen, H Tager-Flusberg, DJ Cohen. Oxford: Oxford University Press. Baron-Cohen S (1989). The autistic child’s theory of mind: a case of specific developmental delay. J Child Psychol Psychiatry 30:285–97. Baron-Cohen S, Leslie A, Frith U (1985). Does the autistic child have a ‘‘theory of mind’’? Cognition 21:37–46. Barthelemy C, Bruneau N, Conet-Eymard JM (1988). Urinary free and conjugated catecholamines and metabolites in autistic children. J Autism Dev Disord 18:583–91. Bauman ML (1991). Microscopic neuroanatomic abnormalities in autism. Pediatrics 87(Suppl):791–6. Berman KF, Illowsky BP, Weinberger DR (1988). Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia: further evidence for regional and behavioral specificity. Arch Gen Psychiatry 45:616–22. Bettes BA, Walker E (1987). Positive and negative symptoms in psychotic and other psychiatrically disturbed children. J Child Psychol Psychiatry 28:555–68. Birmaher B, Quintana H, Greenhill LL (1988). Methylphenidate treatment of hyperactive autistic children. J Am Acad Child Adolesc Psychiatry 27:248–51. Borghese IF, Herman BH, Asleson GS et al. (1991). Effects of acutely administered naltrexone on social behavior of autistic children. Soc Neurosci Abs 17:1252. Bouvard MP, Leboyer M, Launy JM et al. (1995). Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res 58:191–201. Bowler DM (1992). ‘‘Theory of mind’’ in Asperger’s syndrome. J Child Psychol Psychiatry 33:877–93. Brasic JR, Barnett JY, Kaplan D et al. (1994). Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation.

297


Neurology 44:1309–12. Brasic JR, Barnett JY, Sheitman BB et al. (1997). Adverse effects of clomipramine (letter). J Am Acad Child Adolesc Psychiatry 36:1165. Braverman M, Fein D, Lucci D et al. (1989). Affective comprehension in children with pervasive developmental disorders. J Autism Dev Disord 19:301–16. Brodkin ES, McDougle CJ, Naylor ST et al. (1997). Clomipramine in adults with pervasive developmental disorders: a prospective open-label investigation. J Child Adolesc Psychopharmacol 7:109–21. Brook SI, Bowler DM (1992). Autism by another name? Semantic and pragmatic impairments in children. J Autism Dev Disord 22:61–81. Bryson SE, Wainwright-Sharp JA, Smith IM (1990). Autism: a developmental spatial neglect syndrome? In The Development of Attention: Research and Theory, (Ed.) J Enns. Amsterdam: Elsevier. Buitelaar JK, van der Gaag RJ, van der Hoeven J (1998). Buspirone in the management of anxiety and irritability in children with pervasive developmental disorders: results of an open-label study. J Clin Psychiatry 59:56–9. Buitelaar JK, van Engeland H, de Kogel K et al. (1980). The adrenocorticotrophic hormone (4–9) analogue ORG 2766 benefits autistic children: report on a second controlled clinical trial. J Am Acad Child Adolesc Psychiatry 31:1149–56. Buitelaar J, van Engeland H, van Ree J et al. (1990). Behavioral effects of Org 2766, a synthetic analog of the adrenocorticotrophic hormone (4–9), in 14 outpatient autistic children. J Autism Dev Disord 20:467–78. Campbell M, Armenteros JL, Malone RP et al. (1997). Neuroleptic related dyskinesias in autistic children: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 36:835–43. Campbell M, Adams P, Small A et al. (1988). Efficacy and safety of fenfluramine in autistic children. J Am Acad Child Adolesc Psychiatry 27:434–9. Campbell M, Anderson L, Meier M et al. (1978). A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad Child Psychiatry 17:649–55. Campbell M, Anderson LT, Small AM et al (1993). Naltrexone in autistic children: behavioral symptoms and attentional learning. J Am Acad Child Adolesc Psychiatry 32:1283–91. Campbell M, Anderson L, Small A et al. (1990). Naltrexone in autistic children: a double-blind and placebo-controlled study. Psychopharmacol Bull 26:130–5. Campbell M, Fish B, Korein J et al. (1972). Lithium and chlorpromazine: a controlled cross-over study of hyperactive severely disturbed young children. J Autism Child Schizophrenia 1:267–82. Campbell M, Fish B, Shapiro T et al. (1971). Imipramine in preschool schizophrenic and autistic children. J Autism Child Schizophrenia 2:234–64. Campbell M, Small A, Collins P et al. (1976). Levodopa and levoamphetamine: a cross-over study in young schizophrenic children. Curr Ther Res 19:70–83. Cantor DS, Thatcher RW, Hrybyk M et al. (1986). Computerized EEG analysis of autistic children. J Autism Dev Disord 16:169–87. Casaer P, Walleghem D, Vandenbussche I et al. (1994). Pharmacokinetics and safety of risperidone in autistic children. Pediatr Neurol 11:89.

298

S.N. Fisman

Chouinard G, Arnott W (1993). Clinical review of risperidone. Can J Psychiatry 38(Suppl 3): 589–95. Chouinard G, Ross-Canard A, Annable L et al. (1980). The extrapyramidal rating scale. Can J Neurol Sci 7:233. Clomipramine Collaborative Study Group (1991). Clomipramine in the treatment of patients with obsessive-compulsive disorder. Arch Gen Psychiatry 48:730–8. Cohen I, Campbell M, Posner D et al. (1980). Behavioral effects of haloperidol in young autistic children. J Am Acad Child Psychiatry 19:665–7. Cohen DJ, Pauls D, Volkmar FR (1994). Recent research in autism in psychoses and pervasive developmental disorders. Child Adolesc Psychiatr Clin North Am 3:161–71. Cohen I, Tsiouris JA, Pfadt A (1991). Effects of long-acting propranolol on agonistic and stereotyped behaviors in a man with pervasive developmental disorder and fragile-X syndrome: a double-blind, placebo-controlled study. J Clin Psychopharmacol 11:398–9. Cook E, Leventhal B (1995). Autistic disorder and other pervasive developmental disorders in pediatric psychopharmacology II. Child Adolesc Clin North Am 4:381–99. Cook EH, Rowlett R, Jaselskis C et al. (1992). Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 31:739–45. Courchesne E, Saitoh O, Yeung Courchesne R et al. (1994). Abnormalities of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups by MR imaging. Am J Roentgenol 162:123–30. Creak M (1963). Schizophrenic syndrome in childhood: further progress of a working party. Dev Med Child Neurol 6:530–5. Dahlgren SO, Trillingsgaard A (1996). Theory of mind in non-related children with autism and Asperger’s syndrome. A Research Note. J Child Psychol Psychiatry 37:759–63. DeLong GR, Dwyer JT (1988). Correlation of family history with specific autistic subgroups: Asperger’s syndrome and bipolar affective disease. J Autism Dev Disord 18:593–600. Demb HB (1996). Risperidone in young children with pervasive developmental disorders and other developmental disabilities. J Child Adolesc Psychopharmacol 6:79–80. Dollfus S, Petit M (1992). Amisulpride versus bromocriptine in infantile autism: A controlled crossover comparative study of two drugs with opposite effects on dopaminergic function. J Autism Dev Disord 22:47–60. Dow RS (1974). Some novel concepts of cerebellar physiology. Mt Sinai J Med 41:103–19. Earnst M, Magee HJ, Gonzalez NM et al. (1992). Pimozide in autistic children. Psychopharmacol Bull 28:187–91. Edleman RJ (1996). Risperidone side effects. J Am Acad Child Adolesc Psychiatry 35:4–5. Elkman G, Miranda-Linne F (1989). Fenfluramine treatment of twenty children with autism. J Autism Dev Disord 19:511–32. Eufemia PD, Finocchiaro R, Celli M et al. (1995). Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism. Biomed Pharmacother 49:288–92. Fankhauser MP, Karumanchi VC, German ML et al. (1992). A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry 53:77–82. Findling RL, Maxwell K, Wiznitzer M (1997). An open clinical trial of risperidone monotherapy

299


in young children with autistic disorder. Psychopharmacol Bull 33:155–9. Fish B, Shapiro T, Campbell M (1966). Long-term prognosis and the response of schizophrenic children to drug therapy: a controlled study of trifluoperazine. Am J Psychiatry 123:32–9. Fisman S, Steele M (1996). Use of risperidone in pervasive developmental disorders: a case series. J Child Adolesc Psychopharmacol 6:177–90. Fisman S, Reniers D, Diaz P (1996). Erythromycin interaction with risperidone or clomipramine in an adolescent. J Child Adolesc Psychopharmacol 6:133–8. Fisman S, Steele M, Pipher B (1998). Risperidone in PDD (letter). J Am Acad Child Adolesc Psychiatry 37:15–16. Fisman SN, Wolf LC, Ellison D et al. (2000). A longitudinal study of siblings with chronic disabilities. Can J Psychiatry 45:369–75. Frith U (1991). Autism and Asperger Syndrome. New York: Cambridge University Press. Frith CD, Friston KJ, Herold S et al. (1995). Regional activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 167:342–9. Garreau B, Barthelemy C, Jouve J et al. (1988). Urinary homovanillic acid levels of autistic children. Dev Med Child Neurol 30:93–8. Ghaziuddin M, Tsai L, Ghaziuddin N (1991). Fluoxetine in autism with depression. J Am Acad Child Adolesc Psychiatry 30:508–9. Gillberg C (1995). Clinical Child Neuropsychiatry. New York: Cambridge University Press. Gillberg C (1992). Autism and autistic-like conditions: subclasses among disorders of empathy. J Child Psychol Psychiatry 33:813–42. Gillberg C (1991). Outcome in autism and autistic-like conditions. J Am Acad Child Adolesc Psychiatry 30:375–82. Gillberg C, Svennerholm L (1987). CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry 151:89–94. Gillberg C, Svennerholm L, Hamilton-Hellberg C (1983). Childhood psychosis and monoamine metabolites in spinal fluid. J Autism Dev Disord 13:383–96. Gillberg C, Terenius L, Lonnerholm G (1985). Endorphin activity in childhood psychosis. Arch Gen Psychiatry 42:780–3. Gordon CT, Rapoport RL, Hamburger SD et al. (1992). Differential response of seven subjects with autistic disorder to clomipramine and desipramine. Am J Psychiatry 149:363–6. Green WH (1995). Abnormal involuntary movement scale modified from Department of Health Education and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH. In Child and Adolescent Psychopharmacology, 2nd. edn. Baltimore, MD: Williams and Wilkins, pp. 32–3. Green J (1990). Is Asperger’s a syndrome? Dev Med Child Neurol 32:743–7. Haller E, Binder RL (1990). Clozapine and seizures. Am J Psychiatry 146:1069–71. Hameury L, Roux S, Barthelemy C et al. (1995). Qualified multidimensional assessment of autism and other pervasive developmental disorder: application for bioclinical research. Eur Child Adolesc Psychiatry 4:123–35. Hellings JA, Kelley LA, Gabrielli WF et al. (1996). Sertraline response in adults with mental retardation and autistic disorder. J Clin Psychiatry 57:333–6.

300

S.N. Fisman

Herman B, Arthur-Smith A, Vereby K et al. (1988). Effects of acute administration of naltrexone on plasma concentrations of naltrexone, 6-B-naltrexol, beta-endorphin and cortisol in children. Soc Neurosci Abs 14:465. Herman B, Asleson G, Papero P (1993). Acute and chronic naltrexone decreases the hyperactivity of autism. Soc Neurosci Abs Abstract 732–3. Hobson RP (1988). Beyond cognition: a theory of autism. In Dawson CJ (Ed.), Autism: New perspectives on diagnosis, nature and treatment. New York: Guilford Press. Hobson RP (1991). Methodological issues for experiments on autistic individuals’ perception and understanding of emotion. J Child Psychol Psychiatry 32:1135–58. Horne JA (1993). Human sleep, sleep loss and behavior. Implications for the prefrontal cortex and psychiatric disorder. Br J Psychiatry 162:413–19. Horrigan JP, Barnhill LJ (1997). Risperidone and explosive aggressive autism. J Autism Dev Disord 27:313–23. Horrigan JP, Barnhill LJ, Courvoisie HE (1997). Olanzepine in PDD (Letter). J Am Acad Child Adolesc Psychiatry 36:1166. Hughes, C, Russell, J. (1993). Autistic children’s difficulty with mental disengagement from an object: its implications for theories of autism. Dev Psychology 29:498–510. Insel TR (1992). Oxytocin – a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies. Psychoneuroendocrinology 17:3–35. Janssen PAJ, Niemegeers CJE, Awouters FHL et al. (1988). Pharmacology of risperidone (R64766), a new antipsychotic with serotonin-5-HT2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–93. Jaselskis CA, Cook EH, Fletcher KE et al. (1992). Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 12:322–7. Jones PB, Kerwin RW (1990). Left temporal lobe damage in Asperger’s syndrome. Br J Psychiatry 156:570–2. Joshi PT, Capozzoli JA, Coyle JT (1988). Low-dose neuroleptic therapy for children with childhood-onset pervasive developmental disorder. Am J Psychiatry 145:335–8. Kanner L (1943). Autistic disturbances of affective contact. Nerv Child 2:217–50. Kay SR, Opler LA, Lindenmayer JP (1987). Reliability and validity of the Positive and Negative Symptom Scale for Schizophrenia. Psychiatry Res 23:99–110. Koleman BK, Feldman HM, Handen BL et al. (1997). Naltrexone in young autistic children: replication study and learning measures. J Am Acad Child Adolesc Psychiatry 36:1570–8. Koleman BK, Feldman HM, Handen BL et al. (1995). Naltrexone in young autistic children: a double-blind, placebo-controlled crossover study. J Am Acad Child Adolesc Psychiatry 34:223–31. Kolvin I (1971). Studies in childhood psychosis. I Diagnostic criteria and classification. Br J Psychiatry 118:381–4. Kumra S, Herion D, Jacobsen LK et al. (1997). Case study: risperidone-induced hepatotoxicity in pediatric patients. J Am Acad Child Adolesc Psychiatry 36:701–5. Leboyer M, Bouvard M, Launay J-M et al. (1992). Brief report: a double-blind study of naltrexone in infantile autism. J Autism Dev Disord 22:309–19. Leventhal BL, Cook EH, Morford M et al. (1990). Relationships of whole blood serotonin and

301


plasma norepinephrine within families of autistic children. J Autism Dev Disord 20:499–511. Lord C, Schopler E (1988). Intellectual and developmental assessment of autistic children from preschool to school age: clinical implications of two follow-up studies. In Diagnosis and Assessment in Autism, (Eds.) E Schopler, GB Mesibov. New York: Plenum Press, pp. 161–81. Marchetti B, Scifo R, Batticane N et al. (1990). Immunological significance of opioid peptide dysfunction in infantile autism. Brain Dysfunction 3:346–54. Martineau J, Barthelemy C, Jouve J et al. (1992). Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age related changes and drug effects. Dev Med Clin Neurol 34:593–603. McDougle CJ, Brodkin ES, Yeung PP et al. (1995). Risperidone in adults with autism or pervasive development disorder. J Child Adolesc Psychopharmacol 5:273–82. McDougle CJ, Holmes JP, Bronson MR et al. (1997). Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study. J Am Acad Child Adolesc Psychiatry 36:685–93. McDougle CJ, Naylor ST, Cohen DJ et al. (1996a). A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 53:1001–8. McDougle CJ, Naylor ST, Cohen DJ et al. (1996b). Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 53:993–1000. McDougle CJ, Price LH, Volkmar FR et al. (1992). Clomipramine in autism: preliminary evidence of efficacy. J Am Acad Child Adolesc Psychiatry 31:746–50. Mehlinger R, Scheftner WA, Poznanski E et al. (1990). Fluoxetine and autism (letter). J Am Acad Child Adolesc Psychiatry 29:985. Minderaa RB, Anderson GM, Volkmar FR et al. (1994). Noradrenergic and adrenergic function in autism. Biol Psychiatry 36:237–41. Minderaa RB, Anderson GM, Volkmar FR et al. (1989). Neurochemical study of dopamine functioning in autistic and normal subjects. J Am Acad Child Adolesc Psychiatry 28:190–4. Morgan S (1988). The autistic child and family functioning: a developmental-family systems perspective. J Autism Dev Disord 18:263. Mundy P. (1995). Joint attention and social-emotional approach behavior in children with autism. Dev Psychopathol 7:63–82. Nagamitsu S, Matsuishi T, Kisa T et al. (1997). CSF beta-endorphins in patients with infantile autism. J Autism Dev Disord 27:155–63. Narayan M, Srinath S, Anderson GM et al. (1993). Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry 33:630–5. Naruse H, Nagahata M, Nakane Y et al. (1982). A multi-center double-blind trial of pimozide (Orap), haloperidol and placebo in children with behavioral disorders, using crossover design. Acta Paedopsychiatr 48:173–84. Nicolson R, Awad G, Sloman L (1988). An open trial of risperidone in young autistic children. J Am Acad Child Adolesc Psychiatry 37:372–6. O’Leary DS, Schlaggar BL, Tuttle R (1994). Specification of neocortical areas and thalamic connections. Ann Rev Neurosci 17:419–39. Ornitz EM (1985). Neuropsychology of infantile autism. J Am Acad Child Psychiatry 24:251–62.

302

S.N. Fisman

Ozonoff S, McEvoy RE (1994). A longitudinal study of executive dysfunction and theory of mind development in autism. Dev Psychopathol 6:415–31. Ozonoff S, Rogers SJ, Pennington BF (1991). Asperger’s syndrome: evidence of an empirical distinction from high functioning autism. J Child Psychol Psychiatry 32:1107–22. Panksepp J, Sahley TL (1987). Possible brain opioid involvement in disrupted social intent and language development in autism. In Schopler E, Mesibov GB (Eds.): Neurobiological Issues in Autism. New York: Plenum Press, pp. 357–72. Perry R, Campbell M, Adams P et al. (1989). Long-term efficacy of haloperidol in autistic children: continuous versus discontinuous drug administration. J Am Acad Child Adolesc Psychiatry 28:87–92. Perry R, Pataki C, Munoz-Silva DM et al. (1997). Risperidone in children and adolescents with pervasive developmental disorder: pilot trial and follow-up. J Child Adolesc Psychopharmacol 7:167–79. Piven J, Arndt S, Bailey J et al. (1995). Regional brain enlargement in autism: a magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry 35:530–6. Piven J, Saliba K, Bailey J, Arndt S (1997). An MRI of autism: the cerebellum revisited. Neurology 49:546–51. Piven J, Tsai G, Nehme E et al. (1991). Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord 21:51–9. Plioplys A (1994). Autism: electroencephalographic abnormalities and clinical improvement with valproic acid. Arch Pediatr Adolesc Med 148:220–2. Posner MI, Peterson SE (1990). The attention span of the human brain. Ann Rev Neurosci 13:25–42. Potenza MN, Holmes JP, Kanes SJ, McDougle CJ (1999). Olanzapine treatment of children, adolescents and adults with pervasive development disorders: an open-label pilot study. J Clin Psychopharmacol 19:37–44. Purdon SE, Wilson L, Labelle A et al. (1994). Risperidone in the treatment of pervasive developmental disorder. Can J Psychiatry 39:400–5. Quintana H, Birmaher B, Stedge D et al. (1995). Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 25:283–94. Rajakumar M, Williamson PC, Stoessl AJ et al. (1998). Dopaminergic hyperresponsivity following neonatal lesions of the mediodorsal thalamic nuclei in the rat: a neurodevelopmental model of schizophrenia. Dev Neurosci 604:822–35. Ratey JJ, Mikkelsen EJ, Smith GB et al. (1986). B-blockers in the severely and profoundly mentally retarded. J Clin Psychopharmacol 6:103–7. Ratey J, Mikkelsen E, Sorgi P et al. (1987). Autism: the treatment of aggressive behaviors. J Clin Psychopharmacol 7:35–41. Ratey J, Sovner R, Mikkelsen E et al. (1989). Buspirone therapy for maladaptive behavior and anxiety in developmentally disabled persons. J Clin Psychiatry 50:382–4. Realmuto GM, August GJ, Garfinkel B (1989). Clinical effect of buspirone in autistic children. J Clin Psychopharmacol 9:122–5. Ross DL, Klykylo WM, Hitzemann R (1987). Reduction of elevated CSF beta-endorphin by

303


fenfluramine in infantile autism. Pediatr Neurol 3:83–6. Rourke, B. (1989). Nonverbal Learning Disabilities: The Syndrome and the Model. New York: Guilford Press. Rutter M, Schopler E (1992). Classification of pervasive developmental disorders: some concepts of practical considerations. J Autism Dev Disord 22:459–82. Sandman CA, Walker BB, Lawton CA (1980). An analog of a–MSH/ACTH 4–9 enhances interpersonal and environmental awareness in mentally retarded adults. Peptides 1:109–14. Schatzberg AF, Nemeroff CB (1988). Tricyclics and Tetracyclics. In Textbook of Psychopharmacology, 2nd edn. Washington, DC: American Psychiatry Association Press, pp. 199–218. Schopler E, Reichler RJ, Renner BR (1988). The Childhood Autism Rating Scale (CARS). Los Angeles: Western Psychological Services. Schuster C, Lewis M, Seiden L (1986). Fenfluramine: neurotoxicity. Psychopharmacol Bull 22:148– 51. Scifio R, Batticane N, Quattropani MC et al. (1991). A double-blind trial with naltrexone in autism. Brain Dysfunction, 4:301–7. Semrud-Clikeman M, Hynd GW (1990). Right hemispheric dysfunction in nonverbal learning disabilities: social, academic, and adaptive functioning in adults and children. Psychol Bull 197:196–209. Shaffer D, Gould M, Brasic J et al. (1983). A children’s global assessment scale (CGAS). Arch Gen Psychiatry 40:1228–31. Shay J, Sanchez LE, Cueva JE et al. (1993). Neuroleptic related dyskinesias and stereotypies in autistic children: videotaped ratings. Psychopharmacol Bull 29:359–63. Short AB, Schopler E (1988). Factors relating to age of onset in autism. J Autism Dev Disord 18:207–16. Sigman M, Arbelle S, Dissanayake C (1995). Current research findings in childhood autism. Can J Psychiatry 40:289–94. Simeon JG, Carrey NJ, Wiggins DM et al. (1995). Risperidone effects in treatment-resistant adolescents: preliminary case reports. J Child Adolesc Psychopharmacol 5:69–79. Smith IM, Bryson SE (1994). Imitation and action: a critical review. Psychol Bull 116:259–73. Sparrevohm R, Howie PM (1995). Theory of mind in children with autistic disorder: evidence of developmental progression and the role of verbal ability. J Child Psychol Psychiatry 36:249–63. Sporn A, Pinsker H (1981). Use of stimulant medication in treating pervasive developmental disorder. Am J Psychiatry 138:997. Steingard RJ, Zimnitzky B, DeMaso DR et al. (1997). Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. J Child Adolesc Psychopharmacol 7:9–15. Strayhorn JM Jr, Rapp N, Donina W et al. (1988). Randomized trial of methylphenidate for an autistic child. J Am Acad Child Adolesc Psychiatry 27:244–7. Szatmari P, Archer L, Fisman S et al. (1995). Asperger’s syndrome and autism: differences in behavior, cognition and adaptive functioning. J Am Acad Child Adolesc Psychiatry 34:1662–71. Szatmari P, Tuff L, Finlayson AJ et al. (1990). Asperger’s syndrome and autism. Neurocognitive aspects. J Am Acad Child Adolesc Psychiatry 29:130–6. Tanguay PE (1974). A tentative hypothesis regarding the role of hemispheric specialization in

304

S.N. Fisman

early infantile autism in cerebral dominance. BIS report 34:27–9, University of California, Los Angeles. Todd RD (1991). Fluoxetine in autism. Am J Psychiatry 148:1089. Venter A, Lord C, Schopler E (1992). A follow-up of high-functioning autistic children. J Child Psychol Psychiatry 33:489–507. Volkmar FR, Cicchetti DV, Bregman J et al. (1992). Three diagnostic systems for autism: DSMIII, DSMIII-R and ICD-10. J Autism Dev Disord 22:483–92. Volkmar FR, Stier DM, Cohen DJ (1985). Age of recognition of pervasive developmental disorder. Am J Psychiatry 142:1450–2. Weizman R, Weizman A, Thano S et al. (1984). Humoral-endorphin blood levels in autistic schizophrenic and healthy subjects. Psychopharmacology 82:368–70. Willemsen-Swinkels MS, Buitelaar JK, Nijhof GJ et al. (1995). Failure of naltrexone hydrochloride to reduce self-injurious and autistic behavior in mentally retarded adults: double-blind placebo-controlled studies. Arch Gen Psychiatry 52:766–73. Williams DT, Mehl R, Yudofsky S et al. (1982). The effect of propranolol on uncontrolled rage outbursts in children and adolescents with organic brain dysfunction. J Am Acad Child Adolesc Psychiatry 21:129–35. Wing L (1986). Clarification of Asperger’s syndrome. J Autism Dev Disord 16:513–15. Wing L (1981). Asperger’s syndrome. A clinical account. Psychol Med 11:115–29. Wing L, Gould J (1979). Severe impairments of social interaction and associated abnormalities in children; epidemiology and classification. J Autism Dev Disord 9:11–29. Wolf L, Goldberg B (1986). Autistic children grow up: an eight to twenty-four year follow-up study. Can J Psychiatry 31:550–6. World Health Organization (1992). ICD-10. Classification of Mental and Behavioral Disorders, Clinical Description and Diagnostic Guidelines. Geneva: World Health Organization. Young GJ, Kavanaugh ME, Anderson GM et al. (1982). Clinical neurochemistry of autism and associated disorders. J Autism Dev Disord 12:147–65. Zilbovicius M, Garreau B, Samson Y et al. (1995). Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry 152:248–52. Zohar J, Insel TR, Zohar-Kadouch RC et al. (1988). Serotonergic responsivity in obsessivecompulsive disorder: effects of chronic clomipramine treatment. Arch Gen Psychiatry 45:167– 72. Zuddas A, Ledda MG, Fratta A et al. (1996). Clinical effects of clozapine on autistic disorder. Am J Psychiatry 153:738.

11 Aggressive behavior Deborah Lynn1 and Bryan H. King2 1

UCLA Neuropsychiatric Institute, Los Angeles, California, USA Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA

2

Aggression and violence are often not precisely defined, and their study is complicated as a result. Moreover, there is no consensus definition, and many qualifiers occur in the literature including affective, instrumental, impulsive, reactive, and environmental aggression. Rippon (2000) recently reviewed definitions of aggression and identified some constants: intent on the part of the aggressor, an act (physical or verbal, active or passive, direct or indirect), and resultant physical or psychologic harm. The psychopharmacology of aggression in humans typically focuses on physical, active, and direct aggressive acts. Broadly defined, aggression is a significant problem in child psychiatry, with some studies showing that aggression, conduct problems, and antisocial behavior account for one-third to one-half of all child and adolescent psychiatric clinic referrals (Kazdin, 1987). In some special populations – for example, persons with mental retardation or traumatic brain injury – the percentage may be even higher (King et al., 1994). The treatment of aggression in children with medications is also complex (Connor and Steingard, 1996; Stewart et al., 1990). Of the many issues involved, two stand out in bold relief. The first issue is that aggression as a symptom is seen in the context of a variety of psychiatric diagnoses. These include disruptive behavior disorders like Attention-deficient/hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD). Aggression can also occur in post-traumatic stress disorder (PTSD), psychotic disorders, mood disorders, seizure disorder, pervasive developmental disorders, mental retardation, and traumatic brain injuries (Fava, 1997). The second issue is that aggression is poorly understood in terms of its neurobiologic underpinnings and environmental precipitants. Is aggression in the context of CD different from that which occurs in mood disorders? Does it make sense to isolate aggressive behavior as a symptom for treatment? Theorists have attempted to clarify the study of aggression by conceptually 305

306

D. Lynn, B.H. King

categorizing its various forms. A commonly accepted way of categorizing aggression is to sort aggression into a dual system of an impulsive-reactivehostile-affective subtype vs. a controlled-proactive-instrumental-predatory subtype (Vitiello and Stoff, 1997). Another way to subtype aggression is by its target. To this end, we typically discriminate between aggression to one’s self, aggression toward others, and aggression to objects. The focus of this chapter will be aggression directed outside of one’s self. Biologic and developmental markers of aggression Our basic understanding of the neurobiologic underpinnings of aggression is limited. Some studies have attempted to chisel away at the complexity of human aggression from a neurophysiologic stand-point. These studies have looked for potential markers for aggression including stress hormones, indices of neurotransmitter function, and androgens. Schulz et al. (1997) identified a subgroup of boys with ADHD and a history of physical cruelty to animals, forcing someone into sexual activity, using a weapon in more than one fight, frequent initiation of physical fights, stealing with confronting a victim, or physical cruelty to others. When compared with a group of boys with ADHD alone, the ‘‘aggressive’’ group was no different with regard to plasma cortisol levels in single serum samples. This finding differs from the general experience in studies of adults where an inverse correlation between aggression and cortisol levels seems to exist; interestingly, similar associations have been described for inattention and overactivity in children (Scerbo and Kolko, 1994). Halperin et al. (1997, 1994) also studied boys with ADHD with or without aggression, but examined serotonergic function. Using the prolactin response to a fenfluramine challenge, they observed only a significant age-group interaction with aggression. Thus, young aggressive boys had a significantly greater prolactin response to fenfluramine than young nonaggressive boys, but this difference did not persist in the older age-group. This study implies that there is perhaps a ‘‘developmental lesion’’ that begins as aggression in children and may change as maturation occurs, resulting in variation in adult aggressive behavior. However, adult studies have not consistently supported a relationship between aggression and the prolactin response to fenfluramine (Coccaro et al., 1997; Stoff et al., 1992). Pine et al. (1996) studied 126 younger brothers of convicted delinquents in New York City. Results showed associations between elevated score on the Childhood Behavior Checklist (CBCL) delinquency scale and elevated blood

307

Aggressive behavior

pressure, obesity, a family history of hypertension, and heart period variability (HPV). The finding of associated abnormalities with HPV may be due to high comorbidity between the externalizing score on the CBCL and anxiety disorder per the Diagnostic Interview Schedule for Children (DISC), which is also a predictor for HPV abnormalities. Associations between aggression and serotonergic measures were in agreement with Halperin’s findings (Halperin et al., 1997, 1994). The 10 boys identified with ODD or CD had an augmented prolacting response to fenfluramine relative to a group of 13 other boys going through the procedure. There have been many studies that have tried to elucidate the proposed link between the serotonergic system and aggression. Unis et al. (1997) found a significant increase in whole blood serotonin (5-HT) levels in adolescents with a childhood-onset of CD compared with adolescents with adolescent-onset of CD. There was a positive correlation between whole blood 5-HT levels and global measures of aggression. Appropriate social skills were negatively correlated with whole blood 5-HT as were self-report scores on impulsivity and recalcitrant symptoms. Indeed, most of the data linking serotonin and aggression indicate that a relative deficiency state or reduced serotonergic function predicts aggressive behavior. Birmaher and colleagues (1990), for example, studied platelet imipramine binding, another index of serotonergic function, in children and adolescents with impulsive behavior. This group also used the CBCL to capture the severity of aggressive behavior, and observed that platelet imipramine binding was inversely correlated with the degree of aggression and impulsivity. The relationship between testosterone and aggression in childen and adolescents has also been investigated. Constantino and colleagues (1993) did not observe significant differences in serum testosterone, DHEA (dehydroepiandrosterone), DHEAS (dehydrosterone sulfate) or serum SHBG (sex hormone binding globulin) in aggressive vs. nonaggressive preadolescent children. However, these investigators had relatively small sample and control groups as well as only a single measurement of the hormones. Scerbo and Kolko (1994) studied 37 boys and three girls from a 7-week treatment program for children with disruptive disorders, 7–14 years old. They found a positive correlation with salivary testosterone and teacher- and staff-rated aggression. There was also a positive correlation with hormone and inattention/overactivity ratings by parents and teachers.

System

Vervet monkey

Firemouth cichlid (fish) Rhesus monkey

Mouse

Rat

Mouse

Rat

Transgenic mouse

Author

Raleigh et al. (1991)

Adams et al. (1996) Kraemer et al. (1997)

Brunner and Hen (1997)

McMillen et al. (1988)

Sanchez and Meier (1997)

De Almeida and Lucion (1994)

Moechars et al. (1998)

Reuptake inhibitor Reuptake inhibitor Reuptake inhibitor 5-HT-1A agonist 5-HT-2A antagonist

Sertraline Fluvoxamine Fluoxetine 8-OH DPAT Ritanserin

5-HT-1A agonist 5-HT-1B/1D agonist 5-HT-2A agonist 5-HT-1A agonist 5-HT-1A partial agonist 5-HT-2A antagonist

Reuptake inhibitor

Citalopram

8-OH DPAT TFMPP DOI 8-OH DPAT Buspirone Risperidone

Reuptake inhibitor

5-HT-1A partial agonist

Gepirone Paroxetine

5-HT-1A partial agonist

Serotonin depletion Serotonin depletion 5-HT-1A partial agonist 5-HT-1B receptor knockout

Serotonin depletion

Receptor/mechanism

Buspirone

Parachlorophenyl alanine (PCPA) PCPA PCPA Buspirone

Drug

Table 11.1. Serotonergic modulation of aggression in animal models

Increased social aggression No effect Reduced Increased aggression and impulsivity No effect on predatory aggression No effect on predatory aggression No effect on isolation-induced aggression No effect on isolation-induced aggression Reduced Reduced Reduced Reduced Potentiated reductions in combination with DPAT Reduced Reduced Reduced Reduced Reduced Reduced

Increased aggression

Effect on aggression

309

Aggressive behavior

Animal models of aggression This interest in serotonergic involvement in aggression is supported by a number of animal studies in which aggression is modified by serotonergic drugs. These data are highlighted in Table 10.1, from which it would appear that drugs acting as agonists at the 5-HT-1A receptor might be particularly good candidates for the treatment of aggression in humans. Other models of aggression in animals invoke the dopaminergic system (Blackburn et al., 1992), the opioid system (Siegel and Schubert, 1995), substance P (De Felipe et al., 1998), arginine vasopressin (Ferris and Delville, 1994), nitric oxide (Nelson et al., 1995), and other neuroendocrine and hormonal systems (Lopez et al., 1997). The most consistent idea across studies is that interactions among multiple neurotransmitter, neuroendocrine, and hormonal systems regulate aggression of all forms. Pharmacotherapy Given the data briefly reviewed above, one might predict that drugs that affect anxiety or mood might be particularly useful in the treatment of aggression. Indeed, the medications most widely employed in the treatment of aggression, regardless of etiology, include major tranquilizers, antidepressants, and mood stabilizers. These drugs are reviewed below. Lithium

Among the extensive list of drugs used clinically, lithium stands out as one of the better studied medications employed to target aggression in children. Alessi et al. (1994) have summarized the literature on the use of lithium to treat childhood aggression. Of the 58 reports of lithium in child and adolescent psychopathology, 26 (45%) were case series, 22 (39%) were case reports, and only nine (16%) were double-blind placebo-controlled studies. Of the case reports, 16 involved treating manic-depressive disorder (Carlson et al., 1992), only one used lithium to treat aggression, three were treating adolescents with Kleine–Levin syndrome, and two used lithium to treat children who were psychotic or post head trauma. Of the case series, 16 of 26 involved treating manic-depressive disorder, two discussed treating depression with lithium, four addressed treating aggression, one looked at Kleine–Levin syndrome, and one discussed a child with lithium-responsive parents. Out of the double-blind placebo-controlled studies, two of nine treated manic-depressive disorder with lithium, three for aggression, one for psychotic disorders, one for ADHD, one

310

D. Lynn, B.H. King

for disruptive behavioral disorder, and one for either bipolar or major depressive disorder. The authors were able to conclude that the use of lithium to treat aggression is widely supported as a possibly effective pharmacologic strategy. Campbell et al. (1995a,b) studied 50 hospitalized children aged 5–12 years, with a diagnosis of CD, undersocialized (impulsive, affective-aggressive) type, severe aggression with explosiveness, and failure to respond to previous outpatient treatments. Of interest, 18 out of the 79 subjects failed to display severe aggressiveness and explosiveness during the initial 2-week placebo baseline period. For the 25 children on lithium, the mean daily dosage was 1248 mg (mean serum level 1.12 mEq/l). The investigators noted significant improvement on the Clinical Global Improvement (CGI) for those children on lithium after 6 weeks of treatment. On the Children’s Psychiatric Rating Scale (CPRS), only the aggression factor indicated a significant superiority for lithium over placebo. Side effects Hagino et al. (1995) reviewed the treatment of 20 children, aged 4 years 5 months–6 years 10 months old to assess the side effects of lithium in this age group. Lithium was administered to these children in an inpatient setting for severe aggression, mood instability, or bipolar symptomatology, and a positive family history of recurrent or chronic depression or mania. Starting lithium doses ranged from 12.2 to 48.9 mg/kg per day, and were adjusted to achieve serum levels between 0.6 and 1.2 mEq/l during the first 2 weeks of lithium treatment. Lithium levels were obtained at 24 hours after the first test dose, 12 hours after each change of dose at 8 a.m., and at least once after 5 days at the maintenance dose. Results showed that 12 children had adverse effects in one or more organ systems. Central nervous system effects were most common (50%), followed by gastrointestinal (25%), genitourinary (10%), and ocular effects (10%). No child had cardiovascular, pulmonary, autonomic, hematologic, or integumental side effects. Eight children (40%) experienced nuisance side effects – i.e., those that were noted, but did not provoke an urgent physician response. Four children manifested serious side effects – confusion, ataxia, and dysarthria, for example. Nine of the children had adverse lithium effects in the first week of treatment and three others had side effects emerge during the second week of treatment. Side effects could not be predicted by age, plasma creatinine or creatinine clearance, receipt of other psychotropic medications, the use of antibiotics, or duration of lithium treatment. The children who did experience side effects in the first week of treatment

311

Aggressive behavior

had no significant difference in the dose level in the first week of treatment compared with the children that did not experience side effects, but their lithium levels were significantly higher. Children diagnosed as bipolar were at greater risk of developing side effects of lithium, and there was a trend toward children with concurrent medical illness having a higher chance of getting more serious side effects from lithium. Based on their experience, the authors suggested that initial lithium doses of 30 mg/kg per day, as suggested by Weller et al. (1986), appear to be appropriate for children in this age group, although higher doses may be tolerated later in treatment. Lithium levels in excess of 1.2 mEq/l are not well tolerated and should be avoided. In addition, measurement of lithium levels every other day during the first 2 weeks of treatment may be necessary to pre-empt potential toxicity. Children should be carefully monitored for adverse effects during the first weeks of treatment, and lithium should be administered with caution during any acute or chronic medical illness. Anxiolytic medications

Benzodiazepines Although some data indicate that benzodiazepines may be useful in attenuating aggression in animal models (Miczek, 1987), the data in humans are generally unfavorable. Indeed, in some cases, reports suggest that drugs from this class may actually increase the likelihood of aggressive behavior. For example, Sheth et al. (1994) observed ‘‘catastrophic personality disintegration’’ characterized by aggression, agitation, self-injurious behavior, insomnia, and incessant motor activity in seven children treated for refractory epilepsy with clobazam, a 1,5-benzodiazepine. The dose was 0.5–1.35 mg/kg/day, and onset was within 10–55 days. The aggression resolved in 7–21 days after clobazam was stopped. In a population, primarily adults, with mental retardation, Barron and Sandman (1985) noted that individuals were at greater risk of exhibiting paradoxical disinhibition to a sedative–hypnotic drug if they had a lower mental age, a history of perinatal trauma, self-injurious behavior, or aggressive behavior. Given appropriate concerns about the development of tolerance and dependence, and the fact that aggression is typically a symptom of a disorder which may require long-term treatment, the use of benzodiazepines in children and in persons with developmental disorders is generally discouraged. Buspirone In their study of self-injury in isolate-reared rhesus monkeys, Kraemer and

312

D. Lynn, B.H. King

Clarke (1996) observed that buspirone had a slight palliative effect at doses comparable to those that would be used in humans. As highlighted above, buspirone and other 5-HT-1A agonists appear to attenuate aggression in other animal models. Thus, buspirone would appear to be a logical drug to explore in humans. Quiason et al. (1991) published a brief case report of an 8-year-old boy with ADHD and CD admitted to an inpatient unit due to recalcitrant aggression toward peers and school staff. He was put on buspirone 5 mg t.i.d., then titrated to 15 mg p.o. t.i.d. Over 65 days on this dose, a gradual and significant clinical reduction in aggression was noted. This was measured by seclusion and time-out requirements; he required none by the end of 6 days. King and Davanzo (1996) examined the effect of buspirone on aggression and self-injury in a sample of adults with mental retardation. Diagnoses of record included anxiety and impulse-control disorders. Few subjects were described as clinically improved in this open trial. Interestingly, with regard to aggression, while there were reductions in both frequency and severity measures in subjects without autism, most of the patients with autism showed the opposite, worsening, response. In contrast, Verhoeven and Tuinier (1996) were favorably impressed with buspirone in a sample of eight adults with mental retardation and long-standing aggression. Effective doses ranged from 20 to 50 mg per day. Pfeffer and colleagues (1997) reported their open experience with buspirone to treat aggression in prepubertal psychiatric inpatients. Although the drug produced a significant reduction in some measures of aggression, the clinical significance of the effects was less clear, and the majority of children treated did not remain on the drug. Antidepressants

Selective serotonin reuptake inhibitors Due to the ample support in preclinical studies as noted above, and owing to a relatively benign side effect profile, the use of selective serotonin reuptake inhibitors (SSRIs) is of increasing interest in treating aggression. Coccaro and colleagues (1997) studied adults with diagnoses of personality disorder and intermittent explosive disorder. These investigators found that the greater the physiologic response to 5-HT stimulation (as assessed by prolactin response to fenfluramine challenge), the greater the antiaggressive efficacy observed after 12 weeks of treatment with fluoxetine. On the other hand, King and colleagues (1991) published a case report describing intense self-injurious ideation and/or behavior in six children or

313

Aggressive behavior

adolescents who received fluoxetine. Doses ranged from 20 to 60 mg/day (0.33–0.73 mg/kg per day). Apter and colleagues (1994) reported an 8-week open trial of fluvoxamine in 20 adolescent inpatients (10 girls and 10 boys). While only two out of the four patients with comorbid major depression and borderline personality disorder showed clinical improvement in impulsivity and suicidality, self-injury and aggression measures did not worsen for any subject in the study. On a cautionary note, Levy et al. (1996) reported a severe case of serotonin syndrome with increased aggression and agitation with the addition of fluoxetine (20 mg) to amitriptylene (100 mg) and clonidine (15 mg). Taken together, while a theoretical rationale exists for the consideration of SSRIs for the treatment of aggression in children and adolescents, the available literature supporting the administration of these medications for this purpose is both sparse and mixed. Anticonvulsant drugs

Of all the antiepileptic drugs, carbamazepine has received most attention for its possible use in treating aggression in adults and children. A number of studies have identified positive effects on aggression across a variety of psychiatric diagnoses, but most recent interest appears to be predominately in the management of aggression in dementia of the Alzheimer’s type. As regards children, Kafantaris and colleagues (1992) studied 10 hospitalized, aggressive and behaviorally explosive children, diagnosed with CD. The children, aged 5.25–10.25 years, received 3 weeks of carbamazepine (600–800 mg/day), mean 630 mg/day, in an open study. The authors found clinically and statistically significant declines in aggression in all measures in the patients that were treated with carbamazepine. Interestingly, four out of the 10 carbamazepine responders had been lithium nonresponders. Cueva and colleagues (1996) evaluated carbamazepine in a double-blind, placebo-controlled parallel groups design. Twenty-two children were studied, aged 5.33–11.7 years. Aggression and other effects were assessed using a comprehensive battery of instruments. Nevertheless, carbamazepine was not helpful at doses of 400–800 mg/day (serum levels of 4.98–9.1 g/ml) to reduce the target symptom of aggression. The study has been criticized for its small sample size and for having only a 6-week trial period. Nonetheless, data specifically supporting carbamazepine use for aggression in children must be regarded as limited. Newer antiepileptic drugs are being used with increased frequency in children and also with mixed results. Wolf et al. (1996) reported three children

314

D. Lynn, B.H. King

with histories of intractable complex partial seizures treated with gabapentin. In all three cases, gabapentin had to be discontinued due to severe behavioral problems including moodiness, unprovoked outbursts of anger, oppositional behavior, bizarre behavior, and physical abuse to parents. This was highly unusual behavior for each of these children. The outbursts, which would last 1–2 hours, returned to baseline in 2 weeks after gabapentin was discontinued. Davanzo and King (1996) reported that lamotrigine improved self-injurious behavior in an open trial for an adolescent with mental retardation. On the other hand, in some children with epilepsy and mental retardation treated with lamotrigine, worsening aggression has been described (Beran and Gibson, 1998). Other case reports have suggested possible benefit from other anticonvulsants including vigabatrin (Robinson et al., 1990) and valproate (Wroblewski et al., 1997). Adrenergic drugs

Beta-blockers are competitive antagonists of noradrenaline and adrenaline binding at beta-adrenergic receptor sites, centrally and peripherally. B1 is a positive cardiac chronotrope and ionotrope; B2 agonism causes bronchodilation and vasodilation. Beta-blockers have long been used for aggression in adults, especially those with a history of head trauma, and this class of drug has received attention as a possible treatment for aggression in children. In some studies, the doses employed greatly exceed those that would effectively confer beta blockade, thus raising questions about the underlying mechanism of action. In addition, questions have been raised about whether the primary effects are indeed central, or whether it is the peripheral actions of these drugs that ultimately are responsible for benefit. Connor and colleagues (1997) studied nadolol, a primarily centrally acting beta antagonist, with this question in mind, in an open prospective study of nadolol in aggressive, inattentive, overactive children and young adults with mental retardation. Behaviors had been refractory to standard multidisciplinary psychoeducational treatments. Twelve inpatients and outpatients were studied. They were all male, aged 9–24 years with an average IQ of 59.7. Aggression was cross-situational, with physical assaults, verbal threats of violence, self-injurious behavior, and explosive episodes of property destruction. Nadolol was started at 10 mg b.i.d. and increased over 4 weeks to a total of 30–220 mg (0.6–5.8 mg/kg/day). Results showed that there were significant decreases on daily Over Aggression Scale scores, especially verbal aggression, physical assault, and self-aggression. There were no significant effects for

315

Aggressive behavior

inattention or overactivity. Eighty-three percent improved in terms of the CGI Global Improvement scores and 10 of the subjects wanted to continue their treatment. Matthews-Ferrari and Karroum (1992) published a case report, showing that metoprolol improved severe aggressive outbursts in an 11-year-old boy with severe ADHD, disorders of reading and math, verbal and visual memory deficits, and visuospatial, visuomotor, and motor task problems. His aggression went from ratings of severe to none. Metoprolol was used because it is only a B1 blocker, and this child had asthma. No studies have directly compared a peripheral vs. centrally acting drug, and thus the question remains regarding the mechanism of action of the betaadrenergics. Also, as noted above, in some studies, the doses employed greatly exceed those which would be required for beta-blockade, thus raising the question about collateral serotonergic effects in the mechanism of action of some of these compounds (Weinstock and Weiss, 1980). Clonidine The presynaptic alpha-2 agonist clonidine has been explored for possible utility in reducing aggression and irritability in children, largely in the context of ADHD. As with other drugs used for this purpose, data are mixed. Kemph and colleagues (1993) presented an open trial involving 17 aggressive children (14 boys and three girls) aged 5–15 years, who were characterized by cruel behavior to others and destruction of property. The investigators observed decreased aggression in 15 children. In the context of autistic disorder, clonidine has also been explored in children where, in open trials, reductions of irritability and hyperactivity have been reported ( Jaselskis et al., 1992). In a double-blind placebo-controlled study by Fankhauser and colleagues (1992), nine autistic males (aged 5–33 years) received either clonidine (approximately 0.005 mg/kg/day) or placebo by a weekly transdermal patch. Each trial lasted 4 weeks with a 2-week washout period between treatment phases. On several measures of hyperarousal, significant improvement in comparison with placebo was observed. On the other hand, it is perhaps worth remembering that clonidine is actually used to induce aggression in some animal models (Nikulina and Klimek, 1993), and has been associated with reports of increased irritability and aggressive behavior during chronic use in some settings. Guanfacine is an alpha-2 noradrenergic agonist similar to clonidine. It is increasingly being explored as an alternative because of its longer half-life and

316

D. Lynn, B.H. King

more favorable side effect profile. Nonetheless, few data exist with regard to its potential effectiveness in the treatment of aggression in children. Antipsychotic drugs

In their chapter on antipsychotic medication, Campbell and colleagues (1993) review studies dating back to 1968 showing the effectiveness of antipsychotic medications to treat children with CD and symptoms of aggressiveness and explosiveness. Haloperidol has most often been used in studies at doses of 0.025–0.20 mg/kg. Most studies have shown short-term effects, but one study (Wong and Cock, 1971) showed long-term improvement. Problems with side effects of sedation, dystonic reactions, and cognitive clouding have long been of concern. An added problem in this context is that children with aggressive behavioral disorders not infrequently have learning disabilities or mental retardation, making any cognitive toxicity a major issue. For children with autism or other pervasive developmental disorders, Campbell and colleagues (1993) have recommended targeting symptoms of hyperactivity, aggressiveness, distractability, temper tantrums, and stereotypy with high-potency antipsychotics. Studies supporting this view date back to 1966. Conservative doses are the rule, and range from 0.019–0.23 mg/kg per day. Some children have required higher doses of 0.25–0.5 mg/kg per day. Dosing increments are typically small and not more frequent than twice a week. In children with autism who may have motor and/or phonic stereotypies, akathisia, and tics, treatment with neuroleptics such as haloperidol becomes a challenge. One difficulty is deciding which movement problems are due to the autism itself vs. the side effects of the medication. Brasic and Barnett (1997) highlighted this point in a case report of a 7-year-old boy who presented for evaluation of hyperactivity, aggression, and disruptive behaviors, including self-injurious behavior. The authors stressed the difficulty in discriminating between the dyskinesias secondary to dopamine receptor-blocking drugs and the stereotypies of children with autism. Adolescents with impulsive aggression, like that which characterizes borderline personality disorder, have not been the subject of many clinical medication trials. In an open prospective study of well-diagnosed teens with borderline personality disorder, Kutcher and colleagues (1995) evaluated the effect of flupenthixol (3 mg daily for 8 weeks). Aggression, as recorded on the Ward scale of impulsivity, was reduced. Thus, a relatively low dose of this, and perhaps other antipsychotic medications, may be worth considering for adolescents with borderline personality disorder and aggression. With new neuroleptics with perhaps more favorable side effect profiles

317

Aggressive behavior

becoming available, there has been renewed interest in exploring their possible benefits in treating aggression. Further, these atypical neuroleptics are being evaluated for a possible therapeutic advantage with regard to aggression in some contexts. McDougle et al. (1997) published a prospective 12 week open-label study of risperidone’s effects on children and adolescents with pervasive development disorder. A total of 18 children, 15 boys, three girls, aged 5–18 years, were studied. In addition to a significant decrease in Yale–Brown Obsessive Compulsive Scale (Y-BOCS) scores, scores on the Self-Injurious Behavior Questionnaire also showed decreased aggression. There was a significant decrease in maladaptive behavior on the Vineland, and on the Clinician-Rated Visual Analog Scales there was an improvement in measures of well-being. Many other studies, all open trials, are suggesting an antiaggressive effect for atypical neuroleptics in children and adolescents including olanzapine (Krishnamoorthy and King, 1998), risperidone (Schreier, 1998; Horrigan and Barnhill, 1997), and clozapine (Troutman et al., 1998). Although reason for optimism exists, these medications will no doubt reveal side effects with chronic administration, and weight gain can be particularly problematic. Psychostimulants

Stimulants are widely and successfully used in pediatric and child psychiatric clinics to treat disruptive behavior symptoms. It has been an ongoing question whether these medicines are uniquely effective for aggression. Gadow et al. (1990) published a double-blind, placebo-controlled study specifically addressing this question. They studied 11 boys, 5.9–11.9 years old, who were referred as outpatients, with ADHD and aggression. One group received a low dose of 0.3 mg/kg methylphenidate, one group received a high dose of 0.6 mg/kg, and one group received placebo in twice a day dosing. Behavioral measurements were completed in three settings, the classroom, lunchroom, and playground, over 4 days. Results showed that methylphenidate can suppress physical aggression directed toward peers in a child’s natural environment. Matier et al. (1992), in a blinded controlled study of nonaggressive ADHD children vs. aggressive ADHD children and normal controls, showed that there was a significant improvement in Continuous Performance Test (CPT) measures of inattention in both ADHD groups. Only the nonaggressive ADHD children exhibited a significant decrease in CPT measures of activity level. In another study, looking at stimulants as a possible treatment for aggression in children with ADHD, Gadow et al. (1992) studied 11 boys with comorbid tic disorder referred to a clinic primarily for ADHD. The subjects were assigned at

318

D. Lynn, B.H. King

random to either placebo or one of three doses of methylphenidate under double-blind conditions. Classroom, lunchroom, and playground observations were made for 4 days. Physical aggression initiated by the hyperactive child and directed toward his peers, and nonphysical aggression in the lunchroom were both decreased with medication. Nonphysical aggression was reduced only during recess. In a more recent study, Gadow et al. (1995) studied 34 children (31 boys and three girls) who met criteria for ADHD and a tic disorder, in a double-blind design. Each received either placebo or one of three doses of methylphenidate (0.1 mg/kg, 0.3 mg/kg, or 0.5 mg/kg) for 2 weeks each. Results showed significantly reduced aggression measures with either 0.3 mg/kg or 0.5 mg/kg without significant worsening of tics. Blum et al. (1996) reported the cases of three children with severe to profound mental retardation who were given behavioral interventions plus methylphenidate to address disruptive behavior. Both methylphenidate and behavior interventions each reduced the behavior, but aggression was significantly decreased in two of three children taking the 0.6 mg/kg dose. The use of PRN medications

PRN medicines, or pro re nata, ‘‘according to circumstances,’’ constitute a common method for treating acute aggression. In a multihospital survey by Fishel et al. (1994), most of the PRN medications were given during the evening shift and on the weekend. The most prevalent reason for giving PRN medication was agitation at a state hospital, in contrast to insomnia at the medical center. Measham (1995) reviewed the effectiveness of aggression in management techniques on child psychiatric units. He examined techniques, such as pharmacotherapy, psychotherapy, seclusion, restraint, and the use of PRN medication, and concludes that PRN medication is largely ineffective. In fact, PRN medications are often given after the fact, and their utility in such circumstances is reasonably questioned. Vitiello and colleagues (1991) studied PRN medications in children. In a double-blind, placebo-controlled study, the PRN use of diphenhydramine was investigated in 21 male inpatients, 5–13 years old. They received either oral or i.m. doses of diphenhydramine, 25–50 mg, or placebo in response to physical aggression toward another person, temper tantrum, or other disruptive behavior such as yelling, cursing, or restlessness. Connors Abbreviated 10-Item Teacher Rating Scales and CBI scale were completed before and after the dose. Significant time effects emerged on analysis, but no difference due to drug. IM dosage, whether placebo or diphenhydramine, tended to be more effective.

319

Aggressive behavior

Thus, the vehicle, rather than the drug, seemed to be more salient. The results demonstrated a powerful placebo effect when acute aggressive episodes are ‘‘treated,’’ especially with ‘‘the needle.’’

The approach to the aggressive patient: vignettes The following clinical vignettes highlight some of the issues discussed above with respect to the approach to the patient with aggression. In each case, the choice of medication follows from the working diagnosis, and the importance of psychosocial factors for the generation and maintenance of aggressive behavior is clear. Case vignette 1

Justin is a 13-year-old boy with a diagnosis of an unspecified learning disorder who presented for treatment with his father and stepmother for behavioral outbursts. He had recently come to live with his father after living mostly with his mother in a small town several hundred miles away. His mother had given custody to the father due to her frustration with Justin’s oppositional behavior, emotional outbursts, and temper tantrums, all of which included physical violence to objects, to himself, and to others. His father and stepmother observed that Justin became very angry when demands were placed on him. He would hit his younger half-brother, father, and stepmother, throw objects, and bang his own head on the wall. On examination, Justin reported that he was beaten up by his mother and older brother. His mother would also severely criticize him. He had been in a program at school to help him overcome his learning disability, but records were not available. He clearly displayed difficulty concentrating, and an aversion to writing due to thinking that his writing made him ‘‘look stupid.’’ He described persistent problems with obeying authority and rules at home, and clearly had intense memories of being maltreated in his mother’s home. The initial differential diagnoses included ADHD, ODD, PTSD, and a disorder of written language. After a thorough psychologic and psychoeducational battery of testing and further assessment, Justin was started on a stimulant, methylphenidate. He called within a week of being on the medication with complaints of ‘‘feeling weird in his head.’’ A dosage change to taking 20 mg of a sustained release preparation of methylphenidate in the morning, along with a regular dose of 10 mg, and then no other doses throughout the day was tried. This did not

320

D. Lynn, B.H. King

change his odd, heady, somewhat ‘‘revved-up feeling’’ in his head. He had no other problems such as expansive mood, hypersexuality, or insomnia. Justin’s father has a history of obsessive–compulsive disorder and generalized anxiety disorder, which had responded well to SSRIs. As a result of this family history, and because of Justin’s persistent low self-esteem, dysphoria, and concomitant aggressive behavior, fluoxetine was started at 5 mg daily. He had no side effects at this dose and few positive psychologic/behavioral changes, and therefore the dose was increased to 10 mg daily. After a month at this dose, both his father and stepmother reported a decrease in his aggressive behavior and temper tantrums. At approximately 6 weeks, Justin still displayed dysphoric affect and oppositionality, but had only one temper tantrum with aggression. Fluoxetine was increased to 20 mg daily. His oppositionality and low self-esteem remain issues being addressed in therapy, but this aggressive behavior to others, to himself, and to objects remains significantly reduced. Case vignette 2

Angel was a 4-year-old boy with a significant psychiatric history for being severely abused and neglected from infancy. He presented with his foster parent with complaints of poor sleep and sudden temper tantrums with aggression toward others, objects, and himself. He was dismissed from one nursery school and one karate class due to aggression toward the other students. On examination, Angel was able to verbalize being afraid of big men, reported nightmares, was aggressive in his play, and had an increased startle response. His foster mother was very concerned about his pattern of getting up in the middle of the night and staying up until the morning. During these times, when the foster mother could secretly observe him, she observed that he would neatly straighten up his clothes and his room and quietly play for hours. He was hypervigilant about his toys and belongings. A diagnosis of PTSD was made, and Angel was started on clonidine to target his hyperarousal, aggression, and poor sleep. The clonidine was slowly increased to one 3 mg patch per week with the option of using one additional 0.05 mg oral dose daily as needed for severe agitation or insomnia. Angel did very well for many months with this medication regimen and was eventually able to return to both school and karate class. The biopsychosocial approach Among the challenging aspects of treating a child or adolescent who presents with aggression is the fact that the family is usually in crisis and the patient’s

321

Aggressive behavior

diagnosis is often unclear. In these circumstances, the top priority is making sure the aggressive patient is ‘‘safe.’’ In other words, the clinician must ensure that the patient’s aggression is contained, and minimize the risk of the patient hurting others, damaging objects, or hurting himself. Once safety has been established, the clinician is charged with getting a full history of present behavior, past aggression, and past psychiatric and medical diagnoses from all possible sources, including the patient, the parents, any foster parents or other caretakers, and other family members. One important topic to cover in detail is the level of aggression in the home. It is not unusual for aggressive behavior to either be a result of the child being a victim of aggression himself, or, alternatively, the child’s aggression can sometimes disrupt the household to such an extent that other aggression is triggered. Particular laws about reporting abuse and violence in the home or residential facility will dictate the clinician’s responsibility to report such aggression to the authorities. The next step for the clinician will be to come up with initial working diagnoses. This means ruling out any physical abnormality or potential physical abnormality, which can include anything from a urinary tract infection in a patient with severe mental retardation, a brain tumor in an otherwise wellbehaved child, or a hearing problem in a latency-aged child. Once a working psychiatric diagnosis is established, a treatment plan can be formulated. Often a child who is displaying severe aggression comes away with several psychiatric diagnoses and several severe environmental stressors that are exacerbating his behavior. At this point, the clinician is ready to start putting together a treatment plan. Here, it is helpful to consider organizing a treatment plan into three major areas, according to the often cited ‘‘bio-psycho-social’’ approach to the patient. Biologically, as mentioned above and as outlined in the bulk of this chapter, ruling out any physical illness is of paramount importance. Then, deciding if a medication may be helpful is the next order of business. At this point, having a clear notion of what may be the underlying psychiatric problem should guide the clinician’s choice of medications. For example, if a patient is primarily depressed and irritable, and hitting his siblings, a trial of an SSRI may be of interest. If the patient is displaying more erratic moods, is irritable and hypersexual, with disturbed sleep and eating patterns, it may be wise to start with lithium or another mood stabilizer. Lithium, along with some other mood stabilizers, neuroleptics, and beta blockers, may also be considered first-line treatment of primary impulsive aggression, such as that seen in intermittent explosive disorder. As outlined above, the risk/benefit ratio of these medications must be considered as well as monitoring for side effects.

322

D. Lynn, B.H. King

Psychologic treatment modalities, including individual therapy, family treatment, and group therapy, either in the context of an outpatient or inpatient setting, should compliment pharmacotherapy. Behavioral therapy can be especially useful for the aggressive patient. A summary of research of various psychologic treatments for aggressive behavior is beyond the scope of this chapter, but there is an extensive body of knowledge, arguably greater than that for pharmacotherapy, which addresses this perplexing problem. Occasionally, children and adolescents who display intractable and severe aggression may require placement in a residential treatment facility, particularly in an era of ever-decreasing inpatient lengths of stay. In these settings, intensive behavioral interventions are nearly always the anchor of the treatment plan. Parent training and in-home behavioral training can also be helpful to patients and their families both to pre-empt hospitalization or to maintain the gains from treatment in a highly restrictive setting when a child returns home. Social treatment interventions include changing the patient’s environment. As suggested above, the clinician must be aware that the child’s environment may be a major source of aggression in the child. Children may act out with aggression as a reaction to abuse. Particularly in these situations, out of home placements, for example into therapeutic foster care, group homes, or even more restrictive settings, may be necessary. In other venues, such as school and community centers, psychoeducational groups can be of help to teach children and adolescents alternatives to aggression. Summary and conclusions Aggression remains a significant problem in child and adolescent psychiatry, and occurs in the context of a number of different diagnoses. Standard treatment begins with a thorough diagnostic assessment, and pharmacotherapy, when indicated, will typically flow from the diagnosis of record (Campbell and Cueva, 1995). No drugs have yet emerged with a specific indication for aggression broadly or for particular subtypes of aggression, and, while certain transmitter systems or their interactions may be particular candidates for consideration, additional studies in children and adolescents are desperately needed.

REFE REN C ES Adams CF, Liley NR, Gorzalka BB (1996). PCPA increases aggression in male firemouth cichlids. Pharmacology 53:328–30.

323

Aggressive behavior

Alessi N, Naylor MW, Ghaziuddin M, Zubieta JK (1994). Update on lithium carbonate therapy in children and adolescents. J Am Acad Child Adolesc Psychiatry 33:291–304. Apter A, Ratzoni G, King RA et al. (1994). Fluvoxamine open-label treatment of adolescent inpatients with obsessive-compulsive disorder or depression. J Am Acad Child Adolesc Psychiatry 33:342–8. Barron J, Sandman CA. (1985). Paradoxical excitement to sedative-hypnotics in mentally retarded clients. Am J Ment Defic 90:124–9. Beran RG, Gibson RJ (1998). Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine (see comments). Epilepsia 39:280–2. Birmaher B, Stanley M, Greenhill L, Twomey J, Gavrilescu A, Rabinovich AH (1990). Platelet imipramine binding in children and adolescents with impulsive behavior. J Am Acad Child Adolesc Psychiatry 6:914–18. Blackburn JR, Pfauss JC, Phillips AG (1992). Dopamine functions in appetitive and defensive behaviors. Prog Neurobiol 39:247–79. Blum NJ, Mauk JE, McComas JJ, Mace FC (1996). Separate and combined effects of methylphenidate and a behavioral intervention on disruptive behavior in children with mental retardation. J Appl Behav Anal 29:305–19. Brasic JR, Barnett J (1997). Hyperkinesias in a prepubertal boy with autistic disorder treated with haloperidol and valproic acid. Psychol Rep 80:163–70. Brunner D, Hen R (1997). Insights into the neurobiology of impulsive behavior from serotonin receptor knockout mice. Ann NY Acad Sci 836:81–105. Campbell M, Cueva JE (1995). Psychopharmacology in child and adolescent psychiatry: a review of the past seven years. Part II. J Am Acad Child Adolesc Psychiatry 34:1262–72. Campbell M, Adams PB, Small AM et al. (1995a). Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 34:445–53. Campbell M, Gonzalez NM, Ernst M, Silva RR, Werry JS (1993). Antipsychotics. In Practitioner’s Guide to Psychoactive Drugs for Children and Adolescents, (Eds.) JS Werry, MG Aman. New York: Plenum Medical, pp. 269–96. Campbell M, Kafantaris V, Cueva JE (1995b). An update on the use of lithium carbonate in aggressive children and adolescents with conduct disorder. Psychopharmacol Bull 31:93–102. Carlson GA, Rapport MD, Pataki CS, Kelly KL (1992). Lithium in hospitalized children at 4 and 8 weeks: mood, behavior and cognitive effects. J Child Psychol Psychiatry 33:411–25. Coccaro EF, Kavoussi RJ, Hauger RL (1997). Serotonin function and antiaggressive response to fluoxetine: a Pilot study. Biol Psychiatry 42:546–52. Connor DF, Ozbayrak KR, Benjamin S, Ma Y, Fletcher KE (1997). A pilot study of nadolol for overt aggression in developmentally delayed individuals. J Am Acad Child Adolesc Psychiatry 36:826–34. Connor DF, Steingard RJ (1996). A clinical approach to the pharmacotherapy of aggression in children and adolescents. Ann NY Acad Sci 796:290–307. Constantino JN, Grosz D, Saienger P, Chandler DW, Nandi R, Earls FJ (1993). Testosterone and aggression in children. J Am Acad Child Adolesc Psychiatry 32:1217–22. Cueva JE, Overall JE, Small AM, Armenteros JL, Perry R, Campbell M (1996). Carbamazepine in

324

D. Lynn, B.H. King

aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 35:480–90. Davanzo PA, King BH (1996). Open trial lamotrigine in the treatment of self-injurious behavior in an adolescent with profound mental retardation. J Child Adolesc Psychopharmacol 6:273–9. De Almeida RMM, Lucion AB (1994). Effects of intracerebroventricular administration of 5-HT receptor agonists on the maternal aggression of rats. Eur J Pharmacol 264:445–8. De Felipe C, Herrero JF, O’Brien JA et al. (1998). Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–7. Fankhauser MP, Karumanchi VC, German ML, Yates A, Karumanchi SD (1992). A double-blind, placebo-controlled study of efficacy of transdermal clonidine in autism. J Clin Psychiatry 53:77–82. Fava M (1997). Psychopharmacologic treatment of pathologic aggression. Psychiatr Clin North Am 20:427–51. Ferris CF, Delville Y (1994). Vasopressin and serotonin interactions in the control of agonistic behavior. Psychoneuroendrocrinology 19:593–601. Fishel AH, Ferreiro BW, Rynerson BC, Nickell M, Jackson B, Hanan BD (1994). As-needed psychotropic medications: prevalence, indications, and results. J Psychosoc Nurs 32:27–35. Gadow KD, Nolan E, Sprafkin J, Sverd J (1995). School observations of children with attentiondeficit hyperactivity disorder and comorbid tic disorder: effects of methylphenidate treatment. J Dev Behav Pediatr 16:167–76. Gadow KD, Nolan EE, Sverd J (1992). Methylphenidate in hyperactive boys with comorbid tic disorder. II. Short-term behavioral effects in school settings. J Am Acad Child Adolesc Psychiatry 31:462–71. Gadow KD, Nolan EE, Sverd J, Sprafkin J, Paolicelli L (1990). Methylphenidate in aggressivehyperactive boys. I. Effects on peer aggression in public school settings. J Am Acad Child Adolesc Psychiatry 29:710–18. Hagino OR, Weller EB, Weller RA, Washing D, Fristad MA, Kontras SB (1995). Untoward effects of lithium treatment in children aged four through six years. J Am Acad Child Adolesc Psychiatry 34:1584–90. Halperin JM, Newcorn JH, Schwartz ST et al. (1997). Age-related changes in the association between serotonergic functions and aggression in boys with ADHD. Biol Psychiatry 41:682–9. Halperin JM, Sharma V, Siever LJ et al. (1994). Serotonergic function in aggressive and nonaggressive boys with attention deficit hyperactivity disorder. Am J Psychiatry 151:243–8. Horrigan JP, Barnhill LJ (1997). Risperidone and explosive aggressive autism. J Austism Dev Disord 27:313–23. Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL (1992). Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 12:322–7. Kafantaris V, Campbell M, Padron-Gayoi MV, Small AM, Locascio JJ, Rosenberg CR (1992). Carbamazepine in hospitalized aggressive conduct disorder children: an open pilot study. Psychopharmacol Bull 28:193–9. Kazdin AE (1987). Treatment of antisocial behavior in children: current status and future directions. Psychol Bull 102:187–203.

325

Aggressive behavior

Kemph JP, DeVane CL, Levin GM, Jarecke R, Miller RL (1993). Treatment of aggressive children with clonidine: results of an open pilot study. J Am Acad Child Adolesc Psychiatry 32:577–81. King BH, Davanzo P (1996). Buspirone treatment of aggression and self-injury in autistic and nonautistic persons with severe mental retardation. Dev Brain Dysfunct 9:22–31. King BH, De Antonio C, McCrackin JT, Forness SR, Ackerland V (1994). Psychiatric consultation in severe and profound mental retardation. Am J Psychiatry 151:1802–8. King RA, Riddle MA, Chappell PB et al. (1991). Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 30:179–86. Kraemer GW, Clarke AS (1996). Social attachment, brain function, and aggression. Ann NY Acad Sci 794:121–35. Kraemer GW, Schmidt DE, Ebert MH (1997). The behavioral neurobiology of self-injurious behavior in rhesus monkeys. Current concepts and relations to impulsive behavior in humans. Ann NY Acad Sci 836:12–38. Krishnamoorthy J, King BH (1998). Open-label olanzapine treatment in five preadolescent children. J Child Adolesc Psychopharmacol 8:107–13. Kutcher S, Papatheodorou G, Reiter S, Gardner D (1995). The successful pharmacological treatment of adolescents and young adults with borderline personality disorder: a preliminary open trial of flupenthixol. J Psychiatry Neurosci 20:113–18. Levy F, Einfeld S, Looi J (1996). Combined pharmacotherapy or polypharmacy? J Paediatr Child Health 32:265–6. Lopez JF, Vazquez DM, Chalmers DT, Watson SJ (1997). Regulation of 5-HT receptors and the hypothalamic-pituitary-adrenal axis. Implications for the neurobiology of suicide. Ann NY Acad Sci 836:106–34. Matier K, Halperin JM, Sharma V, Newcorn JH, Sathaye N (1992). Methylphenidate response in aggressive and non-aggressive ADHD children: distinctions on laboratory measures of symptoms. J Am Acad Child Adolesc Psychiatry 31:219–25. Matthews-Ferrari K, Karroum N (1992). Metoprolol for aggression. J Am Acad Child Adolesc Psychiatry 31:994. McDougle CJ, Holmes JP, Bronson MR et al. (1997). Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study. J Am Acad Child Adolesc Psychiatry 36:685–93. McMillen BA, Chamberlain JK, Da Vanzo JP (1988). Effects of housing and muricidal behavior on serotonergic receptors and interactions with novel anxiolytic drugs. J Neural Transm 71:123–32. Measham TJ (1995). The acute management of aggressive behaviour in hospitalized children and adolescents. Can J Psychiatry 40:330–6. Miczek KA (1987). The psychopharmacology of aggression. In Handbook of Psychopharmacology, (Eds.) LL Iversen, SD Iversen, SH Snyder. New York and London: Plenum Press, pp. 183–328. Moechars D, Gilis M, Kuiperi C, Laenen I, Van Leuven F (1998). Aggressive behaviour in transgenic mice expressing APP is alleviated by serotonergic drugs. Neuroreport 9:3561–4. Nelson RJ, Demas GE, Huang PL (1995). Behavioral abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 378:383–6.

326

D. Lynn, B.H. King

Nikulina EM, Klimek V (1993). Strain differences in clonidine-induced aggressiveness in mice and its interaction with the dopamine system. Pharmacol Biochem Behav 44:821–5. Pfeffer CR, Jiang H, Domeshek LJ (1997). Buspirone treatment of psychiatrically hospitalized prepubertal children with symptoms of anxiety and moderately severe aggression. J Child Adolesc Psychopharmacol 7:145–55. Pine DS, Wasserman G, Coplan J et al. (1996). Serotonergic and cardiac correlates of aggression in children. Ann NY Acad Sci 794:391–3. Quiason N, Ward D, Kitchen T (1991). Buspirone for aggression. J Am Acad Child Adolesc Psychiatry 30:1026. Raleigh MJ, McGuire MT, Brammer GL, Pollack DB, Yuwiler A (1991). Serotonergic mechanisms promote dominance acquisition in adult male ververt monkeys. Brain Res 559:181–90. Rippon TJ (2000). Aggression and violence in health care professions. J Adv Nurs 31:452–60. Robinson MK, Richens A, Oxley R (1990). Vigabation and behaviour disturbances (letter; comment). Lancet 336:504. Sanchez C, Meier E (1997). Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they alike? Psychopharmacology 129:197–205. Scerbo AS, Kolko DJ (1994). Salivary testosterone and cortisol in disruptive children: relationship to aggressive, hyperactive, and internalizing behaviors. J Am Acad Child Adolesc Psychiatry 33:1174–84. Schreier HA (1998). Risperidone for young children with mood disorders and aggressive behavior. J Child Adolesc Psychopharmacol 8:49–59. Schulz KP, Halperin JM, Newcorn JH, Sharma V, Gabriel S (1997). Plasma cortisol and aggression in boys with ADHD. J Am Acad Child Adolesc Psychiatry 36:605–9. Sheth RD, Goulden KJ, Ronen GM (1994). Aggression in children treated with clobazam for epilepsy. Clin Neuropharmacol 17:332–7. Siegel A, Schubert K (1995). Neurotransmitters regulating feline aggressive behavior. Rev Neurosci 6:47–61. Stewart JT, Myers WC, Burket RC, Lyles WB (1990). A review of the pharmacotherapy of aggression in children and adolescents. J Am Acad Child Adolesc Psychiatry 29:269–77. Stoff DM, Pasatiempo AP, Yeung J, Cooper TB, Bridger WH, Rabinovich H (1992). Neuroendocrine responses to challenge with dl-fenfluramine and aggression in disruptive behavior disorders of children and adolescents. Psychiatry Res 43:263–76. Troutman B, Myers K, Borchardt C, Kowalski R, Bubrick J (1998). Case study: when restraints are the least restrictive alternative for managing aggression. J Am Acad Child Adolesc Psychiatry 37:554–8. Unis AS, Cook EH, Vincent JG et al. (1997). Platelet serotonin measures in adolescents with conduct disorder. Biol Psychiatry 42:553–9. Verhoeven WM, Tuinier S (1996). The effect of buspirone on challenging behaviour in mentally retarded patients: an open prospective multiple-case study. J Intellect Disabil Res 40:502–8. Vitiello B, Stoff DM (1997). Subtypes of aggression and their relevance to child psychiatry. J Am Acad Child Adolesc Psychiatry 36:307–15. Vitiello B, Hill JL, Elia J, Cunningham E, McLeer SV, Behar D (1991). P.R.N. medications in child

327

Aggressive behavior

psychiatric patients: a pilot placebo-controlled study. J Clin Psychiatry 52:499–501. Weinstock M, Weiss C (1980). Antagonism by propranolol of isolation-induced aggression in mice; correlation with 5-hydroxytryptamine receptor blockage. Neuropharmacology 19:653–6. Weller EB, Weller RA, Fristad MA (1986). Lithium dosage guide for prepubertal children: a preliminary report. J Am Acad Child Psychiatry 25:92–5. Wolf SM, Shinnar S, Kang H, Gil KB, Moshe SL (1996). Gabapentin toxicity in children manifesting as behavioral changes. Epilepsia 36:1203–5. Wong GH, Cock RJ (1971). Long-term effects of haloperidol on severely emotionally disturbed children. Aust N Z J Psychiatry 5:296–300. Wroblewski BA, Joseph AB, Kupfer J, Kalliel K (1997). Effectiveness of valproic acid on destructive and aggressive behaviors in patients with acquired brain injury. Brain Inj 11:37–47.

12 Adolescent substance use disorder K.A. Hussain Mirza Institute of Psychiatry, London, UK

Introduction Substance use disorder (SUD) in adolescents is a relatively common psychiatric disorder associated with a substantial level of morbidity and mortality. Substance use by young people has been the subject of considerable public, political, and media attention over the previous decades. The recent worldwide epidemic of HIV infection has produced a paradigm shift in the management of SUDs. Early identification of young people at risk of developing SUD and ‘‘harm minimisation’’ are now seen as the most important strategies in our efforts to contain the transmission of HIV disease (Strang, 1990). The importance of early intervention for SUB was again highlighted by the finding that most children in their middle childhood are exposed to various drugs including alcohol and tobacco, and that a substantial minority (as high as 10%) continue to use drugs into their adolescence and adulthood (Newcomb and Bentler, 1988). Indeed, SUD is now seen as a major public health problem, in view of the high prevalence rate of the disorder and the high toll it takes in terms of health care costs, violent crimes, accidents, suicide, social and interpersonal difficulties, and educational impairment (Glass, 1991). Systematic studies over the past decade (Anderson et al., 1987; Lewinsohn et al., 1993) have clearly demonstrated that there is a greater than chance co-occurrence of psychiatric disorders in young people with SUD. In addition, comorbid SUD is recognized as one of the most important risk factors for suicide in adolescents with major depression, schizophrenia, and other psychiatric disorders (Mirza and Michael, 1996; Mirza and Mirza, 1987; Mirza, in press). Despite the high morbidity and mortality associated with SUD, there has been little empirical research into the safety and efficacy of treatment modalities employed in the management of young people with SUD. The current treatment scene for young people with SUD is largely dominated by psychoso328

329

Adolescent substance use disorder

cial interventions, including group and individual psychotherapy, Alcoholic Anonymous (AA)-based 12-step programs, and therapeutic communities. Unfortunately, conflicting treatment philosophies, narrow-minded reductionism, and territorial anxieties have polarized professionals working in the fields of addiction and mental health, especially in North America. Professionals working within the addiction field have largely ignored the impressive advances in the neurobiology of addictive disorders. Clinical experience indicates that the majority of young people with SUD, and many young people with comorbid psychiatric disorders, have not been receiving adequate pharmacotherapy. However, the situation is changing. For example, specialized treatment units are currently being established to treat young people with SUD and comorbid psychiatric disorders, and clinicians and researchers are engaging in multidisciplinary efforts to address the complex interaction of biology and environment in the etiology and management of addictive disorders. Clinicians and researchers are challenging Cartesian mindbody dualism, a dichotomy bedeviling the behavioral sciences. Thus, the stage is set for an unprejudiced attempt to develop comprehensive treatment programs for young people with SUD, integrating both pharmacologic and psychosocial interventions. This chapter begins with an overview of SUD in adolescents. This is followed by a review of the neurobiologic mechanisms of SUD. Pharmacologic studies in adults with SUD are subsequently addressed, followed by pharmacologic studies in young people with SUD. The chapter ends with some practical guidelines for the management of young people with SUD and comorbid psychiatric disorders. Substance use disorder Definition

According to the Diagnostic and Statistical Manual (DSM-IV, American Psychiatric Association, 1994), SUDs are characterized by a constellation of symptoms and maladaptive behavioral changes associated with the regular use of psychoactive substances, which would be viewed as undesirable across cultures. DSM-IV makes a distinction between substance abuse and substance dependence.

∑

Substance abuse (DSM-IV) A maladaptive pattern of substance use leading to clinically significant impairment or distress as evidenced by one or more of the following: Recurrent substance use resulting in a failure to fulfil major role obligations;

330

K.A. Hussain Mirza

∑ ∑ ∑

Recurrent substance use in situations in which it is physically hazardous; Recurrent substance use-related legal problems; and Continued use despite persistent or recurrent social or interpersonal problems.

(1) (2)

Substance dependence (DSM-IV) The essential feature of substance dependence is a cluster of cognitive, behavioral, and physiologic symptoms indicating that the individual continues use of the substance despite significant substance-related problems. The criteria include: A maladaptive pattern of substance use leading to clinically significant impairment or distress as evidenced by three of the following: Tolerance. Withdrawal symptoms/relief or avoidance of withdrawal symptoms with the substance. Consumption of the substance in larger amounts or over longer periods than intended. Persistent desire or unsuccessful efforts to reduce consumption. A great deal of time spent in drug related activities. Giving up or reducing important social, occupational, or recreational activities. Continued use despite physical or psychologic harm.

(3) (4) (5) (6) (7)

A characteristic pattern of compulsive substance use is the sine qua non of dependence and not necessarily tissue tolerance and withdrawal symptoms. International Classificatory System of Diseases (ICD-10)

The tenth revision of ICD (World Health Organization, 1992) uses an approach somewhat different from DSM-IV in defining SUDs. Instead of the term ‘‘substance abuse’’, ICD-10 uses the term ‘‘harmful use’’. The criteria for harmful use and dependence are described below. Harmful use a. There must be clear evidence that the substance use was responsible for, or substantially contributed to, physical or psychologic harm, including impaired judgement or dysfunctional behavior, which may lead to disability or have adverse consequences for interpersonal relationships. b. The nature of the harm should be clearly identifiable. c. The pattern of use has persisted for at least 1 month or has occurred repeatedly within a 12-month period.

331

∑ ∑

∑ ∑ ∑

∑


Dependence syndrome Three or more of the following manifestations should have occurred together for at least 1 month or should have occurred together repeatedly within a 12-month period: Strong desire or sense of compulsion to take the substance. Impaired capacity to control substance-taking behavior, as evidenced by the substance often being taken in large amounts or by a persistent desire and unsuccessful efforts to reduce or control substance use. Physiological withdrawal syndrome. Tolerance to the effects of the substance. Preoccupation with substance use, as manifested by a great deal of time being spent in activities necessary to obtain, consume, or recover from the effects of substance use. Persistent substance use despite clear evidence of harmful consequences. ICD-10 and DSM-IV criteria were developed for application across all age groups. However, many criticisms have been raised against the application of the adult criteria in relation to adolescents (Burkstein et al., 1989; Piacentini, 1990). Such criticisms include: Lack of developmental perspective in psychopathology Symptoms of tolerance and withdrawal typically develop in response to long periods of chronic substance use. There is no evidence to suggest that tolerance and withdrawal occur to any significant degree in adolescent substance users (Halikas et al., 1984). Difficulty in meeting certain criteria because of younger age Criterion two of DSM-IV, (i.e., substance use in situations in which use is physically hazardous) refers to driving while intoxicated or operating heavy machinery. Given that young people under the age of 16 are neither allowed to drive alone nor likely to be allowed to operate machinery, they are much less likely to satisfy this criterion. The independence of the criteria of impairment of social functioning Substance use by adolescents is almost always illicit, leading to some negative consequences following from this proscription rather than simply from the properties of the substance being used or the behavior of the young person who uses them (Burkstein et al., 1989). In addition, it is not easy to disentangle the relative contributions of substance use and a general pattern of deviant behavior/comorbid psychopathology to impairment in function.

332

K.A. Hussain Mirza

Lack of validity of the syndromes There are very limited data on the validity of the syndromes of substance use and dependence in young people. There are also very limited data on the internal consistency of the criteria (Smith et al., 1995). Alternative criteria for substance use disorder in young people

Alternative criteria have been proposed by some researchers to rectify some of the difficulties in employing categoric definitions (as exemplified in DSM-IV) of SUD in young people (Halikas et al., 1984; Blum, 1987). They have suggested the elimination of criteria for tolerance, withdrawal, and dependence in young people. Instead, they place a greater emphasis on the presence of age-appropriate adverse consequences directly related to substance use which may occur in multiple areas of life such as home, school, family, and peer relationships. Definition of SUD: a neurobiologic perspective

The scientific literature on SUD is rife with semantic confusion. Thus, the definition of a number of pharmacologic terms is important in understanding the neurobiology of SUD. Tolerance refers to a situation in which repeated administration of a drug at the same dosage results in a markedly diminished effect. Sensitisation is the opposite of tolerance, in which repeated administration of the same drug dosage elicits an escalating effect. Dependence is defined as the need for continued drug use to avoid a withdrawal syndrome, which is characterized by physical or motivational disturbances. Neurobiologists have criticized the pivotal role ascribed to concepts of tolerance and withdrawal in the definitions of SUD. They allude to the lack of characteristic withdrawal syndromes or tolerance in many dependence-producing substances, particularly cannabis and hallucinogens. In addition, it has been shown that several nondependence-producing psychotropic drugs (e.g., tricyclic antidepressants [TCAs], specific serotonin reuptake inhibitors [SSRIs] and antipsychotics) can produce withdrawal syndromes after chronic use. In view of the above, neurobiologists have proposed that the central tenets of addictive behavior should include the preoccupation with acquisition of alcohol or other drugs, compulsive use, and relapse. Neurobiologists have preferred to retain the term addiction, despite its controversial history. The term addiction is used in this chapter to refer to a chronic, compulsive pattern of substance use leading to tolerance, withdrawal symptoms, and/or other physiologic changes. It is important, however, to point out that the majority of young people with SUD do not present with clinical signs of dependence. Drugs of abuse are unique in terms of their reinforcing properties. People

333


report that they take drugs for a variety of reasons: to gain pleasure, to produce alterations in consciousness, to conform to the attitudes and values of the peer group, and to relieve stress and other negative emotions. On acute exposure, most abused drugs function as positive reinforcers, presumably because they produce a positive affective state (e.g., euphoria) or relieve a negative affective state (dysphoria). The rapid and powerful mind-altering effects of the drugs are probably mediated by pre-existing, species-specific brain reward mechanisms which normally modulate the reinforcement produced by natural reinforcers such as food, sex, or other pleasurable stimuli. However, over time, the subject’s enjoyment of drug taking is decreased because tolerance develops or medical complications arise. Despite diminished enjoyment, the life of the substance-dependent person revolves around obtaining, using and recovering from the adverse effects of the drugs, which often leads to grave consequences. Thus, the central tenet of SUD is the development of a pattern of compulsive seeking and taking of a drug, as a result of chronic exposure to reinforcing drugs. Epidemiology of SUD in young people

Early studies which used symptom checklists or questionnaires reported prevalence rates of SUD ranging from 8% to 20% ( Johnston et al., 1982; Boyle and Offord, 1991). Large-scale, epidemiologic studies using standardized diagnostic criteria (as defined in DSM-IV or ICD-10) that could yield true prevalence rates of substance use and dependence among young people are not available. The current estimates of prevalence are based on school-based surveys and smallscale epidemiologic studies conducted in the general population. An extensive school-based survey of drug use among American adolescents between the ages of 12 and 17 years ( Johnston et al., 1993) reported that alcohol (nearly 90%) and tobacco (62%) were the most commonly used drugs. This survey revealed that over 25% of American high school seniors had consumed five or more drinks on at least one occasion in the 2 weeks before the survey. One out of 10 children leave high school addicted to cigarettes, smoking 12 or more cigarettes per day. Marijuana was by far the most commonly used illicit substance, with a lifetime prevalence rate of 33%, whereas only 2% reported daily cannabis use. About 17% of high school seniors reported using inhalants, 65% had tried cocaine, and 9% had tried hallucinogens at some time in their lives ( Johnston et al., 1993). A survey of 3333 British secondary school children aged 11–16 years (Swadi, 1988) found that 60–90% drank alcohol on more than a few occasions and that 10% drank ‘‘more than moderately.’’ Ten to twenty percent were smoking cigarettes regularly. Prevalence rates for illicit drug use were lower, with 20% of children having tried at least one drug (cannabis being the most common drug)

334

K.A. Hussain Mirza

and 2–5% of children having used regularly. A recent survey of 3790 randomly selected junior and high school students in Nova Scotia, Canada, reported that 27.1% of the student population had experienced at least one alcohol-related problem and that 6% had experienced at least one drug-related problem in the 12 months prior to the survey (Poulin and Elliott, 1996). There are several methodologic limitations to the above school-based surveys. For example, they tend to exclude youths who tend to truant or drop out of schools, and have limited access to other adolescents who are considered to be at particularly high risk for the development of SUD such as the homeless youth, ‘‘throw-away’’ teenagers, and inner city gang members. It is also possible that students might have underreported or overreported the frequency and quantity of drugs used, leading to imprecise approximations of drugs of abuse. Finally, information obtained from the surveys cannot be easily translated into clinical diagnostic entities. Despite these methodologic shortcomings, a number of consistent findings emerged from the above studies. An alarmingly high number of young people continue to experiment with both legal and illegal drugs at very early ages (i.e., 11–13 years), and many children may progress to continued use and dependence. There have been marked increases in the frequency of use of cannabis, cocaine, amphetamines, LSD, and inhalants in various countries around the world, such as Canada, the United Kingdom, and the United States (Adlaf et al., 1995, 1996; Substance Abuse and Mental Health Services Administration, 1995; Miller and Plant, 1996). Finally, there has been very little decrease in the rates of use of alcohol and tobacco, the most commonly abused drugs by young people. Despite the substantial reasons for concern regarding the use of alcohol and tobacco by young people, a concerted effort to focus attention on these drugs seems to be conspicuously absent in the ‘‘War on Drugs’’ waged by most Western governments (Newcomb, 1992). Comorbidity

The concept of comorbidity implies the co-occurrence of two or more independent conditions. The most common psychiatric diagnoses associated with SUD are conduct disorder, major depression, oppositional defiant disorder, attention-deficit/hyperactivity disorder (ADHD; with co-morbid conduct disorder), anxiety disorders (post-traumatic stress disorder [PTSD] and phobias), and bulimia nervosa. Studies of comorbidity in adults The Epidemiologic Catchment Area (ECA) study (Regier et al., 1990) reported

335


that, for those with a psychiatric disorder, the odds ratio of having an addictive disorder was 2.7, with a lifetime prevalence rate of about 29%. Eighty-four percent of people with antisocial personality disorder (ASPD) reported an SUD at some time in their lives compared with 17% of the general population. By definition, people with adult ASPD have had conduct disorder before the age of 15 years (DSM-IV, American Psychiatric Association, 1994). An analysis of the ECA data by Robins and McEvoy (1990) showed that, in people with ASPD, the number of conduct symptoms predicted the probability of substance use in that individual. Moreover, it was noted that the larger the number of conduct symptoms, the younger was the onset of drug use and the higher the risk for substance-related complications. An epidemiologic survey of five communities in the United States (NIMH Epidemiologic Catchment Program) revealed that the presence of an early-onset major depressive disorder (i.e., an onset in late adolescence or young adulthood) was a significant risk factor for future SUD (Christie et al., 1988).

Studies of comorbidity in adolescent populations Compared with the adult literature, there is a paucity of data on the relationship between substance use and other psychiatric disorders in adolescents. The vast majority of the studies were conducted in inpatient substance-using populations and reported high rates of major depressive disorder, ranging from 20% to 59%, and conduct disorder, ranging from 70% to 100% (Grilo et al., 1985; Hubbard et al., 1985; Kashani et al., 1987; Burkstein et al., 1989; De Milio, 1989; Kaminer et al., 1992; Milin et al., 1991; Stowell and Estroff, 1992; Blood, 1995; Crowley and Riggs, 1995; King et al., 1996). The wide range in the rates of comorbidity is likely to be due to methodological differences such as sampling bias, definitions of SUD etc. In a cross-sectional community study of college students, Deykin et al. (1987) reported a lifetime prevalence of 6.8% for major depression, 8.2% for alcohol abuse, and 9.4% for other substance abuse. Those subjects with major depression were three times as likely as those without depression to have met criteria for SUD. In a community sample of 1507 high school students, Rohde and colleagues (1996) found that 48% of adolescents with alcohol abuse or dependence had a history of major depressive disorder and 58% of these had an onset of depression prior to the onset of SUD. Another community study in Oregon, United States (Lewinsohn et al., 1993) reported that disruptive behavior disorder and bulimia were the most common comorbid psychiatric disorders in young people with SUD.

336

K.A. Hussain Mirza

Comorbidity: implications for research and clinical practice

Information regarding the patterns of comorbidity between various child psychiatric disorders poses a number of interesting problems for researchers (Caron and Rutter, 1991; Lewinsohn et al., 1995). First of all, the degree of comorbidity between specific disorders may have implications for etiology. For example, many of the findings of the studies of major depression are likely to be misleading because the correlates of the disorder being studied (e.g., depression) may represent the correlates of some unspecified comorbid condition (e.g., SUD). Secondly, comorbidity may have implications for a number of clinical issues such as response to treatment and course of SUD and the comorbid psychiatric disorder. Thirdly, the degree of comorbidity may have implications for nosology. For example, if there are significant differences in the symptom profile and course of the illness of ‘‘pure depression’’ as opposed to depression with comorbid substance use, it may be necessary to develop a third diagnostic category (such as schizo-affective disorder) to represent the comorbid disorder. Comorbidity may pose special challenges to clinicians as well, especially in terms of assessment, prioritization of treatment strategies, and management of potentially self-harming behavior (King et al., 1996). The coexistence of depressive symptoms has been found to affect negatively treatment outcome and continued abstinence in adult substance users (McClellan et al., 1986). Coexisting substance use has been found to be associated with a greater number of previous episodes of depression, extensive utilization of mental health services (Rohde et al., 1991) and increased risk of suicide in adolescents with major depressive disorder (Kovacs et al., 1993, Pfeiffer et al., 1993). One of the very few longitudinal studies that addressed the specific effect of concurrent SUD in young people with major depression (Sanford et al., 1995) found that, at 1 year follow-up, persistence of depression was significantly associated with substance use. A prospective treatment outcome study in an adolescent inpatient unit reported that comorbid conduct disorder was significantly associated with dropout from the SUD treatment program (Kaminer et al., 1992), whereas comorbid mood disorder and adjustment disorders were associated with lower attrition rates. Comorbidity: explanatory models

∑

A number of etiologic models/pathways have been proposed in order to understand the relationship between SUD and other psychiatric disorders (Burkstein et al., 1989) such as: Substance use may develop in response to pre-existing psychiatric disorders (‘‘self-medication hypothesis’’);

337


∑

Substance abuse may play an etiologic role in the development of future psychiatric disorders (secondary psychopathology hypothesis); and Both substance use and psychiatric disorders may arise concurrently, and may arise from a shared genetic and/or environmental etiologic basis (Merikangas et al., 1985). The existing literature does not allow us to choose the ‘‘best fit model’’ to explain the significance of the association between SUD and other psychiatric disorders. From a pragmatic point of view, irrespective of whether the psychopathology is primary or secondary, SUD, once developed, takes a life of its own and must always be directly addressed in treatment.

∑

Etiology

Substance use does not occur in a vacuum. Newcomb and Bentler (1988) stated that: ‘‘even though adolescent drug use is an individual behaviour, it is embedded in a socio-cultural context that strongly determines its character and manifestations.’’ At the risk of using a rather worn-out cliche´, one can certainly conceptualize SUD as one of the perfect examples of a ‘‘bio-psycho-social disorder.’’ In vulnerable individuals, SUD is produced by the interaction of drugs with genetic, environmental, behavioral, psychosocial, and cultural factors. A brief summary of the risk factors for the development of SUD is given in Table 12.1. A comprehensive account of the etiologic theories of SUD is beyond the scope of this chapter. Interested readers may refer to excellent recent reviews or textbooks (Lettieri, 1985; Ciraulo and Shader, 1991; Hawkins et al., 1992).

Neurobiology of SUD During the last decade, geneticists and neurobiologists have made considerable advances in our understanding of the biology of addiction. Preclinical studies (involving various homologous animal models of addictive behavior) as well as clinical studies in humans have provided important insights into the neurochemical and molecular actions of drugs of abuse. Preclinical studies dating back to the 1950s and the more recent neuroimaging studies have enabled investigators to link the reinforcing properties of abused drugs to their effects on specific brain sites. More recently, advances in molecular and cellular biology have helped clarify the neuroadaptive processes that are presumably responsible for craving and relapse phenomena in human beings. Development of ‘‘knock-out’’ animal models in molecular genetics has enabled the study of

338

K.A. Hussain Mirza

Table 12.1. Risk factors for the development of adolescent substance use disorder Domain

Risk factor

a. Neurobiologic

Genetic susceptibility to drug use Psychophysiologic vulnerability Neurochemical abnormalities Depressive disorder Anxiety disorder Early/persistent conduct symptoms Physical and sexual abuse Traumatic/stressful life events Early onset of drug use Sensation seeking/instant need for gratification Drug use by parents/other family members Family conflict and disruption Inconsistent discipline Peer rejection/alienation Association with drug-using peer group Academic failure/underachievement Availability of drugs Laws favorable to drug use Social norms favorable to drug use Extreme economic deprivation Cultural norms favoring immediate gratification Fragmented/alienated communities

b. Psychologic

Personality variables c. Family/peer group/school

d. Social/cultural

the relationships between specific serotonergic, gamma-aminobutyric acid (GABA)ergic and dopaminergic receptors and drug and alcohol self-administration in rodents. New developments in neuroimaging such as PET (positron emission tomography) and SPECT (single photon emission computerized tomography) have provided, for the first time, an opportunity for testing in humans theories of drug addiction derived from animal studies (Nutt, 1996). For a comprehensive account of the neurobiology of addiction, please refer to recent reviews (Meyer and Mirin, 1991; Nestler et al., 1995). Our current understanding of the neurobiologic theories of addiction will be described under the following subheadings: biogenetic vulnerabilities, putative neuroanatomic pathways involved in addiction, and neurochemical and pharmacologic evidence for the actions of drugs on the brain. This will be followed by a comprehensive hypothesis of the biology of addiction, derived from molecular biology.

339


Individual vulnerabilities to addiction

There is an impressive body of evidence which suggests that genetic, biochemical, and psychophysiologic factors increase the risk of development of alcoholism in those with a family history of alcoholism. However, there is very limited research evidence, at present, to substantiate the potential genetic contributions in opiate, stimulant, or nicotine addiction. Genetic studies Family, twin, and adoption studies have demonstrated that early-onset (type II) alcoholism is strongly influenced in males and females by genetic factors (Cloninger et al., 1979; Kendler et al., 1992; Heath et al., 1994). However, the specific nature of the heritable risk factor (i.e., what is inherited) is still unclear. Ethnic differences in alcohol pharmacokinetics were noted in many studies, which provided another strand of evidence for the genetic basis of alcoholism. ‘‘Alcohol flush reaction’’, which is a strong aversive reaction to alcohol, is characterized by facial flushing, nausea, headache, and loss of consciousness on ingestion of alcohol. It has been reported to be found in up to 50% of people with Chinese and Japanese ancestry, and about 30% of people with Korean ancestry (Wolff, 1972; Harada et al., 1983). The biologic basis of this flush reaction is a variation in two genes that code for two principal enzymes of alcohol metabolism, alcohol dehydrogenase and aldehyde dehydrogenase (ALDH2). Absence of ALDH2 results in accumulation of acetaldehyde, a metabolic product of alcohol leading to the flush reaction (Agarwal et al., 1981). Absence of ALDH2 occurs in 42% of Japanese nonalcoholics, but in only 2% of alcoholics, suggesting that the flush reaction may represent a physiologic protective factor that tends to prevent affected individuals from developing addiction to alcohol (Harada et al., 1983). Genetic vulnerability to alcohol and other drug addictions has been studied in animal models including rats, mice, and even fruit flies. Several rat and mice strains have been developed through selective inbreeding, which exhibit high or low preference to alcohol, opiates, or cocaine in self-administration models (George and Goldberg, 1989; Li et al., 1992). Using a novel molecular genetic method called quantitative trait loci genetic mapping (QTL), specific gene sequences have been identified in animals that are associated with a variety of alcohol-related traits, such as alcohol preference, sensitivity, tolerance, and withdrawal (Crabbe et al., 1994). The search for specific genes that may confer enhanced risk for the development of alcoholism in humans is currently underway. One study reported that the A1 allele of the dopamine D2 receptor gene was common in alcoholics, but not in nonalcoholics (Blum et al., 1990)

340

K.A. Hussain Mirza

and the authors suggested that a gene located on chromosome 11 may lead to susceptibility to at least one form of alcoholism. However, this finding was not replicated in another study (Bolos et al., 1990).

∑ ∑ ∑

∑

Biologic markers High-risk studies in children of alcoholics have demonstrated a number of biologic abnormalities compared with control groups of children. These include: Biochemical abnormalities such as lower platelet monoamine oxidase (MAO) activity (Giller and Hall, 1983); Neuropsychologic test differences suggestive of frontal ‘‘executive function’’ abnormalities (Drejer et al., 1985); Electrophysiologic abnormalities including excess beta activity, high EEG coherence, and abnormalities in P300 amplitude and latency (Gabrielli et al., 1982; Begleiter et al., 1984; Michael and Mirza, 1993); and Abnormal reaction to ethanol challenge as manifested by less intensive subjective feelings of intoxication, despite high blood concentration, and less body sway (Schukit et al., 1988). It has been suggested that these abnormalities represent genetic vulnerability to alcoholism. The predictive validity of these markers is far from certain at the present time. However, in a recent landmark study, Schukit (1994) reported that low levels of response to alcohol in young men with a family history of alcoholism predicted the development of alcoholism a decade later.

Brain circuits involved in drug addiction

Mesolimbic and mesocortical dopamine pathways: the ‘‘reward pathways’’ Since the 1950s, animal studies have demonstrated that discrete brain centers (brain reward regions) and circuits play a significant role in the etiology of addictive behavior. The primary brain circuit is the dopamine pathway extending from the ventral tegmental area (VTA, a region within the midbrain), through nucleus accumbens to prefrontal cortex. All drugs of abuse, except benzodiazepines, produce release of dopamine in either the nucleus accumbens, or prefrontal cortex, or both (Di Chiara and Imperato, 1988). Cocaine blocks the dopamine transporter, causing a build-up of dopamine in the synapse, because it is not inactivated by reuptake. Amphetamine causes the presynaptic neurons to release more dopamine (Hyman, 1996). Opioids increase the cell firing at the level of the cell bodies (Izenwasser et al., 1993). Direct injection of drugs into these brain sites is reinforcing as evidenced by the

341


increased self-administration of these drugs by laboratory animals. Moreover, drug withdrawal is associated with reduced dopamine transmission in the above pathways. ‘‘Emotional circuits’’ – role of limbic system and basal ganglia structures The human brain contains multiple circuits that are involved in the processing of emotions, learning, and conditioning. These ‘‘emotional circuits’’ play a significant role in the adaptation of the organism to the environment that is important for survival of the species. They assign significance (such as desirable, dangerous, edible etc.) to individuals and events in the external environment, and then regulate the functioning of both the input and output circuits of the brain to produce adaptive responses including escape, approach, and avoidance. The neuroanatomic substrate for these emotional circuits includes the limbic system and its connections. The nucleus accumbens and the dopaminergic pathway have close connection with structures of the limbic system (e.g., amygdala, hippocampus) and basal ganglia (corpus striatum) that are primarily involved in the control of emotions, learning, memory, and the initiation and control of goal-directed movements. Connections between brain circuits mediating emotional states and those that mediate the encoding of memories underlie the development of memories with strong or weak emotional components. When an event or stimulus is highly rewarding (e.g., sexual experience or drugs that produce euphoria), the encoded memories of that experience are likely to be vivid, and complex, with positive emotional overtones. The developing memories are also likely to contain specific environmental cues such as smells and lights associated with the experience. There is increasing evidence, derived largely from the PTSD literature, which suggests that information learned in the context of strong emotional activation is most indelibly etched into distinct memories. The dopaminergic reward pathways activated by drugs of abuse may be directly involved in setting the strength of memories associated with drug use through its connections with the limbic system. Thus, places, persons, and physical sensations associated with drug use may be stored in memory in such a way that cues recalling drug experiences may elicit strong cravings and facilitate drug-seeking behavior (O’Brien, 1976; Wikler, 1973). The exact role of these cue-dependent memories in addiction is currently a matter of intense investigation. Mechanisms by which these emotional circuits produce drug addiction are quite complex and far from fully understood.

342

K.A. Hussain Mirza

Monoaminergic nuclei of locus coeruleus and median raphe The locus coeruleus contains the major noradrenergic nucleus in the brain with widespread projections to both the cerebral cortex and spinal cord. This diffuse innervation allows the locus coeruleus to regulate the organism’s general state of arousal, attention, and autonomic tone. Animal studies have established an important role for the locus coeruleus in opioid withdrawal states (Aghajanian, 1978; Rasmussen et al., 1990; Koob et al., 1992). Overactivation of the nucleus coeruleus, mediated by glutaminergic and opiate neurotransmission, is thought to be responsible for the opioid withdrawal state. This discovery led to the use of noradrenergic drugs such as clonidine and lofexidine in the treatment of opiate withdrawal states (Gold et al., 1978; Rasmussen and Aghajanian, 1989). Median raphae nuclei contain serotonergic neurons that project to the ventral tegmental area and nucleus accumbens, among many other projections to various parts of brain. Activation of this system is thought to facilitate dopamine release in the nucleus accumbens. Neurochemical and pharmacologic aspects of substance use disorder

Neurotransmitters and neuropeptides All drugs of abuse affect the brain functions by influencing the amount of neurotransmitter present at the synapse or by interacting with specific receptors. See Table 12.2 for a list of the putative neurotransmitters involved in addiction. Dopamine Most drugs that produce elevations of mood or euphoria, including stimulants, opiates, nicotine, and alcohol, release dopamine in either the nucleus accumbens or the prefrontal cortex. Several studies have shown that blockade of D1 and D2 dopamine receptors attenuates the reinforcing effects of both stimulants and opiates, which suggests a central mediating role of dopamine receptor activation in the initiation of addiction (Hubner and Moreton, 1991). Neuroimaging techniques such as PET and SPECT allow in vivo measurement of D1 and D2 dopamine receptors and dopamine metabolism in humans. PET studies have demonstrated that cocaine binds predominantly to the dopamine-rich areas of the basal ganglia (Pike, 1993). It has also been shown that cocaine produces a global reduction in brain metabolism (London et al., 1990). PET/ SPECT studies are currently underway to measure the endogenous dopamine release after amphetamine administration to test the hypothesis that stimulants act by releasing endogenous dopamine. Chronic cocaine administration is hypothesized to lead to dopamine depletion, which results in cocaine craving

343


Table 12.2. Putative neurotransmitters involved in substance use disorders Alcohol Nicotine Opioids Cocaine Amphetamine Cannabinoids Benzodiazepines Phencyclidine LSD Solvents

GABA, NMDA glutamate, endorphins, DA, NA, 5-HT Acetylcholine, NA, DA, 5-HT Endorphins/encephalins, glutamate, DA, NA DA, NA, glutamate DA, NA ? Anandamide, DA, 5-HT, NA GABA, glutamate NMDA, glutamate 5-HT ? NA

DA = dopamine, NA = noradrenaline, 5-HT = serotonin, GABA = gamma amino butyric acid, NMDA = N-methyl D-aspartate

and withdrawal symptoms. Bromocriptine, a dopamine antagonist, appears to be effective in the treatment of these states (Dackis and Gold, 1985). Similarly, chronic dysregulation of dopamine function has been demonstrated in detoxified alcoholics, as evidenced by decreased numbers of dopamine uptake sites in SPECT studies (Tiihonen et al., 1995). Tiapride, a D2 antagonist, appears to be effective in reducing relapses in alcoholism (Shaw et al., 1994). Noradrenaline Alteration in noradrenergic function has been reported in patients withdrawing from alcohol and central nervous system (CNS) stimulants (such as cocaine and amphetamine). Increased adrenergic activity is held to be responsible for withdrawal symptoms such as anxiety, tremor, sweating, etc. Similarly, the activity of noradrenergic neurons is suppressed by opiates, and withdrawal is thought to be due, in part, to the unopposed expression of compensatory processes. Alpha 2 adrenergic agonists such as clonidine and lofexidine (which inhibit central noradrenergic activity) are effective in the treatment of opioid withdrawal syndrome (Brunning et al., 1986). Serotonin (5-HT) Animal studies show that, with chronic alcohol administration, there is a decrease in 5-HT turnover, an increase in 5-HT receptor numbers, and depletion of 5-HT stores in the brain (Wong et al., 1988; Badaway, 1996). Pandey et al. (1992) reported decreased 5-HT-induced phosphoinositide turnover in the brain after long-term exposure to alcohol and also during the withdrawal

344

K.A. Hussain Mirza

phase. Selective breeding of rats has shown that alcohol-preferring rats have lower levels of serotonin in many regions of the brain (especially nucleus accumbens), compared with alcohol nonpreferring rats (Li et al., 1987). Studies conducted in ‘‘knock-out’’ mice have suggested that 5-HT-1B receptors are particularly important in the regulation of alcohol intake (Crabbe and Phillips, 1996). Again, in rodents trained to self-administer alcohol, 5-HT receptor antagonists such as ritanserin and amperozide reduced alcohol intake. Earlyonset alcoholics (type II) with a history of violent crimes have been found to have low central spinal fluid (CSF) 5HIAA (5 hydroxy indole acetic acid) levels and altered 5-HT receptor sensitivity (Linnoila et al., 1989). In clinical trials, it was shown that increasing brain 5-HT function by SSRIs reduces voluntary alcohol consumption in social drinkers and early problem drinkers (Naranjo et al., 1990). Buspirone, a 5-HT receptor agonist, is reported to reduce relapse in detoxified alcoholics with comorbid anxiety disorders. (For a detailed account of the role of serotonin in alcoholism, see Michael and Mirza, 1995.) Endogenous opioids Abused opioids mimic the natural opioid transmitters such as endorphins and encephalins. They act at the same receptors as the natural opioid system, producing a markedly exaggerated response. Endogenous opioids are also thought to be involved in the action of other drugs such as alcohol and stimulants. Chronic alcohol administration may lead to an increase in the release of endogenous opioids. It has been reported that naloxone, an opioid antagonist, reduced alcohol preference in rodents (Altshuter and Shippenberg, 1980). Clinical studies have shown that naltrexone is effective in reducing craving in detoxified alcoholics (Volpicelli et al., 1992). Studies using PET and SPECT are currently underway to determine the proportion of brain opioid receptors occupied during maintenance therapy with methadone. It is hoped that neuroimaging techniques may help to optimize dosing schedules of methadone (Nutt, 1996). GABA and glutamate GABA and glutamate (the major inhibitory and excitatory neurotransmitters, respectively) are thought to be involved in the addiction to alcohol, benzodiazepines, opiates, and barbiturates. Animal studies have demonstrated that chronic alcohol intake leads to a reduction in the number and affinity of central GABA receptors (Hwang et al., 1990). Children of alcoholics seem to have altered benzodiazepine receptor sensitivity, thus increasing the risk of developing addiction to both alcohol and benzodiazepines (Cowley et al., 1992). Plasma

345


GABA levels are reported to be lower in abstinent alcoholics compared with nonalcoholics and CSF GABA levels have been reported to be lower in alcoholics who have seizures during the withdrawal phase (Goldman et al., 1981). GABA agonists such as benzodiazepines are the cornerstone of the treatment of alcohol withdrawal states. Acamprosate (calcium acetyl homotaurinate), a structural analog of GABA, has been reported to have reduced the risk of relapse in alcoholics (Lhuintre et al., 1990). Gamma hydroxybutyric acid, a metabolite of GABA, which is thought to enhance GABAergic activity, has been reported to reduce mean daily alcohol intake and to maintain abstinence in alcoholism (Gallimberti et al., 1992). Acute administration of alcohol and barbiturates inhibits N-methyl D-aspartate (NMDA) glutamate receptor function. However, with chronic use, there is a compensatory increase in the number of brain glutamate receptors, which may be responsible for the hyperexcitable state found in alcohol withdrawal and for the reduction in threshold for seizures. Investigational drugs such as MK-801, an NMDA receptor-antagonist, decrease the frequency and severity of alcohol withdrawal seizures in rats (Grant et al., 1990). Glutamate receptors are also involved in addiction to opiates. Animal studies have shown that dizocilpine, a blocker of the NMDA class of glutamate receptor, reduces the development of tolerance to opiates (Trujillo and Akil, 1991). Other neurotransmitters, peptides, and neurohormones Recently, a specific receptor for cannabinols has been identified which is found in highest concentration in the basal ganglia, hippocampus, and the cerebellum, and in lower concentrations in the cerebral cortex. The cannabinoid receptor is linked to the inhibitory G proteins and animal studies have shown that the cannabinoids affect monoamine and GABAergic neurons. Several possible endogenous transmitters for these receptors have been suggested, with anandamide being the best candidate at present (Devane et al., 1992). Other neurotransmitters such as cholecystokinine (CCK), adrenocorticotrophic hormone (ACTH), and thyrotrophin-releasing hormone (TRH) are also implicated in addiction to various drugs. Neurobiologic hypothesis of addictive behavior

At the heart of current understanding of addiction is the idea that acute exposure to addictive drugs appears to commandeer brain circuits intimately involved in the control of emotions and motivation, producing powerful reinforcing experiences. Chronic use of drugs, in adequate dosage, frequency, and duration, leads to longstanding molecular and cellular adaptations

346

K.A. Hussain Mirza

throughout specific brain sites, which are thought to be responsible for tolerance, sensitization, dependence, withdrawal, and relapse. An impressive body of research literature has accumulated over the past decade from studies in laboratory animals, which gives valuable insights into the molecular and cellular adaptation presumed to be responsible for the development of drug addiction. Acute pharmacologic actions of drugs of abuse such as alterations in neurotransmitter levels do not explain per se the longterm effects of repeated drug use. Given the gradual development of most features of drug addiction in response to repeated drug use and the persistence of these changes for a long period of time after the cessation of drug exposure, it has been proposed that mechanisms involving protein synthesis and altered gene expression are of particular significance (Nestler et al., 1993). Chronic cocaine and morphine administration has been shown to produce alterations in protein synthesis and gene expression, leading to long-term adaptive changes in the neurons of the locus coeruleus and the mesolimbic dopamine pathway (Self and Nestler, 1995). The classical view of synaptic transmission, whereby the binding of a neurotransmitter to a receptor leads to alteration of ionic channels and immediate electrical activation, is rather insufficient to explain the hypothetical role played by the regulation of gene expression in drug addiction. We now know that an initial extracellular effect of a drug of abuse would trigger complex changes in multiple intracellular messenger pathways in target neurons (Nestler et al., 1995). Drugs of abuse such as cocaine and morphine release neurotransmitters (first messengers) which bind to receptors on extracellular membranes (see Figure 12.1). The neurotransmitter-receptor activation sets forth a cascade of biochemical changes involving G proteins (guanosine-5'triphosphate-binding membrane proteins), regulation of various second messengers such as cyclic AMP, calcium, phosphatidyl inositol, and nitric oxide, finally leading to protein phosphorylation. Protein phosphorylation describes the process wherein phosphate groups are added to proteins by protein kinase enzymes or removed from proteins by protein phosphatase enzymes. Altered phosphorylation of proteins is one of the key processes in synaptic transmission that influences the functional activity of proteins, and leads to a myriad of biologic responses. Altered phosphorylation of neurotransmitters and transporter proteins, for example, can modulate the synthesis, storage, and release of neurotransmitters from presynaptic nerve terminals. Altered phosphorylation of receptors and ion channels can mediate the ability of neurotransmitters to alter the physiologic responsiveness of their

347


Drug

1st messengers Receptors G proteins

2nd messengers

Multiple phosphoproteins (3rd messengers) and multiple physiologic responses

Protein kinases

CREB-like proteins nucleus 3rd messengers Fos-like proteins 4th messengers Target genes e.g., G proteins adenylyl cyclase cyclic AMP kinase tyrosine hydroxylase other phosphoproteins

Adaptive changes in neuronal function

Figure 12.1. Schematic representation of the synaptic changes and the hypothetical role played by gene expression in drug addiction. Source: Nestler et al., 1995.

target neurons to different neurotransmitter stimuli. In addition, altered phosphorylation of cytoskeletal proteins can mediate the ability of neurotransmitters to regulate the structural properties of the target neurons. Finally, altered phosphorylation of nuclear or ribosomal proteins can mediate the ability of neurotransmitters to alter gene transcription and protein synthesis, affecting various types of proteins in the target neurons. Many classes of nuclear DNA binding proteins, termed transcription factors,

348

K.A. Hussain Mirza

are involved in altered gene expression, including CREB (cyclic AMP response element)-binding protein (third messenger) and fos-like proteins (fourth messenger). Both types of transcription factors would then result in altered levels of expression of specific target proteins (e.g., G proteins, adenyl cyclase, cyclic AMP kinase, etc.) that underlie the adaptive changes in brain function presumably associated with addiction (Nestler et al., 1995). These long-lasting effects on the structural and functional properties of receptors are thought to be responsible for the tolerance, dependence, sensitization, and withdrawal symptoms associated with chronic drug use. Relationship between environmental and genetic factors in addictions Animal studies have provided important information regarding the role of environmental factors in determining individual vulnerability to drug addiction. For example, it has been shown that exposure to environmental stress can augment the reinforcing properties of cocaine and morphine in animals (Piazza et al., 1991). It has also been shown that chronic exposure to glucocorticoids (hormones that are related to stress) produce different behavioral effects and molecular adaptations in the mesolimbic dopamine systems in genetically different strains of rats (Guitart et al., 1992). Studies are currently underway to determine specific proteins that underlie inherent differences in an individual’s responsiveness to drugs of abuse (Kosten et al., 1994). Eventually, these studies may be able to yield information regarding specific genetic and environmental factors that control individual variations in susceptibility to drug addiction. Clinical implications

Homologous animal models that accurately reproduce important features of drug addiction in humans have made it possible to identify the specific brain pathways and molecular sites of action of most drugs of abuse. The neurotransmitters involved in addictions have been identified and many of the receptors (opioid and GABA receptors) and transporter sites (e.g., dopamine transporters in cocaine addiction) have been cloned and sequenced. Such discoveries will help clinicians in rationalizing existing treatment regimens and developing novel therapeutic agents. For example, new mu opioid receptor antagonist drugs such as clocinnamox or partial agonist drugs such as buprenorphine have been designed for the treatment of opiate addiction (Aceto et al., 1989). Similarly, drugs acting on GABA and glutamate receptors such as acamprosate are being studied in the treatment of alcoholism (Littleton, 1995). Relapse in opiate, cocaine, and alcohol addiction is most likely to occur during the first 3–6 months of abstinence, a period characterized by physiologic abnormalities,

349


mood dysregulation, and somatic symptoms (Meyer, 1989). Changes in gene expression affecting the receptor functions may represent the neurobiologic correlates of such protracted abstinence syndromes. Treatment with receptor antagonists or other drugs that may modify neurotransmitter, receptor, or second messenger function has the potential for altering the residual abnormalities of receptor function seen in protracted abstinence syndromes. Thus, it has been suggested that active treatment of the signs and symptoms of protracted withdrawal syndromes may help in preventing relapse in cocaine and opiate addictions (Kreek, 1992). There is an impressive body of evidence from addiction treatment research to suggest that time spent in treatment programs and/or abstinence from drugs is the single best predictor of treatment success. The time required for the reinstatement of the predrug neural homeostasis (alterations in intracellular messenger pathways and changes in receptor functions) may reflect the neurobiologic mechanisms underlying the significance of time spent in treatment as a predictor of treatment success. Finally, recent studies have underscored the striking similarities in the pathophysiologic mechanisms (e.g., neurotransmitters and receptor pathways) that underlie drug addiction and other psychiatric disorders. Further studies will help to refine the treatment strategies for people with comorbid SUD and other psychiatric disorders. Pharmacologic treatment of SUD Pharmacotherapies for patients with SUD are primarily adjunctive at this time, and are not intended to be stand-alone treatments. However, pharmacologic therapies can provide a window of opportunity to engage in comprehensive treatment programs for many patients who are severely dependent on drugs and leading lifestyles that would preclude them from accessing treatment services. Thus, the primary aims of treatments are to help patients to remain abstinent from drugs, help reduce drug-seeking behavior, treat withdrawal syndromes, and manage comorbid psychiatric conditions. Pharmacologic treatment of young people with SUD is a relatively uncharted area. Most of our understanding about the psychopharmacology of SUD is derived from studies conducted in adult populations. Even though there are many similarities in clinical presentation and neurobiological aspects between adolescent and adult populations with SUD, it is far from certain whether we can directly translate evidence derived from adult studies in treating young people with SUD. However, a thorough appreciation of the complexity of psychopharmacotherapy in adults with SUD is an important first step in our attempts to

350

K.A. Hussain Mirza

unravel the virgin wool of psychopharmacologic treatment of young people with SUD. Psychopharmacotherapy in adult SUD

(1) (2) (3) (4) (5)

Efficacy and safety of the medications used in the treatment of alcohol, nicotine, stimulant, opiate, and sedative–hypnotic abuse/dependence are well established. Searches for specific pharmacologic agents in the treatment of addiction with other drugs such as cannabis, phencyclidine, hallucinogens, and inhalants are currently underway. Presently available pharmacotherapies can be described under five broad categories that include: Medications to treat intoxication or withdrawal states. Medications to decrease the reinforcing effects of drugs of abuse. Pharmacologic deterrents. Agonist substitution therapy. Medications to treat comorbid psychiatric disorders.

Pharmacotherapy of acute intoxication and withdrawal states

Treatment of withdrawal states can typically be achieved by replacing the abused drug with a drug of similar pharmacologic actions. Examples include the use of methadone in the treatment of opiate withdrawal and benzodiazepines in the treatment of alcohol withdrawal. Nicotine, one of the active ingredients of cigarettes, has been used to treat symptoms of nicotine withdrawal. Other drugs can ameliorate the withdrawal symptoms by blocking alterations in neurotransmitter/receptor activity that underlies withdrawal states. For example, clonidine and lofexidine block the hyperadrenegic state observed in opiate withdrawal. Medications that decrease the reinforcing effects of drugs of abuse

A variety of medications have been used to reduce the reinforcing effects of drugs or the craving for drugs by counteracting the physiologic effects of the drugs of abuse. For example, naltrexone, a narcotic antagonist, blocks the subjective euphoria and other physiologic effects of subsequently administered opiates or alcohol (Meyer and Mirin, 1991; Volpicelli et al., 1992). It has been proposed that repetitive experience of the antagonist-induced blockade of the euphoric effects of opiates or alcohol would lead to the extinction of conditioned craving for opiates and alcohol (Wikler, 1973). Acamprosate, which is believed to act as a GABA receptor agonist, has been reported as a safe and

351


effective treatment in reducing craving and alcohol consumption for patients with alcohol dependence (Lhuintre et al., 1990; Ladewig et al., 1993).

Pharmacologic deterrents

The most prominent example within this category is disulfiram, which was approved for use in humans as early as 1951. Disulfiram inhibits a key enzyme, aldehyde dehydrogenase, that metabolizes acetaldehyde, the first metabolic breakdown product of alcohol. When alcohol is consumed after disulfiram pretreatment, serum levels of acetaldehyde reach toxic levels, leading to a host of unpleasant and potentially dangerous signs and symptoms including facial flushing, vomiting, hypotension, and cardiovascular collapse. Medications have also been used as part of chemical aversion treatment paradigms in which conditioned stimuli, such as the abused drug, are paired with drugs that produce unpleasant effects such as succinyl choline or emetine. Chemical aversion treatments have been used for the treatment of individuals with alcohol dependence or cocaine dependence with some success (Frawley and Smith, 1990; Howard et al., 1991). However, these treatments are currently not recommended outside specialized treatment settings (American Psychiatric Association practice guidelines, 1996).

Agonist substitution therapy

The use of an agonist or partial agonist medication may help patients to decrease the use of illicit drugs by reducing withdrawal symptoms or reducing craving for that particular class of drug of abuse. The classic examples include the use of methadone, levoalpha acetylmethadol (LAAM), or buprenorphine (a partial opiate agonist) in the treatment of opiate dependence.

Treatment of comorbid psychiatric disorders

Many patients with SUD will require specific treatment for comorbid psychiatric disorders. Indeed, specific treatments for comorbid psychiatric disorders have been shown to improve the prognosis for SUD. For example, it has been reported that fluoxetine decreased depressive symptoms and alcohol consumption in people with comorbid major depression and alcohol dependence (Cornelius et al., 1997).

352

K.A. Hussain Mirza

Review of treatment studies in adults with SUD Alcohol

Treatment of withdrawal Significant progress has been achieved in establishing the safety and efficacy of medications used in alcohol detoxification. Benzodiazepines are the treatment of choice for the prevention and treatment of alcohol withdrawal syndrome (Nutt et al., 1989). There is no evidence to suggest that any particular benzodiazepine is superior to another. However, most clinicians generally prefer to use long-acting benzodiazepines such as chlordiazepoxide or diazepam. The usual initial dosage on the first day for chlordiazepoxide is 25–50 mg and 10 mg for diazepam, administered every 6 hours. The dosage may be tapered off over a 5–7 day period (Schukitt, 1991). Although benzodiazepines are safe, effective, and well tolerated by most patients, they can lead to adverse effects including memory disruption, drowsiness, lethargy, and motor impairment. Given this class of drug’s crosstolerance with alcohol, there is an increased potential for benzodiazepine addiction in some patients. Studies have demonstrated that patients in good physical health, presenting with uncomplicated, mild to moderate alcohol withdrawal symptoms, can usually be treated on an outpatient basis (Hayashida et al., 1989). It is important to remember that there is about a 5% risk of mortality in patients who are treated for severe alcohol withdrawal symptoms (Schukitt, 1987). Consequently, those with severe withdrawal symptoms or with medical/psychiatric complications should be detoxified in an inpatient setting. Other drugs Beta-adrenergic drugs such as propranolol have been shown to be useful in reducing tachycardia, hypertension, and sweating, but are ineffective in preventing seizures and delirium (Liskow and Goodwin, 1987). Alpha-adrenergic agonists such as clonidine and lofexidine have been shown to reduce many withdrawal symptoms such as tremors, tachycardia, and high blood pressure. One study suggested that trans-dermal clonidine is more effective than orally administered chlordiazepoxide in ameliorating symptoms of withdrawal and anxiety (Baugmartner and Rowen, 1991). However, several studies have shown that alpha-2 agonists are less useful than benzodiazepines in decreasing other withdrawal symptoms such as restlessness, insomnia, and seizures (Liskow and Goodwin, 1987; Schultz, 1991; Sellers and Romach, 1991). Controlled studies have reported that carbamazepine was equally efficacious to oxazepam in reducing alcohol withdrawal symptoms (Malcolm et al., 1989). Carbamazepine

353


is less sedating than benzodiazepines and has anticonvulsant properties. However, one should be aware of such side effects as skin rashes and lowering of white blood cell counts. Early studies suggest that flumazenil, a benzodiazepine antagonist, is effective in decreasing withdrawal symptoms (Nutt et al., 1993; Potokar et al., 1997). Large-scale, controlled studies have not been undertaken to establish the safety and efficacy of flumazenil. In conclusion, despite the development of a number of other promising drugs with a wide variety of pharmacologic actions, benzodiazepines continue to be the drug of choice in the management of alcohol withdrawal. Medications that decrease reinforcing effects of alcohol and/or reduce craving Two controlled studies have reported that naltrexone is effective in reducing alcohol consumption in adults who present with alcohol dependence (O’Malley et al., 1992; Volpicelli et al., 1992). A double-blind study of naltrexone, in a dosage of 50 mg/day, was demonstrated to reduce craving for alcohol, as reflected by a decreased total number of drinking days and resolution of alcohol-related problems (O’Malley et al., 1992). A 6-month follow-up study reported that subjects treated with naltrexone continued to enjoy a more favorable outcome, in terms of reduced consumption and resolution of alcoholrelated problems (O’Malley et al., 1992). Recently, the safety profile of naltrexone was examined in a large, open usage study of a heterogeneous patient population who presented with alcohol dependence in 40 treatment centers across North America (Croop et al., 1997). Of the 865 patients who participated, 570 received naltrexone. Naltrexone was well tolerated; the most common adverse events observed included nausea (9.8%) and headache (6.6%). In North America, naltrexone is the only narcotic antagonist licensed by the Food and Drug Administration as an anticraving drug. The usual dose of naltrexone is 50 mg/day, although doses of 25–100 mg/day have been shown to be effective. The most common side effects include sedation, nausea, and anxiety, which occur in approximately 10% of individuals treated with this drug. Hepatic toxicity is another potential side effect, especially at dosages exceeding 300 mg per day and routine monitoring of liver function is recommended. In a pilot study, Mason et al. (1994) found that patients with alcohol dependence who were treated with nalmefene (another opioid antagonist) experienced fewer drinking days and fewer relapses compared with the placebo group. In this study, nalmefene was shown to be safe and well tolerated. It also binds better to opioid receptors, in comparison with naltrexone. However,

354

K.A. Hussain Mirza

large-scale studies need to be undertaken to establish the safety and efficacy of nalmefene. A number of studies have shown that SSRIs such as fluoxetine, citalopram, and viqualine have succeeded in decreasing alcohol consumption in nondepressed heavy drinkers and early problem drinkers (Naranjo et al., 1987, 1990; Gorelick and Paredes, 1992). In contrast, a 12-week, double-blind trial did not report any significant difference between patients treated with fluoxetine and a placebo-treated group (Kranzler et al., 1993). It was shown that adverse effects, particularly the effects on psychomotor performance, reduced efficacy and safety of the use of fluvoxamine in patients with alcohol dependence (Kranzler et al., 1993). Recent pilot studies have demonstrated that 5-HT-2 antagonists such as ritanserin have reduced the desire for alcohol and diminished depressive and anxious symptoms in patients with alcohol dependence (Monti and Alterwain, 1991). Buspirone, a 5-HT-1 agonist, was shown to be superior to placebo in reducing both alcohol consumption and anxiety symptoms in patients with alcohol dependence (Bruno, 1989; Tollefson et al., 1992). However, another controlled study did not replicate these findings (Malcolm et al., 1992). In summary, drugs acting on the serotonergic system appear to be promising as potential agents to suppress craving and drinking behavior in alcoholics. However, further research is needed to establish the long-term effectiveness and possible risks of long-term use of serotonergic drugs. A large number of anecdotal reports and a small placebo-controlled study have suggested that lithium may be useful in the treatment of alcoholics who do not have comorbid bipolar mood disorder (Fawcett et al., 1987). However, a large controlled study of 457 patients with alcohol dependence showed no benefits of lithium over placebo for patients with or without depressive symptoms (Dorus et al., 1989). A recent review of the published controlled and uncontrolled studies concluded that lithium is not an effective treatment of depressive symptoms in alcoholics and does not reduce alcohol intake in nondepressed alcoholic patients (LeJoyeux and Ades, 1993). Dopaminergic drugs such as bromocriptine (a D2 agonist) have been reported to reduce craving for alcohol and improve social functioning in patients with alcohol dependence (Borg, 1983). Similarly, Dongier et al. (1991) found that those subjects treated with bromocriptine experienced less alcohol craving and drank less frequently. However, as the patients in the placebo group also experienced similar reductions, the value of dopaminergic agents in the treatment of alcoholism remains unclear at present.

355


Medications that discourage the use of alcohol Disulfiram has a long track record as an effective pharmacologic deterrent in the management of alcoholism. Although earlier studies attested to the efficacy of disulfiram, there were many methodologic shortcomings in several of these studies (see Fuller et al., 1986 for a detailed discussion). Recent double-blind studies have shown mixed results. For example, two studies (Fuller and Roth, 1979; Arana and Hyman, 1991) did not demonstrate any advantage of disulfiram over placebo in achieving total abstinence, in delaying relapse, or in improving employment status or social stability. A carefully designed study conducted by Chick and colleagues (1992) evaluated the usefulness of supervised disulfiram as an adjunct to outpatient treatment of alcoholism. In addition to medication, patients received marital therapy, individual counseling, and relaxation training, and participated in community recreational activities; patients were also encouraged to attend AA (Alcoholic Anonymous) meetings. After 6 months of treatment, the disulfiram treatment group demonstrated more days of abstinence and a lower total alcohol consumption compared with the placebo group. In summary, it appears that, in selected groups of patients who are intelligent, well motivated, and not impulsive, disulfiram is an effective adjunct to other treatment modalities. Contingency contracting or, where feasible, supervised administration of disulfiram can improve compliance with medication and, hence, treatment effectiveness. Individuals who are impulsive, demonstrate poor judgement, or are suffering from comorbid schizophrenic illness or major depression are poor candidates for disulfiram treatment. Disulfiram should be avoided in patients with moderate to severe hepatic dysfunction, peripheral neuropathies, pregnancy, renal failure, and cardiac diseases. Calcium carbimide is a drug similar to disulfiram, but with an early onset (within l hour of oral administration) and shorter duration of action (i.e., less than 24 hours). The shorter onset of action may make calcium carbimide especially suitable for treating alcoholics with poor impulse control (Fuller and Allen, 1991). Acamprosate and other GABAergic agents Acamprosate (calcium acetylhomotaurine) is a structural analog of GABA that appears to have agonist activity at GABA receptors and inhibitory activity at NMDA receptors (Daoust et al., 1992; Gewiss et al., 1991; Zeise et al., 1993). In two controlled trials, acamprosate reduced relapse drinking and craving for alcohol in adults with alcohol dependence (Lhuintre et al., 1990; Ladewig et al., 1993). Use of acamprosate was associated with lowered levels of gamma glutamyl transpeptidase GT levels in alcoholics. A recent double-blind study

356

K.A. Hussain Mirza

compared different doses of acamprosate (1332 mg/day and 1998 mg/day) in the treatment of patients with alcohol dependence (Pelc et al., 1997). In this study, it was observed that acamprosate was superior to placebo for all efficacy parameters, with a trend toward increased effectiveness at higher dosage levels. There were no significant adverse effects associated with the use of acamprosate. It is currently available for clinical use in Europe. In a 3-month controlled trial, gamma hydroxybutyric acid, a metabolite of GABA, was reported to result in higher rates of abstinence and reduced mean daily alcohol intake (Gallimberti et al., 1992). Further study is needed to determine the safety and efficacy of this medication. Treatment of comorbid psychiatric disorders The most common comorbid psychiatric disorders associated with alcoholism include SUD, major depressive disorder, anxiety disorders, and antisocial personality disorder in adults (and disruptive behavior disorder in young people). Early studies have reported equivocal evidence for the efficacy of TCAs in alcoholic patients with major depression (Liskow and Goodwin, 1987). However, a recent controlled study reported that imipramine produced improvement in depressive symptoms and decreased alcohol consumption for patients with alcoholic dependence and comorbid major depressive disorder (Nunes et al., 1993). A small controlled study of fluoxetine in depressed alcoholics reported no significant benefit of medication over placebo in reducing alcohol consumption, although there were significant differences in depressive symptoms (Kranzler et al., 1995b). Another recent study found that fluoxetine reduced both depressive symptoms and alcohol consumption for patients with comorbid major depression and alcohol dependence (Cornelius et al., 1997). In conclusion, antidepressants appear to be effective in treating comorbid major depressive disorder in patients presenting with alcohol dependence. Benzodiazepines, despite their relative safety and efficacy in the short-term management of anxiety disorders in the general population, are an unappealing choice for those with dual disorders, given the high risk of tolerance and dependence (Busto et al., 1986). Benzodiazepines such as alprazolam and lorazepam have the highest addiction potential because of their short half-life, high potency, and rapid absorption (Gastfriend and McClellan, 1997). Controlled studies have demonstrated that both imipramine and trazodone are effective in relieving anxiety symptoms as well as diazepam, but without the risk of inducing dependence (Rickels et al., 1993). It is possible that SSRIs may be a parsimonious class of agents in the management of anxiety symptoms. How-

357


ever, sufficient controlled studies have not been done to establish their efficacy and safety. Buspirone, a partial 5-HT-1A agonist, is an effective antianxiety agent with a high safety profile. Two controlled studies found buspirone to be effective in relieving anxiety and depression and in improving global psychopathology in alcohol-dependent patients with comorbid anxiety symptoms (Bruno, 1989; Tollefson et al., 1992). However, this finding was not replicated in another controlled study (Malcolm et al., 1992). Further research is needed to establish the efficacy of buspirone in the treatment of comorbid anxiety disorder in patients with alcohol dependence. A 6-month prospective study of patients with alcohol dependence and comorbid anxiety and/or depressive disorders found that treatment with tiapride, a D2 antagonist, resulted in a 43% reduction in daily alcohol intake and abstinence rates approaching 79% (Shaw et al., 1987). There was an overall decrease in anxiety and depressive symptoms as well. A large-scale, multicentre trial is currently underway to explore the potential clinical implications of the above study. Opiates

Management of withdrawal The classical method of opioid detoxification was and remains short-term substitution with oral methadone in tapering doses. Detoxification can usually be accomplished within 7 days in inpatient settings and within 14–21 days in outpatient settings. Gossop and colleagues from the Institute of Psychiatry, UK (1986) have demonstrated the safety and efficacy of short-term detoxification with methadone in a number of controlled studies. More recently, a controlled trial undertaken in outpatients with opioid dependence reported that buprenorphine, a partial narcotic agonist, was as effective as oral methadone in suppressing the withdrawal symptoms (Bickel et al., 1988). In an open trial, Kosten and Kleber (1988) compared three doses of buprenorphine and found that 4 mg of this drug administered sublingually was superior to 2 or 8 mg of buprenorphine in managing the abstinence syndrome. Clonidine, an alpha-adrenergic agonist, has been found to be effective in ameliorating the withdrawal symptoms in inpatients with opiate dependence (Gold et al., 1978, 1980). Inpatient studies have reported high success rates ranging between 80% to 90%. However, success rates reported in outpatient studies have been disappointingly low, with rates ranging between 31% to 36% (Cornish et al., 1998). Troublesome side effects of clonidine such as sedation, insomnia, lethargy, and dizziness may have contributed to the lower rates of

358

K.A. Hussain Mirza

success reported in outpatient settings. In addition, easy access to illicit drugs may have acted as a confounding variable. Alpha-receptor agonists including lofexidine, guanabenz, and guanfacine present with better side effect profiles than clonidine and have been successfully utilized in opiate detoxification. In a randomized double-blind trial comparing methadone, clonidine, and guanfacine in a 12-day inpatient detoxification program, methadone was found to be superior to both clonidine and guanfacine in ameliorating withdrawal symptoms (San et al., 1990). It was also noted that guanfacine was more effective in reducing withdrawal symptoms and demonstrated fewer cardiovascular effects than clonidine. Naltrexone, a competitive antagonist of opiates, was added to the clonidine regimen in the outpatient detoxification of patients with the intention of shortening the course of withdrawal and to block the effects of any illicit opiates concurrently used by the patients. This regimen showed encouraging results. Eighty-two percent of the patients were successfully detoxified on an outpatient basis within 4–5 days using a single daily dose of clonidine and 12.5 mg of naltrexone (Stine and Kosten, 1992). Furthermore, the above protocol permitted early engagement of the patients into maintenance therapy with naltrexone. Medications to decrease the reinforcing effects of opiates A variety of medications have been used to block or otherwise counteract the physiologic effects and subjective effects of abused opiates. Maintenance treatment with the opiate antagonist naltrexone has the potential to block the euphoric effects of illicit opiates, hence discouraging opiate use and facilitating extinction of classically conditioned drug craving (Wikler and Pescor, 1967). Given the sustained duration of action of naltrexone (i.e., between 24 and 72 hours), less frequent dosage strategies may be employed to facilitate medication compliance (e.g., 100 mg on Monday and Wednesday and 150 mg on Friday). Although naltrexone is highly effective in reducing opiate use, its utility is often limited by the lack of medication compliance and/or high dropout rates. For example, it was reported that of 300 inner city patients offered naltrexone, only 5% initially agreed to take the medication, with only 1% continuing to take naltrexone 2 months later (Fram et al., 1989). In contrast, higher rates of success have been reported for court-mandated treatment and for professionals (i.e., physicians and attorneys) who are at risk of losing their professional licenses if they do not comply with treatment (Washton et al., 1984). Compliance with treatment has been shown to be facilitated by the supervised administration of medication by a designated healthcare professional, family member, or work supervisor (Meyer et al.,

359


1979). Retention in the treatment program can be facilitated by involving the family in the treatment process and by the use of behavioral contingencies (Kleber, 1989). Agonist substitution therapy Maintenance treatment with agonists is designed to support many patients with chronic relapsing opioid dependence, while the person engages in psychosocial treatment programs to change their lives. The primary aims of treatment as established by the American Psychiatric Association (1996) include (a) ‘‘to achieve a stable maintenance dose that reduces opioid craving and illicit opioid use,’’ and (b) ‘‘to facilitate engagement of the patient in a comprehensive treatment program designed to prevent abuse or dependence on other drugs and to promote rehabilitation.’’ Methadone is the most thoroughly studied and most commonly used agonist. Other agonists include LAAM, a longer-acting agonist, and buprenorphine, a partial agonist. Methadone Since methadone was first introduced in 1965 by Dole and Nyslander, about 1.5 million people across the world have been treated with methadone, and the safety and efficacy of methadone has been well established (Gerstein, 1992). The most significant benefits of methadone include a decrease in criminal behavior (up to 85%), as measured by self-reports and arrest records, and an increase in employment status ranging from 40% to 80% in patients engaged in methadone maintenance programs (Cornish et al., 1998). Methadone maintenance has been shown to be effective in reducing general medical morbidity, decreasing mortality, and improving social functioning. Several studies have supported the usefulness of methadone maintenance programs in reducing the likelihood of transmission of the HIV virus among intravenous drug users (Ball et al., 1988; Metzger et al., 1993). However, methadone maintenance has not been shown to be effective in achieving abstinence from opiates. Long-term follow-up studies of patients discharged from methadone maintenance programs demonstrate that only 10–20% of patients are abstinent at 3–5 years after discharge (Maddux and Desmond, 1992). There is no one dosage of methadone that is optimal for all patients. Although 40–60 mg/day of methadone is usually sufficient to block opioid withdrawal symptoms, higher dosages (i.e., 60 mg/day) were found to be associated with longer retention in treatment, decreased use of illicit drugs, and a lower incidence of HIV infection (Hartel et al., 1988; Hartel and Schoenbaum, 1989). Among patients receiving at least 71 mg/day of methadone, no heroin use was detected. This is in contrast to patients receiving doses of 46 mg/day of

360

K.A. Hussain Mirza

methadone or lower, who were five times more likely to abuse illicit opiates than those receiving higher doses (Ball and Ross, 1991). A number of studies conducted by Strang and colleagues from the Maudsley Hospital, London suggested that flexible dosage regimens were associated with better retention rates and an overall more successful outcome (Gossop et al., 1986). They recommended that clinicians should not hesitate to choose the option of temporarily increasing the dosage of methadone to help patients cope with stressful life events. The role of psychosocial interventions in enhancing response to methadone maintenance treatment has been underscored by the findings from a number of recent studies (Rounsville, 1983; Khantzian, 1990; McClellan et al., 1993; Woody et al., 1995). McClellan and colleagues (1993) compared three levels of treatment services in which all patients received at least 60 mg of methadone. The three treatment levels included: (a) ‘‘enhanced methadone services’’ (methadone + contingency-based counseling + on-site general medical/psychiatric care + employment services + family therapy); (b) ‘‘standard services’’ (methadone + contingency-based counseling); and (c) ‘‘minimum services’’ (methadone alone). The enhanced services group demonstrated the best outcomes as evidenced by fewer positive urine tests for illicit drug use and generalized improvement in psychosocial functioning. It was also observed that the standard services group had significantly better outcome than the minimum service group. Methadone alone was effective only for a small percentage of patients. In fact, 69% of the minimum service group required transfer to the standard program 12 weeks into the study, as a result of unremitting use of illicit drugs. LAAM This drug is a long-acting opioid agonist which has been shown to be comparable to methadone with respect to decreasing illicit opiate use (Ling et al., 1978; Tennant et al., 1986; Zangwell et al., 1986). However, retention rates are reportedly higher for patients maintained on methadone at doses of 80–100 mg/day (Ciraulo and Shader, 1991). The major advantage of the use of LAAM relative to methadone is its longer duration of action, with a plasma half-life of LAAM and its active metabolites ranging from 47 to 162 hours, compared with 35 hours for methadone. It is possible to use a three-times/week dosage schedule of LAAM, thus allowing for fewer clinic visits and enhanced integration into the work environment or other rehabilitative activities. The potential problem of diversion of opioid agonists into the black market can also be avoided by supervised administration of LAAM at the clinics. The long plasma half-life of LAAM has other potential clinical implications. For example, it is

361


crucial to remember that LAAM will not reach steady state plasma levels for 2–3 weeks after the medication is started or the dose is altered, and too rapid an increase in the dose of LAAM may result in an unintentional overdose (Cornish et al., 1998). Treatment of comorbid psychiatric disorders About 90% of patients with opioid dependence have been shown to have comorbid psychiatric disorders (Kaplan and Sadock, 1998). The most common psychiatric disorders include major depressive disorder, alcohol-related disorder, antisocial personality disorder, and anxiety disorder. Despite the substantial level of comorbidity, treatment studies specifically addressing the safety and efficacy of psychopharmacotherapy of comorbid psychiatric disorders have been few and far between. Imipramine has been shown to be effective in the treatment of major depression associated with opioid dependence (Kleber et al., 1983). Patients with opiate dependence and chronic psychosis generally fare better with methadone maintenance in contrast to treatment regimens involving detoxification and total abstinence (McClellan et al., 1983). A review of treatment studies by Woody et al. (1984) supports the recommendation that psychotropic drugs should be used cautiously in patients with opiate dependence, taking into account possible drug–drug interactions (e.g., MAOIs) and the abuse potential of the drugs (i.e., benzodiazepines). Random blood or urine testing may be used to ascertain compliance with medication. In patients with comorbid depression or other psychopathology, various forms of psychotherapies (such as supportive–expressive, cognitive–behavioural, or interpersonal psychotherapies) have been found to be effective in reducing comorbid psychopathology and in improving the outcome of treatment of opioid use disorder (Rounsville, 1983; McClellan et al., 1993; Woody et al., 1995). Cocaine

Management of withdrawal Cocaine has not been associated with a physiologically distinct or medically serious withdrawal syndrome (Khantzian et al., 1979). Reports of a common triphasic withdrawal syndrome including an early period of severe psychologic symptoms (i.e, ‘‘crash’’) have not been confirmed by prospective, controlled studies (Gill et al., 1991). The withdrawal syndrome generally consists of somnolence, lack of energy, intense craving for cocaine, and depressive symptoms (Cornish et al., 1998). It usually remits spontaneously over a period of several days. However, recent evidence from neuroimaging studies suggests that receptor changes and brain metabolic effects from chronic use of cocaine

362

K.A. Hussain Mirza

may persist for weeks or months after the last dose of cocaine (Nutt, 1996). It has been proposed that the treatment of putative biochemical changes associated with the ‘‘protracted withdrawal syndrome’’ may play a role in relapse to cocaine use (Cornish et al., 1998). In certain individuals, cocaine withdrawal symptoms may be associated with suicidal ideation and acts. Such individuals might attempt to self-medicate with alcohol and benzodiazepines. TCAs (e.g., desipramine) and dopaminergic agents (e.g., bromocriptine and amantadine) have been used by many clinicians for the treatment of cocaine withdrawal states. Further research is clearly needed to establish the safety and efficacy of these agents in the treatment of cocaine withdrawal states (Kosten, 1989; Kosten and McCanze-Katz, 1995). Drugs intended to reduce craving for cocaine and assist in maintaining abstinence Over 20 medications, including SSRIs, TCAs, anticonvulsants, and dopaminergic agonists, have been studied in the search for an effective pharmacological treatment for cocaine dependence. Unfortunately, most of these medications have failed to meet the expectations initially raised by open trials or small controlled studies (American Psychiatric Association, 1996). Desipramine has probably the longest and best track record of all medications used in the treatment of cocaine dependence. Recent controlled clinical trials indicate that desipramine has at least a modest effect in inducing abstinence to cocaine (Arndt et al., 1992; Gawin et al., 1986; Kosten et al., 1992). Two controlled studies found that fluoxetine was not superior to placebo in reducing craving for cocaine (Grabowski et al., 1995). A multicenter trial of bupropion also reported negative results (Margolin et al., 1994). Initial studies of carbamazepine yielded some favorable results (Halikas et al., 1991), but subsequent large-scale controlled studies failed to confirm these positive results (Montoya et al., 1994; Cornish et al., 1995; Kranzler et al., 1995a). Although amantadine was shown to be effective in reducing craving for cocaine in initial studies (Alterman et al., 1992), a large-scale study failed to replicate the positive effects of amantadine over placebo (Kampman et al., 1996). Buprenorphine has shown some promise in open trials in the management of patients dually dependent on cocaine and opiates (Kosten et al., 1989), although a large-scale study using small doses of buprenorphine failed to demonstrate any superiority of medication over placebo in reducing cocaine intake ( Johnson et al., 1992). Drugs to block the subjective effects of cocaine Attempts to identify a drug that would attenuate the subjective effects of

363


cocaine have included trials of TCAs, amantadine, bromocriptine, trazodone, antipsychotics, and mazindol (Dackis and Gold, 1985; Gawin, 1986; Margolin et al., 1994). Presently, no convincing evidence exists to justify the use of these medications to reduce the euphorigenic effects of cocaine. Experimental treatments Despite the lack of success in identifying effective medications in the treatment of cocaine dependence, there is renewed interest in studying new methods of altering the physiologic effects of cocaine. Cocaine produces its specific pharmacologic effects by attaching to the target-binding site of the dopamine transporter. Attempts to produce specific antibodies to the cocaine-binding site at the dopamine transporter are currently underway, in the hope of developing a cocaine vaccine (Fox et al., 1996). Another strategy involves acceleration of cocaine catabolism by augmenting natural cholinesterase activity (Hoffman et al., 1996). Large-scale trials are currently underway to explore the efficacy of this strategy in the treatment of cocaine overdose (Gorelick, 1997). Nicotine

Management of withdrawal and nicotine replacement therapy Several well-controlled studies have demonstrated the efficacy of nicotine gum in the treatment of nicotine-related withdrawal symptoms including irritability, poor concentration, restlessness, and sleep disturbance (Schneider et al., 1983; Gross and Stitzer, 1989). However, nicotine gum does not appear to be effective in reducing craving for cigarettes. Transdermal nicotine has been shown to be effective in relieving the withdrawal symptoms as well as reducing the craving for cigarettes (Daughton et al., 1991; Tonnesen et al., 1991). A large body of research evidence has accumulated over the past 10 years to establish the efficacy of both nicotine gum and nicotine patches in achieving smoking cessation in the short term. Abstinence rates at 4–6 weeks for nicotine gum were 73% in comparison with 49% for placebo gums. Similarly, nicotine patches were associated with abstinence rates of 39–71% in comparison with 13–41% for placebo patches (see Stitzer, 1991 and Palmer et al., 1992 for succinct reviews). Recent trials using nicotine nasal spray and inhalers have shown results similar to nicotine gum and patches (Sutherland et al., 1992; Tonnenson et al., 1993). Despite the usefulness of both nicotine gum and patches in the initiation of smoking cessation, these agents have not been shown to be effective in maintaining abstinence in the long term. After 1 year, abstinence rates are reported to be approximately 25% for the nicotine gum and patches, as

364

K.A. Hussain Mirza

compared with 12% for placebos (Benowitz, 1993). Controlled studies have indicated that the combination of treatment with nicotine gum and behavior modification therapy was superior to either treatment applied alone. Other drugs Five controlled studies have demonstrated the efficacy of clonidine, an alphaadrenergic agonist, in reducing nicotine withdrawal symptoms and craving for cigarettes (Glassman and Covey, 1990). Two small controlled studies found that doxepine, a TCA, was useful in reducing withdrawal symptoms and enhancing cessation of smoking (Edwards et al., 1988; Murphy et al., 1989). A recent double-blind trial reported that bupropion was significantly more effective in maintaining abstinence from nicotine compared with placebo. The effects were maintained both in the short and long term (i.e., 6–12 months after cessation of smoking) (Hurt et al., 1997). Review of treatment studies in adolescents with SUD Psychopharmacotherapy for young people with SUD is still in its infancy. Very little empirical research has been undertaken to evaluate the safety and efficacy of psychotropic medications in the treatment of adolescents with SUD. Anecdotal reports suggest that desipramine may be of help in facilitating abstinence from cocaine (Kaminer, 1992). Descriptive case studies suggest that naltrexone may be useful in the treatment of young people with alcohol-related disorder (Lifrak et al., 1997; Wold and Kaminer, 1997). Descriptive case reports also suggest that supervised naltrexone treatment is effective in maintaining abstinence in young people with opioid dependence (Mirza, in press). Treatment of comorbid psychiatric disorders

A recent double-blind study exploring the use of lithium for adolescents with bipolar mood disorder and comorbid SUDs found that lithium was effective in controlling mood disturbances and in reducing substance use (Geller et al., 1998); alcohol and cannabis were the most commonly abused substances by the subjects in this study. Further research is warranted, with particular attention being paid to a long-term maintenance phase. An open trial of fluoxetine in adolescents with SUD and comorbid major depression and conduct disorder reported a significant improvement in depressive symptoms in seven out of eight adolescents (Riggs et al., 1997). One of the very few longitudinal studies that addressed the specific effect of concurrent SUD in young people with major depressive disorder (Sanford et al., 1995)

365


found that, at 1-year follow-up, persistence of depression was significantly associated with substance use. The effect of substance use on outcome was found to be independent of the symptom severity of major depression and the level of global functioning at baseline. Further systematic research is required to establish the efficacy and safety of treatment modalities for adolescent major depression such as antidepressants and psychosocial treatments in young people with major depressive disorder and comorbid SUD. Guidelines for psychopharmacotherapy in adolescent SUD Successful treatment of SUD is likely to involve the use of multiple specific treatment modalities. The frequency, intensity, and focus of interventions should be tailored to meet the individual needs of each young person. Pharmacotherapy should be offered as part of a comprehensive treatment package involving individual, group, and family/systemic therapies. The goals of pharmacologic treatments include reduction in craving/subjective effects of abused substances, prevention of relapse, and treatment of comorbid psychiatric disorders. Specific treatment for withdrawal syndromes is rarely required in young people with SUD; the probable exceptions include young people with early-onset alcohol dependence and protracted withdrawal symptoms associated with cocaine use. The majority of the drugs used in the treatment of adults with SUD can also be utilized in the management of adolescents with SUD. However, in determining dosage strategies for adolescents, developmental aspects of pharmacokinetics and pharmacodynamics should be taken into consideration. Potential drug–drug interactions and abuse potential of drugs should be addressed in every individual case. Many young people with SUD have pre-existing or comorbid impulsive, oppositional behaviors and/or conduct symptoms. The risk of lethality in overdose should always be considered in choosing an appropriate pharmacologic agent, especially for young people with the above ‘‘personality’’ profile. Other potential problems in prescribing medications for individuals with SUD and comorbid psychiatric disorders include potentiation of acute effects of the prescribed medication by abused substances (e.g., antidepressants and alcohol) and unintentional overdose. Prescribed psychotropic drugs may have a potential to be abused as well. Examples include abuse of benzodiazepines by patients with alcohol dependence and panic disorder, and abuse of antiparkinsonian drugs by patients with comorbid schizophrenia and SUD. Involving the family and/or other caregivers can substantially improve compliance with treatment, particularly for drugs such as naltrexone for the

366

K.A. Hussain Mirza

treatment of alcohol and opiate dependence. Assessment of the risk vs. benefit ratio of the medication should be undertaken in collaboration with the young person and his/her caregivers. A concerted effort should be made to recognize the insufficiency of empirical evidence surrounding the issues of safety and efficacy of most pharmacologic agents used in the treatment of adolescents with SUD. Objective rating scales should be used, whenever possible, to document improvement in target symptoms and adaptive functioning. Specific treatment recommendations for comorbid psychiatric disorders

Major depression and dysthymia Many young people with alcohol use disorders report pre-existing depressive and anxiety symptoms. Many psychiatrists are of the opinion that young people with SUD and depressive symptoms should be monitored for a 3–4 week period during which they are substance free, prior to initiating antidepressant treatment. However, efforts to maintain the individual’s abstinence from drugs for a protracted time can often be difficult. Inpatient hospital beds or residential places are not always easily accessible. In the author’s experience, earlier initiation of treatment is often justified for young people with SUD and disabling depressive symptoms, especially if there is a prior history of dysthymia and/or major depression or if there is a strong family history of affective disorder. SSRIs pose less risk of morbidity and mortality and have a potential for reducing craving for alcohol. Among the SSRI drug class, it is better to avoid fluvoxamine, given its potential for impairment of psychomotor performance when coadministered with alcohol. Schizophrenia Young people with schizophrenia and comorbid SUD may require longer periods of hospitalization to facilitate full engagement to a multimodal treatment program. Newer antipsychotics such as olanzapine or risperidone are preferred in the initial treatment of schizophrenic symptoms, given their favorable side effect profile and lack of significant cognitive effects. Clozapine is usually indicated in the treatment of resistant cases. Recently, it has been suggested that clozapine may have a special role for patients with schizophrenia and comorbid SUD. A number of case reports and one open study have demonstrated that clozapine reduces both schizophrenic symptoms and substance use (Lee et al., 1998).

367


ADHD Anecdotal reports suggest that adolescents with ADHD are at higher risk of abusing CNS stimulants such as methylphenidate, compared with children without ADHD (Schenk, 1996). However, the existing empirical evidence is insufficient to draw any firm conclusions as to whether therapeutic use of stimulants is in fact associated with an increased risk of abuse. There is certainly a risk of prescribed methylphenidate being diverted for sale on the black market. Consequently, careful monitoring of the prescription of stimulants is warranted. Alternatives to stimulant medications include bupropion, a newer antidepressant with noradrenergic and dopaminergic effects, or clonidine, an alpha-adrenergic agonist (see Chapter 9 for details of side effects, dosage, etc.). Conclusions SUD in adolescence is a significant public health problem with a potential for altering the developmental trajectory of affected young people. Comorbid psychiatric disorders are observed in many young people with SUD. The presence of psychiatric comorbidity has implications for the onset, clinical course, treatment, compliance, and prognosis for young people with SUD. Over the past 10 years, neurobiologists have made considerable gains in establishing the neurobiologic basis of SUD. The safety and efficacy of many pharmacologic agents used in the treatment of adults with SUD have been reasonably well established. There is a burgeoning interest in research into the psychopharmacotherapy of comorbid psychiatric disorders in young people with SUD. However, the current research evidence represents islands of knowledge in a vast sea of ignorance. Future research will hopefully improve methods for the diagnosis and treatment of comorbid psychiatric disorder and SUD in young people, including approaches to defining the precise temporal relationships between substance use and other psychiatric disorders. Systematic research is clearly needed to evaluate the safety and efficacy of pharmacologic agents in adolescents. In particular, developmental aspects of pharmacokinetics and pharmacodynamics in young people should be thoroughly explored to develop appropriate dosage strategies. Research is needed in the development of comprehensive treatment programs that integrate pharmacotherapy and psychosocial therapies. Clinicians dealing with young people with SUD should make every effort to involve the family and the other ‘‘systems of concern’’, such as school, the judicial system, and social/community services, etc., in the treatment program. One of the enduring myths about addiction is that treatment for these disorders is gen-

368

K.A. Hussain Mirza

erally ineffective. Integrative, multimodal treatments involving medication and psychotherapies have the potential for dispelling this myth and in fostering therapeutic optimism. It is highly unlikely that we will ever develop a pharmacologic agent that will stop young people from using drugs and alcohol. However, to paraphrase Carroll and Rounsville, pharmacologic treatment may prove to be the first step in the road to recovery for many young people, a journey that will allow the young people to attend schools, ‘‘to love and to see that they have lives beyond substance abuse’’ (Carroll and Rounsville, 1995).

Acknowledgements I am grateful to Ms. Angela Guptil, Dr. Normand Carrey, Ms. Jackie Barkley, and Ms. Tena Jackson for their discerning comments on an earlier draft of this chapter.

REFE REN C ES Aceto MD, Bowman ER, May EL et al. (1989). Very long acting narcotic antagonists: the 14 – B-p substituted cinnmoylaminomorphines and their partial mu agonist codeimone relatives. Arzneim-Forsch/ Drug Research 39:570–5. Adlaf EM, Ivis FJ, Smart RG et al. (1995). Ontario Student Drug Use Survey: 1977–1995. Ontario, Canada: Addiction Research Foundation. Adlaf EM, Ivis FJ, Smart RG et al. (1996). Enduring resurgence or statistical blip? Recent trends from the Ontario Student Drug Use Survey. Can J Public Health 87:189–92. Agarwal DP, Harada S, Goedde H (1981). Racial differences in biological sensitivity to ethanol: the role of alcohol dehydrogenase and aldehyde dehydrogenase enzymes. Alcohol Clin Exp Res 5:12–16. Aghajanian GK (1978). Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine. Nature 267:186–8. Alterman AI, Droba M, O’Brien et al. (1992). Amantadine may facilitate detoxification of cocaine addicts. Drug Alcohol Depend 31:19–29. Altshuter HL, Shippenberg TS (1980). Alteration of ethanol self administration by naloxone. Life Science 26:679–88. American Academy of Pediatrics (1987). Chemical dependency. Paediatr Clin North Am 34. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. American Psychiatric Association (1996). Practice guidelines for the treatment of patients with substance use disorder. In Practice Guidelines. Washington, DC: American Psychiatric Association.

369


Anderson JC, Williams S, McGee R, Silva PA (1987). DSM III disorders in preadolescent children: prevalence in a large sample from the general population. Arch Gen Psychiatry 44:69–78. Arana GW, Hyman SE (1991). Handbook of Psychiatric Drug Therapy. 2nd edition. Boston: Little Brown. Arndt IO, Dorozynsky Z, Woody GE et al. (1992). Desipramine treatment of cocaine dependence in methadone maintained patients. Arch Gen Psychiatry 49:888–93. Badawy AAB (1996). Alcohol as a psychopharmacological agent. In Alcohol and Aggression, (Ed.) PF Brian, Dover, NH: Croom Helm, pp. 55–83. Ball J, Ross A (1991). The Effectiveness Of Methadone Maintenance Treatment. New York: Springer Verlag. Ball JC, Lange WR, Myers CP et al. (1988). Reducing the risk of AIDS through methadone maintenance treatent. J Health Soc Behav 29:214–26. Baugmartner GR, Rowen RC (1991). Transdermal clonidine versus chlordiazepoxide in the treatment of alcohol withdrawal. South Med J 84:312–21. Begleiter H, Porjesz S (1977). Persistence of brain hyper-excitability following chronic alcohol exposure in rats. Adv Exp Med Biol 85:209–22. Begleiter H, Porjesz B, Bihari B et al. (1984). Event-related brain potentials in boys at risk of alcoholism. Science 225:1493–6. Benowitz NL (1993). Nicotine replacement therapy: what has been accomplished, can we do better? Drugs 45:157–70. Bickel WK, Stitzer ML, Bigelow GE et al. (1988). A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts. Clin Pharmacol Ther 43:72–8. Blood L (1995). Preliminary results: A Treatment Outcome Study of the Choices Program Drug Dependency Services. Nova Scotia Department of Health, Canada. Blum K, Noble EP, Sheridan PJ et al. (1990). Allelic association of human dopamine D2 receptor in alcoholism. J Am Med Assoc 263:2055–60. Blum RW (1987). Adolescent substance abuse: diagnostic and treatment issues. Pediatr Clin North Am 34:523–37. Bolos AM, Dean M, Lucas-Derse S et al. (1990). Population and pedigree studies reveal a lack of association between the dopamine d2 receptor gene and alcoholism. J Am Med Assoc 264:3156– 60. Borg V (1983). Bromocriptine in the treatment of alcohol dependence. Acta Psychiatr Scand 68:100–10. Boyle MH, Offord DR (1991). Psychiatric disorder and substance use in adolescents.Can J Psychiatry 36:699–705. Brunning J, Mumford JP, Keaney FP (1986). Lofexidine in alcohol withdrawal states. Alcohol Alcohol 21:167–70. Bruno F (1989). Buspirone in the treatment of alcoholic patients. Psychopathology 1:49–59. Burkstein O, Brtent DA, Kaminer Y (1989). Co-morbidity of substance abuse and other psychiatric disorders in adolescents. Am J Psychiatry 146:1131–41. Busto U, Sellers EM, Naranjo CA et al. (1986). Withdrawal reaction after long term therapeutic use of benzodiazepines. N Engl J Med 315:854–9.

370

K.A. Hussain Mirza

Caron C, Rutter M (1991). Co-morbidity in child psychopathology: concepts, issues and research strategies. J Child Psychol Psychiatry 32:1063–80. Carroll KM, Rounsville BJ (1995). Psychosocial treatments. In American Psychiatric Press Review of Psychiatry, (Eds.) JM Oldham, MB Riba. Washington, DC and London: American Psychiatric Press, pp. 126–48. Ciraulo DA, Shader RI (Eds.) (1991). Clinical Manual of Chemical Dependence. Washington, DC, London: American Psychiatric Press. Chick J, Gough K, Falkowski W (1992). Disulfiram treatment of alcoholism. Br J Psychiatry 161:84–9. Christie KA, Burke JD, Regier DA et al. (1988). Epidemiologic evidence for early onset of mental disorders and higher risk of drug abuse in young adults. Am J Psychiatry 145:971–5. Cloninger CR, Reich T, Weitzel R (1979). Alcoholism and affective disorders: familial associations and genetic models. In Alcoholism and the Affective Disorders, (Eds.) D Goodwin, C Ericson, New York: Spectrum, pp. 57–86. Cornelius JR, Salloum IM, Ehler JG et al. (1997). Fluoxetine in depressed alcoholics: a double blind, placebo-controlled trial. Arch Gen Psychiatry 54:700–5. Cornish JW, Maany I, Fudala PJ et al. (1995). Carbamazepine treatment for cocaine dependence. Drug Alcohol Depend 38:221–7. Cornish JW, McNicholas LF, O’Brien CP (1998). Treatment of substance related disorders. In Textbook of Psychopharmacology, (Eds.) AF Schatzberg, CB Nemeroff. Washington, DC and London: American Psychiatric Association, pp. 851–68. Cowley DS, Roy-Byrne PP, Godon C et al. (1992). Response to diazepam in sons of alcoholics. Alcohol Clin Exp Res 16:1057–63. Crabbe JC, Belknap JK, Buck KJ, Metten P (1994). Use of recombinant inbred strains for studying genetic determinants of response to alcohol. Alcohol Alcohol (Suppl). 2:67–71. Crabbe JC, Phillips TJ (1996). The serotonin 5HT 1B receptor: a QTL for alcohol preference drinking. Paper presented at the Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 1996. Croop RS, Faulkner EB, Labriola DF (1997). The safety profile of naltrexone in the treatment of alcoholism. Results from a multi-centre usage study. The naltrexone study group. Arch Gen Psychiatry 54:1130–5. Crowley TJ, Riggs PD (1995). Adolescent substance use disorder with conduct disorder and comorbid conditions. In Adolescent Drug Abuse: Clinical Assessment and Therapeutic Interventions. NIDA research monograph series, (Eds.) E Rahdert, D Czechowicz, Rockville, MD: National Institute of Drug Abuse, pp. 49–111. Dackis CA, Gold MS (1985). Bromocriptine as treatment of cocaine abuse. Lancet 1:1151–2. Daoust M, Heidbreder C, Opsomer L et al. (1992). Acamprosate modulates synaptosomal GABA transmission in chronically alcoholised rats. Pharmacol Biochem Behav 41:669–74. Daughton DM, Heatley SA, Pendergast JJ et al. (1991). Effect of transdermal nicotine delivery as an adjunct to low intervention smoking cessation therapy. Arch Intern Med 151:749–52. De Milio L (1989). Psychiatric syndromes in adolescent substance abusers. Am J Psychiatry

371


146:1212–14. Devane WA, Hanus I, Brewer A et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 158:1946–8. Deykin EY, Levy JC, Wells VW (1987). Adolescent depression, alcohol and drug abuse. Am J Public Health 77:178–82. Di Chiara G, Imperato A (1988). Drugs abused by humans preferentially increase synaptic dopamine transmission in the mesolimbic system of freely moving rats. Proc Nat Acad Sci USA 85:5274–82. Dole VP, Nyslander M (1965). A medical treatment for heroin (diacetyl morphine) addiction: a clinical trial with methadone hydrochloride. J Am Med Assoc 193:646–50. Dongier M, Vachon L, Schwartz G (1991). A controlled study of bromocriptine in reducing craving in patients with alcohol dependence. Alcohol Clin Exp Res 15:970–7. Dorus W, Ostrow D, Anton R et al. (1989). Lithium treatment of depressed and non-depressed alcoholics. J Am Med Assoc 262:1646–52. Drejer K, Theilgaard A, Teasdale TW et al. (1985). A prospective study of young men at high risk for alcoholism: neuropsychological assessment. Alcohol Clin Exp Res 9:498–502. Edwards NB, Simmons RC, Rosenthal TL et al. (1988). Doxepin in the treatment of nicotine withdrawal. Psychosomatics 29:203–6. Fawcett J, Clark DC, Aagesen CA et al. (1987). A double blind placebo controlled trial of lithium carbonate therapy for alcoholism. Arch Gen Psychiatry 44:248–56. Fox BS, Kantak KM, Edwards MA et al. (1996). Efficacy of a therapeutic cocaine vaccine in rodent models. Nature Med 2:1129–32. Fram DH, Marmo J, Holden R (1989). Naltrexone treatment: the problem of patient acceptance. J Subst Abuse Treat 6:199–22. Frawley PJ, Smith JW (1990). Chemical aversion therapy in the treatment of cocaine dependence as part of a multimodal treatment program: treatment outcome. J Subst Abuse Treat 7:21–9. Fuller RF, Roth HP (1979). Disulfiram for the treatment of alcoholism: an evaluation of 128 men. Ann Inter Med 90:901–4. Fuller RF, Branchey L, Brightwell DR (1986). Disulfiram in the treatment of alcoholism. J Am Med Assoc 256:1449–55. Gabrielli WF, Mednick SA, Volavka J et al. (1982). Electroencephalogram in children of alcoholic fathers. Psychophysiology 19:404–7. Gallimberti L, Ferri M, Ferrara D et al. (1992). Gamma hydroxy butyric acid in the treatment of alcohol dependence. Alcohol Clin Exp Res 16:673–6. Gastfriend DR, McClellan A, (1997). Treatment matching: theoretic basis and practical implications. Med Clin North Am 81:945–66. Gawin FH (1986). Neuroleptic reduction of cocaine-induced paranoia but not euphoria? Psychopharmacology 90:142–43. Gawin FH, Kleber HD, Kosten TR et al. (1989). Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 46:117–21.

372

K.A. Hussain Mirza

Geller B, Cooper TB, Sun K et al. (1998). Double blind and placebo controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 37:171–8. George FR, Goldberg SR (1989). Genetic approaches to the analysis of addiction processes. Trend Pharmacol Sci 10:78–83. Gerstein DR (1992). The effectiveness of drug treatment. In Addictive States, Vol 70, (Ed.) O’Brien CP, Jaffe JH, New York: Raven Press, pp. 253–82. Gewiss M, Heidbreder C, Opsomer L (1991). Acamprosate and diazepam differentially modulate alcohol induced behavior and cortical alterations in rats following chronic inhalation of ethanol vapor. Alcohol Alcohol 26:129–37. Gill K, Gillespie, HK, Hollister LE et al. (1991). A prospective, controlled study of cocaine abstinence state. Hum Psychopharmacol 6:25–8. Giller E, Hall H (1983). Platelet MAO activity in recovered alcoholics after long term abstinence. Am J Psychiatry 140:114–15. Glass IB (Ed.) (1991). The International Handbook of Addiction Behaviour. London: Routledge. Glassman AH, Covey LS (1990). Future trends in the pharmacological treatment of smoking cessation. Drugs 40:1–5. Gold MS, Pottach AC, Sweeney DR et al. (1980). Opiate withdrawal using clonidine. J Am Med Assoc 243:343–6. Gold MS, Redmond DE, Kleber HD (1978). Clonidine blocks acute opiate withdrawal symptoms. Lancet 2:599–602. Goldman GD, Volicer L, Gold BF (1981). Cerebrospinal fluid GABA and cyclic nucleotides in alcoholics with and without seizures. Alcohol Clin Exp Res 5:431–4. Gorelick DA (1997). Enhancing cocaine metabolism with butyryl cholinesterase as a treatment strategy. Drug Alcohol Depend 48:159–65. Gorelick DA, Paredes A (1992). Effect of fluoxetine on alcohol consumption in male alcoholics. Alcohol Clin Exp Res 16:261–5. Gossop M, Griffiths P, Bradley B, Strang J (1986). Opiate withdrawal symptoms in response to 10-day and 21-day methadone withdrawal programmes. Br J Psychiatry 154:360–3. Grabowski J, Rhoades H, Elk R et al. (1995). Fluoxetine is ineffective for the treatment of cocaine dependence or concurrent opiate and cocaine dependence: two placebo controlled double blind trials. J Clin Psychopharmacol 15:163–73. Grant K A, Valverius M, Hudspith M et al. (1990). NMDA abnormalities in chronic alcoholism, Eur J Pharmacol 176:289–96. Grilo CM, Becker DF, Walker ML et al. (1985). Psychiatric co-morbidity in adolescent inpatients with substance use disorders. J Am Acad Child Adolesc Psychiatry 34:1085–91. Gross J, Stitzer ML (1989). Nicotine replacement: ten weeks’ effect on tobacco withdrawal symptoms. Psychopharmacology 93:334–41. Guitart X, Beitner-Johnson D, Marby DW et al. (1992). Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and their regulation by chronic morphine in the mesolimbic dopamine system. Synapse 12:242–53.

373


Halikas JA, Crosby RD, Carlson GA (1991). Cocaine reduction in unmotivated crack users using carbamazepine versus placebo in a short term, double blind crossover design. Clin Pharmacol Ther 50:81–95. Halikas JA, Lyttle MD, Morse CL, Hoffman RG (1984). Proposed criteria for the diagnosis of alcohol abuse in adolescents. Comp Psychiatry 25:581–5. Harada S, Agarwal DP, Goedde HW et al. (1983). Aldehyde dehydrogenase isoenzyme variation and alcoholism in Japan. Pharmacol Biochem Behav (Suppl 1) 18:151–3. Hartel D, Schoenbaum EE (1989). Temporal patterns of cocaine use and AIDS in intravenous drug users in methadone maintenance. In Fifth International Conference on AIDS: Montreal, Canada, Abstract. Hartel D, Selwyn PA, Schoenbaum EE (1988). Methadone maintenance and reduced risk of AIDS and AIDS specific mortality in intravenous drug users. In Fourth International Conference on AIDS: Stockholm, Sweden, Abstract 8526. Hawkins JD, Catalano RF, Miller RF (1992). Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: Implications for substance abuse problems. Psychol Bull 112:64–105. Hayashida M, Alterman AJ, McClellan A et al. (1989). Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with mild to moderate alcohol withdrawal syndrome. N Engl J Med 320:358–65. Heath AC, Slutske WS, Madden PA et al. (1994). Genetic effects on alcohol consumption patterns and problems in women. Alcohol Alcohol (Suppl 2):53–7. Hoffman RS, Morasco R, Goldfrank LR (1996). Administration of purified human plasma cholinesterase protects against cocaine toxicity in mice. J Toxicol Clin Toxicol 34:259–66. Howard MO, Elkins RL, Rimmele C et al. (1991). Chemical aversion treatment of alcohol dependence. Drug Alcohol Depend 29:107–43. Hubbard RL, Cavanaugh ER, Craddock SG et al. (1985). Characteristics, behaviours and outcomes for youth in the TOPS. In AS Friedman, GM Beschner (Eds.), Treatment Services for Adolescent Substance Abusers. Rockville, MD: US Department of Health and Human Services, pp. 49–65. Hubner CB, Moreton JE (1991). Effects of selective D1 and D2 dopamine antagonists on cocaine self administration in the rat. Psychopharmacology 105:151–6. Hurt RD, Sachs DP, Glover ED et al. (1997). A comparison of sustained release bupropion and placebo in smoking cessation. N Engl J Med 337:1195–202. Hwang BH, Lumeng L, Wu JY, Li TK (1990). Increased number of GABA-ergic terminals in the nucleus accumbens is associated with alcohol preference in rats. Alcohol Clin Exp Res 14:503–7. Hyman SE (1996). Addiction to cocaine and amphetamine. Neuron 16:901–4. Izenwasser S, Buzas B, Cox BM (1993). Differential regulation of adenyl cyclase activity by mu and delta opioids in rat caudate-putamen and nucleus accumbens. J Pharmacol Exp Ther 267:145–52. Johnson RE, Jaffe JH, Fudala PJ (1992). A controlled trial of buprenorphine treatment for opioid dependence. J Am Med Assoc 267:2750–5.

374

K.A. Hussain Mirza

Johnston L, Bachman J, O’Malley P et al. (1982). Student Drug Use, Attitudes and Beliefs. National Trends, 1975–1982. Rockville, MD: National Institute of Drug Abuse. Johnston LD, O’Malley PM, Bachman PG (1993). National survey results: drug use in secondary school students. In Measuring The Future Study 1975–1992. Rockville, MD: National Institute of Drug Abuse. Kaminer Y (1992). Desipramine facilitation of cocaine abstinence in an adolescent. J Am Acad Child Adolesc Psychiatry 31:14–15. Kaminer Y, Burkstein O, Tarter R et al. (1992). Comparison between treatment completers and non-completers among dually diagnosed substance abusing adolescents. J Am Acad Child Adolesc Psychiatry 31:1046–9. Kampman K, Volpicelli JR, Alternman AI et al. (1996). Amantadine in the early treatment of cocaine dependence: a double blind-placebo controlled trial. Drug Alcohol Depend 41:25–33. Kaplan HI, Sadock BJ (1998). Synopsis of Psychiatry, 8th edn. Baltimore, MD: Williams and Wilkins. Kashani JH, Beck NC, Hoeper EW et al. (1987a). Psychiatric disorders in a sample of adolescents. Am J Psychiatry 144:584–9. Kashani JH, Carlson GA, Beck NC et al. (1987b). Depression, depressive symptoms and depressed mood among a community sample of adolescents. Am J Psychiatry 144:931–4. Khantzian EJ, McKenna GJ (1979). Cocaine withdrawal: is there evidence for a distinctive withdrawal syndrome? Ann Intern Med 90:361. Khantzian EJ, Halliday KS, McAuliffe WE (1990). Addiction and the Vulnerable Self: Modified Dynamic Group Therapy for Substance Abusers. New York: Guilford Press. Kendler KS, Heath AC, Neole MC et al. (1992). A population-based twin study of alcoholism in women. J Am Med Assoc 268:1877–82. King CA, Ghaziuddin N, McGovern L et al. (1996). Predictors of co-morbid alcohol and substance abuse in depressed adolescents. J Am Acad Child Adolesc Psychiatry 35:743–51. Kleber HD (1989). Treatment of drug dependence: what works. Int Rev Psychiatry 1:81–100. Kleber HD, Weissman MM, Rounsaville BJ (1983). Imipramine as a treatment of depression in addicts. Arch Gen Psychiatry 40:643–53. Koob GF (1992). Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–84. Koob GF, Maldonaldo MJD, Stinus L (1992). Neural substrates of opiate withdrawal. Trends Neurosci 15:186–91. Kosten TR (1989). Treatment of cocaine abuse with bromocriptine and amantadine. J Nerv Ment Dis 177:379–82. Kosten TR, Kleber HD (1988). Buprenorphine detoxification from opioid dependence: a pilot study. Life Sci, 42:635–41. Kosten TR, McCanze-Katz E (1995). New pharmacotherapies. In American Psychiatric Press Review of Psychiatry, vol. 14, (Eds.) Olham JM, Riba MS. Washington, DC and London: American Psychiatric Press, pp. 105–26. Kosten TR, Kleber HD, Morgan C (1989). Treatment of cocaine abuse with buprenorphine.

375


Biological Psychiatry 26:170–2. Kosten TR, Morgan CM, Falcione J et al. (1992). Pharmacotherapy for cocaine abusing, methadone maintenance patients using amantadine or desipramine. Arch Gen Psychiatry 49:894–8. Kosten TR, Miserendino MJ, Chi S et al. (1994). Fischer and Lewis rat strains show differential cocaine effects in conditioned place preference and behavioural sensitization but not in locomotor activity or conditioned taste aversion. J Pharmacol Exp Ther 269:137–44. Kranzler HR, Bauer LO, Hersh D et al. (1995a). Carbamazepine treatment of cocaine dependence: a placebo controlled trial. Drug Alcohol Depend 38:203–11. Kranzler HR, Burleson JA, Korner P et al. (1995b). Placebo controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry 152: 391–7. Kranzler HR, Del Boca F, Korner P et al. (1993). Adverse effects limit the usefulness of fluvoxamine for the treatment of alcoholism. J Subs Abuse Treat 10:283–7. Kreek MJ (1992). Effects of opiates, opiate antagonists and cocaine on the endogenous opioid system: clinical and laboratory studies. NIDA Res Monogr 119:44–8. Kovacs M, Goldstone D, Garsoms C (1993). Suicidal behaviours and childhood onset depressive disorders: a longitudinal investigation. J Am Acad Child Adolesc Psychiatry 32:8–20. Ladewig D, Knecht T, Leher P et al. (1993). Acamprosate – a stabilizing factor in long term withdrawal of alcoholic patients. Therap Umsch, 50:182–8. Lee M, Dickson RA, Campbell M et al. (1998). Clozapine and substance abuse in patients with schizophrenia. Can J Psychiatry 43:855–6. LeJoyeux M, Ades J (1993). Evaluation of lithium treatment in alcoholism. Alcohol Alcohol 28:273–9. Lettieri DJ (1985). Drug abuse: a review of explanations and models of explanations. Adv Alcohol Subs Abuse 4:9–40. Lewinsohn PM, Hops H, Roberts RE et al. (1993). Adolescent psychopathology. I. Prevalence and incidence of depression and other DSM-IIIR disorders in high school students. J Abnorm Psychol 102:133–44. Lewinsohn PM, Rohde P, Seeley JR (1995). Adolescent psychopathology: III the clinical consequences of co-morbidity. J Am Acad Child Adolesc Psychiatry 34:510–19. Lhuintre JP, Moore ND, Tran G et al. (1990). Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol 25:613–22. Li TK, Lumeng L, McBride WJ et al. (1987). Rodent line selected for factors affecting alcohol consumption. Alcohol Alcohol (Suppl 1):91–6. Li TK, Lumerg L, McBride WJ (1992). An experimental approach to understanding the genetic basis of alcoholism. Trans Am Clin Climatol Assoc 104:61–71. Lifrak PD, Alterman AI, O’Brien CP, Volpicelli JR (1997). Naltrexone for alcoholic adolescents (letter). Am J Psychiatry 154:439–41. Ling W, Klett CJ, Gillis RD (1978). A cooperative clinical study of methadyl acetate. Arch Gen Psychiatry 35:345–53. Linnoila M, De Jong, I, Virkunnen M (1989). Family history of alcoholism in violent offenders

376

K.A. Hussain Mirza

and impulsive fire setters. Arch Gen Psychiatry 46:679–81. Liskow BI, Goodwin D (1987). Pharmacological treatment of alcohol intoxication, withdrawal and dependence: a critical review. J Stud Alcohol 48:356–70. Litten RZ, Allen JP (1991). Pharmacotherapies for alcoholism, promising agents and clinical issues. Alcohol Clin Exp Res 15:620–33. Littleton J (1995). Acamprosate in alcohol dependence: how does it work? Addiction 90:1179–88. London ED, Cascella NG, Wong DF (1990). Cocaine induced reduction of glucose utilisation in human brain. Arch Gen Psychiatry 47:567–74. Maddux JF, Desmond DP (1992). Ten year follow up after administration of methadone maintenance. Am J Drug Alcohol Abuse 18:63–74. Malcolm R, Anton RF, Randall CL et al. (1992). Buspirone does not reduce drinking behaviour in alcoholics. Alcohol Clin Exp Res 16:1007–13. Malcolm R, Ballenger JC, Sturgis ET et al. (1989). Carbamazepine in the treatment of alcohol withdrawal. Am J Psychiatry 146:617–21. Margolin A, Azants SK, Kosten TR et al. (1994). A double blind study of mazindol for the treatment of cocaine abuse in newly abstinent cocaine abusing methadone maintenance patients, a preliminary report. NIDA Res Monogr 141:446. Mason BJ, Ritvo EC, Morgan RO et al. (1994). A double blind placebo controlled pilot study to evaluate the safety and efficacy of oral nalmefene Hcl for alcohol dependence. Alcohol Clin Exp Res 18:1162–7. McClellan AT, Arndt IO, Metzger DS et al. (1993). The effects of psychosocial services on substance abuse treatment. J Am Med Assoc 269:1953–9. McClellan AT, Luborsky L, Eoody GE (1983). Predicting response to alcohol and drug abuse treatments. Arch Gen Psychiatry 40:620–5. Merikangas KR, Leckman JF, Prusoff BA et al. (1985). Familial transmission of depression and alcoholism. Arch Gen Psychiatry 42:367–72. Metzger DS, Woody GE, McClellan AT et al. (1993). HIV virus seroconversion among intravenous drug users in and out treatment: 18 month prospective follow up. J Acquir Immune Defic Syndr 6:1049–56. Meyer RE (1989). Prospects for a rational pharmacotheraphy of alcoholism. J Clin Psychiatry 50:403–12. Meyer RE, Mirin SM (1991). A psychology of craving: implications of behavioural research. In Substance Abuse: Clinical Problems and Perspectives, (Eds.) JH Lowinson, P Ruiz, Baltimore, MD: Williams and Wilkins. Meyer RE, Mirin SM, Zackon F (1979). Community outcome on narcotic antagonists. In The Heroin Stimulus: Implications for a Theory of Addiction, (Eds.) RE Meyer, SM Mirin. New York: Plenum Press. Michael A, Mirza KAH (1993). Serotonin in alcoholism. J Serotonin Res 4:243–56. Michael A, Mirza KAH, Mukundan CR, Channabasavanna SM (1993). Interhemispheric EEG coherence in alcoholism. Acta Psychiatr Scand 87:213–17. Milin R, Halikas JA, Meller JE et al. (1991). Psychopathology among substance using juvenile

377


offenders. J Am Acad Child Adolesc Psychiatry 30:569–74. Miller PM, Plant M (1996). Drinking, smoking and illicit drug use among 15 and 16 year olds in the United Kingdom. BMJ 313:394–9. Mirza KAH (in press). Substance use disorder in adolescents with co-morbid psychiatric disorders: implications for clinical management. Br J Hosp Med. Mirza KAH, Michael A (1996). Major depression in children and adolescents. Br J Hosp Med 55:57–61. Mirza KAH, Mirza S (1998). Assessment and management of major depressive disorder in children and adolescents. Psychiatry in practice 2:12–16. Mirza KAH, Mirza S (in press). Naltrexone in the treatment of young people with opioid dependence. Br J Addict. Monti JM, Alterwain P (1991). Ritanserin in the treatment of alcoholism. Lancet 337:60. Montoya ID, Levin FR, Fudala P et al. (1994). A double blind comparison of carbamazepine and placebo treatment of cocaine dependence. NIDA Res Monogr 141:435. Murphy JK, Edwards NB, Downs AD et al. (1989). Effects of doxepin on withdrawal symptoms in smoking cessation. Am J Psychiatry 147:1353–7. Naranjo CA, Kadlec KE, Sanheuza P et al. (1990). Fluoxetine differentially alters alcohol intake and other consummatory behaviour in problem drinkers. Clin Pharmacol Ther 47:490–8. Naranjo CA, Sellers EM, Sullivan JT et al. (1987). Serotonin uptake inhibitor citalopram attenuates alcohol intake. Clin Pharmacol Ther 35:374–81. Nestler EJ, Fitzgerald LW, Self DW (1995). Neurobiology. In American Psychiatric Press Review of Psychiatry, (Eds.) JM Oldham, MB Riba. Washington, DC and London: American Psychiatric Press, pp. 51–81. Nestler EJ, Hope BT, Widnell KL (1993). Drug addiction: a model for the molecular basis for neuronal plasticity. Neuron 11:995–1006. Newcomb MD (1992). Substance use and control in the United States: ethical and legal issues. Soc Sci Med 35:471–9. Newcomb MD, Bentler PM (1988). Consequences of Adolescent Drug Use: Impact on the Lives of Young Adults. Beverly Hills, CA: Sage Publications. Nunes EV, McGrath PJ, Quitkin FM et al. (1993). Imipramine treatment of alcoholism with co-morbid depression. Am J Psychiatry 150:963–5. Nutt DJ (1996). Addiction: brain mechanisms and their treatment implications. Lancet 347:31–6. Nutt DJ, Adinoff B, Linnoila M (1989). Benzodiazepines in the treatment of alcoholism. In Recent Developments in Alcoholism, Treatment and Research, volume 7 (Ed.) M Galanter, New York: Plenum Press, pp. 283–313. Nutt D, Glue P, Wilson S et al. (1993). Flumazenil in alcohol withdrawal. Alcohol Alcohol (Suppl) 2:337–41. O’Brien CP (1976). Experimental analysis of conditioning factors in human narcotic addiction. Pharmacol Rev 27:533–43. O’Malley SS, Jaffe A, Chang G (1992). Naltrexone and coping skills therapy for alcohol depen-

378

K.A. Hussain Mirza

dence: a controlled study. Arch Gen Psychiatry 49:881–7. Palmer KJ, Buckley MM, Faulds D (1992). Transdermal nicotine: a review of pharmacokinetic and pharmacodynamic properties and therapeutic efficacy as an aid to smoking cessation. Drugs 44:498–529. Pandey SC, Piano MR, Schwertz DW et al. (1992). Effect of ethanol administration and withdrawal on serotonin receptor subtypes and receptor mediated phosphoinositide hydrolysis in rat brain. Alcoholism 16: 1110–16. Pelc I, Verbanck P, Le-Bon O et al. (1997). Efficacy and safety of acamprosate in the treatment of detoxified alcohol dependent patients; a 90 day placebo controlled study. Br J Psychiatry 171:73–7. Pfeiffer CR, Klerman GL, Hurt SW et al. (1993). Suicidal children grown up: rates and psychosocial risk factors for suicide attempts during follow-up. J Am Acad Child Adolesc Psychiatry 32:106–13. Piacentini JC, Klein RC, Koplewicz H et al. (1990). Co-morbidity of depression in substance abuse in adolescents. Scientific Proceedings of the Annual meeting of the American Academy of Child and Adolescent Psychiatry 6:69. Piazza PV, Maccari S, Deminiere JM et al. (1991). Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Nat Acad Sci USA 88:2088–92. Pike VW (1993). Positron-emitting radio-ligands for studies in vivo: probes for human psychopharmacology. J Psychopharmacol 7:139–58. Poulin C, Elliott D (1996). Alcohol, tobacco and cannabis use among Nova Scotia adolescents: implications for prevention and harm reduction. Can Med Assoc J 156:1387–93. Potokar J, Coupland N, Glue P, Nutt D (1997). Flumazenil in alcohol withdrawal: a double blind placebo controlled study Alcohol Alcohol 32:605–11. Rasmussen K, Aghajanian GK (1989). Withdrawal-induced activation of locus coeruleus neurons in opiate dependent rats: attenuation by lesions of the nucleus paragiganto cellularis. Brain Res 505:346–50. Rasmussen K, Beitner-Johnson D, Krystal JH et al. (1990). Opiate withdrawal and the rat locus coeruleus: behavioural, electrophysiological and biochemical correlates. J Neurosci 10:2308–17. Reiger DA, Farmer ME, Rae DS et al. (1990). Co-morbidity of mental disorders with alcohol and other drug abuse. Results from the ECA study. JAMA 264:2511–18. Rickels K, Downing R, Hassman H (1993). Antidepressants for the treatment of generalised anxiety disorder: a placebo controlled comparison of imipramine, trazodone and diazepam. Arch Gen Psychiatry 50:884–95. Riggs PD, Mikulich SK, Coffman LM, Crowley TJ (1997). Fluoxetine in drug dependent delinquents with major depression: an open trial. J Child Adolesc Psychopharmacol 7:87–95. Robins LN, McEvoy L (1990). Conduct problems and substance abuse. In Straight And Deviant Pathways From Childhood To Adulthood, (Eds.) Robins LN, Rutter M. Cambridge: Cambridge University Press, pp. 456–89. Rohde P, Lewinshon PM, Seeley JR (1991). Co-morbidity of unipolar depression. II. Co-morbid-

379


ity with other mental disorders in adolescents and adults. J Abnorm Psychol 100:214–22. Rohde P, Lewinshon PM, Seeley JR (1996): Psychiatric co-morbidity with problematic alcohol use in high school students. J Am Acad Child Adolesc Psychiatry 35:101–9. Rounsville BJ, Glazer W, Wilber CH et al. (1983). Short term interpersonal psychotherapy in methadone-maintained opiate addicts. Arch Gen Psychiatry 40:629–36. San I, Cami J, Pen JM et al. (1990). Efficacy of clonidine, guanfacine and methadone in the rapid detoxification of heroin addicts: a controlled clinical trial. Br J Addict 85:141–7. Sanford M, Szatmari P, Spinner M et al. (1995). Predicting the one year course of adolescent major depression. J Am Acad Child Adolesc Psychiatry 34:1618–28. Schenk S (1996). Is the treatment with psychostimulants a risk factor for substance abuse? Conference report: Stimulants in the Treatment of ADHD. Drug Enforcement Administration. Washington, DC: Department of Justice. Schneider NG, Jarvik ME, Forsythe AB et al. (1983). Nicotine gum in smoking cessation: a placebo controlled, double blind trial. Addict Behav 8:253–61. Schukitt MA (1987). Alcohol and alcoholism. In Harrison’s Principles of Internal Medicine. (Eds.) E Braunwald, KJ Isselbascher, RG Petersdorf et al. New York: McGraw Hill, pp. 2106–11. Schukitt MA (1991). Alcohol and alcoholism. In Harrison’s Principles of Internal Medicine. (Eds.) JD Wilson, E Braunwald, KJ Isselbascher et al. New York: McGraw Hill, pp. 2149–51. Schukitt MA (1994). Low level of response to alcohol as a predictor of future alcoholism. Am J Psychiatry 151:184–9. Schukitt MA, Gold EO (1988). A simultaneous evaluation of multiple markers of ethanol/ placebo challenges in sons of alcoholics and controls. Arch Gen Psychiatry 45:211–16. Scultz TK (1991). Drugs used in the treatment of alcohol withdrawal. In Comprehensive Handbook of Drug and Alcohol Addiction. (Ed.) N Miller, D Marcel. New York: McGraw Hill, pp. 1091–112. Self DW, Nestler EJ (1995). Molecular mechanisms of drug reinforcement and craving. Ann Rev Neurosci 18:463–95. Sellers EM, Romach MK (1991). Benzodiazepines in the treatment of alcohol withdrawal. Drug Alcohol Rev 10:215–24. Shaw GK, Majumdar SK, Waller S et al. (1987). Tiapride in the long term management of alcoholics of anxious or depressive temperament. Br J Psychiatry 150:164–8. Shaw GK, Waller S, Majumdar SK et al. (1994). Tiapride in the prevention of relapse in recently detoxified alcoholics. Br J Psychiatry 165:515–23. Smith GT, McCarthy DM, Goldman MS (1995). Self reported drinking and alcohol related problems among early adolescents: dimensionality and validity over 24 months. J Stud Alcohol 56: 383–94. Stine SM, Kosten TR (1992). Use of drug combinations in the treatment of opioid withdrawal. J Clin Psychopharmacol 12:203–9. Stitzer ML (1991). Nicotine delivery products: demonstrated and desirable effects. In New Developments in Nicotine Delivery systems. (Eds.) JE Henningfield, ML Stitzer, NY Ossining. New York: Cortland Communications, pp. 35–45. Stowell RJ, Estroff TW (1992). Psychiatric disorders in substance abusing adolescent inpatients: a

380

K.A. Hussain Mirza

pilot study. J Am Acad Child Adolesc Psychiatry 31:1036–40. Strang J (1990). Intermediate goals and the process of change. In (Eds.) J Strang, G-V Stimpson. AIDS and Drug Misuse: the Challenge for Policy and Practice in the 1990s. London: Routledge. Substance Abuse and Mental Health Services Administration (1995). Preliminary Estimates from the 1994 National Household Survey on Drug Abuse. Advance Report Number 10. Washington, DC: US Department of Health and Human Services. Sutherland G, Stapleton JA, Russell MAH et al. (1992). Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 340:324–9. Swadi H (1988). Drug and substance use among 3,333 London adolescents. Br J Addict 83:935–42. Tennant FS Jr, Rawson RA, Pumphrey E et al. (1986). Clinical experiences with 959 opioid dependence patients treated with LAAM. J Subs Abuse Treat 3:195–202. Tiihonen J, Kuikka J, Bergstorm K et al. (1995). Altered striatal dopamine reuptake site densities in habitually violent and non-violent alcoholics. Nature Med 1:654–7. Tollefson GD, Montague-Clouse J, Tollefson SL (1992). Buspirone reduces anxiety and drinking behaviour in alcoholics. J Clin Psychopharmacol 12:19–26. Tonnesen P, Norregaard J, Simonsen K et al. (1991). A double blind trial of 16 hour transdermal nicotine patch in smoking cessation. N Engl J Med 325:311–15. Tonnesen P, Norregaard J, Mikkelson K et al. (1993). A double blind trial of a nicotine inhaler for smoking cessation. J Am Med Assoc 269:1268–71. Trujillo KA, Akil M (1991). Inhibition of morphine tolerance and dependency by the NMDA receptor antagonist MK-801. Science 251:85–7. Volpicelli JR, Alterman AI, Hayashida M, O’Biren CP (1992). Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876–80. Washton AM, Pottash AC, Gold MS (1984). Naltrexone in addicted business executives and physicians. J Clin Psychiatry 45:39–41. Wikler A (1973). Dynamics of drug dependence: implications of a conditioning theory for research and treatment. Arch Gen Psychiatry 28:611–16. Wikler A, Pescor FT (1967). Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid drinking behaviour, and ‘relapse’ in morphine addicted rats. Psychopharmacologia 10:255–84. Wold M, Kaminer Y (1997). Naltrexone for alcohol abuse (letter). J Am Acad Child Adolesc Psychiatry 36:6–7. Wolff PH (1972). Ethnic difference in alcohol sensitivity. Science 175:449–50. Wong DT, Lumeng I, Threkeld P et al. (1988). Serotonergic and adrenergic receptors in alcohol preferring and non-preferring rats. J Neural Transm 71:207–18. Woody GE, McClellan AT, Luborsky L et al. (1995). Psychotherapy in community methadone programs: a validation study. Am J Psychiatry 152:1302–8. Woody GE, McClellan AT, O’Brien CP (1984). Treatment of behavioral and psychiatric problems associated with opioid dependence. NIDA Res Monogr 46:23–35. World Health Organization (1992). The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization. Zangwell BC, McGahan P, McLellan AT et al. (1986). How effective is LAAM treatment? Clinical

381


comparison with methadone. NIDA Res Monogr 67:249–55. Zeise ML, Kasparov V, Capogna M et al. (1993). Acamprosate decreases post-synaptic potentials in rat neocortex. Possible involvement of excitatory amino acid receptors. Eur J Pharmacol 231:47–52.

13 Tic disorders and Tourette’s syndrome John T. Walkup Johns Hopkins Hospital, Baltimore, Maryland, USA

Introduction The pharmacologic treatment of Tourette’s syndrome (TS) changed our fundamental understanding of TS. Prior to the 1960s, TS was characterized as a disorder of the mind, and tic symptoms the result of psychologic mechanisms. The discovery in the early 1960s that haloperidol is an effective tic suppressant (Caprini and Melotti, 1961; Seignot, 1961) resulted in a new conceptualization of TS – a condition of the brain, not a condition of the mind. This conceptual change stimulated an increase in both basic and clinical research, but also decreased the stigma people with severe TS so often endured. The responsiveness of tics to medications has given us clues as to which brain regions, neurocircuits, and neurochemicals are likely to be involved in the pathophysiology of TS. The responsiveness of tics to medications has also increased our hope that by identifying persons with the disorder we could provide effective treatment. Subsequent to the identification of effective treatments, studies were undertaken of this seemingly rare disorder to identify the prevalence, life course, clinical phenomenology, and associated conditions. The results of this research suggest that TS is not as rare as previously thought, that TS is not only brain based but also heritable, and that other psychiatric disorders frequently co-occur in people with TS. The discovery that haloperidol suppressed tics has also resulted in a whole class of medications, normally used for the treatment of psychosis, being used for tic suppression. Perhaps more importantly, the fact that tics could be suppressed by one medication has led researchers to study other medications for tic suppression. Many medications have been tried. Some TS experts have suggested that nearly every available medication has been tried in TS – a review of all the treatment trials and case reports of medications used in TS supports this claim (Abuzzahab and Anderson, 1973 as referenced in Shapiro et al., 1988). We have not only learned about TS from medications that attempt to suppress tics but from medications that appear to exacerbate tic symptoms. A number of reports from the early 1970s suggested that stimulant medications 382

383


could either cause TS or cause a permanent increase in tic severity (Shapiro et al., 1988 for review). To avoid this complication, other medications with dopaminergic and noradrenergic properties were studied for the treatment of attention-deficit/hyperactivity disorder (ADHD), benefiting children with and without TS. Arguably, the pharmacologic treatment of TS has stimulated the development of the current TS knowledge base. However, much more work needs to be done. Despite the findings that tic symptoms can be decreased with medications, the presence of significant side effects often preclude the use of tic-suppressing medications. As new neuroleptics are developed for psychosis, they are inevitably tried in TS. With more medications under development, the goal of an effective tic suppressant with few side effects is increasingly likely to be met. Although the treatment of tics with medication has revolutionized our understanding of TS, most clinicians are shifting away from the tic suppression as the critical treatment for people with TS (Walkup and Riddle, 1996; Walkup et al., 1998). Comorbid conditions, now more than tics, are the object of clinical attention. A number of factors support this change in clinical emphasis: (1) available tic-suppressing medications often have more problems than benefits; (2) tics appear to decrease in severity in the majority of people with TS after the teen years; (3) comorbid conditions such as ADHD, obsessive–compulsive disorder (OCD), and other psychiatric disorders are more disabling over the lifetime of a person with TS than tics; and (4) improvement in comorbid conditions makes it easier for people with TS to cope with their tics. Overview TS is a familial, neuropsychiatric disorder characterized by motor and phonic tics. Tics are brief, rapid, and stereotyped movements and sounds that wax and wane in intensity and change in kind and character over time (Walkup et al., 1998). TS begins in childhood and, for most patients, symptom severity peaks in latency and early adolescence and decreases in adulthood (Leckman et al., 1998). A number of other conditions are frequently seen in people with TS including ADHD and OCD. While prevalence estimates vary, TS is no longer considered a rare disorder, with a minimum estimate of 5–10 in 10 000 children affected (Zohar et al., 1999 for review). Twin and family studies of TS support a role for a genetic etiology in TS. Efforts to identify the gene(s) for TS, however, have not yet been successful. New and promising genetic strategies are currently underway including a large international collaborative sib pairs study supported by the

384

J.T. Walkup

Tourette Syndrome Association (Pauls et al., 1999 for review). Treatments for TS include the use of medications for tic suppression and management of comorbid psychiatric disorders. Psychosocial treatment approaches for persons with TS are less well studied, but are critical for long-term adaptation (Singer and Walkup, 1991; Walkup and Riddle, 1996; Walkup et al., 1998). Diagnostic criteria The diagnosis of TS and other tic disorders is dependent on the presence of motor and vocal tics. Tics are brief, rapid, and repetitive movements and sounds, which are either simple or complex in presentation. Simple motor tics include movements such as eye blinking, facial grimaces, head jerks or shoulder shrugs. Complex motor tics involve the contraction of multiple muscle groups simultaneously or in sequence such as a simultaneous eye deviation, head turn, and shoulder shrug. Some complex motor tics can even appear more purposeful such as stereotyped hopping, touching, rubbing, or obscene gestures (copropraxia). Simple vocal tics include repetitive sniffing, throat clearing, grunting, or barking-type sounds. Complex vocal tics usually consist of words or phrases, or the repetition of one’s own words (palilalia) or the words of others (echolalia). Coprolalia (obscene language), often incorrectly considered essential for the diagnosis of TS, is very infrequent, with only 2–6% of cases affected (Bruun and Budman, 1992). Two diagnostic schemes are commonly used for the tic disorders. The Diagnostic and Statistical Manual of Mental Disorders – IV (American Psychiatric Association, 1994) includes diagnoses for Tourette’s Disorder, Chronic Motor or Vocal Tic Disorder, Transient Tic Disorder, and Tic Disorder Not Otherwise Specified. Diagnostic criteria for TS and chronic motor or vocal tic disorder require tics to begin prior to age 18 years, and to have been present for more than 12 months. In addition, an impairment criteria has been included in the most recent edition. For research purposes, the Tourette’s Syndrome Classification Study Group supported by the Tourette’s Syndrome Association (1993) developed similar diagnostic criteria, but added diagnostic modifiers (probable, definite, and by history) to reflect diagnostic confidence. No impairment criterion is required under this diagnostic scheme. Comorbid conditions Problems with mood and impulse control, obsessive–compulsive behaviors, anxiety, disruptive behavior, attention, and learning are common in clinically

385


ascertained populations of TS subjects. For some individuals, these problems can be impairing, but in others the symptoms are less severe and do not fulfill diagnostic criteria. The most common co-occurring disorders in TS are ADHD (50–60%) and OCD (30–70%). The nature of the relationship between TS and its co-occurring problems is controversial. ADHD

In clinical populations, approximately 50% of children with TS have problems with attention, concentration, activity level, and/or impulse control (Pauls et al., 1986; Comings and Comings, 1987). Community-based epidemiologic studies of TS estimate the frequency of comorbid ADHD to be lower (8–41%) than in clinic populations (Caine et al., 1988; Apter et al., 1993). Problems with attention and concentration in TS are not always related to primary deficits in attention and concentration (ADHD), but may be secondary to the tic disorder itself (Pauls et al., 1993) or even secondary to other conditions such as learning disorders, OCD, depression, or anxiety. Attention and concentration difficulties that begin in childhood may continue into adulthood. Many adults with TS are beginning to recognize these symptoms and are seeking treatment. Obsessive–compulsive symptoms

Obsessions and compulsions are stereotyped, persistent, and intrusive thoughts and behaviors that are experienced as senseless. As many of these thoughts and behaviors can be quite common, persons are considered as ‘‘disordered’’ only when the obsessions or compulsions become severe, disabling, or time consuming. While it is not difficult to differentiate simple tics from classic compulsions, it is often more difficult to differentiate the physical sensation or urge which can precede a tic from an obsession and to differentiate some complex tics from compulsive behaviors. In spite of difficulties characterizing obsessive– compulsive (OC) symptoms, the rates of OC symptoms in TS subjects are high, with between 30–70% of TS patients affected (Montgomery et al., 1982; Frankel et al., 1986; Pauls and Leckman, 1986; Grad et al., 1987; Apter et al., 1993). OC symptoms in persons with TS appear to be more sensory–motor in nature than in persons with just OCD (Miguel et al., 1995). For example, persons with TS describe physical sensations prior to tics or other repetitive behaviors (Leckman et al., 1993; Miguel et al., 1995), whereas persons with OCD describe specific thoughts and anxiety prior to their compulsions (Miguel et al., 1995). Three subtypes of OC symptoms have been identified (Baer, 1994): a symmetry/hoarding group; a contamination/checking group; and a pure

386

J.T. Walkup

obsessional group. The symmetry/hoarding group of symptoms which includes ordering, repeating, and counting is associated with an 8-fold increase in risk for a tic disorder. The other subtypes of OCD, especially the contamination/checking group, do not appear to be associated with an increased risk for TS. Learning disorders

Children with TS have been reported to have a variety of difficulties in school, yet not all school difficulties are related to learning disorders (Walkup et al., 1995 for review). Symptoms of TS, ADHD, OCD, or disruptive behavior can impact on a child’s ability to learn. Motor tics can physically interfere with written work or attending to the teacher and may be associated with poor peer relationships. Other psychiatric disorders can impact on learning by their effect on attention, concentration, motivation, and social relationships. Some children with TS do have specific learning weaknesses that make academic tasks difficult, but whether these weaknesses are associated with the same neurologic abnormality that causes tics is unknown. A number of studies have identified a variety of disabilities in children with TS, but most studies failed to control for the presence of co-occurring conditions. More recent studies that controlled for the presence of other conditions have not been able to identify learning weaknesses in math, reading, or written language specific to TS. A recent study of children with TS, with and without ADHD, identified significant slowness on measures of time productivity compared with controls. The ‘‘slowness’’ finding was present in TS regardless of whether the children had ADHD or not, suggesting a unique learning weakness specific to TS (Schuerholz et al., 1996). Other psychiatric disorders

There is considerable controversy regarding the extent of the TS phenotype. Some investigators suggest a narrow TS phenotype with few conditions integrally related to TS (Pauls et al., 1993). Other disorders present in TS are likely to be related to ascertainment bias. Other investigators describe TS as a spectrum disorder with multiple associated problems including problems with learning and ADHD, anxiety and mood disorders, impulse control problems, and pervasive developmental disorder (Comings, 1995). Comings (1995) hypothesizes that the phenotypic expression of the TS spectrum is caused by multiple genetic defects in serotonin and dopamine metabolism which are responsible for the broad spectrum of clinical features in TS.

387


Central nervous system mechanisms of TS Methods of investigating central nervous system (CNS) function are inferential and limit our ability to identify the specific pathophysiology of TS. Therefore, hypotheses regarding the pathophysiology of TS, especially hypotheses regarding neuroanatomic site and neurochemical abnormalities, come from indirect sources: (1) known function of CNS sites, circuits, and neurochemical mediators; (2) similarities between TS and other movement disorders with known CNS pathology; (3) responsiveness of tics to pharmacologic agents; (4) analysis of postmortem brains; and (5) neuroevaluative procedures, such as spinal fluid analysis, EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) scanning. Research on the role of CNS functioning in TS supports abnormalities of the basal ganglia and its interconnections with frontal and limbic structures. Abnormalities in these brain regions or the circuitry that connects these regions could be responsible for the complex presentation seen in people with TS. The abnormalities may be within a specific brain region with secondary effects on other structures, within the circuitry which connects these brain regions, or within a broader chemical abnormality that affects the functioning of the various brain regions (Singer and Walkup, 1991). Currently, there is intense interest in the circuitry involved in TS. Leckman and colleagues (1997b), based on the work of Alexander (1994) and Alexander and Crutcher (1990), hypothesize that TS is associated with a failure to inhibit subsets of the cortical-striatothalamo-cortical minicircuits (‘‘loops’’) or, more specifically, basal ganglia thalamo-cortical circuits (Wright et al., 1999). Neuroanatomic location

The exact location of the neurologic dysfunction in TS remains unknown. The clear role of basal ganglia dysfunction in Parkinson’s disease and Huntington’s disease supports a role for the basal ganglia in the movement control abnormalities in TS. In addition, problems with the modulation of emotion, cognition, and aggression in some patients with TS suggest problems in the frontaltemporal and limbic systems. Efforts to identify anatomic abnormalities specifically have focused on specialized structural and functional imaging techniques and evaluation of postmortem brains. Imaging studies have identified a range of abnormalities in basal ganglia size and function. The nature and cause of these abnormalities, however, is unknown. Two MRI studies comparing subjects with TS with controls identified the absence of the normal left/right asymmetry (i.e., larger left-sided basal

388

J.T. Walkup

ganglia structures in unaffected right-handed individuals) in the basal ganglia of subjects with TS. In an MRI study of monozygotic twins, the more severely affected twin demonstrated a more pronounced loss of normal asymmetry compared with their lesser-affected twin. Speculation regarding the loss of mass of the left basal ganglia structures in TS focuses on early developmental factors: either hypoplastic development or atrophy of the left basal ganglia (Peterson et al., 1993; Singer et al., 1993). Supporting the hypothesis of hypoplastic development, two postmortem brain studies identified a pattern of immature cell development in portions of the basal ganglia (Balthasar, 1957; Haber et al., 1986). MRI-T2 relaxation times also identified a small, but highly significant functional asymmetry of the basal ganglia, with the right side having a much longer T2 relaxation time than the left in TS subjects compared with controls (Peterson et al., 1994a). The association of relatively decreased T2 relaxation times with reduced left-side basal ganglia volumes in TS subjects (Peterson et al., 1993; Singer et al., 1993) is not well understood. Yet, the link between decreased T2 relaxation and changes in tissue structure (increased cell density and increased ratio of intracellular to extracellular volume) is supportive of hypotheses of hypoplastic or immature development (Balthasar, 1957; Haber et al., 1986) in the basal ganglia in subjects with TS. Functional differences in the basal ganglia have also been identified. Single photon emission computed tomography (SPECT) studies have identified abnormalities in blood flow within the basal ganglia (Hall et al., 1991; Klieger et al., 1997) in general and, more specifically, the left lenticular region (Riddle et al., 1992) combined with relative hyperperfusion of the frontal regions (George et al., 1992). In a large SPECT study, similar left-sided hypoperfusion was identified as well as correlation between tic severity and hypoperfusion of the left caudate, anterior cingulate, and left medial temporal regions (Moriarty et al., 1995). Similarly, relative differences in blood flow between regions have been identified by PET. In TS subjects, there appears to be a reversal from normal in the relative metabolic patterns of the ventral striatum and the sensorimotor cortex. In TS, increased metabolism in the superior cortical convexities responsible for motor movement regulation is associated with decreased metabolism in ventral areas of the brain responsible for the integration of limbic and motor function (Stoetter et al., 1992). Neurochemical abnormalities in TS

Hypotheses regarding neurotransmitter abnormalities in TS are inferred from neurochemical functioning of the basal ganglia; the impact of pharmacologic

389


agents on tic severity, and neurotransmitter level, and function in blood and cerebral spinal fluid (CSF); neurochemical measures in postmortem brain samples; and recent findings from functional neuroimaging studies. A number of neurochemical mediators are present in the basal ganglia and its interconnection with the frontal cortex including dopamine, noradrenaline, serotonin, acetylcholine, gamma-aminobutyric acid (GABA), glutamate, and endogenous opiates. The effectiveness of dopamine-blocking agents and alphaadrenergic agonists on tic severity suggests a role for these neurochemical systems in TS. The involvement of other neurochemical modulators has been postulated, but less evidence supports a role for these systems in TS. Dopamine Supporting the role of dopamine in TS is the clinical observation that D2 receptor antagonists such as haloperidol, fluphenazine, and pimozide suppress motor and phonic tics. Agents that inhibit accumulation of dopamine in the presynaptic neurons (e.g., tetrabenazine) are also effective in reducing tic severity ( Jankovic and Orman, 1988). In contrast, tics often worsen after the administration of agents that increase central dopaminergic activity, such as amphetamine, methylphenidate, or pemoline. Initial speculation regarding the specific dopamine abnormality in TS has centered on either an excessive amount of dopamine or an increased dopamine receptor sensitivity. The few efforts to characterize dopamine, its precursors, and metabolites in CSF, or postmortem tissues, however, have not found excessive dopamine production (Singer et al., 1982, 1990; Leckman et al., 1995a) or increased receptor sensitivity (Singer et al., 1991; George et al., 1994). The finding of increased dopamine reuptake binding in a few postmortem brains (Singer et al., 1991; Malison et al., 1995) suggests either an increased number of dopamine neurons or an increased number of reuptake sites. Increased dopamine reuptake is consistent with the finding of decreased homovanillic acid in the CSF of TS patients (Cohen et al., 1978; Butler et al., 1979; Singer et al., 1982). Although PET studies have not identified abnormalities in dopamine metabolism in the striatum (Brooks et al., 1992; Turjanski et al., 1994) more recent SPECT studies have identified decreased dopamine-transporter site density (Malison et al., 1995) and an association between tic severity and increased D2 receptor density in the caudate in monozygotic twins (Wolf et al., 1996). Noradrenaline There is only limited evidence for noradrenergic involvement in TS. The evidence is mainly based on pharmacologic studies of the alpha-adrenergic

390

J.T. Walkup

agonist clonidine (Leckman et al., 1985; Goetz et al., 1987a,b) and, more recently, guanfacine (Chappell et al., 1995). Most studies of noradrenaline and its metabolites show normal values in the blood (Silverstein et al., 1985; Riddle et al., 1988), CSF (Butler et al., 1979; Singer et al., 1982), and in postmortem brains (Singer et al., 1991). Serotonin Serotonergic dysfunction can be inferred from the efficacy of serotonin reuptake inhibitors in OCD and the relationship between OCD and TS. Levels of serotonin’s primary metabolite, 5-hydroxyindolacetic acid, in the CSF in TS patients are inconsistent (Cohen et al., 1978; Butler et al., 1979; Leckman et al., 1995b). In studies of postmortem brains, levels of 5-hydroxyindolacetic acid are normal in the cerebral cortex (Singer et al., 1990) and decreased in some basal ganglia regions (Anderson et al., 1992a,b). Acetylcholine Support for the cholinergic system in TS is primarily related to the known relationship between cholinergic and dopaminergic function. Singer et al. (1984, 1990) has shown that the cholinergic system functioning is normal in TS based on normal acetylcholinesterase and butylcholinesterase activity in the CSF, and normal acetyltransferase and muscarinic receptor binding. Pharmacologic trials of cholinergic and anticholinergic medication have been inconclusive (Stahl and Berger, 1981; Tanner et al., 1982). Results from open trials of nicotine augmentation of neuroleptics (McConville et al., 1992; Silver et al., 1999) provide support for the interactive role of cholinergic and dopaminergic functioning in TS. A double-blind trial of nicotine augmentation is currently underway (Silver et al., 1999). Glutamate The role of glutamanergic function in TS has not been well studied. In a small sample of postmortem brains, levels of glutamate in the globus pallidus internal and external segments and the substantia nigra pars reticulata are reduced (Anderson et al., 1992a,b). GABA Despite the usefulness of benzodiazepines in open clinical trials for tic reduction, there is no serious speculation regarding the role of GABA in TS. Glutamate decarboxylase activity, which is a marker for GABAergic interneurons in the cerebral cortex, is normal in postmortem brain samples (Singer

391


et al., 1990), as are levels of GABA in blood and CSF (Van Woert et al., 1982; Anderson et al., 1992a,b).

Opioids Opioid peptides interact with (Broderick, 1986; Li et al., 1986) and modulate (Angulo and McEwen, 1994; Xu et al, 1994) dopamine neuron terminals in the striatum. The finding of decreased levels of opioid peptide dynorphin A(1-17) immunoreactivity in postmortem tissue (Haber et al., 1986; Haber and Wolfer, 1992) is difficult to reconcile with a report of elevated CSF dynorphin-A concentrations in TS patients compared with controls (Leckman et al., 1995b). Treatment with opiate antagonists is limited by the few studies available and conflicting outcomes (Sandyk, 1985; Erenberg and Lederman, 1989).

Second messengers Initial reports of decreased levels of cyclic AMP in postmortem brain samples (Singer et al., 1990, 1991) provided support for a relatively simple defect which could underlie the various neurotransmitter abnormalities identified above and the complex clinical presentation of TS. Subsequent efforts to characterize cAMP and phosphoinositide function in TS were unable to identify a significant role for these systems in TS (Singer, 1994).

TS as a neuropsychiatric sequela of group A, -hemolytic streptococcal infection

The development of tics, as well as OC symptoms, in children and adolescents has been associated with group A -hemolytic streptococcal infections (Kiessling et al., 1994; Swedo et al., 1994). The pathophysiologic mechanism proposed for the development of tics and obsessions and compulsions is similar to the mechanism hypothesized to be involved in Sydenham’s chorea – antibodies to the streptococcal bacillus crossreact with basal ganglia tissues resulting in movement symptoms and obsessions and compulsions. Evidence supporting these early findings included: (1) associated antineuronal antibody level increases and symptom exacerbations; (2) symptom reduction with plasmapheresis in a few patients; (3) neuroanatomic changes associated with antineuronal antibody levels and symptom reduction (Allen et al., 1995); and (4) increased rates of a rheumatic fever marker D8/17 in childhood-onset TS and OCD (Murphy et al., 1997; Swedo et al., 1997). Treatment trials based on this hypothesis are reviewed below.

392

J.T. Walkup

Treatment of tic symptoms Assessment strategies

Assessment of people with tic disorders begins with documentation of current tic movements and their characteristic frequency, intensity, and interference. Identifying what tics are present sequentially, starting with the face, head, and neck followed by the trunk and extremities, parallels the most common pattern of tic progression. Similarly, one should assess for the presence of vocal tics after questioning about motor tics. Assessment of the common comorbid conditions – ADHD, OCD and learning difficulties – is next. Other psychiatric disorders can be disabling in persons with TS and may go unrecognized unless patients are comprehensively evaluated (Walkup et al., 1998). Social and developmental history, as well as a detailed family psychiatric history, are critical. Understanding what the patient and family knows about TS is also important as erroneous ideas about TS (i.e., it is a progressive disabling condition) need to be addressed early in the patient education phase of treatment. As there are no specific laboratory or neuroradiologic tests for TS the use of such evaluation tools will be guided by the results of the history. A variety of diagnostic interviews and self-report questionnaires can be very useful for the evaluation of tics, OCD, ADHD, and other psychiatric disorders. Instruments particularly useful for clinicians to evaluate and follow changes in tic severity include the Yale Global Tic Severity Scale (YGTSS; Leckman et al., 1989), the Tourette’s Syndrome Severity Scale (TSSS; Shapiro et al., 1988), and the Hopkins Motor and Vocal Tic Scale (Walkup et al., 1992). The diagnostic formulation of a person with TS should identify all conditions present. Even though patients and their families may focus clinical attention on their tics, it is not uncommon for other conditions to co-occur with TS and actually be more impairing than the tic disorder itself. Creating a diagnostic hierarchy based on impairment is useful for prioritizing interventions and maximizing the chance that the patient’s overall functioning will improve. Patient and parent education

Patient and parent education is perhaps the most important component of treatment. Many families bring their children for assessment after having heard about TS on the television or radio, or having read about TS in magazines or newspapers. Media reports that feature individuals with dramatic or even sensational TS symptoms can be frightening to families, as they may believe that such outcomes are common and inevitable. Information about TS and its natural course, including prognosis, can be an important antidote for what

393


parents learn about TS in the media. Recent evidence suggesting the prognosis for most individuals with TS improves beginning in middle adolescence is especially reassuring for families of children with TS (Leckman et al., 1998). For many families, education regarding the psychologic management of a child with TS can often lead to a reduction in tic symptoms by reducing tensions in daily living and enhancing overall adaptation. Even though patient and parent education begins the treatment process, it must continue throughout the course of illness. Today, many parents have increasing access to medical information about new treatments and research findings in TS. Physicians will find that staying current with the medical and popular literature is critical to their ongoing relationship with their patients and families. Information from the Tourette’s Syndrome Association can also be useful for doctors and families. Tic suppression – pharmacologic

Tic suppression with medication should not be considered an essential component of the treatment plan for persons with TS. For many TS patients, the treatment of OCD, ADHD, or other psychiatric disorders may be the most important first step, as these disorders are often more impairing than tics. By treating the most impairing conditions first, the patient has the greatest chance for overall improvement in functioning. If, after treating the more impairing comorbid conditions, tic symptoms are still a problem then a trial of ticsuppressing medication may be considered. Dopamine-blocking agents or neuroleptics are the ‘‘gold standard’’ for tic suppression. Haloperidol is the best known and most studied, but perhaps less often used by TS experts due to more prominent side effects than with other neuroleptics such as fluphenazine or pimozide. A variety of alternative antidopaminergic agents have also been used for tic suppression. Among the new neuroleptics, risperidone shows promise in open trials (Lombroso et al., 1995; Bruun and Budman, 1996), while clozapine appears to be less effective (Caine et al., 1979). In Europe, the substituted benzamides, tiapride and sulpiride, are the agents of choice for tic suppression due to their efficacy and apparently milder side effect profile. Treatment trials in the United States are being considered for tiapride and sulpiride in support of a marketing indication for tic suppression. Tetrabenazine, which depletes the amount of dopamine produced in the presynaptic neurons, has also been shown to be effective. The major drawback with neuroleptic agents is the frequent and impairing side effects that preclude continued use of the medication. Studies suggest that even though neuroleptics decrease tic severity in the majority of people with

394

J.T. Walkup

TS, most patients do not tolerate the side effects. As one patient stated. ‘‘I was glad when you put me on and glad when you took me off.’’ The major error observed in using neuroleptics for tic-suppression is the mistaken belief that tic suppressing medications should be used at doses high enough to suppress all tics. Using the lowest possible dose that offers optimum reduction in tic severity, but without side effects, is a more prudent approach. Of the nondopaminergic agents used for TS, the most common are the alpha-adrenergic agonists, clonidine and guanfacine. Both clonidine and guanfacine were developed as antihypertensives. These agents do not offer the clear tic-reduction benefits of the neuroleptics and are often ineffective (Goetz, 1993; Singer et al., 1995). Since occasional patients do benefit with minimal side effects, clonidine or guanfacine may be reasonable first agents for tic suppression in young children (Leckman et al., 1991). Also, clonidine and guanfacine may benefit some people with ADHD symptoms, making them perhaps the first choice for young children with TS and ADHD. Dopamine antagonists Haloperidol Haloperidol is a potent butryphenone with D2 receptor-blocking properties. For haloperidol, daily doses in the 0.5–3.0 mg/day range will reduce, but not necessarily eliminate, tics. Beginning treatment with 0.25–0.5 mg/day and conservative increases in dose (0.25–0.5 mg/day) every 5–7 days is prudent. Neuroleptics are most often given at bedtime, but two divided doses may be required for good tic control during the day. Judicious use of neuroleptics such as haloperidol will result in moderate tic reduction with few significant side effects. Excessive use of neuroleptics often does not offer significantly better tic control, but does increase the risk of unacceptable side effects. Although most patients benefit from medications like haloperidol, most do not continue on the medication due to problematic side effects (Erenberg et al., 1987; Shapiro et al., 1989). Traditional neuroleptic side effects include sedation, acute dystonic reactions, and extrapyramidal symptoms including akathisia, weight gain, cognitive dulling, and the common anticholinergic side effects. Subtle and difficult to recognize side effects include the development of clinical depression, separation anxiety, panic attacks, and school avoidance (Bruun, 1988). The best approach to the management of side effects is dosage reduction. The addition of anticholinergic medications such as benzotropine may be more useful than dosage reduction for extrapyramidal symptoms. Dosage reduction

395


after chronic neuroleptic treatment may be associated with withdrawal dyskinesias and tic worsening (rebound). Withdrawal dyskinesias tend to resolve in 1–3 months. Tic worsening even above pretreatment baseline (i.e., rebound) can last up to 1–3 months after neuroleptic discontinuation or dosage reduction. Tardive dyskinesia has only rarely been reported in TS patients treated with neuroleptics (Riddle et al., 1987). Fluphenazine Experience with fluphenazine in tertiary care centers suggests that it is as effective, with somewhat fewer side effects, as haloperidol (Goetz et al., 1984). Fluphenazine has both dopamine D1 and D2 receptor-blocking activity. Initiating treatment with fluphenazine is similar to haloperidol – start with low doses and slowly increase the dose until the improvement in tic severity is balanced with side effects. Fluphenazine is slightly less potent than haloperidol, but effective doses (2–7 mg/day) are similar to those used for haloperidol. Pimozide Pimozide is a very potent and specific blocker of dopamine D2 receptors. In general, pimozide is effective and appears to have fewer sedative and extrapyramidal side effects than the other neuroleptics used for TS (Ross and Moldofsky, 1978; Shapiro and Shapiro, 1984; Regeur et al., 1986; Shapiro et al., 1989; Sallee et al., 1994). Pimozide does have calcium channel-blocking properties that can cause prolongation of cardiac conduction times. The coadministration of other medications that impact on cardiac conduction, such as the tricyclic antidepressants, is generally not recommended unless very careful monitoring of the EKG is possible. Coadministration of pimozide with medications that inhibit cytochrome P-450 metabolism (i.e., some antibiotics and the specific serotonin reuptake inhibitors) may also result in unanticipated increases in cardiac conduction times and require careful EKG monitoring. The US Food and Drug Administration recently released a warning on the coadministration of pimozide and some erythromycin antibiotics after a man in Europe died on the combination of pimozide 10 mg/day and clanthromycin (Biaxin). It is very important to note that this patient was treated for psychosis and doses of pimozide for tics are much less than those used for psychosis. Clearly, baseline and follow-up EKGs are important for patient management. Beginning treatment with pimozide 0.5 mg/day is prudent. Increases in dose of 0.5–1 mg/day can occur every 5–7 days until symptoms are controlled (1–4 mg/day). As with all neuroleptics, higher doses are often associated with more side effects but not necessarily better tic control.

396

J.T. Walkup

Sulpiride and tiapride Sulpiride and tiapride are substituted benzamides only available in Europe. They have relatively specific dopamine D2-blocking activity and appear to have a reduced risk of extrapyramidal side effects and tardive dyskinesia. Both agents have demonstrated efficacy in tic suppression and mild side effect profiles (Eggers et al., 1988; Robertson et al., 1990). Experts who have had the chance to compare these agents with those readily available in the US prefer tiapride and sulpiride, but note more similarities than differences with agents commonly available in the US. The manufacturer of these agents is currently considering bringing these agents to the market in the US. Alpha-adrenergic agonists Clonidine and guanfacine The effect of clonidine on tic severity and ADHD is substantially less than that achieved with the ‘‘gold standards’’ for these conditions (Goetz, 1993). Given clonidine’s mild side effect profile, however, it is often the first drug used for tic suppression, especially in those children with both TS and ADHD. The few controlled trials suggest a lack of efficacy (Goetz et al., 1987b; Singer et al., 1995), but clinicians continue to use these medications as they may offer some children benefit without significant side effects. Treatment begins with 0.025–0.05 mg/day and increased in increments of 0.025–0.05 mg/day every 5–7 days. Sedative side effects most often determine dose size and duration between doses. Treatment doses range from 0.1 mg/day to 0.3 mg/day and are given in 2–4 divided doses. Improvement in ADHD symptoms often occurs prior to the reduction of tic severity, which can take as long as 3–6 weeks. Higher doses are not necessarily more effective, but are more frequently associated with sedation. Other side effects of clonidine include irritability, headaches, decreased salivation, and, at higher doses, hypotension and dizziness. Increases in autonomic activity and tic severity (rebound) can occur if clonidine is discontinued abruptly (Leckman et al., 1986). After children are stabilized on oral clonidine, transition to the transdermal patch can provide a more consistent clinical effect. Skin rash at the site of the patch is a common complication of treatment. Guanfacine is another alpha 2a-adrenergic agonist that may offer more benefits with fewer side effects than clonidine. Unlike clonidine, guanfacine binds preferentially to alpha 2a-adrenergic receptors in prefrontal cortical regions associated with attentional and organizational functions. Therefore, guanfacine is more likely to impact on attention and organizational abilities with less sedation than clonidine (Arnsten et al., 1988). Guanfacine’s long

397


half-life also offers the advantage of more convenient twice a day dosing. In an open trial of guanfacine for TS and ADHD symptoms, improvements in attention, hyperactivity, and tic severity were noted; side effects were minimal (Chappell et al., 1995). A small controlled trial is currently underway (L. Scahill, personal communication). Minor tranquilizers Benzodiazepines Benzodiazepines can be very useful in decreasing comorbid anxiety disorders in patients with TS (Coffey et al., 1992). Open trials of clonazepam for tic suppression support the use of this agent for some patients (Gonce and Barbeau, 1977; Steingard et al., 1994). Most studies, however, do not control for the presence of comorbid anxiety. It is possible that treatments oriented toward the treatment of anxiety may have secondary beneficial effects on tic severity. In open trials, higher than usual doses, up to 6 mg/day, were used. As sedation can be significant at these dosages, an extended titration phase of 3–6 months may be necessary. Similarly, a slow taper of clonazepam is required to avoid precipitation of withdrawal symptoms (Goetz, 1992). Other agents Botulinum toxin Botulinum toxin is injected intramuscularly to decrease tic symptoms by induction of a long-lasting but reversible local paralysis of the affected muscle. This treatment is best for a specific tic in a single muscle group. While it is often used after other treatments have failed, it can be quite useful for a single tic that is significantly impairing, especially dystonic tics of large muscles of the head and neck. Recent reports of an injection of botulinum toxin in the vocal cords of a patient with severe coprolalia suggest that this agent can be used for unique and complex tic presentations ( Jankovic, 1994). Interestingly, the observation that botulinum toxin injections appeared to decrease the premonitory sensation associated with the targeted tic symptoms suggests a secondary not primary role for premonitory sensations in tic symptoms. Antiandrogen agents The increased rates of tic disorders in men compared with women suggest a role for androgens as a hormonal risk factor for tic development and severity. In a double-blind, placebo-controlled trial of the antiandrogen flutamide,

398

J.T. Walkup

modest improvement in tic severity was noted, but clinical effects were short lived (Peterson et al., 1994b). Apparently, homeostatic compensatory mechanisms quickly overcame the blocking effects of flutamide. The potential of these agents to impact on sexual function and behavior suggests that these agents should be reserved for only the most severe cases – especially in those patients where sexual maturation is incomplete. Dopaminergic agents A number of dopamine agonists have been tried in TS based on the hypothesis that presynaptic dopamine agonist activity may decrease dopamine release and overall tic severity. In addition, the function of some of the newer dopamine agonists is dependent on the level of function of the dopamine system itself, decreasing dopamine activity when systemic dopamine activity is elevated and increasing dopamine activity when systemic activity is low (Gerlach and Peacock, 1995). Low-dose pergolide most often used in restless leg syndrome was found to be useful and well tolerated in an open trial (Lipinski et al., 1997). In contrast, talipexole was ineffective and adverse events were common in a double-blind, placebo-controlled crossover trial (Goetz et al., 1987a). Other pharmacologic agents Almost all psychopharmacologic agents have been used in TS including all antidepressants and mood stabilizers, medications with cholinergic activity, calcium channel blockers, beta-blockers, and, more recently, nicotine in combination with low-dose neuroleptics. Most of the trials have assessed the impact of the medication on tic severity alone and did not control for the presence of other disorders. Generally, results of open trials have been encouraging, but the lack of controlled trials is a serious shortcoming in the evaluation of these medications. Due to the frequent spontaneous changes in tic severity and reactivity of tic severity to environmental factors, any trial that is not well controlled needs to be viewed with skepticism (Shapiro et al., 1988). Immunologic treatments Recent reports concerning the development of tics and OC symptoms after a streptococcal infection suggest that tics and OC symptoms may be caused by an autoimmune process similar to Sydenham’s chorea, the major CNS complication of rheumatic fever (Kiessling et al., 1993; Swedo et al., 1994; Singer et al., 1998; Swedo et al., 1998). It is hypothesized that antibodies to the group A -hemolytic Streptococcus crossreact with brain tissue resulting in the symptoms of Sydenham’s chorea (Husby et al., 1976). Early speculation that this same mechanism is responsible for the development of tics and OCD has lead quickly

399


to the use of immunologic treatment for tics and OC symptoms. The novelty of the hypothesized etiology and the opportunity to use new treatment approaches or perhaps even prevent illness has resulted in a number of case reports and one controlled trial of antibiotic prophylaxis. Immune treatments have included medications and procedures that inhibit the immune response such as corticosteroids, nonsteroidal anti-inflammatory agents, intravenous immunoglobulin, plasmapheresis, or treatments that attempt to prevent infection such as antibiotics. Immunologic treatments for tics and OC symptoms are not new. The first report of reduction in tic severity after treatment with corticosteroids occurred in the 1970s (Kondo and Kabasawa, 1978). This treatment approach did not get much attention from mainstream reviews of the treatment of TS until recently when others have suggested an autoimmune etiology of TS. More recent case reports have focused on intravenous immunoglobulin, plasmapheresis, and penicillin prophylaxis. One controlled trial of penicillin prophylaxis was unsuccessful in demonstrating decreased episodes of symptom exacerbation due in part to significant methodologic problems with the study (Garvey et al., 1999). Controlled trials of plasmapheresis and intravenous immunoglobulin are underway at the US National Institute of Mental Health under the leadership of Susan Swedo. Tic suppression – nonpharmacologic

There is a small, but interesting, literature on the behavioral treatment of tics. Behavioral approaches have included a variety of interventions. Simple nonspecific behavioral interventions such as relaxation training and biofeedback have been associated with decreased tic severity in some patients. Other more focused interventions such as mass practice, where the tic movement is voluntarily repeated, have not been demonstrated to be helpful. The behavioral technique shown to be most effective in reducing tic symptoms is habit reversal training (HRT). For TS, HRT is the use of the competing muscle that opposes the tic movement. This method is usually combined with relaxation training, self-monitoring, awareness training, and positive reinforcement. In the few published studies of HRT, there were marked overall reductions in tic frequency which included a decrease in the premonitory urges after up to 3–4 months’ treatment. Treatment was intensive, with an average 20 training sessions over an 8–11 month period (Azrin and Peterson, 1990). Psychosocial treatment of TS There are no systematic studies of psychosocial treatment of TS. Yet, as mentioned above, patient and family education is critical for adequate patient and family adjustment. Also, individual psychotherapy can be helpful to ad-

400

J.T. Walkup

dress patients’ reactions to their movements and sounds, changes in selfesteem, and the response of others to their tics. Psychotherapy can also be useful in the development of communication and social skills, anger and impulse control, and assertiveness. For children with TS, perhaps the most important psychosocial intervention is with the child’s school. Principals, teachers, and other students can benefit from carefully administered educational efforts on the behalf of a child with TS. Special school placement may be necessary for children with TS and comorbid disruptive behavior disorders or learning disorders. Parents often have much difficulty determining which behaviors their child can and cannot control. Parental guidance with appropriate discipline strategies can prevent the development of nontic behavioral problems. Treatment of comorbid conditions in TS Treatment for conditions that co-occur with TS is best approached using the guidelines set forth in this book, with two exceptions. First, the treatment of psychiatric disorders and even some medical disorders can be complicated by the presence of tics. More specifically, patients treated with medications for comorbid conditions may experience increased tic severity temporally associated with medication use. Most notable has been the controversy about stimulants causing the new onset of tics or causing a nonreversible increase in tic severity. The concern that stimulants can negatively impact on tic severity is so widespread that patients, families, and physicians are often anxious and sometimes paralyzed in their approach to the treatment of comorbid ADHD in TS patients. Ironically, the widespread concern is in contrast to the lack of data supporting the concern. A number of reports in the early 1970s did document increases in tic severity, but not in the majority of patients, and tic decreases were also documented (Shapiro et al., 1988). A recent controlled trial of stimulants in children with tics and ADHD failed to observe a consistent pattern of increases in tic severity in those children on stimulants (Gadow et al., 1995a,b). Most TS experts are now backing away from the concept that stimulant medication can cause tics de novo or that stimulants will cause a permanent increase in tic severity, but do remain cautious in their prescribing practices. It is also important to understand that, in addition to stimulants, a number of other medications have been reported to be associated with increases in tic severity, including allergy and asthma medications and other psychotropic medications. As a result of the potential for tics to increase on almost any medication, it is

401


critical to discuss a few issues with patients and their families prior to initiating treatment, especially with stimulants. (1) Short-term treatment trials with medications allow families to identify the benefit of medication against the risk of tic increases. (2) If the medication is ineffective, it will be discontinued; the long-term risk of short-term trials is small. (3) If the medication is associated temporally with an acute increase in tic severity, it can be discontinued with a good chance that tic symptoms will decrease. (4) The natural course of tic severity is to wax and wane, so that tic increases observed on stimulants may be associated with the natural waxing and waning of tic symptoms. (5) Changes in tic severity may be temporally associated with any medication treatment. (6) If tics do appear to increase, even after long-term use of medication, discontinuation often leads to decreases in tic severity (Riddle et al., 1995). (7) Even though all of the above appear to be true, or at least logical, it is still possible, due to the natural course of TS, that discontinuation of a medication temporally associated with tic increases will not lead to a decrease in tic severity. The fact that tic severity does not decrease with discontinuation does not necessarily mean that the medication caused the tic increase, but more that the natural course of illness is unpredictable. (8) Critical to informed consent is an appreciation and tolerance of these clinical issues. The second exception relates to the fact that OC symptoms seen in patients with TS may not be as treatment sensitive as symptoms seen in classic OCD. A number of authors have differentiated tic-related OC symptoms from those seen in classic OCD. Tic-related OC symptoms have a sensory–motor character and more classic OCD symptoms have a cognitive–affective character (Miguel et al., 1995). Assessment of OCD subtypes suggests tic-related OCD is more likely to include obsessions with aggressive, sexual, religious, and somatic content, preoccupation with symmetry, ordering, checking, and hoarding. More classic OCD is characterized by obsessions with dirt, germs, and cleaning compulsions (Baer, 1994; Leckman et al., 1997a). Although treatment studies of OCD have not evaluated the efficacy of medication on specific subtypes, clinical experience suggests that sensory–motor OC symptoms may not respond as robustly as cognitive–affective OC symptoms. If this observation is true, clinicians need to characterize the patient’s OCD subtype and, when faced with a patient with sensory–motor OCD subtype, adjust treatment expectations.

402

J.T. Walkup

Summary TS is a model neuropsychiatric disorder in many respects. TS has a childhood onset, clear phenomenology, clear genetic and environmental contributions to etiology, and a responsiveness to both somatic and environmental interventions. Researchers of TS have used the latest methodologic advances that reflect the state-of-the-art in neuropsychiatric research. The finding of a common marker for the susceptibility to rheumatic fever and TS/OCD may offer the first replicable evidence for an infectious etiology to a common neuropsychiatric disorder. While much has been learned about TS in the past 15 years, more research needs to be done. Efforts to identify the pattern of inheritance and the genes responsible for TS are probably the top priority. Advances in neuroimaging also offer the opportunity to advance our knowledge of the structural and functional abnormalities in TS. In addition, treatment studies that identify pharmacologic agents that effectively reduce tic severity with minimal side effects are needed for those patients with severe TS. Perhaps least understood and most critical from the child and his/her family’s point of view is the method for best coping with this often difficult disorder. At the current time, little is truly known about the best way of living with TS, making it difficult for families to evaluate critically their child’s needs and treatment approaches. Acknowledgements This work was supported in part by a grant from the National Institute of Mental Health K20 MH01059 ( John T. Walkup). Substantial portions of this chapter were previously published in Walkup et al. (1998). Tic disorders. In (Eds.) Coffey and Brumback, Pediatric Textbook of Neuropsychiatry, American Psychiatric Press. Reprinted by permission.

REFE REN C ES Abuzzahab FS, Anderson FO (1973). Gilles de la Tourette’s syndrome. First International Registry. Minn Med 56:492–6. Alexander GE (1994). Basal ganglia-thalamocortical circuits: their role in control of movements. J Clin Neurophysiol 11:420–31. Alexander GE, Crutcher M (1990). Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–71. Allen AJ, Leonard HL, Swedo SE (1995). Case study: a new infection-triggered, autoimmune

403


subtype of pediatric OCD and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 34:307–11. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. 4th edn. Washington, DC: American Psychiatric Press. Anderson GM, Pollack ES, Chatterjee D, Leckman JF, Riddle MA, Cohen DJ (1992a). Brain monoamines and amino acids in Gilles de la Tourette’s syndrome: a preliminary study of subcortical regions. Arch Gen Psychiatry 49:584–6. Anderson GM, Pollack ES, Chatterjee D, Leckman JF, Riddle MA, Cohen DJ (1992b). Postmortem analysis of subcortical monoamines and amino acids in Tourette syndrome. Adv Neurol 58:123–33. Angulo JA, McEwen BS (1994). Molecular aspects of neuropeptide regulation and function in the corpus striatum and nucleus accumbens. Behav Brain Res 19:1–28. Apter A, Pauls DL, Bleich A et al. (1993). An epidemiologic study of Gilles de la Tourette’s syndrome in Israel. Arch Gen Psychiatry 50:734–8. Arnsten AF, Cai JX, Goldman-Rakic PS (1988). The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8:4287–98. Azrin NH, Peterson AL (1990). Treatment of Tourette syndrome by habit reversal: a waiting list control group comparison. Behavior Therapy 21:305–18. Baer L (1994). Factor analysis of symptom subtypes of obsessive compulsive disorder and their relation to personality and tic disorders. J Clin Psychiatry 55 (Suppl), 18–23. Balthasar K. (1957). Uber das anatomische Substrat der generalisierten Tic-Krankheit (maladie des tics, Gilles de la Tourette): entwicklungshemmung des corpus striatum. Arch Psychiatr Berl, 195:531–49. As referenced in Neuropathological Studies of Tourette Syndrome, by EP Richardson Jr, in Advances in Neurology, Volume 35, Raven Press, New York, 1982, pp. 83–7. Broderick PA (1986). Rat striatal dopamine release mechanisms of cocaine. NIDA Res Monogr, 75:367–70. Brooks DJ, Turjanski N, Sawle GV, Playford ED, Lees AJ (1992). PET studies on the integrity of the pre- and postsynaptic dopaminergic system in Tourette syndrome. Adv Neurology 58:227– 31. Bruun RD (1988). Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette’s disorder. Am J Psychiatry 145:621–4. Bruun RD, Budman CL (1992). The natural history of Tourette syndrome. In Advances in Neurology, Volume 58. Tourette Syndrome Genetics, Neurobiology, and Treatment, (Eds.) TN Chase, AJ Friedhoff, DJ Cohen. New York: Raven Press, pp. 1–6. Bruun RD, Budman CL (1996). Risperidone as a treatment of Tourette’s syndrome. J Clin Psychiatry 57:29–31. Butler IJ, Koslow SH, Seifert WE Jr, Caprioli RM, Singer HS (1979). Biogenic amine metabolism in Tourette syndrome. Ann Neurol 6:37–9. Caine ED, McBride MC, Chiverton P, Bamford KA, Rediess S, Shiao J (1988). Tourette’s syndrome in Monroe County school children. Neurology 38:472–5. Caine ED, Polinsky RJ, Kartzinel R, Ebert MH (1979). The trial use of clozapine for abnormal

404

J.T. Walkup

involuntary movement disorders. Am J Psychiatry 136:317–20. Caprini G, Melotti V (1961). Un grave sindrome ticcosa guarita con haloperidol. Riv Sper Freniat 85:191–6. Chappell PB, Riddle MA, Scahill L et al. (1995). Guanfacine treatment of comorbid attention deficit hyperactivity disorder in Tourette syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry 34:1140–6. Coffey B, Frazier J, Chen S (1992). Comorbidity, Tourette syndrome, and anxiety disorders. In Advances in Neurology Volume 58. Tourette Syndrome: Genetics, Neurobiology, and Treatment, (Eds.) TN Chase, AJ Friedhoff, DJ Cohen. New York: Raven Press. Cohen DJ, Shaywitz BA, Caparulo BK, Young JG, Bowers MB Jr (1978). Chronic, multiple tics of Gilles de la Tourette’s disease: CSF acid monoamine metabolites after probenecid administration. Arch Gen Psychiatry 35:245–50. Comings DE (1995). Tourette’s syndrome: a behavioral spectrum disorder. In Advances in Neurology, Volume 65: Behavioral Neurology of Movement Disorders, (Eds.) WJ Weiner, AE Lang. New York: Raven Press, pp. 293–303. Comings DE, Comings BG (1987). A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems. Am J Hum Genet 41:701–41. Eggers CH, Rothenberger A, Berghaus U (1988). Clinical and neurobiological findings in children suffering from tic disease following treatment with tiapride. Eur Arch Psychiatr Neurol Sci 237:223–9. Erenberg G, Lederman RJ (1989). Naltrexone in the treatment of Tourette’s syndrome. Neurology 39(Suppl 1):232. Erenberg G, Cruse RP, Rothner AD (1987). The natural history of Tourette syndrome: a follow up study. Ann Neurol 22:383–5. Frankel M, Cummings JL, Robertson MM, Trimble MR, Hill MA, Benson DF (1986). Obsessions and compulsions in Gilles de la Tourette’s syndrome. Neurology 36:378–82. Gadow KD, Nolan E, Sprafkin J, Sverd J (1995a). School observation of children with attentiondeficit hyperactivity disorder and comorbid tic disorder: effects of methylphenidate treatment. Dev Behav Pediatr 16:167–76. Gadow KD, Sverd J, Sprafkin J, Nolan EE, Ezor SN (1995b). Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with tic disorder. Arch Gen Psychiatry 52:444–55. Garvey MA, Perlmutter SJ, Allen AJ et al. (1999). A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry 45:1564– 71. George MS, Robertson MM, Costa DC et al. (1994). Dopamine receptor availability in Tourette’s syndrome. Psychiatry Res Neuroimaging 55:193–203. George MS, Trimble MR, Costa DC, Robertson MM, Ring HA, Ell PJ (1992). Elevated frontal cerebral blood flow in Gilles de la Tourette syndrome: a 99Tcm-HMPAO SPECT study. Psychiatry Res 45:143–51. Gerlach J, Peacock L (1995). New antipsychotics: the present status. Int Clin Psychopharmacol 10:39–48.

405


Goetz CG (1992). Clonidine and clonazepam in Tourette syndrome. Adv Neurol 58:245–51. Goetz CG (1993). Clonidine. In Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders (Ed.) R. Kurlan. New York: Marcel Dekker, pp. 377–88. Goetz CG, Stebbins GT, Thelen JA (1987a). Talipexole and adult Gilles de la Tourette syndrome: double-blind, placebo-controlled clinical trial. Mov Disord 9:315–17. Goetz CG, Tanner CM, Klawans HL (1984). Fluphenazine and multifocal tic disorder. Arch Neurol 41:271–2. Goetz CG, Tanner CM, Wilson RS, Carroll VS, Como PG, Shannon KM (1987b). Clonidine and Gilles de la Tourette’s syndrome: a double-blind study using objective rating methods. Ann Neurol 21:307–10. Gonce M, Barbeau A (1977). Seven cases of Gilles de la Tourette’s syndrome: partial relief with clonazepam: a pilot study. Can J Neurol Sci 3:279–83. Grad LR, Pelcovitz D, Olson M, Matthews M, Grad GJ (1987). Obsessive-compulsive symptomatology in children with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 26:69–73. Haber SN, Wolfer D (1992). Basal ganglia peptidergic staining in Tourette syndrome. A follow-up study. Adv Neurol 58:145–50. Haber SN, Kowall NW, Vonsattel JP, Bird ED, Richardson EP Jr (1986). Gilles de la Tourette’s syndrome. A postmortem neuropathological and immunohistochemical study. J Neurol Sci 75:225–41. Hall M, Costa DC, Sheilds J et al. (1991). Brain perfusion patterns with Tc-99mHMPAO-SPECT in patients with Gilles de la Tourette syndrome – short report. In Nuclear Medicine: The State of the Art of Nuclear Medicine in Europe, (Eds.) HAE Schmidt, JB van der Schoot. Stuttgart: Schattauer, pp. 243–5. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC (1976). Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 144:1094–110. Jankovic J (1994). Botulinum toxin in the treatment of dystonic tics. Mov Disord 9:347–9. Jankovic J, Orman J (1988). Tetrabenazine therapy of dystonia, chorea, tics and other dyskinesias. Neurology 38:391–4. Kiessling LS, Marcotte AC, Culpepper L (1993). Antineuronal antibodies in movement disorders. Pediatrics 92:39–43. Kiessling LS, Marcotte AC, Culpepper L (1994). Antineuronal antibodies: tics and obsessivecompulsive symptoms. J Dev Behav Pediatr 15:421–5. Klieger PS, Fett KA, Dimitsopoulas T, Kurlan R (1997). Asymmetry of basal ganglia perfusion in Tourette’s syndrome shown by technetium-99m-HMPAO SPECT. J Nucl Med 38:188–91. Kondo K, Kabasawa T (1978). Letter to the editor: improvement in Gilles de la Tourette syndrome after corticosteroid therapy. Ann Neurol 4:387. Leckman JF, Detlor J, Hercheric DF, Ort S, Shaywitz BA, Cohen DJ (1985). Short- and long-term treatment of Tourette syndrome with clonidine: a clinical perspective. Neurology 35:343–51. Leckman JF, Goodman WK, Norht WG et al. (1995a). CSF biogenic amines in obsessive compulsive disorder and Tourette’s syndrome. Neuropsychopharmacology 12:73–86. Leckman JF, Grice DE, Boardman J et al. (1997a). Symptoms of obsessive compulsive disorder.

406

J.T. Walkup

Am J Psychiatry 154:911–17. Leckman JF, Ort S, Caruso KA, Anderson GM, Riddle MA, Cohen DJ (1986). Rebound phenomena in Tourette’s syndrome after abrupt withdrawal of clonidine. Behavioral, cardiovascular, and neurochemical effects. Arch Gen Psychiatry 43:1168–76. Leckman JF, Peterson BS, Anderson GM, Arnsten AF, Pauls DL, Cohen DJ (1997b). Pathogenesis of Tourette’s syndrome. J Child Psychol Psychiatry 38:119–42. Leckman JF, Riddle MA, Berrettini WH et al. (1995b). Elevated CSF dynorphan A[1–8] in Tourette’s syndrome. Life Sci 43:2015–23. Leckman JF, Riddle MA, Hardin MT et al. (1989). The Yale Global Tic Severity Scale (YGTSS): initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 28:566–73. Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ (1991). Clonidine treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 48:324–8. Leckman JF, Walker DE, Cohen DJ (1993). Premonitory urges in Tourette’s syndrome. Am J Psychiatry 150:98–102. Leckman JF, Zhang H, Vitale A et al. (1998). Trajectories of tic severity in Tourette’s syndrome: the first two decades. Pediatrics 102:14–19. Li S, Sivam SP, Hong JS (1986). Regulation of the concentration of dynorphin A1–8 in the striatonigral pathway by the dopaminergic system. Brain Res 398, 390–2. Lipinski JF, Sallee FR, Jackson C, Sethuraman G (1997). Dopamine agonist treatment of Tourette disorder in children: results of an open label trial of pimozide. Mov Disord 12:402–7. Lombroso PJ, Scahill LD, King RA et al. (1995). Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report. J Am Acad Child Adolesc Psychiatry 34:1147–52. Malison RT, McDougle CJ, van Dyck CH et al. (1995). [123I]beta-CIT SPECT imaging of striatal dopamine transporter binding in Tourette’s disorder. Am J Psychiatry 152:1359–61. McConville BJ, Sanberg PR, Fogelson MH et al. (1992). The effects of nicotine plus haloperidol compared to nicotine only and placebo nicotine only in reducing tic severity and frequency in Tourette’s disorder. Biol Psychiatry 31:832–40. Miguel EC, Coffey BJ, Baer L, Savage CR, Rauch SL, Jenike MA (1995). Phenomenology of intentional repetitive behaviors in obsessive-compulsive disorder and Tourette’s disorder. J Clin Psychiatry 56:246–55. Montgomery MA, Clayton PJ, Friedhoff AJ (1982). Psychiatric illness in Tourette syndrome patients and first-degree relatives. In Advances in Neurology, Volume 35, (Eds.) AJ Friedhofff, TN Chase. New York: Raven Press, pp. 335–9. Moriarty J, Costa DC, Schmitz B, Trimble MR, Ell PJ, Robertson MM (1995). Brain perfusion abnormalities in Gilles de la Tourette syndrome. Br J Psychiatry 167:249–54. Murphy TK, Goodman WK, Fudge MW et al. (1997). B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome? Am J Psychiatry 154:402–7. Pauls DL, Leckman JF (1986). The inheritance of Gilles de la Tourette’s syndrome and associated behaviors. Evidence for autosomal dominant transmission. N Engl J Med 315:993–7.

407


Pauls DL, Alsobrook JP, Gelernter J, Leckman JF (1999). Genetic vulnerability. In Tourette’s Syndrome: Tics, Obsessions and Compulsions. Developmental Psychopathology and Clinical Care, (Eds.) JF Leckman, DJ Cohen. New York: John Wiley, pp. 194–211. Pauls DL, Hurst CR, Kruger SD, Leckman JF, Kidd KK, Cohen DJ (1986). Gilles de la Tourette’s syndrome and attention deficit disorder with hyperactivity. Evidence against a genetic relationship. Arch Gen Psychiatry 43:1177–9. Pauls DL, Leckman JF, Cohen DJ (1993). Familial relationship between Gilles de la Tourette’s syndrome, attention deficit disorder, learning disabilities, speech disorders, and stuttering. J Am Acad Child Adolesc Psychiatry 32:1044–50. Peterson BS, Gore JC, Riddle MA, Cohen DJ, Leckman JF (1994a). Abnormal magnetic resonance imaging T2 relaxation time asymmetries in Tourette’s syndrome. Psychiatry Res Neuroimaging 55:205–21. Peterson BS, Leckman JF, Scahill L et al. (1994b). Steroid hormones and Tourette’s syndrome: early experience with antiandrogen therapy. J Clin Psychopharmacol 14:131–5. Peterson BS, Riddle MA, Cohen DJ et al. (1993). Reduced basal ganglia volumes in Tourette’s syndrome using three-dimensional reconstruction techniques from magnetic resonance images. Neurology 43:941–9. Regeur L, Pakkenberg B, Fog R, Pakkenberg H (1986). Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette’s syndrome. J Neurol Neurosurg Psychiatry 49:791–5. Riddle MA, Hardin MT, Towbin KE, Leckman JF, Cohen DJ (1987). Tardive dyskinesia following haloperidol treatment in Tourette’s syndrome. Arch Gen Psychiatry 44:98–9. Riddle MA, Leckman JF, Anderson GM et al. (1988). Tourette’s syndrome and associated disorders: clinical and neurochemical correlates. J Am Acad Child Adolesc Psychiatry 27:409–12. Riddle MA, Lynch KA, Scahill L, de Vries AL, Cohen DJ, Leckman JF (1995). Methylphenidate discontinuation and re-initiation during long-term treatment of children with Tourette’s disorder and attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychopharmacol 5:205–14. Riddle MA, Rasmusson AM, Woods SW, Hoffer PB (1992). SPECT imaging of cerebral blood flow in Tourette syndrome. Adv Neurol 58:207–11. Robertson MM, Schneiden V, Lees AJ (1990). Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol 3:229–35. Ross MS, Moldofsky H (1978). A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette syndrome. Am J Psychiatry 135:585–7. Sallee FR, Sethuraman G, Rock CM (1994). Effects of pimozide on cognition in children with Tourette syndrome: interaction with comorbid attention deficit hyperactivity disorder. Acta Psychiatr Scand 90:4–9. Sandyk R (1985). The effects of naloxone in Tourette’s syndrome. Ann Neurol 18:367–8. Schuerholz LJ, Baumgardner TL, Singer HS, Reiss AL, Denckla MB (1996). Neuropsychological status of children with Tourette’s syndrome with and without attention deficit hyperactivity disorder. Neurology 46:958–65. Seignot MJN (1961). Un cas de maladie des tics de Gilles de la Tourette gueri par le R-1625. Ann

408

J.T. Walkup

Med Psychol 119:578–9. Shapiro AK, Shapiro E (1984). Controlled study of pimozide vs. placebo in Tourette syndrome. J Am Acad Child and Adolesc Psychiatry 23:161–73. Shapiro AK, Shapiro ES, Young JG, Feinberg TE (1988). Gilles de la Tourette Syndrome, 2nd edn. New York: Raven Press. Shapiro ES, Shapiro AK, Fulop G et al. (1989). Controlled study of haloperidol, pimozide and placebo for the treatment of GTS. Arch Gen Psychiatry 46:722–30. Silver AA, Shytle D, Sandberg PR (1999). Clinical experience with transdermal nicotine patch in Tourette syndrome. CNS Spectrums 4:68–76. Silverstein F, Smith CB, Johnston MV (1985). Effect of clonidine on platelet alpha 2-adrenoreceptors and plasma norepinephrine of children with Tourette syndrome. Dev Med Child Neurol 27:793–9. Singer HS (1994). Neurobiological issues in Tourette syndrome. Brain Dev 16:353–64. Singer HS, Walkup JT (1991). Tourette syndrome and other tic disorders. Diagnosis, pathophysiology, and treatment. Medicine 70:15–32. Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED, Denckla MB (1995). The treatment of attention-deficit hyperactivity disorder in Tourette’s syndrome: a double-blind placebo-controlled study with clonidine and desipramine. Pediatrics 95:74–81. Singer HS, Butler IJ, Tune LE, Seifert WE, Coyle JT (1982). Dopaminergic dysfunction in Tourette syndrome. Ann Neurol 12:361–6. Singer HS, Giuliano JD, Hansen BH et al. (1998). Antibodies against human putamen in Tourette’s syndrome. Neurology 50:1618–24. Singer HS, Hahn IH, Krowiak E, Nelson E, Moran T (1990). Tourette’s syndrome: a neurochemical analysis of postmortem cortical brain tissue. Ann Neurol 27:443–6. Singer HS, Hahn IH, Moran TH (1991). Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette’s syndrome. Ann Neurol 30:558–62. Singer HS, Oshida L, Coyle JT (1984). CSF cholinesterase activity in Gilles de la Tourette’s syndrome. Arch Neurol 41:756–7. Singer HS, Reiss AL, Brown JE et al. (1993). Volumetric MRI changes in basal ganglia of children with Tourette’s syndrome. Neurology 43:950–6. Stahl SM, Berger PA (1981). Physostigmine in Tourette syndrome: evidence for cholinergic underactivity. Am J Psychiatry 138:240–2. Steingard RJ, Goldberg M, Lee D, DeMaso DR (1994). Adjunctive clonazepam treatment of tic symptoms in children with comorbid tic disorders and ADHD. J Am Acad Child Adolesc Psychiatry 33:394–9. Stoetter B, Braun AR, Randolf C et al. (1992). Functional neuroanatomy of Tourette syndrome: limbic motor interactions studied with FDG PET. In Advances in Neurology, Volume 58: Tourette Syndrome: Genetics, Neurobiology and Treatment, (Eds.) TN Chase, AJ Friedhoff, DJ Cohen. New York: Raven Press, pp. 213–26. Swedo SE, Leonard HL, Kiessling LS (1994). Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood. Pediatrics 93:323–6. Swedo SE, Leonard HL, Garvey M et al. (1998). Pediatric autoimmune neuropsychiatric

409


disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155:264–71. Swedo SE, Leonard HL, Mittleman B et al. (1997). Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 154:110–12. Tanner CM, Goetz CG, Klawans HL (1982). Cholinergic mechanisms in Tourette syndrome. Neurology 32:1315–17. Turjanski N, Sawle GV, Playford ED et al. (1994). PET studies on the presynaptic and postsynaptic dopaminergic system in Tourette syndrome. J Neurol Neurosurg Psychiatry 57:688–92. Tourette Syndrome Classification Study Group (1993). Definitions and classification of tic disorders. Arch Neurol 50:1013–16. Van Woert MH, Rosenbaum D, Enna SJ (1982). Overview of pharmacological approaches to therapy for Tourette syndrome. Adv Neurol 35:369–75. Walkup J, Riddle MA (1996). Tic disorders. In Psychiatry, (Eds.) A Tasman, J Kay, JA Lieberman. Philadelphia: WB Saunders, pp. 702–19. Walkup J, Amos T, Riddle MA (1998). Tics and Tourette syndrome. In Textbook of Pediatric Neuropsychiatry, (Eds.) CE Coffey, RA Brumback. Washington, DC: American Psychiatric Press. Walkup JT, Rosenberg LA, Brown J, Singer HS (1992). The validity of instruments measuring tic severity in Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 30:472–7. Walkup JT, Scahill LD, Riddle MA (1995). Disruptive behavior, hyperactivity, and learning disabilities in children with Tourette’s syndrome. In Advances in Neurology, Volume 65, (Eds.) MD Weiner, AE Lang. New York: Raven Press, pp. 259–72. Wolf SS, Jones DW, Knable MB et al. (1996). Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate D2 receptor binding. Science 273:1225–7. Wright CI, Peterson BS, Rauch SL (1999). Neuroimaging studies in Tourette syndrome. CNS Spectrums 4:54–61. Xu M, Moratalla R, Gold LH et al. (1994). Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell 79:729– 42. Zohar AH, Apter A, King RA, Pauls DL, Leckman JF, Cohen DJ (1999). Epidemiological studies. In Tourette’s Syndrome: Tics, Obsessions and Compulsions. Developmental Psychopathology and Clinical Care, (Eds.) JF Leckman, DJ Cohen. New York: John Wiley, pp. 177–92.

14 Eating disorders and related disturbances Lisa A. Kotler, Michael J. Devlin, and B. Timothy Walsh Columbia University/New York State Psychiatric Institute, New York, USA

Introduction In the last several decades, there have been significant advances in our knowledge of the pharmacologic treatment of the eating disorders in adults. The short-term efficacy of antidepressant agents in bulimia nervosa has been well documented in double-blind, placebo-controlled trials. Although the role of medication in anorexia nervosa remains less clearly established, recent studies have suggested that there may be a role for medication in some stages of the illness. Additionally, the syndrome of binge eating disorder has been recently described and will likely be a focus of future psychologic and pharmacologic treatment research. Despite the fact that these eating disorders frequently have their onset during adolescence and early adulthood, most of the medication trials have been conducted with subjects over the age of 18, and their results may not be generalizable to children and adolescents. In DSM-III-R (American Psychiatric Association, 1987), the eating disorders anorexia nervosa and bulimia nervosa were grouped with other disorders usually first evident in infancy, childhood, or adolescence. In DSM-IV (American Psychiatric Association, 1994), they have been moved into a separate category, titled Eating Disorders. Nonetheless, anorexia nervosa and bulimia nervosa can exist in childhood, typically have their onset in adolescence, and are intimately related to growth and development. The feeding disorders of infancy or early childhood remain in the childhood section of the DSM-IV and will not be discussed in this chapter as they largely occur prior to age 6 and are overwhelmingly treated with psychotherapeutic techniques. This chapter will review our current understanding of the role of medication in the treatment of eating disorders, with particular emphasis on trials conducted in children and adolescents where available. The American Psychiatric Association has recently updated its Practice Guidelines for Eating Disorders, which provides an excellent overview of the definition, epidemiology, natural 410

411


history, and treatment recommendations for individuals with eating disorders (Yager et al., 2000). Anorexia nervosa: overview of the disorder Anorexia nervosa is characterized by a refusal to maintain a minimally normal body weight. The disorder appears to be more prevalent in industrialized societies, where food is plentiful and attractiveness for females includes being thin. The mean age at onset is approximately 17 years, with some data suggesting bimodal peaks at ages 14 and 18. More than 90% of all cases of anorexia nervosa occur in females. Prevalence studies among females in late adolescence and early adulthood have found rates of 0.5–1.0% (Eagles et al., 1995; Rooney et al., 1995; Walters and Kendler, 1995; Lucas et al., 1991). In addition, many studies report a substantial number of subjects with mild eating disturbances that do not meet full criteria for anorexia nervosa or bulimia nervosa, but which would be categorized in DSM-IV as ‘‘Eating Disorder Not Otherwise Specified’’ (Flament et al., 1995; Lucas et al., 1991). There have been no epidemiologic surveys focusing specifically on the prevalence of childhood eating disorders, usually defined as those occurring among individuals younger than 15 (Bryant-Waugh and Lask, 1995). Retrospective case surveys suggest that a number of anorexia nervosa cases seem to have had an onset in childhood (Irwin, 1984). There are suggestions that the severity of associated mental illnesses may be greater among prepubertal individuals who develop anorexia nervosa, yet other data suggest that the onset of anorexia nervosa in early adolescence may be associated with a better prognosis. The essential features of anorexia nervosa include a refusal to maintain a minimally normal body weight, an intense fear of gaining weight, and a significant distortion in the perception of body weight and shape (American Psychiatric Association, 1994). In postmenarchal females, amenorrhea, defined as the absence of at least three consecutive menstrual cycles, is required. As a criterion for being underweight, DSM-IV suggests less than 85% of the expected weight for age and height. When anorexia nervosa develops during childhood or early adolescence, there may be a failure to attain expected weight gain while growing in height, instead of weight loss. DSM-IV describes two subtypes of anorexia nervosa: (1) restricting type, in which weight loss is achieved primarily through dieting and excessive exercise, and (2) binge eating/purging type, in which binge eating, self-induced vomiting, or the misuse of laxatives, diuretics, or enemas also occur.

412

L. A. Kotler et al.

Symptoms of depression and anxiety are common among patients with anorexia nervosa. The depressive features may be secondary, at least in part, to the physiologic sequelae of semistarvation and should be reassessed after partial or complete weight restoration. Axis II comorbidity includes a relatively high prevalence of avoidant and obsessive–compulsive traits. Hypothesized mechanisms of anorexia nervosa Hypothesized biologic mechanisms for anorexia nervosa have included disturbances in the monoamine neurotransmitters serotonin, dopamine, and noradrenaline, as well as in neuropeptides and peripheral hormones. Extensive reviews of the neurobiology of the eating disorders are available elsewhere (Mayer and Walsh, 1998; Kaye, 1996; Mauri et al., 1996; Halmi, 1996). Although many abnormalities in these systems have been reported among patients hospitalized for anorexia nervosa, it has been difficult to differentiate changes specific to anorexia nervosa from non-specific changes resulting from nutritional deprivation. Several recent studies have assessed patients following weight restoration in an effort to identify predisposing factors that may have predated the original onset of weight loss, or might predispose to recurrence of low-weight episodes (Kaye et al., 1985). It is of interest that the functional activity of central serotonin systems appears to be diminished during lowweight episodes, but may be abnormally increased in long-term weightrecovered patients (Kaye et al., 1991a). Psychopharmacologic treatment of anorexia nervosa Although anorexia nervosa was clearly described over 100 years ago, it remains relatively refractory to pharmacologic interventions. There are several methodologic points to consider when evaluating trials of medication efficacy in anorexia nervosa. Most studies have examined the effects of various medications on weight gain in underweight, hospitalized patients. These patients are usually simultaneously enrolled in behavioral treatment programs, also focused on weight gain, and an additional benefit of medication may be difficult to detect. Most of these studies have only evaluated the usefulness of shortterm medication interventions (i.e., 4–8 weeks). The potential benefits of pharmacologic treatment on the natural history of anorexia nervosa have not been well studied. Although recent research has provided increasing knowledge about various neurobiologic disturbances in anorexia nervosa, its etiology remains unknown and its core cognitive psychopathology remains relatively refractory to medica-

413


tion. Rather, pharmacotherapy is often used as an adjunct to a multidisciplinary approach including nutritional counseling, and family and cognitive– behavioral psychotherapies. Antipsychotics

Dally and Sargent (1966, 1960) were the first to study systematically the use of psychopharmacologic treatment for anorexia nervosa. They used chlorpromazine in doses up to 1600 mg/day, often in combination with insulin and bed rest, to promote weight gain in hospitalized patients. Those treated with chlorpromazine gained weight faster than those who did not receive medication, but the chlorpromazine-treated patients experienced significant side effects including seizures and increased purging behavior. On long-term followup, chlorpromazine was not superior in terms of weight gain on general outcome. Pimozide (Vandereycken and Pierloot, 1982) and sulpiride (Vandereycken, 1984) have been examined in double-blind, placebo-controlled studies, with only a trend for higher weight gain on pimozide, no significant difference in weight gain over placebo on sulpiride, and no advantage for either drug on eating attitudes and eating behavior. Thus, given their potential for both short- and long-term side effects, antipsychotic medications are not recommended for the standard treatment of anorexia nervosa. Antidepressants

The observation of an increased frequency of major depression among patients with anorexia nervosa and their first-degree relatives prompted a number of case reports, open trials, and, eventually, controlled trials of antidepressant medications. The clinical assessment of depressive symptoms in anorexia nervosa is complicated by the fact that many of these symptoms resolve with refeeding and may be a secondary effect of starvation. In contrast to the results in bulimia nervosa, controlled trials have not provided consistent evidence of the efficacy of antidepressant drugs in the treatment of anorexia nervosa. Three placebo-controlled trials of tricyclic antidepressants (TCAs) including clomipramine (50 mg/day), amitriptyline (175 mg/day), and amitriptyline (160 mg/day) did not demonstrate any significant advantage of these medications over placebo (Halmi et al., 1986; Biederman et al., 1985; Lacey and Crisp, 1980). Given the recent concern surrounding a possible association between TCAs and sudden death in children and adolescents, the association of anorexia nervosa with a variety of cardiac disturbances, and the lack of evidence supporting their utility, TCAs should not routinely be used in underweight patients with anorexia nervosa. Due to their side effect profile and safety in overdose, the selective serotonin

414

L. A. Kotler et al.

reuptake inhibitors (SSRIs) have largely replaced previously available antidepressants in general psychiatric practice. A recent double-blind, placebocontrolled trial reported the superiority of fluoxetine over placebo in the acute phase of treatment of major depressive illness in children and adolescents, with side effects only rarely prompting discontinuation (Emslie et al., 1997). The efficacy of SSRI’s in the treatment of anorexia nervosa is only now being studied in adults, and has not been examined in children and adolescents. A recently completed placebo-controlled trial of fluoxetine in conjunction with a behaviorally based inpatient treatment for underweight patients with anorexia nervosa found no significant advantage for fluoxetine in the treatment of anorexia nervosa (Attia et al., 1998). Once again, the above studies focus on the treatment of acute anorexic patients, mostly with inpatient settings and with severely underweight patients. A slightly different approach to the psychopharmacology of anorexia nervosa has been based on the idea that psychotropic medications may be useful in preventing relapse in weight-recovered patients. Kaye et al. (1991b) reported an open trial of fluoxetine (dose 10–80 mg) in 31 women with anorexia nervosa, and reported improvement in weight maintenance. The same group (Kaye et al., 1997) recently reported a study of 35 women with the restricting subtype of anorexia nervosa who had gained weight during an inpatient stay. Patients were randomized to either fluoxetine or placebo for 11 months following discharge from the hospital. The women in the fluoxetine group had a significantly lower rate of relapse than those in the placebo group. In contrast is a naturalistic case-controlled follow-up study reported by Strober et al. (1997), in which 33 women with anorexia nervosa who were given fluoxetine prior to discharge were compared with similar patients who received no medication. Both groups received weekly psychotherapy with the addition of family therapy and nutritional counseling if necessary. Patients were followed at 6-month intervals for 2 years’ duration. There was no significant difference found between the fluoxetine and control groups on need for rehospitalization or tendency to drop below target weight. The conflicting data from these studies indicate the importance of further pharmacologic investigation of interventions at times other than the acute weight-gain phase of the illness. Appetite enhancers

Cyproheptadine, a serotonin and histamine antagonist, has been noted to produce weight gain in the treatment of children with asthma. This observation led to three controlled trials of cyproheptadine in women with anorexia nervosa. Vigersky and Loriauz (1977) treated 24 outpatients with either cyproheptadine (12 mg/day) or placebo over 8 weeks and found no difference in

415


weight gain between the two groups. Goldberg et al. (1979) used doses of cyproheptadine up to 32 mg/day and again found no significant difference in weight gain between the cyproheptadine and placebo groups, although there was a suggestion that cyproheptadine induced weight gain in a portion of the patients who had a more severe form of the illness. Halmi and coworkers (1986) compared cyproheptadine (32 mg/day), amitriptyline, and placebo, and found that the time to reach target weight was shorter in the cyproheptadine group vs. placebo, but that overall there were no significant differences in weight gain between the medication and placebo groups. However, when patients were subdivided by subtype status, restricting anorexic patients appeared to benefit somewhat from cyproheptadine, while it had a negative impact on treatment efficacy in anorectic patients who also binged and purged. Although this study provides tentative evidence that cyproheptadine may be of use in a subgroup of restricting patients with anorexia nervosa, the available data do not suggest that this agent has a major impact on the symptoms of anorexia nervosa. Gross and coworkers (1983) conducted a controlled trial of tetrahydrocannabinol, the active component of marijuana, to see if its appetite-stimulating effect could be beneficial in the treatment of anorexia nervosa. A 4-week double-blind crossover study in 11 women, comparing tetrahydrocannabinol with diazepam, showed no significant effect on food intake or weight. The tetrahydrocannabinol group had higher levels of somatization, interpersonal sensitivity, and sleep disturbance, and three patients who received tetrahydrocannabinol experienced severe dysphoria and dropped out of the study. The authors concluded that tetrahydrocannabinol is not a useful agent in the treatment of anorexia nervosa. Lithium

In an attempt to take advantage of the weight gain associated with the mood stabilizer lithium, Gross and colleagues (1981) conducted a 4-week placebocontrolled trial with 16 women with anorexia nervosa. The authors found some indication of an advantage for the lithium-treated patients, particularly in the final 2 weeks of the trial. Further studies of longer duration with larger samples are needed to document this effect. Prokinetic agents

Delayed gastric emptying, early satiety, and bloating have often been described among patients with anorexia nervosa. These symptoms may contribute to the food avoidance in these patients and thus a number of prokinetic agents have been examined. The administration of metaclopramide (Domstad et al., 1987)

416

L. A. Kotler et al.

and cisapride (Stacher et al., 1987) has been shown to improve gastric emptying in the short-term treatment of anorexia nervosa. However, some of these drugs have significant central nervous system (CNS) side effects. One 4-week doubleblind controlled trial of metaclopramide (Moldofsky et al., 1977) could not be completed due to the high frequency of depression produced by the central effects of the drug. Stacher et al. (1993) conducted a 12-week double-blind controlled trial of cisapride that demonstrated accelerated gastric emptying in 12 patients with anorexia nervosa. The authors suggested that this effect might be beneficial in augmenting weight gain, although the significance of any drug–placebo difference was not reported. Szmukler et al. (1995) reported the results of an 8-week randomized, controlled trial of cisapride in 29 anorexic patients. Some gastrointestinal symptoms were improved in the active drug group, although there was no difference in gastric emptying time or weight gain between the groups. These studies leave the precise role for prokinetic agents in anorexia nervosa poorly defined. In addition, a recent report cited that the US Food and Drug Administration (FDA) has received information on 38 deaths in the US since 1993 in patients taking cisapride (Ault, 1998). Under certain circumstances cisapride can prolong the cardiac QT interval and lead to life-threatening arrhythmias. For this reason, cisapride has effectively been removed from the US market. Since anorexia nervosa is also associated with QT prolongation, the use of cisapride in this disorder for modest symptomatic relief cannot be justified. Zinc

The nutritional deprivation in anorexia nervosa and the overlap in clinical presentation between anorexia nervosa and zinc deficiency, including weight loss, changes in appetite, and depressed mood, suggested a possible zinc deficiency in anorexia nervosa and a potential role for zinc supplementation in its treatment. Many of the studies investigating the relationship between zinc and anorexia nervosa have been conducted in adolescents. Safai-Kutti (1990) reported an open trial of zinc supplementation in 20 females aged 14–26 with anorexia nervosa. Seventeen of the 20 patients increased their body weight by more than 15% over the 8–56 month follow-up period. The authors described a double-blind controlled clinical trial with 50 female anorexics, but these data have not yet been reported in the literature. Katz and coworkers (1987) reported on a 6-month double-blind, controlled trial of zinc supplementation (50 mg elemental zinc daily) for anorexia nervosa. At baseline, patients with anorexia nervosa had zinc intakes significantly below the recommended daily allowance, and lower levels of urinary zinc excretion

417


compared with noneating disorder controls. Zinc supplementation was followed by a decrease in the levels of depression and anxiety in adolescents with anorexia nervosa, and a trend toward greater weight gain compared with patients who did not receive zinc. Lask and colleagues (1993) described a 12-week double-blind, placebocontrolled crossover trial with 26 hospitalized children aged 9–14 (mean 11.8 years) who were randomized to either 50 mg zinc sulfate for 6 weeks, then placebo for 6 weeks, or the reverse sequence. There was no significant difference in the rate of weight gain between the zinc-treated and placebo groups. The authors note that zinc deficiency is common in this population, and that zinc levels correlated with the degree of malnutrition and returned to normal with refeeding. They found little evidence to support the efficacy of zinc supplementation in childhood anorexia nervosa. In contrast, Birmingham and coworkers (1994) reported a double-blind, placebo-controlled trial of zinc gluconate (up to 100 mg/day) supplementation in 35 adult female inpatients. The rate of increase in body mass index per day was significantly greater in those patients receiving zinc supplementation vs. placebo. These authors suggest that zinc may be helpful in augmenting weight gain in anorexia nervosa. In summary, the possible role of zinc in the pathogenesis of anorexia nervosa is still controversial, and its usefulness in the treatment of anorexia nervosa has not clearly been established. Clinically useful treatment guidelines for anorexia nervosa Weight gain is a critical element in the acute treatment of anorexia nervosa. This often requires a combined treatment approach including psychologic, nutritional, and cognitive–behavioral elements to restore body weight and normalize distorted thinking about food and body shape. Family interventions are particularly important for children and adolescents with this disorder. No psychopharmacologic agent has clearly been established to be of benefit in the treatment of the primary symptoms of anorexia nervosa. Medication may be considered as an adjunct to a multifaceted treatment approach, especially when there is evidence of a comorbid mood or anxiety disorder. Due to their superior side effect profile, the SSRIs are currently the preferred class of agents for patients with anorexia nervosa who concurrently exhibit significant depressive symptoms. As described above, depressive symptoms in severely underweight patients may not respond to antidepressant medications and it is often prudent to defer the consideration of a medication trial until significant weight gain has taken place. There are hints that antidepressant medication may be useful in preventing relapse in patients who have achieved their target weights, but the

418

L. A. Kotler et al.

evidence to support this is still limited at this time. There is no strong evidence that other medications including zinc are routinely of benefit in the acute treatment of anorexia nervosa. In addition, the physiologic disturbances associated with anorexia nervosa merit the careful assessment of medication side effects in this population, including regular monitoring of weight, serum electrolytes, and cardiac status. Bulimia nervosa: overview of the disorder The essential behavioral features of bulimia nervosa are frequent binge eating and the recurrent use of inappropriate compensatory methods to prevent weight gain (DSM-IV, American Psychiatric Association, 1994). The formal definition of a binge has two components: (1) eating, in a discrete period of time, an amount of food significantly larger than most people would normally eat, and (2) a sense of loss of control over the eating during the episode. The compensatory behaviors employed by individuals with this disorder to prevent weight gain include self-induced vomiting, misuse of laxatives and diuretics, fasting, and excessive exercise. To meet DSM-IV criteria, the binge eating and compensatory behaviors must both occur an average of at least twice a week for 3 months. In addition, persons with bulimia nervosa place an undue emphasis on shape and weight in their regulation of self-esteem. DSM-IV describes two types of bulimia nervosa, the purging type, in which the individual engages in self-induced vomiting, laxatives, diuretics, or enemas, and the nonpurging type, in which the individual uses other inappropriate compensatory behaviors such as fasting or exercise. Bulimia nervosa is more prevalent than anorexia nervosa, with estimates ranging from 1 to 5% of adolescent and young adult females (Hsu, 1996; Whitaker, 1992; Stein 1991). The rate of occurrence of this disorder in males is approximately one-tenth that in females. Most researchers in the field have the impression that bulimia nervosa almost always occurs during or after puberty (Lask and Bryant-Waugh, 1997). Schmidt and coworkers (1992) reported 23 cases of early-onset bulimia nervosa with a mean age of onset of 13.9 and a range of 11–15. All of the girls had started menstruating prior to the onset of the eating disorder. Patients with bulimia nervosa often present with symptoms of comorbid psychiatric disorders. The most frequent include depressive disorders, anxiety disorders, substance abuse, and a history of anorexia nervosa. Estimates of the prevalence of axis II disorders in bulimia nervosa vary widely (Ames-Frankel et al., 1992).

419


Hypothesized mechanisms of bulimia nervosa Although the clinical features of bulimia nervosa have been defined, relatively little is known about the role of neurobiologic disturbances in the pathogenesis of this disorder. Many of the recent biologic studies of bulimia nervosa have focused on neurotransmitters and neuromodulators thought to influence eating behavior and mood. As in anorexia nervosa, since neurobiologic changes may precede, accompany, or follow behavioral changes, it is difficult to ascertain what role these changes play in the etiology and maintenance of these disorders. Particular attention has been directed toward regulation of CNS pathways involving serotonin, noradrenaline, and endogenous opiates. The focus of much of the research has centered on serotonin because of its established role in the control of feeding behavior and the evidence for therapeutic response to the SSRIs in bulimia nervosa. There has been some suggestion that reduced activity in central serotonin pathways may contribute to impaired satiety signals in individuals with bulimia nervosa (Brewerton et al., 1992; Jimerson et al., 1992). In addition, there is some evidence that the release of the satiety hormone cholecystokinin from the small intestine is impaired (Devlin et al., 1997).

Psychopharmacologic treatment of bulimia nervosa In contrast to anorexia nervosa, there has been significant recent progress in the development of effective therapies, both psychopharmacologic and psychotherapeutic, for the treatment of bulimia nervosa. Treatment studies of bulimia nervosa are more easily accomplished because of its higher prevalence and the fact that bulimia nervosa can be managed largely on an outpatient basis. The greatest enthusiasm has focused on the use of antidepressants, although anticonvulsants, serotonergic agents, opiate antagonists, and lithium have also been examined.

Anticonvulsants

Medication trials in bulimia nervosa have been based on a variety of conceptual models. The notion that bulimia nervosa was a form of a seizure disorder led to the first controlled trials for bulimia nervosa, examining phenytoin (Wermuth et al., 1977) and carbamazepine (Kaplan et al., 1983). These studies suggested that a small number of patients may benefit from these medications, but a robust response was not found.

420

L. A. Kotler et al.

Serotonergic agents

Based on preclinical studies that suggested that serotonin plays an important role in the regulation of food intake and satiety, and, specifically, that an increase in serotonergic function typically decreases food intake, controlled pharmacologic trials have examined the SSRIs, which will be discussed later, as well as two other serotonergic agents, tryptophan and fenfluramine. In a placebo-controlled trial, Krahn and Mitchell (1985) gave L-tryptophan, an essential amino acid and the precursor of serotonin, to 13 patients with bulimia nervosa and found it had no appreciable effect on binge eating. Trials of fenfluramine, a serotonergic agonist that blocks reuptake and also directly releases serotonin, have also been conducted in bulimia nervosa. It should be noted that both d,l- and d-fenfluramine were withdrawn from marketing in 1997 because of cardiac abnormalities associated with their use in the treatment of obesity. Blouin and coworkers (1988) reported the results of a double-blind, placebo-controlled crossover trial of d,l-fenfluramine; use of the active medication was associated with a significant decrease in binge and purge frequencies. In contrast, Russell and colleagues (1988) conducted a 12-week trial of dfenfluramine (30 mg/day) and reported no significant benefit of medication over placebo, although their results were limited by a high dropout rate. In a later study by the same group, Fahy et al. (1993) examined the role of d-fenfluramine (45 mg/day) given with weekly cognitive–behavioral therapy (CBT), and found that there was no difference between those treated with fenfluramine compared with placebo. Opiate antagonists

Based on the idea that changes in CNS endogenous opiates might be linked to changes in appetite, and bulimic patients’ clinical descriptions of their relationship to food as an ‘‘addiction’’, Jonas and Gold (1987) conducted an open trial of naltrexone in which seven out of 10 subjects showed complete or partial remission. However, subsequent placebo-controlled investigations of naltrexone have demonstrated no difference between naltrexone and placebo in the reduction of binge frequency (Alger et al., 1991; Mitchell et al., 1989). Lithium

Hsu and coworkers (1991) examined the efficacy of lithium vs. placebo in 91 patients with bulimia nervosa in an 8-week study. There was a significant decline in binge frequency in both groups, although there was no evidence that the lithium-treated patients fared better than those who received placebo. The modest lithium levels (mean of 0.62 mEq/l) in these patients may have contributed to the negative findings in this study.

421


Antidepressants

The observation that depressive symptoms are frequent among patients with bulimia nervosa and their first-degree relatives led to medication trials using antidepressants in this population. Early reports in the 1980s from open trials (Pope and Hudson, 1982; Walsh et al., 1982) led to randomized, controlled, double-blind studies of various classes of antidepressants using both parallel and crossover designs. Almost all of these showed a statistically significant short-term decrease in binge eating and purging compared with placebo. The individual studies have been extensively summarized (Mitchell et al., 1993; Walsh and Devlin, 1992). On the basis of this body of information, several generalizations can be made. Almost all types of antidepressants including TCAs, monoamine oxidase inhibitors (MAOIs), and SSRIs have been shown to produce benefits relative to placebo. All appear to have roughly equal efficacy, and there are no studies which have compared one antidepressant directly with another. The abstinence rates for short-term treatment (on average 8 weeks) are about 30%, with overall reductions in bulimic symptoms about 70%. The presence or absence of depressive symptoms at the time of antidepressant treatment does not predict the degree of improvement in bulimic symptoms with these medications. Thus, the precise mechanism of action of antidepressant medications in bulimia nervosa is still an unanswered question. Overall, dropout rates tend to be high in these studies, partially due to medication side effects and also due to to patients’ attitudes toward medication use. These points may be especially relevant to future studies in younger populations of patients. It should be noted that, in a placebo-controlled study of the antidepressant bupropion in the treatment of nondepressed patients with bulimia nervosa, four out of 55 women experienced grand mal seizures during treatment, prompting a termination of the study (Horne et al., 1988). On the basis of this study, the drug company GlaxoSmithKlein has recommended that bupropion not be prescribed in this population. Most of the treatment studies described above have assumed that the optimal dose of antidepressant medication is the same as that for depression. A multicenter trial of fluoxetine has challenged this assumption, by comparing the response of patients on placebo, on 20 mg fluoxetine, and on 60 mg fluoxetine (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992). The higher dose was significantly more effective than placebo while the lower dose was not clearly effective. The only SSRI examined in placebo-controlled trials of outpatients for bulimia nervosa has been fluoxetine, leaving unresolved the optimal dosing strategy for other SSRIs. Fichter and colleagues (1996) report a relapse prevention study of the

422

L. A. Kotler et al.

efficacy of fluvoxamine in maintaining improvement in 72 patients with bulimia nervosa who were successfully treated with inpatient psychotherapy. Patients were randomly assigned to receive fluvoxamine (100–300 mg/day, average of 182 mg/day) or placebo, for a period of 15 weeks, including a 2–3 week inpatient titration phase and 12 weeks of outpatient maintenance treatment. Fluvoxamine had a significant effect in reducing the return of bulimic symptoms measured by both self-ratings and expert ratings, although differential dropout rates in the medication (26%) vs. placebo (14%) groups represent a significant limitation of the study. Despite the multitude of positive evidence supporting the use of antidepressant medication in the treatment of bulimia nervosa, there are some limitations in this body of literature. The duration of treatment in these treatment studies is brief, typically 6–8 weeks. Thus, the data about the efficacy of medications from controlled trials are mostly confined to short intervals, and little is known about long-term outcome. Optimal doses and durations of antidepressant medication intervention have not yet been clearly established. The populations of patients in these studies usually consist of adult women of normal weight who vomited or used laxatives after eating binges and who would be classified according to DSM-IV as having the purging type of bulimia nervosa. Thus, the results of these studies may not be generalizable to others with bulimia nervosa including adolescents, males, overweight patients, or individuals who only use fasting or exercise to compensate for binge eating. In summary, although antidepressant medication has efficacy in the short-term treatment of bulimia nervosa, it is often not adequate, when given without other treatment interventions, to bring about clinical remission. In addition, not enough is known about its efficacy over longer periods of time. Medication and psychotherapy

Recent investigations have focused on the relative efficacy of antidepressant medications, psychotherapeutic interventions, and on the potential utility of combined treatment for individuals with bulimia nervosa. Modalities that have been studied include nutritional counseling, individual psychotherapy (often CBT), and group psychotherapy. In terms of medications, early studies compared psychotherapy with the TCAs, usually imipramine or desipramine, although more recent studies have used the SSRI fluoxetine, based on its efficacy in controlled trials and its superior side effect profile. In the first published trial comparing medication and psychotherapy, Mitchell and coworkers (1990) studied 174 patients with bulimia nervosa who were randomized to one of four treatment groups: placebo, imipramine,

423


placebo and group psychotherapy, and imipramine and group psychotherapy. Patients who received placebo and group psychotherapy did substantially better, in terms of reducing binge eating and purging, than those receiving imipramine alone. The combination of imipramine and structured group therapy was no more effective in reducing these symptoms than group therapy alone. However, patients receiving imipramine, both with and without group therapy, showed greater improvement in mood and anxiety symptoms, suggesting an advantage to the combination of medication and psychotherapy. Using an inpatient sample of patients who were actively engaged in intensive behavioral treatment, Fichter and colleagues (1991) compared fluoxetine (60 mg/day) with placebo. Although the study was not designed to address the relative efficacies of combined treatment, the authors found no difference between fluoxetine and placebo-treated groups and assert that the high response to behavioral treatment prevented the observation of any additional medication effect. Agras et al. (1992) compared individual CBT, imipramine, and their combination. They found that CBT alone was more effective than medication alone, although there was some suggestion that the combination of CBT and medication for 24 weeks gave the best result. Leitenberg et al. (1994) also compared CBT with desipramine and their combination, reporting that CBT was superior to desipramine alone. This study was severely limited by a high dropout rate on desipramine and a small sample size. Goldbloom and colleagues (1997) recently reported the results of a 16-week randomized, controlled trial of individual CBT, fluoxetine, and their combination in 76 patients with bulimia nervosa. All of the treatment groups showed substantial reduction of objective binges during the study. The combination of the drug plus psychotherapy was superior to the drug alone, but the absence of a placebo group and a 43% dropout rate limit the interpretation of these data. Beaumont and colleagues (1997) compared the efficacy of fluoxetine vs. placebo for 67 patients receiving intensive nutritional counseling in an 8-week active treatment trial with follow-up at 12 and 20 weeks. Fluoxetine was superior to placebo on measures of dietary restraint, and concern about weight and shape. However, the fluoxetine- and placebo-treated groups had similar levels of behavioral symptoms at the end of treatment and at follow-up, suggesting that fluoxetine does not provide major augmentation of the benefit of nutritional counseling. With only 8 weeks of active treatment, the fluoxetine trial was relatively brief, and, with a high rate of remission (61% of the patients reported no binge eating episodes during week 8 of treatment), the study perhaps had a limited ability to detect an additional benefit from medication.

424

L. A. Kotler et al.

The authors’ group at Columbia (Walsh et al., 1997) recently published a placebo-controlled trial comparing individual CBT, psychodynamically oriented supportive psychotherapy, and their combination with a two-stage medication intervention (desipramine, followed by fluoxetine for patients who did not respond to or could not tolerate desipramine) in 120 women with bulimia nervosa. CBT was clearly superior to supportive psychotherapy, with the combination with medication modestly but significantly augmenting the effect of the psychotherapies. The results of these seven trials suggest that the symptoms of bulimia nervosa respond both to psychotherapeutic interventions and antidepressant medication. The results of early studies using TCAs found that psychotherapy was superior to a single course of antidepressant medication, although later studies, including those using fluoxetine, suggest there may be a modest benefit to medication augmentation in the short term. The proper sequence of treatments has not been established. Presently, only structured psychotherapeutic interventions have been shown to have lasting benefit for the symptoms of bulimia nervosa, and it appears easier to detect an additional benefit of medication when the effects of the psychotherapeutic intervention are less robust.

Clinically useful treatment guidelines for bulimia nervosa The results of the above trials provide the foundation for the current practice in treating individuals with bulimia nervosa. Although pharmacologic treatments have been well investigated in adult populations, no systematic and controlled studies have been conducted with adolescents. The clinician is left with the common problem in child and adolescent psychiatry – extrapolating from adult data to a younger and perhaps clinically different population. As evidence exists for significant short- and long-term benefits of psychotherapeutic interventions in bulimia nervosa, it seems appropriate to recommend a trial of psychotherapy as the first line of treatment. CBT is helpful for many patients, although it requires specialized training and may not always be readily available. The pharmacotherapy of bulimia nervosa is based on the use of antidepressant medications. Medication should be particularly considered for patients with significant comorbid symptoms and those who have not responded to psychotherapeutic interventions. There is no evidence to suggest that any particular antidepressant is more effective than another in the treatment of bulimia

425


nervosa, and medication should be selected on the basis of minimizing side effects and enhancing compliance. In comparison with TCAs and MAOIs, the SSRIs present a more favorable side effect profile for patients with bulimia nervosa. Fluoxetine, with its side effect profile, long half-life, and extensive data on efficacy in adults, is the authors’ suggested initial choice. In adults, the recommended dose is 60 mg/day, which can be started all at once or titrated up from 20 mg/day. This is in contrast to the dose of 20 mg/day typically used in the treatment of depression. It is currently unclear whether children and adolescents with bulimia nervosa will respond to antidepressant medications as adults do, or whether perhaps they will respond to lower doses of medications, or even experience greater side effects from the 60 mg dose than adults. There is little systematic information concerning the optimal duration of antidepressant treatment in patients with bulimia nervosa. At present, a period of 4–6 months seems reasonable, but some individuals may require longer treatment while others may relapse on medication. It is unclear if separate medication trials with different classes of antidepressant medication will provide greater results when patients do not respond favorably to one class of medication. Although there has been no well-documented evidence of teratogenic effects of the SSRIs, the potential harmful effects of medications taken during pregnancy should be discussed with sexually active individuals and the consistent use of birth control ensured (Kulin et al., 1998; Nulman et al., 1997). In addition, baseline and periodic monitoring of laboratory measures are necessary as vomiting and laxative and/or diuretic abuse can lead to metabolic disturbances in this population.

Binge eating disorder In 1994, DSM-IV suggested diagnostic criteria for a new eating disorder, binge eating disorder (American Psychiatric Association, 1994). The critical behavioral characteristics are recurrent binge eating without purging behavior. Although most studies of binge eating disorder describe middle-aged, obese adults, many of these individuals report that their binge eating started in adolescence. The prevalence of this disorder in adolescents is currently unknown. The roles of psychotherapeutic and psychopharmacologic intervention in this new disorder are under active investigation.

426

L. A. Kotler et al.

Summary and conclusions This chapter has reviewed the development of psychopharmacologic treatments for the eating disorders. While the studies on the acute treatment of anorexia nervosa fail to show a significant response of its core symptoms to medication, a potentially important refocusing of attention toward the use of medication in the prevention of relapse among weight-restored patients has recently occurred. Studies of antidepressant medications in the acute treatment of bulimia nervosa continue to document that almost all classes of antidepressants are effective in the short term. However, a single course of antidepressant medication seems to be insufficient when patients are followed for a longer period of time. The potential utility of combining antidepressant medication with various psychotherapeutic techniques has shown promise in a number of recent studies in patients with bulimia nervosa, but there are many unanswered questions about combined treatment modalities. The majority of these treatment studies have been conducted in adult subjects and their results may not be generalizable to child and adolescent populations. The precise role of psychopharmacologic agents in the treatment of eating disorders in children and adolescents is a fertile area for future research.

REFE REN C ES Agras WS, Rossiter EM, Arnow B et al. (1992). Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: a controlled comparison. Am J Psychiatry 149:82–7. Alger SA, Schwalberg MD, Bigaouette JM et al. (1991). Effect of a tricyclic antidepressant and opiate antagonist on binge-eating in normal weight bulimic and obese binge-eating subjects. Am J Clin Nutr 53:865–71. Ames-Frankel J, Devlin MJ, Walsh BT et al. (1992). Personality disorder diagnoses in patients with bulimia nervosa: clinical correlates and changes with treatment. J Clin Psychiatry 53:90–6. American Psychiatric Association (1987). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn (revised). Washington, DC: American Psychiatric Association. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Attia E, Haiman C, Walsh BT, Flater SR (1998). Does fluoxetine augment the inpatient treatment of anorexia nervosa? Am J Psychiatry 155:548–51. Ault A (1998). US FDA warns doctors to use cisapride as last resort only. Lancet 16:35–7. Beaumont PJV, Russell J, Touyz S et al. (1997). Intensive nutritional counseling in bulimia nervosa: a role for supplementation with fluoxetine? Aust N Z J Psychiatry 31:514–24. Biederman J, Herzog DB, Rivinus TM et al. (1985). Amitriptyline in the treatment of anorexia

427


nervosa: a double-blind, placebo-controlled study. J Clin Psychopharmacol 5:10–16. Birmingham CL, Goldner EM, Bakan R (1994). Controlled trial of zinc supplementation in anorexia nervosa. Int J Eat Disord 15:251–5. Blouin AG, Blouin JH, Bushnik T, Zuro C, Mulder E (1988). Treatment of bulimia with fenfluramine and desipramine. J Clin Psychopharmacol 8:261–9. Brewerton TD, Mueller EA, Lesem MD et al. (1992). Neuroendocrine responses to m-chlorophenylpiperazine and L-tryptophan in bulimia. Arch Gen Psychiatry 49:852–61. Bryant-Waugh R, Lask B (1995). Annotation: eating disorders in children. J Child Psychol Psychiatry 36:191–202. Dally P, Sargant W (1960). A new treatment of anorexia nervosa. BMJ 1:1770–3. Dally P, Sargant W. (1966). Treatment and outcome of anorexia nervosa. BMJ 2:793–5. Devlin MJ, Walsh BT, Guss J, Kissileff HR, Liddle RA, Petkova E (1997). Postprandial cholecystokinin release and gastric emptying in patients with bulimia nervosa. Am J Clin Nutr 65:114–20. Domstad PA, Shis WJ, Humphries L, DeLand FH, Digenis GA (1987). Radionuclide gastric emptying studies in patients with anorexia nervosa. J Nucl Med 28:816–19. Eagles JM, Johnston MI, Hunter D et al. (1995). Increasing incidence of anorexia nervosa in the female population of Northeast Scotland. Am J Psychol 152:1266–71. Emslie GJ, Rush J, Weinberg WA et al. (1997). A double-blind randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–7. Fahy TA, Eisler I, Russell GFM (1993). A placebo-controlled trial of d-fenfluramine in bulimia nervosa. Br J Psychiatry 162:597–603. Fichter MM, Kruger R, Rief W, Hollan R, Dohne J (1996). Fluvoxamine in prevention of relapse in bulimia nervosa: effects of eating-specific psychopathology. J Clin Psychopharmacol 16:9–18. Fichter MM, Leibl K, Rief W, Brunner E, Schmidt-Auberger S, Engel RR (1991). Fluoxetine versus placebo: a double-blind study with bulimic inpatients undergoing intensive psychotherapy. Pharmacopsychiatry 24:1–7. Flament M, Ledou S, Jeammet P, Choquet M, Simon Y (1995). A population study of bulimia nervosa and subclinical eating disorders in adolescence. In Eating Disorders in Adolescence: Anorexia and Bulimia Nervosa, (Ed.) HD Steinhausen, pp. 21–36. New York: De Gruyter. Fluoxetine Bulimia Nervosa Collaborative Study Group (1992). Fluoxetine in the treatment of bulimia nervosa: a multicenter, placebo-controlled, double-blind trial. Arch Gen Psychiatry 49:139–47. Goldberg SC, Halmi KA, Eckert ED, Casper RC, Davis JM (1979). Cyproheptadine in anorexia nervosa. Br J Psychiatry 134:67–70. Goldbloom DS, Olmstead M, Davis R et al. (1997). A randomized controlled trial of fluoxetine and cognitive behavioral therapy for bulimia nervosa: short-term outcome. Behav Res Ther 35:803–11. Gross HA, Ebert MH, Faden VB et al. (1981). A double-blind controlled trial of lithium carbonate in primary anorexia nervosa. J Clin Psychopharmacol 1:376–81. Gross HA, Ebert MH, Faden VB et al. (1983). A double-blind trial of 9-tetrahydrocannabinol in primary anorexia nervosa. J Clin Psychopharmacol 3:165–71.

428

L. A. Kotler et al.

Halmi KA (1996). The psychobiology of eating behavior in anorexia nervosa. Psychiatry Res 61:23–9. Halmi KA, Eckert ED, LaDu TJ, Cohen J (1986). Anorexia nervosa: treatment efficacy of cyproheptadine and amitriptyline. Arch Gen Psychiatry 43:177–81. Horne RL, Fergusen JM, Pope HG et al. (1988). Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry 49:262–6. Hsu LKG (1996). Epidemiology of the eating disorders. Psychiatr Clin North Am 19:681–700. Hsu LKG, Clement L, Santhouse R, Ju E (1991). Treatment of bulimia nervosa with lithium carbonate: a controlled study. J Nerv Ment Dis 179:51–5. Irwin M (1984). Early onset of anorexia nervosa. South Med J 77:611–14. Jimerson DC, Lesem MD, Kaye WH et al. (1992). Low serotonin and dopamine metabolite concentrations in cerebrospinal fluid from bulimic patients with frequent binge episodes. Arch Gen Psychiatry 49:132–8. Jonas JM, Gold MS (1987). Treatment of antidepressant-resistant bulimia with naltrexone. Int J Psychiatry Med 16:305–9. Kaplan AS, Garfinkel PE, Darby PL et al. (1983). Carbamazepine in the treatment of bulimia. Am J Psychiatry 140:1225–6. Katz RL, Keen CL, Litt IF, Hurley LS, Kellams-Harrison KM, Glader LJ (1987). Zinc deficiency in anorexia nervosa. J Adolesc Health Care 8:400–6. Kaye WH (1996). Neuropeptide abnormalities in anorexia nervosa. Psychiatry Res 62:65–74. Kaye WH, Jimerson DC, Lake CR et al. (1985). Altered norepinephrine metabolism following long-term weight recovery in patients with anorexia nervosa. Psychiatry Res 14:333–42. Kaye WH, Gwirtsman HL, George DT et al. (1991a). Altered serotonin activity in anorexia nervosa after long-term weight restoration: does elevated CSF-5-HIAA level correlate with rigid and obsessive behavior? Arch Gen Psychiatry 48:556–62. Kaye WH, Waltzin TE, Hsu LKG, Bulik CM (1991b). An open trial of fluoxetine in patients with anorexia nervosa. J Clin Psychiatry 52:464–71. Kaye WH, Waltzin TE, Hsu G, Sokol M, McConahan C, Plotnicov KH (1997). Relapse prevention with fluoxetine in anorexia nervosa: a double-blind placebo-controlled study. 150th American Psychiatric Association Meeting, 178. Krahn D, Mitchell J (1985). Use of L-tryptophan in treating bulimia (letter). Am J Psychiatry 142:1130. Kulin NA, Pastuszak A, Sage SR et al. (1998). Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. J Am Med Assoc 279:609–10. Lacey JH, Crisp AH (1980). Hunger, food intake and weight: the impact of clomipramine on a refeeding anorexia nervosa population. Postgrad Med J 56:79–85. Lask B, Bryant-Waugh RB (1997). Prepubertal eating disorders. In Handbook of Treatment for Eating Disorders, (Eds.) DM Garner, PE Garfinkel, pp. 476–83. New York: Guilford Press. Lask B, Fosson A, Rolfe U, Thomas S. (1993). Zinc deficiency and childhood-onset anorexia nervosa. J Clin Psychiatry 54:63–6. Leitenberg H, Rosen JC, Wolf J, Vara LS, Detzer MJ, Srebnik D (1994). Comparison of

429


cognitive-behavioral therapy and desipramine in the treatment of bulimia nervosa. Behav Res Ther 32:37–45. Lucas AR, Beard CM, O’Fallon WM et al. (1991). 20 year trend in the incidence of anorexia nervosa in Rochester, Minn: a population based study. Am J Psychol 148:917–22. Mauri MC, Rudelli R, Somaschini E et al. (1996). Neurobiological and psychopharmacological basis in the therapy of bulimia and anorexia. Prog Neuropsychopharmacol Biol Psychiatry 20:227–40. Mayer LES, Walsh BT (1998). Pharmacotherapy of eating disorders. In The Integration of Neurobiology in the Treatment of Eating Disorders, (Ed.) H Hoek, pp. 383–405. London: John Wiley. Mitchell JE, Christenson G, Jennings J et al. (1989). A placebo-controlled, double-blind crossover study of naltrexone hydrochloride in outpatients with normal-weight bulimia. J Clin Psychopharmacol 9:94–7. Mitchell JE, Pyle RL, Eckert ED, Hatsukami D, Pomeroy C, Zimmerman R (1990). A comparison of antidepressants and structured intensive group psychotherapy in the treatment of bulimia nervosa. Arch Gen Psychiatry 47:149–57. Mitchell JE, Raymond N, Specke S (1993). A review of the controlled trials of pharmacotherapy and psychotherapy in the treatment of bulimia nervosa. Int J Eat Disord 14:229–47. Moldofsky H, Jeuniewic N, Garfinkel PE (1977). Preliminary report of metoclopramine in anorexia nervosa. In Anorexia Nervosa, (Ed.) R Vigersky, pp. 373–5. New York: Raven Press. Nulman I, Rovet J, Stewart DE et al. (1997). Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 336:258–62. Pope HG, Hudson JI (1982). Treatment of bulimia with antidepressants. Psychopharmacology 78:176–9. Rooney BL, McClelland A, Crisp AH et al. (1995). The incidence and prevalence of anorexia nervosa in three suburban health districts in southwest London, UK. Int J Eat Disord 18:299– 307. Russell GF, Checkley SA, Feldman J, Eisler I (1988). A controlled trial of d-fenfluramine in bulimia nervosa. Clin Neuropharmacol 11:S146–59. Safai-Kutti S (1990). Oral zinc supplementation in anorexia nervosa. Acta Psychiatr Scand 361:S14– 17. Schmidt U, Hodes M, Treasure J (1992). Early onset bulimia nervosa: who is at risk? A retrospective case-control study. Psychol Med 22:623–8. Stacher G, Abatzi-Wenzel TA, Wiesnagrotzki S, Bergmann H, Schneider C, Gaupmann G (1993). Gastric emptying, body weight and symptoms in primary anorexia nervosa: long term effects of cisapride. Br J Psychiatry 162:398–402. Stacher G, Bergmann H, Wiesnagrotzki S et al. (1987). Intravenous cisapride accelerated delayed gastric emptying and increases antral contraction amplitude with primary anorexia nervosa. Gastroenterology 92:1000–6. Stein DM (1991). The prevalence of bulimia: a review of the empirical research. J Nutr Edu 23:205–13. Strober M, Freeman R, DeAntonio, Lampert C, Diamond J (1997). Does adjunctive fluoxetine

430

L. A. Kotler et al.

influence the post-hospital course of anorexia nervosa? A 24-month prospective, longitudinal follow-up and comparison with historical controls. Psychopharmacol Bull 33:425–31. Szmukler GI, Young GP, Miller G, Lichtenstein M, Binns DS (1995). A controlled trial of cisapride in anorexia nervosa. Int J Eat Disord 17:345–57. Vandereycken W (1984). Neuroleptics in the short-term treatment of anorexia nervosa: a double-blind placebo-controlled study with sulpiride. Br J Psychiatry 144:288–92. Vandereycken W, Pierloot R (1982). Pimozide combined with behavior therapy in the short-term treatment of anorexia nervosa. Acta Psychiatr Scand 66:445–50. Vigersky RA, Loriauz DL (1977). The effect of cyproheptadine in anorexia nervosa: a double blind trial. In Anorexia Nervosa, (Ed.) RA Vigersky, pp. 349–56. New York: Raven Press. Walsh BT, Devlin MJ (1992). The pharmacologic treatment of eating disorders. Psychiatr Clin North Am 15:149–60. Walsh BT, Stewart JW, Wright L et al. (1982). Treatment of bulimia with monoamine oxidase inhibitors. Am J Psychiatry 139:1629–30. Walsh BT, Wilson GT, Loeb KL et al. (1997). Medication and psychotherapy in the treatment of bulimia nervosa. Am J Psychiatry 154:523–31. Walters EE, Kendler SK (1995). Anorexia nervosa and anorexic-like syndromes in a populationbased female twin sample. Am J Psychiatry 152:64–71. Wermuth BM, Davis KL, Hollister LE et al. (1977). Phenytoin treatment of the binge-eating syndrome. Am J Psychiatry 134:1249–53. Whitaker AH (1992). An epidemiological study of anorectic and bulimia symptoms in adolescent girls: implications for pediatricians. Pediatr Ann 21:752–9. Yager J and the American Psychiatric Association Work Group on Eating Disorders (2000). Practice Guidelines for the Treatment of Patients with Eating Disorders – Revision. Am J Psychiatry 157(suppl):1–39.

15 Medical psychiatric conditions Daniel S. Pine1, Elizabeth Cohen2, and Yana Brayman2 1

National Institute of Mental Health, Bethesda, Maryland, USA New York Psychiatric Institute, New York, USA

2

Introduction Over the past 15 years, changes in the approach to psychiatric diagnosis among both children and adults have been paralleled by relatively major changes in the approach to treatment. As outlined in the preceding chapters, these changes are perhaps most visible in the realm of psychopharmacology. Medications are recognized as a viable treatment for a growing number of psychiatric disorders in both children and adults. Preceding chapters discuss the direct use of biologic treatments in children, which almost exclusively includes medications. The current chapter, in contrast, deals with more indirect applications that have resulted from the overall change in modern thinking about childhood psychopathology. These changes have resulted from increasingly closer alliances among child psychiatry, developmental psychology, and pediatric subspecialties, including developmental pediatrics and pediatric neurology. This chapter is devoted to an examination of the implications these fields carry for child psychiatry while considering the relationship between medical and psychiatric syndromes in children. Three specific topics will be briefly reviewed. First, the chapter will review evidence regarding the association between psychiatric and medical disorders in children. This section of the chapter will outline the specific medical and psychiatric disorders which tend to co-occur, focusing mostly on illnesses of the central nervous system (CNS). Secondly, the chapter will highlight some of the more recent advances in pathophysiology, resulting largely from integrative research among psychiatric and medically or neuroscience-oriented research groups. This portion of the chapter will emphasize the potential clinical relevance of these more recent findings for psychiatrists evaluating children with no known history of a medical illness. Finally, the chapter will summarize a set of practical issues related to the evaluation and treatment of children with potentially co-occurring medical and psychiatric syndromes. 431

432

D.S. Pine et al.

The association between medical and psychiatric illness There is an extensive literature on the association between medical and psychiatric illness in children and adolescents. An exhaustive review of this literature is beyond the scope of this chapter, and readers are referred elsewhere for more comprehensive treatments of this topic (Cohen et al., 1998; Kim 1991; Breslau, 1985). In this current review, we emphasize the major conclusions that have emerged from this large body of research. The importance of sampling methodology is often overlooked when examining the association between risk factors and any illness, be it a psychiatric or medical disorder. While Berkson (1946) called attention to the biased nature of clinically derived samples more than 50 years ago, Cohen and Cohen (1984) noted that the impact of this bias on psychiatric research remains relatively underappreciated. Referral or ‘‘Berksonian’’ bias results when individuals with one disorder, such as a medical disorder, are less likely to be sampled than individuals with two disorders, such as a medical and a psychiatric disorder. This bias can create an artificial appearance of a true association among disorders. The influence of referral bias on comorbidity in child psychiatric diagnoses has been increasingly recognized (Caron and Rutter, 1991). Clinicians interested in the relationship between medical and psychiatric disorders must also recognize the influence of referral bias on the association between medical and psychiatric disorders. Due to referral bias, epidemiologically based studies provide the most valid data on associations among medical and psychiatric diagnoses. The general conclusion from these studies is that psychiatric illness in children is most closely linked to neurologic illnesses (Breslau, 1985; Rutter et al., 1970). Accordingly, the bulk of the subsequent section specifically summarizes the data in this area. However, there are emerging data for other medical illnesses to suggest broader associations between somatic and psychiatric disorders. The literature in these areas is also briefly reviewed. Table 15.1 summarizes data from some key studies examining the association between psychiatric and medical illness. Neurologic and psychiatric illness in children

In the field of epidemiology, Rutter et al. (1970) provided some of the earliest data pertaining to associations between medical and psychiatric disorders in children. Examining associations in his classic Isle of White Study, Rutter et al. (1970) noted that medical disorders that affect the brain exert the most profound impact on psychopathology. Nearly 30 years later, this observation stands as a well-supported fact. As reviewed by Breslau (1985), children suffer-

433


ing from diseases of the nervous system exhibit significantly higher rates of psychopathology than children free of medical illness. There remain considerable unresolved issues in this area of research. Specifically, there is debate on the specificity of the association, both for the psychiatric and neurologic sides of the equation. The mechanism accounting for the association has also been debated, with some investigators positing a direct impact of brain injury on psychiatric symptoms and other investigators positing a less direct mechanism. More recent research efforts have extended the well-replicated findings on the association between neurologic and medical illness in children by focusing on specific neurologic conditions. Perinatal brain injury Rutter et al. (1970) originally called attention to the association between perinatal brain injury and psychiatric disorders. Limitations in the earliest studies led to the more current epidemiologically based studies that employed advances both in standardized psychiatric diagnosis and in the assessment of neurologic risk. Prospective studies on children born with perinatal risk factors represent one area where there has been significant advance. Recent studies by Whitaker et al. (1997, 1996), Breslau et al. (1996), and Raine (1996) and Raine et al. (1994) extend Rutter’s original observation in three crucial respects. First, the recent studies emphasize associations between disruptive behavior disorders and perinatal adversity, though there is also some evidence for an association between perinatal adversity and anxiety (Whitaker et al., 1997; Shaffer et al., 1985). Secondly, Whitaker et al. (1997) provide important data on the potential mechanism for the association between perinatal adversity and psychopathology. By showing a specific association between psychopathology and ultrasound-confirmed brain injury, Whitaker et al. (1997) lend support to the view that perinatal adversity contributes to psychiatric risk directly through disruptions in neural pathways. Thirdly, both Raine (1996) and Breslau et al. (1996) suggest that the interaction between perinatal adversity and socioenvironmental factors at least partially explains the association between perinatal adversity and psychopathology. Both studies show that children followed longitudinally with biologic and socioenvironmental risk face elevated rates of disruptive behavior, relative to children with neither risk or with either risk alone. Other recent studies extend Rutter’s original observations by examining neurologic markers that can be assessed distally to the perinatal period. Two such markers illustrate the potential clinical utility of this line of research. First, minor physical anomalies are recognized as potentially clinically useful

118

115

16 163

3519

Pine et al. (1997b)

Epilepsy Caplan et al. (1997)

Verity et al. (1998)

Rutter et al. (1970)

4269

823

Breslau et al. (1996)

Raine (1996)

1105

N

Perinatal adversity Whitaker et al. (1997)

Study

Epidemiologic

Epidemiologic

Clinic based

Epidemiologic

Epidemiologic

Epidemiologic

Epidemiologic

Sampling frame

Cross-sectional

Prospective

Cross-sectional

Prospective

Prospective

Prospective

Prospective

Design

Table 15.1. Associations between medical and psychiatric illness in children

10–12

10

6–14

17

20–22

6–7

6

Age at follow-up

One or more psychiatric diagnoses were found in 63% of complex partial seizure patients and 54% primary generalized epilepsy patients Children who had febrile convulsions had high rates of anxiety at 10 years of age Children with neurologic illness had a high rate of psychiatric disorders while children with other illness did not

Neonatal cranial ultrasound abnormalities suggestive of white matter injury significantly increased risk for attention-deficit/hyperactivity disorders, tic disorders, and separation anxiety Low birth weight was associated with attention-deficit/hyperactivity disorders When early neuromotor deficits and negative family factors cluster together, individuals are particularly likely to become violent and criminal There is an interaction between minor physical anomalies and environmental risk in predicting psychiatric status

Key Finding

Epidemiologic School based

Bell et al. (1990) Lewinsohn et al. (1996)

379 1709

Epidemiologic

Cross-sectional Cross-sectional

Cross-sectional and prospective

Prospective

Clinic based

88

Prospective

Retrospective

Epidemiologic

56–65 Clinic based

776

Immunologic or infectious factors Cohen et al. (1998) 776

Brain Injury Max and Dunisch (1997) Max et al. (1997a) Max et al. (1997b) Brown et al. (1981)

Headache Pine et al. (1996)

17–23 15–19

18–27

7–16

10

18–27

Cross-sectionally, ill health was associated with increased risk of psychiatric disorders at all ages In prospective analyses, ill health increased the risk of new-onset major depression at all ages Shy individuals may exhibit a vulnerability to allergies Recent medical disease at intake was significantly associated with major depression at follow-up

Traumatic brain injury predicts new onset psychiatric disorders

Traumatic brain injury predicts new onset psychiatric disorders

There is a longitudinal and developmental relationship between major depression and headache

436

D.S. Pine et al.

markers. Minor physical anomalies are subtle aberrations in the skin or connective tissue that are thought to indicate underlying neural dysplasias. Consistent with Breslau et al. (1996) and Raine (1996), it was recently shown (Pine et al., 1997b) that the combination of minor physical anomalies and socioenvironmental risk factors markedly increases a child’s risk for conduct disorder. Secondly, childhood abnormalities in motor control are increasingly recognized as markers of brain dysfunction which predict psychopathology. Shaffer et al. (1985) first noted the association between motor abnormalities and internalizing disorders, findings replicated and extended to behavior disorders by Pine et al. (1997c) and Raine (1996). In summary, a long history of research notes the association between brain damage and psychopathology. Current studies have extended earlier work through more valid prospectively based assessments and by developing alternative indices of brain dysfunction that are measurable in the clinic. Epilepsy As with perinatal trauma, the association of childhood psychopathology with epilepsy was also recognized by Rutter et al. (1970). A wealth of data has accumulated confirming these original observations, as reviewed elsewhere (Kim, 1991; Steinhausen and Rauss-Mason, 1991). Controversies in this area are similar to those in the area of perinatal brain injury, where there is debate both on specificity across psychiatric disorders and on the mechanisms that account for the association. With respect to specificity, the data for epilepsy are inconclusive, both for seizure type and psychiatric symptomatology. There is inconsistent evidence that a given seizure type is more associated with psychopathology than other seizure types (Steinhousen and Rauss-Mason, 1991), although seizures associated with brain lesions are thought to be most strongly related to psychopathology (Kim, 1991). Conversely, from the perspective of psychopathology, children with epilepsy have been shown to face an increased risk for various psychiatric syndromes, including cognitive, emotional, and behavioral disorders. Parenthetically, a series of recent studies has examined the specific association between complex partial seizures and thought disorder, noting some evidence of specificity (Caplan et al., 1997). Various mechanisms have been proposed to account for the association between epilepsy and psychopathology. Some investigators emphasize the effects of seizures on self-concept and sense of autonomy. Others note the potential direct role of brain pathology, which is thought to contribute both to the neurologic and psychiatric manifestations of the syndrome. Pharmacologic

437


treatments of epileptic condition may also be considered factors that may account for the association. Finally, some of the most interesting recent research on the association between epilepsy and psychopathology examines the role of limbic seizures in bipolar disorder. As articulated by Post et al. (1996), some forms of bipolar disorder are viewed as psychiatric manifestations of a seizure disorder which begin as subclinical or ‘‘silent’’ brain events. Over time, such seizure-related activity is thought to ‘‘kindle’’ parts of the limbic lobe, leading to a gradual increase in the abnormal neural activity. Ultimately, this process is thought to be clinically manifested as bipolar disorder. While this literature largely focuses on adult-onset bipolar illness, the theory suggests that the process of ‘‘kindling’’ might start relatively early in life. Support for this model derives from recent studies on the efficacy of anticonvulsants in bipolar disorder. Support for this model also derives from a recent prospective epidemiologic study of childhood febrile convulsions. Verity et al. (1998) found that febrile convulsions at one point in childhood predicted anxiety symptoms later in life. Headache There is a vast literature to support the co-occurrence of headache and psychopathology in adults, with a growing literature in children (Pine et al., 1996). Unlike perinatal injury and epilepsy, there are few physical signs or routine tests to validate headache as a specific medical diagnosis. Like psychiatric diagnosis, the diagnosis of headache is based firmly on history. As a result, it is difficult to disentangle a true association between headache and psychopathology from an artifactual association, arising due to somatizing associated with a given psychiatric disorder. Consistent with the possibility of somatization, most of the psychiatric literature on headache describes a specific association with either anxiety or depression, psychiatric illnesses most closely tied to somatic complaints in children. On the other hand, the author and colleagues found that children with major depression but no history of headache faced a 3–5-fold increased risk for developing headache 5–10 years later in life (Pine et al., 1996). Such prospective associations cannot be explained by somatization. This finding, consistent with data on the association between migraine and depression in adults, raises the possibility that neurologic factors related to headache contribute to the development of depression. There has been particular interest in the potential role of the serotonergic nervous system, raising questions on the role of a common neuropharmacology in headache and depression (Post and Silbersten, 1994).

438

D.S. Pine et al.

Head injury Consistent with the earlier work of Rutter et al. (1970) on brain injury perinatally, there is a comparable literature on the association between brain injury during childhood and psychopathology. The seminal work described in Brown et al. (1981) notes that closed head injury during childhood predicts the development of de nova psychopathology. This is particularly true when there is an extended period of postconcussive amnesia following the injury. This work has been extended recently in the United States by Max and colleagues (Max et al., 1997a,b; Max and Dunisch, 1997) and Gerring et al. (1998). Two conclusions emerge from all of these studies. First, there is a ‘‘dose-response’’ type relationship between severity of brain injury and risk for psychopathology in both studies. This finding supports the view that psychopathology is a direct result of neural injury. Secondly, there is only limited specificity in the nature of the association. A variety of psychiatric disorders are seen following the injury, although there is a tendency for children to develop problems with attention and impulse control. Basal ganglia disease

There has been a growing interest in the relationship between the basal ganglia and psychopathology, both among adults and children. A variety of psychiatric disorders have been tied to frank basal ganglia illness or injury, but there has been particular interest in both obsessive–compulsive disorder (OCD) and major depression. The literature in adults has been recently reviewed by Cummings (1993), while the literature in children has been reviewed by Peterson and Cohen (1998). Perhaps the most dramatic illustration of this association follows from the work by Swedo and colleagues (1997) on Sydenham’s chorea. Following the initial observation that children with Sydenham’s chorea frequently exhibit obsessive–compulsive and tic-like symptoms, Swedo et al. (1998) described pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS), as reviewed below. Nonneurological illness and psychiatric illness in children

Immunologic and psychiatric illness in children As noted above, much of the epidemiologic research over the past 20 years emphasizes the association between neurologic and psychiatric syndromes. Early studies generally suggested that the risks associated with nonneurologic medical disorders were generally quite low. Recent findings, however, suggest that limitations in the earlier studies may account for the failure to detect such associations. In particular, many of the earlier studies focused on behavior

439


problems, which are clearly tied to neurologic illnesses, but the studies possessed less comprehensive evaluations of internalizing syndromes, such as depressive and anxiety disorders. Further, most studies were cross-sectional. Given the low reliability of internalizing assessment measures in children, longitudinal studies examining the association between childhood illness and later life psychopathology might possess more statistical power to detect such associations. An emerging literature supports this possibility. Two recent lines of data suggest that internalizing disorders in children and adolescents might be tied to subtle immunologic abnormalities that place children and adolescents at risk for immune-mediated illnesses, such as allergies, atopic dermatitis, asthma, and chronic viral infections, such as mononucleosis. The first line of evidence comes from the studies on behavioral inhibition, the temperamental construct described by Kagan and colleauges (1988). Children with behavioral inhibition display a tendency to withdraw when confronted with novelty. This construct is thought to result from limbic anomalies, tied to abnormalities in the autonomic nervous system, which might concurrently impact on immunologic function and produce an association between behavioral inhibition and allergies (Bell et al., 1990). Emerging evidence among older children also suggests an association between internalizing syndromes and abnormalities in immunologic regulation. The second line of evidence comes from studies on the longitudinal relationship between psychopathology during adolescence and physical health later in life. Lewinsohn et al. (1996) showed that teenage-onset major depression, in particular, predicted an increased risk for a variety of physical illnesses at 2-year follow-up. Cohen et al. (1998) extended these results to adulthood, showing that major depression was associated with a selective increase for immunologically mediated illnesses, including allergies and mononucleosis. This association is consistent with findings suggesting alterations in lymphokine production and T cell-mediated cytotoxicity associated with internalizing syndromes. Taken as a whole, these findings suggest that the association between somatic and psychiatric illness may extend beyond illnesses of the neurologic system. Respiratory and psychiatric illness in children Finally, there has been an increasing appreciation of the relationship between anxiety and disorders of the pulmonary system, particularly disorders which cause smothering sensations. Much of the available research examines the specific association with asthma, as reviewed by Mrazek (1992). Children with asthma face a particularly elevated risk for anxiety disorders, though there is some variation in the strength of the association across studies. A number of

440

D.S. Pine et al.

mechanisms have been put forth to account for the association, including social, cognitive, and biologically based hypotheses. Klein (1993) has suggested that illnesses producing smothering sensations are particularly potent at producing anxiety. This effect is thought to result through activation of a ‘‘suffocation false alarm’’ system. While the existence of such an alarm remains a debated point, there does seem to be a specific association between dyspnea and anxiety in children. It has been shown that children with asthma exhibited elevated rates of anxiety in comparison with other children with physical illnesses, including children with congenital central hypoventilation syndrome, a disorder thought to result from the lack of a ‘‘suffocation alarm’’ system (Pine et al., 1994). As reviewed below, subsequent studies on the association between ventilatory physiology and anxiety in non-ill children are generally consistent with these hypotheses. Advances in pathophysiology and neuroscience Prior to the past 10 years, the fields of neuroscience and clinical psychopharmacology, particularly as they related to children, proceeded relatively independent of each other. Thus, major advances in the pharmacologic treatment of children were largely discovered either serendipitously or by extrapolating from pharmacologic data among adults. The pharmacologic approach for most adult disorders was, in turn, largely a result of serendipity. The past 10 years, however, has witnessed major growth in the neuroscientific knowledge base. Recent advances raise hopes of ushering in a more systematic pharmacologic approach in the treatment of childhood psychiatric disorders. As of this writing, these hopes have yet to translate into concrete changes in the treatment of children, and it is still premature to anticipate the timing of such changes. However, to alert the clinician to the excitement of this approach, we review advances in three areas where the possibilities for advances in treatment seem most promising at this time. PANDAS

As noted earlier, extensive research among both children and adults has examined the association between diseases of the basal ganglia and OCD. Evidence of this association derives from neuroimaging studies among both adults (Aylward et al., 1996; Insel, 1992) and children (Rosenberg et al., 1997), from family-genetic studies (Pauls and Leckman, 1986), and from studies on the association between diseases of the basal ganglia and OCD (Peterson and Cohen, 1998). Perhaps the most dramatic example in children is the association

441


between Sydenham’s chorea and OCD, noted many years ago and emphasized once again by Swedo et al. (1997). The choreoathetoid movements of this syndrome are thought to arise through inflammation of the caudate nucleus through the production of anticaudate antibodies arising as part of the immunomodulatory response to the Streptococcus infection. Such inflammation of the caudate is observable as an increased volume of the caudate on magnetic resonance imaging scans during the acute phase of chorea. Since Sydenham’s chorea is a rare disorder, the relevance of this research for most children with OCD remains unclear. Swedo et al. (1998) have identified a distinct group of young children with OCD who exhibit a relatively abrupt onset or exacerbation of their illness. When such a syndrome follows a recent streptococcal infection, the child is considered to suffer from PANDAS. Swedo et al. (1997) recently showed that the majority of children with PANDAS exhibit a white blood cell rheumatic fever susceptibility marker, termed ‘‘D8/ 17.’’ Findings from Murphy et al. (1997) suggest that a strong proportion of adults with childhood-onset OCD are D8/17 positive, which raises questions on the frequency with which clinicians encounter undetected cases of PANDAS. The recognition of PANDAS may carry potential implications for treatment. If a portion of childhood-onset OCD can eventually be attributed to an autoimmune insult following a poststreptococcal infection in a susceptible host, it may ultimately be possible to prevent the onset of OCD in some cases. Further, if exacerbations of OCD in children with PANDAS follow streptococcal infections, it may be possible to treat or prevent some cases of OCD with either antibiotics or immunotherapies. Ongoing trials at the US National Institute of Health are seeking to answer these and other questions. Perhaps the most pressing question for the clinician relates to the frequency with which patients present with PANDAS in the community. As of this writing, this issue remains unresolved. Respiration and anxiety

Research on the role of respiratory factors in anxiety represents a second area where there has been a confluence of findings from psychiatry, pediatrics, and neuroscience. Among adults, the strong association between respiratory distress and symptoms of panic has been recognized since the time of Freud. Recent studies have stimulated a renewed appreciation of this link. Adults with panic disorder exhibit heightened sensitivity to agents that stimulate the respiratory system (Klein, 1993; Papp et al., 1993). For example, patients with panic disorder show heightened rates of dyspnea and anxiety, coupled with

442

D.S. Pine et al.

abnormalities in ventilatory physiology, while breathing carbon dioxide-enriched air (Papp et al., 1997). Further, these respiratory abnormalities appear to identify a unique type of panic disorder that is highly familial and particularly responsive to agents with effects on the serotonergic nervous system (Horwath et al., 1998; Gorman et al., 1997; Briggs et al., 1993). These findings have stimulated research on adult panic disorder that could carry profound implications for children. First, there is emerging evidence that non-ill individuals who face a high risk for panic disorder also exhibit increased sensitivity to carbon dioxide (Coryell, 1997; Perna et al., 1996), raising questions on carbon dioxide sensitivity in children of parents with panic disorder. Specifically, Coryell (1997) suggests that the CO2 challenge might be used to identify individuals at risk for panic disorder before they develop the disorder. Secondly, there is emerging evidence that effective therapy for panic disorder reverses an underlying defect in respiratory physiology, as both pharmacologic (Gorman et al., 1997) and psychotherapeutic (Schmidt et al., 1997) treatments reverse hypersensitivity to CO2. While there has been limited research extending these data from adult panic disorder to children, recent findings suggest that respiration also plays a role in childhood anxiety disorders, particularly separation anxiety disorder (SAD) (Pine et al., 2000, 1994). Specifically, childhood asthma, a smothering respiratory illnesses, is associated with childhood anxiety disorders, including SAD. Moreover, children with SAD exhibit enhanced sensitivity to CO2. Serotonin and behavior

Serotonin has been as visible in the recent psychiatric literature as any neurochemical. Serotonin is one of the ‘‘classic’’ monoamine neurotransmitters, having neurons which arise from brainstem nuclei to exert modulatory influences on higher structures through widely distributed ascending projections. A wealth of research in adults suggests that dysfunction in the dorsal or median raphe nuclei contributes to a variety of disorders, including behavioral, mood, and anxiety disorders. Theories regarding the role of serotonin in adult psychiatric syndromes have grown in sophistication over the past 10 years. Models positing a simple deficit or excess of serotonin have been refined, based on recent neuroscience advances. These include: (i) an increasing understanding of individual serotonin receptor functions and localization; (ii) an increasing understanding of the interplay among divergent serotonin pathways; and (iii) an increasing understanding of the interplay among serotonergic and other neurotransmitter pathways. For example, Blier et al. (1997) suggest that depression results from a deficit in the 5-HT-1A receptor, particularly as this

443


relates to reduced activity in the raphe–hippocampal ciruit. Similarly, Mann et al. (1996) emphasize the role of the 5-HT-2A receptor and the projection from the raphe to the prefrontal cortex in both mood and impulse control disorders. In this model, impulsivity reflects deficient regulation of the ventral prefrontal cortex by the ascending serotonergic pathways. In panic disorder, Grove et al. (1997) emphasize the regulatory functions of the serotonergic pathways on systems localized to the brainstem, including the noradrenergic and respiratory control systems. Similarly, for anxiety in general, Handley (1995) has emphasized the role of the serotonergic pathways in moderating the interplay among cortical, limbic, and lower brain circuits implicated in the aversive response. For example, a deficit in the projections from the raphe to the periaqueductal gray may relate to the production of panic attacks by releasing an unconditioned response governed by brainstem systems. The excitement for adult psychiatrists engendered by these advances is perhaps even superseded by the excitement for child psychiatrists. Initial work suggested parallels in the relationship between serotonin and behavior across development (Kruesi et al., 1992). However, basic science studies have led to a new appreciation for the serotonin system’s role in neural development (Whitaker-Azimitia et al., 1996). Given that alterations in serotonergic transmission effect development of monoamine systems, one would expect to see developmental variation among humans in the relationship between serotonin and behavior. Emerging evidence suggests that this may indeed be the case. For example, the relationship between aggression and activity in the serotonergic system is more complicated in children than in adults. The factors producing such developmental variations remain poorly understood, though there is evidence consistent with either genetic or environmental effects (Halperin et al., 1997; Pine et al., 1997a). Such findings hold the hope of opening new avenues for prophylaxis and for intervention.

Conclusions

There has been an explosion in our understanding of brain mechanisms influencing behavior and emotion over the past 10 years. As this research increasingly recognizes the developmentally associated plasticity of the human brain, modern advances hold the hope of dramatically affecting the practice of child psychiatry. Although recent neuroscientific advances have had a relatively indirect impact on the field over the past 10 years, we have summarized three areas of research where there promises to be more direct, clinically relevant changes in the field in the future.

444

D.S. Pine et al.

Medical evaluation of children presenting for psychiatric care The first two sections of this chapter are designed to familiarize clinicians with the range of medical or neurobiologic processes that might potentially contribute to the development of childhood psychopathology. These sections will hopefully sensitize the clinician to the potential impact of underlying biologic processes on clinical psychiatric presentation. These sections, however, provide few guidelines for the clinician in the evaluation of children and adolescents presenting with psychopathology. The current section, in contrast, is designed to provide such concrete guidelines. In light of the previously mentioned advances in research, the modern clinician is faced with an increasingly problematic dilemma. On the one hand, it is quite easy for the clinician to become eager to use the available technologies, including imaging modalities and neurophysiologic tests, in light of the excitement engendered by research using these techniques. On the other hand, faced with the ever-increasing sensitivity to cost containment, and the uncertain value of these technologies as screening or diagnostic tests, the clinician is discouraged to make use of modern technologies, from a practical standpoint. The final section of this chapter attempts to assist the clinician in confronting this dilemma by first providing general guidelines for the evaluation of children and adolescents who present with psychiatric syndromes. The section will then discuss specific instances where the tension between technology and practicality seems particularly acute. Before proceeding with these discussions, it is important to note that there are few ‘‘hard and fast’’ rules in this era of rapid change, both in science and economics. As a result, this section provides guidelines from the authors’ perspective as summarized in Table 15.2. These guidelines should move the reader to re-evaluate his or her approach to patients, but they are not intended to provide the ‘‘standard of care’’ for such children presenting with potential medical and psychiatric problems. The search for medical problems in the child with psychiatric problems

Readers are referred to Chapter 3 for a clinical approach to assessing children and adolescents. The current chapter will emphasize three points, within the broader context of treating children for psychiatric problems where issues of medical illness emerge. First, the clinician must document the medical status of all children who present for a psychiatric evaluation. Such documentation requires, at a minimum, a review of a recent physical and neurologic examination, coupled with a review of the medical and developmental history. In particular, the clinician

445


Table 15.2. Clinical guidelines General guidelines 1. All children require a recent physical and neurologic assessment including assessment of growth and development. 2. Potential medical problems should be categorized into acute and chronic problems, with particular care to identify all acute problems. 3. A differential diagnosis should be formulated as part of the psychiatric assessment and should inform medical interventions. Brain injuries 1. Clues for a neurologic component to psychiatric symptoms, atypical presentations of a disorder, or acute cognitive abnormalities. 2. Imaging studies are indicated when there is evidence of an active neurologic process. Seizure disorders 1. Seizures should be considered in children with episodic disorders. 2. Clinical features suggestive of a seizure disorder include: (a) Signs of an aura before clinical episodes (b) Changes in cognition during an episode (c) Confusion after an episode Endocrine disorders Clinical evaluation to rule out endocrine disorders is most important when there are nonpsychiatric signs of endocrine dysfunction.

should document the child’s physical growth and the child’s progress on major developmental milestones. Ideally, this history will be gathered by the examining psychiatrist and confirmed through consultation with the child’s regular pediatrician. Secondly, in considering the overall clinical picture for children in need of psychiatric intervention, it is often helpful to categorize potential medical problems in terms of their acuity. Clinical scenarios can be divided into relatively acute problems, where the psychiatrist’s treatment will be affected by further clarifications of the clinical picture medically, and relatively chronic problems, where treatment will be less affected by such clarifications. Hence, for some problems, it is inappropriate to proceed with psychiatric interventions before nonpsychiatric interventions or assessments have been implemented. For example, for children presenting with episodic peculiar behavior patterns, it is important to consider whether an underlying seizure disorder contributes to the clinical picture, as discussed further below. In this circumstance, the clinician’s immediate therapeutic approach to the child will be directly

446

D.S. Pine et al.

impacted by further evaluation designed to clarify the clinical picture, from the standpoint of medical health. For other problems, the immediate care of the patient will be relatively unaffected by further assessments from the medical perspective. Thirdly, it is important to maintain an orderly approach to patients with potential medical problems, formulating a differential diagnosis as part of the initial evaluation. While many clinicians feel an urge to obtain multiple medical tests before formulating such a differential, tests should be acquired to narrow the differential rather than to expand the list of potential contributing medical problems. Hence, the differential diagnosis should be formulated after a review of the past history from other health professionals, a review with the parent and child of current histories, and a thorough mental status examination. At this point, it is often helpful to consult with a pediatric colleague in cases where there is uncertainty related to potential underlying medical problems. Subsequent medical tests should be ordered to narrow the differential, either by confirming suspected problems or by ruling out other problems. To clarify this process, we review below four specific clinical issues that often confront the clinician during the course of a psychiatric evaluation. These examples are designed to familiarize the clinician with the thought processes that might simplify the approach to patients with the combination of psychiatric and medical problems. Focal brain lesions and psychopathology

As outlined in the first section of this chapter, children with focal brain lesions face an elevated risk for psychiatric disorders, particularly behavior disorders. Based on this well-recognized association, an assessment of perinatal history and a neurologic examination have become an integral component of the comprehensive psychiatric evaluation in children and adolescents. While it is relatively easy to uncover potential signs of perinatal adversity, such as a ‘‘forceps delivery’’ or a ‘‘low Apgar score,’’ it is far more difficult to integrate this information into the comprehensive care of children presenting with psychiatric problems. The first step in these cases should always involve a consideration of acuity. The clinician should be sure that there is no underlying evolving neurologic process. Clues to such an evolving process should be sought both in the history and the examination of the child. In the history, the clinician should be alerted by relatively abrupt changes in symptom patterns or by symptom patterns that are atypical for a given psychiatric disorder. For example, panic attacks are relatively rare before puberty, and, when they do occur, they do not involve changes in cognitive status. A clinician should therefore be suspicious when

447


evaluating a prepubertal child with panic attacks who reports lapses in memory during episodes of panic. In the physical examination, the clinician should be alerted by fluctuating abnormalities in the physical and neurologic examination, with particular attention to the cognitive component of the mental status examination, as well as signs of systemic illness. For example, the clinician might be suspicious when evaluating a child with a history of birth trauma who develops an acute change in gait. Hence, before proceeding, the clinician should be sure that all potential neurological problems have been identified and stabilized. A specific dilemma in this realm relates to the utility of neuroimaging examinations in children with new-onset disorders. Clearly, a neuroimaging examination is not a standard component of most psychiatric assessments, though some have suggested that it is particularly important in cases of new-onset psychosis. Adams et al. (1996) found neuroimaging tests to be of little value in such cases, finding no impact on clinical care in a consecutive series of 111 cases with new-onset psychosis. However, as noted by Ryan (1996), these findings must be interpreted in light of the fact that all children were without signs of physical illness. Taken as a whole, the findings suggest the value of a thorough clinical evaluation in all children with a new onset of psychiatric problems. Further neurologic tests, including brain scans, appear to be indicated only when there is reasonable suspicion of a neurologic illness. Thus, neuroimaging techniques should be considered not as screening but as diagnostic aids. The next step for the clinician is to formulate a psychiatric diagnosis while considering the potential impact of a stabilized underlying neurologic problem on the current clinical picture. Finally, when a comprehensive understanding of the clinical issues is reached, a treatment plan is developed in consultation with a child’s other physicians. In some cases, there may be a relatively indirect impact of brain injury on diagnosis and treatment. For example, in children with a history of cognitive dysfunction following birth trauma, behavior problems may present at the start of school when new demands are placed on the child. In these cases, after consultation with a child’s pediatrician, the approach to treatment may be quite similar to that in children who are free of neurologic insult. In other cases, the impact of neurologic problems on assessment and treatment may be more direct. For example, following closed head trauma, children may develop new-onset psychiatric problems directly related to an underlying neurologic insult. In these cases, the approach to treatment is likely to involve close collaboration among the psychiatrist, pediatric neurologist, and pediatrician.

448

D.S. Pine et al.

Seizure disorders

The role of seizures in childhood psychiatric disorders is also widely noted, as reviewed above. The current discussion focuses largely on assessment and differential diagnosis in children with no known history of a seizure disorder. The treatment of children with concomitant seizure and psychiatric syndromes is discussed in Kim (1991) and Steinhausen and Raus-Masson (1991). Careful elicitation of the medical history can reveal signs of underlying seizure disorders. In the past history, it is useful to probe for a history of febrile convulsions, as these are associated with some forms of later life temporal lobe epilepsy and may also predispose children to anxiety (Verity et al., 1998). In the more recent history, evidence of episodic psychiatric problems is also suggestive. Such episodes should be relatively short in duration if they are indicative of a seizure disorder. When encountering patients with episodic psychiatric disturbance, the clinician should carefully assess the events surrounding the episode. Prior to the episode, the clinician should inquire about neurologic symptoms that may represent auras. During the episode, the clinician should inquire about abrupt changes in consciousness or cognitive abilities, as well as about memory lapses coincident with such episodes. After an episode, the clinician should inquire about any signs of postictal confusion or changes in arousal. All such historical features should prompt consideration for a more extensive neurologic evaluation. A neurologic consultation is recommended for children with episodic behavior problems complicated by one of the above noted signs. This consultation should specifically address the need for extensive electroencephalography and for anticonvulsant medications. Endocrine disorders

As with seizure disorders, the co-occurrence of medical and endocrine syndromes is typically accompanied by signs of a medical illness. For example, signs of metabolic disturbance should be observable in children with adrenal or thyroid disease. Such signs can be found both in the history and the physical examination. The clinical issues surrounding the identification of endocrine illness in children with psychiatric disturbance are generally similar to those discussed above for seizure disorders. Beyond the issue of overt endocrine disorders, extensive research implicates subclinical endocrine abnormalities in a range of adult syndromes. Such abnormalities do not produce the typical clinical signs of endocrine disease but are rather thought to contribute to psychiatric illness or to reflect perturbations

449


in endocrine function which may be the result of a common CNS disturbance that also affects psychiatric functioning. Such abnormalities include the hypothalamic–pituitary–adrenal abnormalities of major depression and posttraumatic stress disorder as well as possible sex steroid abnormalities in syndromes of chronic aggression. For childhood disorders, there has been a particular interest in the role of thyroid abnormalities in psychiatric syndromes. One set of studies examines the link with attention-deficit/hyperactivity disorder (ADHD). Hauser et al. (1994) initially provided provocative evidence of a genetic link with thyroid illness by finding elevated rates of ADHD among individuals with generalized resistance to thyroid hormone, a rare genetic disorder. Subsequent research has shown that this finding is of limited relevance for most children with ADHD typically encountered in the psychiatric clinic (Stein et al., 1995). A second set of studies examines the link between thyroid abnormalities and major depression. While studies in adults find subclinical hypothyroidism in a subgroup of depressed adults, studies in children generally find limited evidence for such associations. Research in both areas had led to suggestions of the importance of thyroid screening in children with depression or ADHD. Systematic research on this issue, however, suggests that such testing is only necessary if there are physical signs of underlying disease (Leo et al., 1997). Again, this illustrates the importance of clinically differentiating the use of laboratory investigations between screening and diagnostic purposes. Respiratory illness and anxiety

Literature on the association between anxiety and pediatric respiratory illness carries implications for the assessment and treatment of anxiety disorders. From the respiratory perspective, clinicians frequently encounter a high degree of anxiety among children with asthma or similar paroxysmal respiratory illnesses. We have found that cognitively oriented treatments, following the principles of Kendall et al. (1997), provide significant benefits for such children. Conversely, it is also not unusual to encounter respiratory symptoms when evaluating children for anxiety. Such children require a thorough medical assessment to rule out potentially unrecognized pulmonary illness which can contribute to the psychiatric picture. Conclusions The field of pediatric psychopharmacology remains in its infancy and is currently grappling with relatively basic clinical questions related to the treatment of

450

D.S. Pine et al.

uncomplicated syndromes. More specialized topics, such as the role for pharmacologic treatments in comorbid medical/psychiatric syndromes, will only be rigorously considered after these more basic clinical questions have been addressed. Accordingly, there are currently no published randomized controlled trials evaluating the utility of pharmacologic treatments in children with comorbid medical/psychiatric syndromes. Given this state of affairs in pediatric psychopharmacology, this chapter has been focused on two issues: (i) the potential for neuroscientific advances to impact on future treatments and (ii) issues of diagnosis and assessment for identifying the co-occurrence of specific psychiatric and medical syndromes. Both discussions hold the hope of providing insights for future clinical trials. For example, as noted above, immunologic therapies are already being studied in children with PANDAS. In the future, given the association between headache or immunologic syndromes and major depression, interest may arise in the role of antidepressants for treating children with depression and one of these syndromes. Alternatively, given the association between respiratory disease and anxiety, interest may arise in the role of anxiolytics for treating children with anxiety and respiratory diseases such as asthma.

REFE REN C ES Adams M, Kutcher S, Antoniw E, Bird D (1996). Diagnostic utility of endocrine and neuroimaging screening tests in first-onset adolescent psychosis. J Am Acad Child Adolesc Psychiatry 35:67–73. Aylward EH, Harris GH, Hoehn-Saric R, Barta PE, Machlin SR, Pearlson GD (1996). Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging. Arch Gen Psychiatry 53:577–84. Bell IR, Jasnoski ML, Kagan J, King DS (1990). Is allergic rhinitis more frequent in young adults with extreme shyness? A preliminary survey. Psychosom Med 52:517–25. Berkson J (1946). Limitations of the application of fourfold table analysis to hospital data. Biometrics 2:47–53. Blier P, Bergeron R, de Montigny C (1997). Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response. Neuropsychopharmacology 16:333–8. Breslau N (1985). Psychiatric disorder in children with physical disabilities. J Am Acad Child Adolesc Psychiatry 24:87–94. Breslau N, Brown GG, DelDotto JE et al. (1996). Psychiatric sequelae of low birth weight at 6 years of age. J Abnorm Child Psychol 24:385–400. Briggs AC, Stretch DD, Brandon S (1993). Subtyping of panic disorder by symptom profile. Br J Psychiatry 163:201–9.

451


Brown G, Chadwick O, Shaffer D, Rutter M, Traub M (1981). A prospective study of children with head injuries: III. Psychiatric sequelae. Psychol Med 11:63–78. Caplan R, Arbelle S, Guthrie D et al. (1997). Formal thought disorder and psychopathology in pediatric primary generalized and complex partial epilepsy. J Am Acad Child Adolesc Psychiatry 36:1286–94. Caron C, Rutter M (1991). Comorbidity in child psychopathology: concepts, issues, and research strategies. J Child Psychol Psychiatry 32:1063–80. Cohen P, Cohen J (1984). The clinician’s illusion. Arch Gen Psychiatry 41:1178–82. Cohen P, Pine DS, Must A, Kasen S, Brook J (1998). Prospective associations between somatic and mental illness from childhood to adulthood. Am J Epidemiol 147:232–9. Coryell W (1997). Hypersensitivity to carbon dioxide as a disease-specific trait marker. Biol Psychiatry 41:259–63. Cummings JL (1993). Frontal-subcortical circuits and human behavior. Arch Neurol 50:873–80. Gerring JP, Brady KD, Chen A et al. (1998). Premorbid prevalence of ADHD and development of secondary ADHD after closed head injury. J Am Acad Child Adolesc Psychiatry 37:647–54. Gorman JM, Brown ST, Papp LA et al. (1997). Effect of antipanic treatment on response to carbon dioxide. Biol Psychiatry 42:982–91. Grove G, Coplan JD, Hollander E (1997). The neuroanatomy of 5-HT dysregulation and panic disorder. J Neuropsychiatry Clin Neurosci 9:198–207. Halperin JM, Newcorn JH, Kopstein I et al. (1997). Serotonin, aggression, and parental psychopathology in children with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36:1391–8. Handley S (1995). 5-hydroxytryptamine pathways in anxiety and its treatment. Pharmacacol Ther 66:103–48. Hauser P, Zametkin AJ, Martinez P et al. (1994). ADHD and the thyroid controversy. J Am Acad Child Adolesc Psychiatry 33:756–8. Horwath E, Wagner V, Wickamarente P, Pine DS, Weismann MM (1998). Panic disorder and smothering symptoms: evidence for increased risk in first degree relatives. Depress Anxiety 6:147–53. Insel TR (1992). Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 49:739–44. Kagan J, Reznick JS, Snidman N (1988). Biological bases of childhood shyness. Science 240:167–71. Kendall PC, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M (1997). Therapy for youths with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol 65:366–80. Kim WJ (1991). Psychiatric aspects of epileptic children and adolescents. J Am Acad Child Adolesc Psychiatry 30:874–86. Klein DF (1993). False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry 50:306–17. Kruesi MJ, Hibbs ED, Zahn TP et al. (1992). A 2-year prospective follow-up with disruptive behavior disorders. Prediction by cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and autonomic measures. Arch Gen Psychiatry 49:429–35.

452

D.S. Pine et al.

Leo RJ, Batterman-Fauncem JM, Pickhardts D, Cartagena M, Cohen G (1997). Utility of thyroid function screening in adolescent psychiatric inpatients. J Am Acad Child Adolesc Psychiatry 36:103–11. Lewinsohn PM, Seeley JR, Hibbard J, Rohde P, Sack WH (1996). Cross-sectional and prospective relationships between physical morbidity and depression in older adolescents. J Am Acad Child Adolesc Psychiatry 35:1120–9. Mann JJ, Malone KM, Diehl DJ, Perel J, Cooper TB, Mintun MA (1996). Demonstration in vivo of reduced serotonin responsitivity in the brain of untreated depressed patients. Am J Psychiatry 153:174–82. Max JE, Dunisch DL (1997). Traumatic brain injury in a child psychiatry outpatient clinic: a controlled study. J Am Acad Child Adolesc Psychiatry 36:404–11. Max JE, Lindgren SD, Knutson C, Pearson CS, Ihrig D, Welborn A (1997a). Child and adolescent traumatic brain injury: psychiatric findings from a pediatric outpatient specialty clinic. Brain Inj 11:699–711. Max JE, Sharma A, Qurashi MI (1997b). Traumatic brain injury in a child psychiatry inpatient population: a controlled study. J Am Acad Child Adolesc Psychiatry 36:1595–1601. Mrazek DA (1992). Psychiatric complications of pediatric asthma. Ann Allergy Asthma Immunol 69:285–90. Murphy TK, Goodman WK, Fudge MW et al. (1997). B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome. Am J Psychiatry 154:402–7. Papp LA, Klein DF, Gorman JM (1993). Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry 150:1149–57. Papp LA, Martinez JM, Klein DF et al. (1997). Respiratory psychophysiology of panic disorder: three respiratory challenges in 98 subjects. Am J Psychiatry 154:1557–65. Pauls DL, Leckman JF (1986). The inheritance of Gilles de la Tourette’s syndrome and associated behaviors. Evidence for autosomal dominant transmission. N Engl J Med 315:993–7. Perna G, Bertani A, Caldiorla D, Bellodi L (1996). Family history of panic disorder and hypersensitivity to CO2 in patients with panic disorder. Am J Psychiatry 153:1060–4. Peterson BS, Cohen DJ (1998). The treatment of Tourette’s syndrome: multimodal, developmental intervention. J Clin Psychiatry 59(Suppl 1):62–74. Pine DS, Cohen P, Brook J (1996). The association between major depression and headache: results of a longitudinal epidemiologic study in youth. J Child Adolesc Psychiatry 6:153–64. Pine DS, Coplan JD, Wasserman GA et al. (1997a). Neuroendocrine response to fenfluramine challenge in boys. Associations with aggressive behavior and adverse rearing. Arch Gen Psychiatry 54:839–46. Pine DS, Klein RG, Coplan JD et al. (2000). Differential sensitivity to CO2 in childhood anxiety disorders. Arch Gen Psychiatry 57:960–7. Pine DS, Shaffer D, Schonfeld IS, Davies M (1997b) Minor physical anomalies: modifiers of environmental risks for psychiatric impairment? J Am Acad Child Adolesc Psychiatry 36:395–403. Pine DS, Wasserman GA, Fried JE, Panides MA, Shaffer D (1997c). Neurological soft signs: one

453


year stability and relationship to psychiatric symptoms in boys. J Am Acad Child Adolesc Psychiatry 36:1579–86. Pine DS, Weese-Mayer DE, Silvestri JM, Davies JM, Whitaker AH, Klein DF (1994). Anxiety and congenital central hypoventilation syndrome. Am J Psychiatry 151:864–70. Post R, Silberstein S (1994). Shared mechanisms in affective illness, epilepsy, and migraine. Neurology 44(Suppl 7):S37–S47. Post RM, Ketter TA, Pazzaglia PJ et al. (1996). Rational polypharmacy in the bipolar affective disorders. Epilepsy Res Suppl 11:153–80. Raine A (1996). Autonomic nervous system factors underlying disinhibited, antisocial, and violent behavior. Biosocial perspectives and treatment implications. Ann NY Acad Sci 794:46– 59. Raine A, Brennan P, Mednick SA (1994). Birth complications combined with early maternal rejection at age 1 year predispose to violent crime at age 18 years. Arch Gen Psychiatry 51:984–8. Rosenberg DR, Keshavan MS, O’Hearn KM et al. (1997). Frontostriatal measurement in treatment-naı¨ve children with obsessive-compulsive disorder. Arch Gen Psychiatry 54:824–30. Rutter M, Tizard J, Whitmore K (1970). Education, Health, and Behavior. Huntington, NY: Longman Group Limited. Ryan N (1996). Diagnostic utility of endocrine and neuroimaging screening tests in first-onset adolescent psychosis. J Am Acad Child Adolesc Psychiatry 35:73. Schmidt N, Trakowski J, Staab J (1997). Extinction of panicogenic effects of a 35% CO2 challenge in patients with panic disorder. J Abnorm Child Psychol 4:630–8. Shaffer D, Schonfeld I, O’Connor PA et al. (1985). Neurological soft signs. Their relationship to psychiatric disorder and intelligence in childhood and adolescence. Arch Gen Psychiatry 42:342– 51. Stein MA, Weiss RE, Refetoff S (1995). Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder. J Dev Behav Pediatr 16:406–11. Steinhausen H-CH, Rauss-Mason C (1991). Epilepsy and anticonvulsive drugs. In Biological Risk Factors for Psychosocial Disorders, (Eds.) M Rutter, P Casaer, pp. 311–39. New York, NY: Cambridge University Press. Swedo SE, Leonard HL, Garvey M et al. (1998). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155:264–71. Swedo SE, Leonard HL, Mittleman BB et al. (1997). Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 154:110–12. Verity CM, Greenwood R, Golding J (1998). Long-term intellectual and behavioral outcomes of children with febrile convulsions. N Engl J Med 388:1723–8. Whitaker AH, Feldman JF, Van Rossem R et al. (1996). Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age. Pediatrics 98:719–29.

454

D.S. Pine et al.

Whitaker AH, Van Rossem R, Feldman JF et al. (1997). Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities. Arch Gen Psychiatry 54:847–56. Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM (1996). Serotonin as a developmental signal. Behav Brain Res 73:19–29.

Index

Aberrant Behavior Checklist (ABC) 294 Abnormal Involuntary Movements Scale (AIMS) 147, 293 academic psychopharmacology 13–14, 21 acamprosate, alcohol abuse treatment 345, 348, 350–1, 355–6 acetylcholine, and Tourette’s syndrome 390 addiction 332 neurobiologic hypothesis of 345–8 see also substance use disorder (SUD) adenylyl cyclase 49 adjustment disorder with depressed mood 162 adrenaline, and pervasive developmental disorder 277–80 adrenocorticotrophic hormone (ACTH) 53 and substance abuse 345 adverse effects 17 developmentally determined drug responses 56–9 see also specific drugs; withdrawal syndromes advertising 20–1 age-related gene expression 107 aggression 305–22 animal models 309 comorbidity 305, 307 markers of 306–8 treatment 282, 309–22 adrenergic drugs 314–16 anticonvulsant drugs 313–14 antidepressants 312–13 antipsychotic drugs 316–17 anxiolytic medications 311–12 biopsychosocial approach 320–2 lithium 309–11 PRN medications 318–19 psychostimulants 317–18 vignettes 319–20 agonist substitution therapy 351, 359–61 agoraphobia 188, 189, 190, 192 comorbidity 192 treatment 199, 213 akathisia 149, 205, 316 alcohol abuse 333–4, 339–40, 343–5, 365 biologic markers of 340 comorbidity 366 fetal alcohol syndrome 56, 60 teratogenic effects 56, 60 treatment 125, 345, 348, 350–1, 352–7 455

withdrawal syndrome 345, 352–3 see also substance use disorder (SUD) alcohol flush reaction 339 allergies 439 alprazolam abuse potential 356 anxiety disorder treatment 204, 207, 208, 209, 213 generalized anxiety disorder 213 dosage 204 panic disorder treatment 189, 199, 207 amantadine 149, 362 amenorrhea 151 amisulpride, pervasive developmental disorder treatment 277 amitriptyline 240 ADHD treatment 3 anorexia nervosa treatment 413 depression treatment 95–6 amotivational syndrome 205 amperozide, alcohol abuse treatment 344 amphetamine 3, 233, 277 abuse of 340 ADHD treatment 237 adverse effects 234 D-amphetamine 232, 233, 234, 237, 290 D,L-amphetamine 232, 233, 234, 237 pervasive developmental disorder treatment 290 and tics 389 amygdala 51 amyotrophic lateral sclerosis 41 anorexia nervosa 411–18 mechanisms 412 treatment 22, 412–18 antidepressants 413–14 antipsychotics 413 appetite enhancers 414–15 guidelines 417–18 lithium 415 prokinetic agents 415–16 zinc 416–17 antibiotic therapy 22, 399 anticipation, genetic 54–5, 111 anticonvulsants 19 adverse effects 60 aggression treatment 313–14 bulimia nervosa treatment 419 see also specific drugs

456

Index

antidepressants 6, 61 developmentally determined drug response 59 see also monoamine oxidase inhibitors (MAOIs); specific drugs; specific serotonin reuptake inhibitors (SSRIs); tricyclic antidepressants (TCAs) antimanic treatment 118–21 antiparkinsonian agents 147–8, 149–50 antisocial personality disorder (ASPD) 335, 361 anxiety disorders 187–219, 439, 441–2 assessment 214–15 behavioral variables amenable to pharmacotherapy 82 central nervous system mechanisms 194–8 classification 188–9 comorbidity 162, 192–3, 214–15 ADHD 210 aggression 307 asthma 439–40 substance abuse 356–7, 361 diagnosis 188, 190–1 mental status chart 80–1 epidemiology 189–94 treatment 87, 125, 203–19, 356–7 adults 198–203 benzodiazepines 125, 189, 195–6, 198, 207–8, 218 buspirone 200, 204, 210–11, 357 duration and tapering of 218–19 guidelines 214–19 moclobemide 211 prepharmacologic interventions 216–17 SSRIs 125, 189, 203–7, 218, 356–7 TCAs 199, 208–10, 218 venlafaxine 212 see also generalized anxiety disorder (GAD); panic disorder; separation anxiety disorder (SAD); social phobia apoptosis 40–1 appetite enhancers, anorexia nervosa treatment 414–15 Asperger’s syndrome 138, 266, 268, 270–1 central nervous system mechanisms 273, 275 diagnosis 269 treatment 280–1 see also pervasive developmental disorder (PDD) asthma 439–40, 442, 449 attention-deficit/hyperactivity disorder (ADHD) 1, 62, 230–52, 449 aggression in 305, 306, 312, 317–18 behavioral variables amenable to pharmacotherapy 82 candidate genes 55–6 comorbidity 232 anxiety disorder 210, 232 bipolar mood disorder 110, 125 conduct disorder 232 impact on pharmacotherapy 247–9 learning disorder 232 substance abuse 367

Tourette’s syndrome 383, 385, 400 diagnosis 73, 74 differential diagnosis 107 mental status chart 79 misdiagnosis 109 MRI studies 52 nicotinic hypothesis 251–2 pathophysiology 230–1 pseudoADHD 214 treatment 87, 232–52, 383 antidepressants 3, 4, 240–5 antipsychotics 245 combined pharmacotherapy 249–50 comorbidity impact 247–9 fatty acids 22–3 future directions 251–2 and growth deficits 238–9 interdose rebound 239–40 overtreatment 11 psychostimulants 1–3, 58, 232–40, 400 autistic disorder 265–6, 270 behavioral variables amenable to pharmacotherapy 82 central nervous system mechanisms 273, 275, 276, 280 diagnosis 268 differential diagnosis 138–9, 164 Kanner’s autism 265, 266 treatment 4, 5, 9, 285–6, 288–90, 316 adults 280–3 clonidine 315 naltrexone 16–17, 280, 290–1 venlafaxine 212 see also pervasive developmental disorder (PDD) avoidant disorder 188, 190, 193 treatment 207, 213 basal ganglia 438, 440 and substance abuse 341 and Tourette’s syndrome 387–8 behavior disorders 3–4, 6 behavioral inhibition 198, 439 Behavioral Summarized Evaluation 277 benign childhood epilepsy 22 benzatropine 148, 149 Benzedrine® 1 benzodiazepines 60 abuse potential 356, 365 adverse effects 208, 352 aggression treatment 311 anxiety disorder treatment 125, 195–6, 198, 200, 207–8 dosage 204 generalized anxiety disorder 189, 201, 202 tapering of 218 bipolar disorder treatment 121 panic disorder treatment 189, 199, 207, 208 schizophrenia treatment 148 substance abuse treatment 350, 352 tic suppression 397

457

Index

Berksonian bias 432 beta blockers aggression treatment 314–15 pervasive developmental disorder treatment 289–90 see also specific drugs beta-hemolytic streptococcal (GABHS) infection 168 and Tourette’s syndrome 391, 398 binge eating disorder 410, 425 binging 418 see also bulimia nervosa biofeedback 399 bipolar mood disorder (BMD) 55, 98, 106–27, 437 comorbidity 110–11, 125, 248, 364 developmental issues 107–8 diagnosis 106–7 differential diagnosis 107, 137 misdiagnosis 109–10 underdiagnosis 109–10 epidemiology 106 etiology 111–15 cognition 113–14 electrophysiology 113 family functioning 115 genetics 111 laterality 112 neuroimaging 112–13 psychosocial factors 114–15 presentation 108–9 treatment 19, 115–27 bipolar depression 121–3 with comorbid conditions 125 female-specific issues 123–4 light therapy 21 lithium 8, 364 maintenance treatment 126–7 nutritional therapy 23 psychoeducation/psychotherapy 117–18, 126–7 therapeutic relationship establishment 115–17 see also bipolar disorder; mania body dysmorphic disorder (BDD) 164 borderline personality disorder/traits 316 differential diagnosis 138 borderline syndrome of childhood 165 botulinum toxin, tic suppression 397 brain development 49–52, 59–60, 61–2 plasticity and sensitive periods 39–40 see also development; neural development brain injury 164, 438 and aggression 305 perinatal 433–6 brain reward regions 340 breast-feeding 124 Brief Psychiatric Rating Scale (BPRS) 118, 146, 156, 208 bromocriptine pervasive developmental disorder treatment 277 substance abuse treatment 343, 354, 362

bufaramine, social phobia treatment 201 bulimia nervosa 418–25 mechanisms 419 treatment 419–25 anticonvulsants 419 antidepressants 421–2 guidelines 424–5 lithium 420 opiate antagonists 420 psychotherapy 422–4 serotonergic agents 420 buprenorphine, substance abuse treatment 348, 351, 357, 362 bupropion 100, 125, 235 ADHD treatment 242, 367 adverse effects 235, 242, 421 depression treatment 96 substance abuse treatment 362, 364 buspirone 177, 201, 278 ADHD treatment 247 adverse effects 211, 247 aggression treatment 311–12 anxiety disorder treatment 200, 204, 210–11, 357 generalized anxiety disorder 201, 202, 210, 213 dosage 204 pervasive developmental disorder treatment 276, 278, 282, 286 substance abuse treatment 344, 354, 357 calcium carbimide, alcohol abuse treatment 355 cannabinoid receptor 345 cannabis use 333 carbamazepine 5–6, 286 ADHD treatment 247 adverse effects 120, 247 aggression treatment 313 bulimia nervosa treatment 419 mania treatment 120 pervasive developmental disorder treatment 289 substance abuse treatment 352–3, 362 teratogenic risks 124 carbon dioxide sensitivity 442 cerebellum, and pervasive developmental disorder 274–5 Child Behavior Checklist 72 Child Symptom Inventory 72 Childhood Autism Rating Scale (CARS) 294 Childhood Behavior Checklist (CBCL) 306–7 childhood disintegrative disorder 268, 271 Children’s Global Assessment Scale (CGAS) 294 Children’s Psychiatric Rating Scale (CPRS) 310 chlordiazepoxide 5 adverse effects 208 anxiety disorder treatment 207 substance abuse treatment 352 chlorpromazine 4, 144 adverse effects 144 anorexia nervosa treatment 413 mania treatment 118 schizophrenia treatment 147

458

Index

cholecystokinin (CCK) and anxiety 196 and substance abuse 345 choline 49–50 cigarette smoking 333 nicotine withdrawal treatment 350, 363–4 see also substance use disorder (SUD) cisapride adverse effects 416 anorexia nervosa treatment 415, 416 citalopram 96, 235, 244, 283 adverse effects 235 metabolism 99 pervasive developmental disorder treatment 286 substance abuse treatment 354 Clinical Global Impressions (CGI) scale 208, 281 clinical uncertainty 9–10 Clinician-Rated Visual Analog Scale 317 clobazam, aggression treatment 311 clocinnamox, substance abuse treatment 348 clomipramine 278, 283 adverse effects 172 anorexia nervosa treatment 413 anxiety disorder treatment 204, 209–10 dosage 204, 281 obsessive–compulsive disorder treatment 169, 172–3, 177 panic disorder treatment 199 pervasive developmental disorder treatment 276, 278, 280–1, 283–5, 293 clonazepam 235 adverse effects 208, 235 anxiety disorder treatment 204, 207, 208, 213 dosage 204 obsessive–compulsive disorder treatment 177 panic disorder treatment 189, 199, 207, 208 schizophrenia treatment 148, 149 clonidine 6, 7, 238, 277 ADHD treatment 245–6, 367 adverse effects 18, 213, 246, 283, 357–8 aggression treatment 315, 320 and anxiety 195 combined medication 18 developmentally determined response 57 dosage 204 pervasive developmental disorder treatment 283, 290 post-traumatic stress disorder treatment 193–4, 212, 214 substance abuse treatment 350, 352, 357–8, 364 tic suppression 177, 390, 394, 396 clopenthixol, mania treatment 118 clorygline, ADHD treatment 243 clozapine 52, 144, 151, 277 adverse effects 289 aggression treatment 317 pervasive developmental disorder treatment 276, 282, 288–9, 293 schizophrenia treatment 143, 152, 366 tic suppression 393

cocaine 58–9 abuse 340, 342, 346, 348, 361–3 teratogenic effects 56 withdrawal management 361–2 cognitive impairment, bipolar mood disorder 113–14 cognitive–behavioral therapy (CBT) anxiety disorder 217 bipolar mood disorder 118 bulimia nervosa 423–4 obsessive–compulsive disorder 170–1, 178 compulsions 160–1, 164 see also obsessive–compulsive disorder (OCD) conduct disorder (CD) aggression in 305, 312 behavioral variables amenable to pharmacotherapy 82 comorbidity 110, 232, 248, 364 differential diagnosis 107 confidentiality 74 Connors Abbreviated 10-Item Teacher Rating Scale 318 Connors Parent Rating Scale 72 Connors Parent Teacher Questionnaire 277 Continuous Performance Test (CPT) 317 coprolalia 384, 397 corpus callosum 51 corticosteroids 399 corticotrophin-releasing factor (CRF) 53 and anxiety 195 creatine 50 cyclothymia 107 cyproheptadine, anorexia nervosa treatment 414–15 deep white-matter hyperintensities (DWMH) 113 delirium 140 delusions 265, 266 mood disorders 137 schizophrenia 135, 141 and substance abuse 137 treatment 148 dementia 140, 313 premature 142 dependence syndrome 330–2 see also substance use disorder (SUD) depression 6, 91–102, 113, 137, 439 at-risk children/adolescents 92 behavioral variables amenable to pharmacotherapy 82 in bipolar mood disorder 108 central nervous system mechanisms 95 comorbidity anorexia nervosa 411 anxiety disorders 192–3, 202–3 pervasive developmental disorder 283 substance abuse 335 course of illness 91–2 diagnosis 92–5 differential diagnosis 153 mental status chart 80–1

459

Index

postpartum depression 124 treatment 4, 6, 87, 95–101 adults 95–7 bipolar depression 121–3 clinical guidelines 100–1 SSRIs 7, 87, 96–101 TCAs 16, 95–101 venlafaxine 212 see also major depressive disorder dermatitis, atopic 439 desipramine 234, 240 ADHD treatment 3, 240–1, 248 combined pharmacotherapy 249–50 adverse effects 17–18, 234 sudden death 241–2 bulimia nervosa treatment 423, 424 combined medication 15 depression treatment 96 pervasive developmental disorder treatment 285 substance abuse treatment 362, 364 desmethylsertraline 99 development macrodevelopment 49–52 microdevelopment 38–49 apoptosis 40–1 cellular migration and growth 41–2 coupling 49 models and concepts 38–9 neuropeptides 47–9 neurotransmitters 42–4 plasticity and sensitive periods 39–40 receptors 44–7, 61–2 stress effects 53–4 see also brain development; neural development developmental psychopharmacology 56–9 dexedrine 125 diagnosis 71 information gathering 72–83 interview with child 77–8 parental interview 76–7 see also specific disorders Diagnostic Interview for Children and Adolescents–Revised (DICA–R) 107 Diagnostic Interview Schedule for Children (DISC) 107, 307 diazepam, substance abuse treatment 352 diencephalon, and pervasive developmental disorder 275 diffusion tensor imaging (DTI) 52 diphenhydramine 4, 5, 149 dissociative disorder 138 distractibility 290 disulfiram, substance abuse treatment 351, 355 divalproex sodium (DVP) adverse effects 120 bipolar disorder treatment 122, 126 mania treatment 119, 120 teratogenic risks 124 dizocilpine 345

L-dopa 277 dopamine 44, 46 and pervasive developmental disorders 276–7 receptors 45, 46–7 and substance abuse 340, 342–3 and Tourette’s syndrome 389 dopamine transporter gene (DAT1) 55 doxepine 240, 364 drug abuse see substance use disorder (SUD) drug advertising 20–1 dysphoric mania 118 dysthymia 107, 121, 192, 366 dystonias 149, 205 eating disorders 410 binge eating disorder 410 differential diagnosis 164 see also anorexia nervosa; bulimia nervosa Ebstein’s cardiac anomaly 124 echolalia 384 effectiveness 14–15 efficacy 14–15 elective mutism 191 treatment 211 see also selective mutism electroconvulsive therapy (ECT) 21 depression 96, 123 mania 118 schizophrenia 153–4 emotional circuits, and substance abuse 341 empirical treatments 10, 11–12 encephalins, and substance abuse 344 endorphins, and substance abuse 344 enuresis 4, 16 epidermal growth factor 49 epilepsy 314, 436–7 differential diagnosis 139–40 ethanol teratogenic effects 56, 60 see also alcohol abuse ethical issues 9–10 evidence-based medicine 11–12 exposure and response prevention (E/RP) 170–1 extrapyramidal side effects 17, 57–8, 144, 150, 287–8 prophylaxis 147–8 SSRIs 205–6 Extrapyramidal Symptom Rating Scale (ESRS) 147, 293 Family Adaptability and Cohesion Evaluation Score (FACES II) 115 family issues, bipolar mood disorder 115 family therapy, obsessive–compulsive disorder 170 fascilins 42 fatty acids, ADHD treatment 22–3 fenfluramine adverse effects 286 bulimia nervosa treatment 420 pervasive developmental disorder treatment 276, 286 prolactin response, and aggression 306, 307

460

Index

fetal alcohol syndrome 56, 60 fibroblast growth factor (FGF) 48 flumazenil, substance abuse treatment 353 fluoxetine 57, 96, 244, 283 ADHD treatment 235, 244 combined pharmacotherapy 250 adverse effects 99, 205, 235 aggression treatment 312–13, 320 anorexia nervosa treatment 413–14 anxiety disorder treatment 204, 213 bulimia nervosa treatment 421, 423, 424, 425 depression treatment 53, 59, 98, 101, 122 major depression 7, 351, 356, 364 dosage 176, 204, 207 metabolism 99, 174, 206 obsessive–compulsive disorder treatment 172, 173–4 panic disorder treatment 199, 207 pervasive developmental disorder treatment 276, 278, 281–2, 285–6 post-traumatic stress disorder treatment 202 selective mutism treatment 213 social phobia treatment 201 substance abuse treatment 351, 354, 356, 362, 364 withdrawal syndrome 175 flupenthixol, borderline personality disorder treatment 316 fluphenazine, tic suppression 393, 395 flutamide, tic suppression 397–8 fluvoxamine 96, 235, 244, 278, 283 adverse effects 235 aggression treatment 313 anxiety disorder treatment 204, 214 bulimia nervosa treatment 422 dosage 204, 207 metabolism 99, 174, 175 obsessive–compulsive disorder treatment 172, 173, 174 panic disorder treatment 199, 207 pervasive developmental disorder treatment 276, 278, 281, 286 social phobia treatment 201 substance abuse treatment 354 withdrawal syndrome 206 focal brain lesions 446–7 fragile X syndrome 55 G proteins 49 GABA (gamma-aminobutyric acid) 47–8 and anxiety 195–6 receptor 48 and substance abuse 344–5, 355–6 and Tourette’s syndrome 390–1 gabapentin 314 GABHS (beta-hemolytic streptococcal infection) 168 galactorrhea 151 gamma hydroxybutyric acid, alcohol abuse treatment 345, 356

gene therapy 22 generalized anxiety disorder (GAD) 187, 188–9, 192 comorbidity 125, 192, 202, 203, 214 diagnosis 190 epidemiology 189 treatment 200, 213–14, 217, 218 adults 201–2 buspirone 210 SSRIs 203–5 TCAs 210 venlafaxine 212 see also anxiety disorders genetic anticipation 54–5, 111 globus pallidus 51, 52 glucocorticoids 53, 54 glutamate 47–8, 50 and substance abuse 344–5 and Tourette’s syndrome 390 growth deficits, and ADHD treatment 238–9 guanabenz, substance abuse treatment 358 guanfacine 235 ADHD treatment 246 adverse effects 235 aggression treatment 315–16 substance abuse treatment 358 tic suppression 177, 390, 394, 396–7 gynecomastia 151 habit reversal training (HRT) 399 hallucinations 265, 266 epilepsy 139 mood disorders 137 bipolar mood disorder 108 post-traumatic stress disorder 138 schizophrenia 135, 141 and substance abuse 137 treatment 148 haloperidol 60–1, 144, 277 adverse effects 287–8, 316, 394–5 aggression treatment 316–17 obsessive–compulsive disorder treatment 177 pervasive developmental disorder treatment 287, 293 schizophrenia treatment 148 tic suppression 382, 393, 394–5 Hamilton Anxiety Scale 208, 215 head injury 438, 447 see also brain injury headache 437 heart period variability (HPV) 307 hippocampal neurogenesis, stress effects 54 history taking 72–83 baseline assessment for treatment 78–83 interview with child 77–8 parental interview 76–7 homovanillic acid (HVA), and pervasive developmental disorder 276–7 Hopkins Motor and Vocal Tic Scale 392 5-HT see serotonin Huntington’s chorea 55, 166

461

Index

hyperprolactinemia 151 hypochondriasis 164 hypothyroidism 449 imipramine 5, 6, 234, 240 ADHD treatment 3 adverse effects 201, 234 anxiety disorder treatment 204, 209–10, 213, 356 generalized anxiety disorder 201–2, 210 bulimia nervosa treatment 422–3 depression treatment 95–6, 97, 98, 356, 361 dosage 204 panic disorder treatment 188, 199 pervasive developmental disorder treatment 290 platelet binding, and aggression 307 substance abuse treatment 356, 361 innovative treatments 21–3 insomnia see sleep disturbance insulin-like growth factor 49 intellectual disability, psychosis in 136 intermittent explosive disorder 312, 321 interpersonal therapy (IPT), bipolar mood disorder 117–18 Interview for Childhood Disorders and Schizophrenia (ICDS) 141 intracerebral metabolic rates for glucose utilization (ICMRGlc) 50 intravenous immunoglobulin therapy 22, 399 involuntary treatment 146 Kanner’s autism 265, 266 Kennard effect 39 kindling 91, 437 Kleine–Levin syndrome 309 lamotrigine adverse effects 17 and aggression 314 bipolar disorder treatment 121, 122, 125 language disorders 74 laterality, and bipolar mood disorder 112 learning disorders 74 comorbidity 232, 386 social learning disorders 236 length of treatment 87–8 levoalpha acetylmethadol (LAAM), substance abuse treatment 351, 360–1 light therapy, bipolar disorder 21, 122–3 limbic–hypothalamic–pituitary–adrenal (LHPA) axis, stress effects 53 limbic system and pervasive developmental disorder 275 and substance abuse 341 lithium 60, 85 adverse effects 119–20, 310–11 aggression treatment 309–11, 321 anorexia nervosa treatment 415 bipolar disorder treatment 126, 364 and breast-feeding 124 bulimia nervosa treatment 420

depression treatment 96, 99, 122 history of use 5, 6, 7, 8 mania treatment 119 pervasive developmental disorder treatment 289 substance abuse treatment 125, 354, 364 locus coeruleus and anxiety 194, 195 and substance abuse 342, 346 lofexidine, substance abuse treatment 350, 352, 358 long night treatment 121 long Q-T syndrome 18 lorazepam abuse potential 356 mania treatment 118 schizophrenia treatment 148 loxapine 144 schizophrenia treatment 148 lysergic acid diethylamide (LSD) 5 lysosymal storage disease 140 magnesium pemoline see pemoline major depressive disorder 6, 7, 8, 438 and anorexia nervosa 413 comorbidity ADHD 250 anxiety disorders 192–3 obsessive–compulsive disorder 162 substance abuse 351, 356, 361, 364–5, 366 treatment 86, 351, 356, 364 see also depression mania 100, 106, 112 behavioral variables amenable to pharmacotherapy 82 in bipolar mood disorder 108 comorbidity 248–9 mental status chart 80–1 and SSRIs 205 treatment 87, 118–21 see also bipolar mood disorder (BMD) Mania Rating Scale 107 marijuana use 333 mazindol 363 median raphe, and substance abuse 342 medical evaluation 444–9 endocrine disorders 448–9 focal brain lesions 446–7 respiratory illness 449 seizure disorders 448 medication advertising 20–1 medication selection 84–7 Medication-Specific Side Effect Scale (MSSES) 147, 156 mental retardation aggression in 305, 312, 314 and autism 270, 282 behavioral variables amenable to pharmacotherapy 82 differential diagnosis 164 mental status chart 79–81 meprobamate 4

462

Index

metaclopramide adverse effects 416 anorexia nervosa treatment 415 methadone 344, 350, 351, 357, 359–60, 361 methylphenidate 125, 232, 233, 234 abuse of 58–9 ADHD treatment 237, 249–50 adverse effects 18, 58–9, 234 aggression treatment 317–18 combined medication 15, 18, 249–50 pervasive developmental disorder treatment 290 and tics 389 methysergide 279 pervasive developmental disorder treatment 276, 279 metoprolol, aggression treatment 315 mirtazapine, depression treatment 97 mitochondrial DNA damage 107 mixed states 118 MK-801, alcohol withdrawal treatment 345 moclobemide 243 adverse effects 211 anxiety disorder treatment 204, 211 dosage 204 post-traumatic stress disorder treatment 202 social phobia treatment 201, 213 Modified Mania Rating Scale (MMRS) 118 money-oriented medicine 11–12 monoamine oxidase inhibitors (MAOIs) 4, 95, 234 ADHD treatment 243–4 adverse effects 234, 243–4 anxiety disorder treatment 199, 200 depression treatment 95, 96, 98–9 drug interactions 210, 243–4 post-traumatic stress disorder treatment 202 social phobia treatment 201 mood disorders 6 aggression in 305 comorbidity 192, 232 differential diagnosis 137 see also bipolar mood disorder (BMD) mood stabilizers 19, 122 mania treatment 119 postpartum depression prevention 124 teratogenic risks 123–4 morphine abuse 346, 348 MPP (1-methyl-phenyl-pyridium) 41 Multidimensional Anxiety Scale for Children (MASC) 215 multiplex developmental disorder 165 N-acetyl aspartate (NAA) 49–50 nadolol 277 ADHD treatment 246–7 aggression treatment 314–15 pervasive developmental disorder treatment 282 NAIP (neuronal apoptosis inhibitory protein) 41 nalmefene, substance abuse treatment 353–4 naloxone, alcohol abuse treatment 344 naltrexone

autistic disorder treatment 16–17, 280, 283, 290–1 substance abuse treatment 344, 350, 353, 358–9, 364 nefazodone 282 adverse effects 17 depression treatment 96 metabolism 99 neural development 38–9, 61–2 apoptosis 40–1 cellular migration and growth 41–2 hippocampal neurogenesis, stress effects 54 neuropeptide role 47–9 see also development neuroglian 42 neuroleptic malignant syndrome 58, 150, 176 neuroleptics 5, 21, 61, 143–4 adverse effects 17, 58, 144–5, 149–51, 156, 287–8 anticholinergic side effects 150–1 dystonias 149 neuroleptic malignant syndrome 58, 150 parkinsonian side effects 58, 61, 149–50 atypical neuroleptics 17, 61, 143–5, 151–3, 288 introduction of 9, 19 pervasive developmental disorder treatment 287–9 schizophrenia treatment 147–8, 151–3 depot injections 154–5 see also specific drugs neuropeptides 47–9 neuropeptide Y, and anxiety 196 and pervasive developmental disorder 280 neurotensin 48 neurotransmitters development 42–4 and pervasive developmental disorders 276–80 and substance abuse 342–5 see also specific neurotransmitters nicotine withdrawal treatment 350, 363–4 nicotinic drugs, ADHD treatment 251–2 N-methyl-D-aspartate (NMDA) receptors 39, 48, 54 and alcohol abuse 345 noradrenaline and pervasive developmental disorder 277–80 and substance abuse 343 and Tourette’s syndrome 389–90 norfluoxetine metabolism 99 nortriptyline 234, 240 ADHD treatment 240, 241 adverse effects 234 depression treatment 96 nutrition-based medicine 22–3 obsessions 160–1, 164 obsessive difficult temperament 165 obsessive–compulsive disorder (OCD) 159–79, 192, 438, 440–1 age effects 162 comorbidity 125, 162–3, 167–8, 283–5 tics 161, 162–3, 167, 383, 385–6, 401 course of illness 161–2

463

Index

diagnosis 163–5, 190 differential diagnosis 139, 164 mental status chart 79 drug-induced 17 epidemiology 159–60 etiology 165–9 genetic basis 168 serotonin hypothesis 166–7 gender effects 162 symptoms 160–1 treatment 22, 169–78, 401 augmentation strategies 177 behavioral treatment 170–1, 178 clomipramine 172–3, 177 dosage 176 duration of 176–7 family therapy 170 psychodynamic psychotherapy 170 selection of 178 SSRIs 173–6, 203, 205 obsessive–compulsive personality disorder (OCPD) 165 olanzapine 144, 277, 279 adverse effects 119 aggression treatment 317 mania treatment 119 pervasive developmental disorder treatment 279, 282 schizophrenia treatment 152, 366 oppositional defiant disorder (ODD) aggression in 305 mental status chart 79 Over Aggression Scale 314 overanxious disorder (OAD) 188, 190 epidemiology 189 treatment 207, 208, 213 see also anxiety disorders overfocusing 237 overtreatment 11 oxytocin 48, 280 palilalia 384 PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) 168–9, 438, 440–1 panic disorder 187, 188–9, 192, 441–2, 443 central nervous system mechanisms 194–5, 446–7 comorbidity 125, 192, 203 diagnosis 190 epidemiology 189–92 treatment 200, 205, 207, 208, 213, 217 adults 199–201, 203 panic-like hyperventilation syndrome 212 pargyline, ADHD treatment 243 Parkinson’s disease 41, 166 paroxetine 53, 96, 244, 283 ADHD treatment 235 adverse effects 205, 235 depression treatment 98, 101, 122

dosage 204, 207 generalized anxiety treatment 201–2, 214 metabolism 99, 174, 175, 206 obsessive–compulsive disorder treatment 52, 173, 174 panic disorder treatment 199–201, 207 pervasive developmental disorder treatment 278, 286 social phobia treatment 201 withdrawal syndrome 175, 206 pemoline 232, 233, 234 ADHD treatment 237 adverse effects 234, 238 and tics 389 pentagastrin, and anxiety 196 pergolide, tic suppression 398 periventricular hyperintensities (PVH) 113 perphenazine 4 schizophrenia treatment 148 personality disorders antisocial personality disorder 335, 361 borderline personality disorder/traits 138, 316 comorbidity 111 obsessive–compulsive personality disorder 165 schizotypal personality disorder 134, 138–9 treatment 312 pervasive developmental disorder (PDD) 134, 265–95 aggression in 305 assessment 291–3 behavioral variables amenable to pharmacotherapy 82 central nervous system mechanisms 271–80 neuroanatomic changes 274–5 neurocognitive deficits 273 neurotransmitter changes 276–80 theoretical concepts 272–3 comorbidity 283 diagnosis 267–9 differential diagnosis 138–9, 164 mental status chart 80–1 negative symptoms 266, 267 positive symptoms 266, 267 treatment 280–95, 316 adults 280–3 baseline evaluations 293–4 choice of 293 inadequate clinical response 294 initiation of 294 long-term treatment 294–5 monitoring of 294 neuroleptics 287–9 opioid antagonists 290–1 serotonin transport inhibitors 280–2, 283–6 stimulants 290 sympatholytic agents 289–90 thymoleptics 289 see also autistic disorder pharmaceutical advertising 20–1

464

Index

phenelzine 234, 243 adverse effects 234 elective mutism treatment 211 panic disorder treatment 199 social phobia treatment 201 phenobarbital 3 adverse effects 60 phenytoin 4 bulimia nervosa treatment 419 phobic disorders 4 comorbidity 162 diagnosis 190 epidemiology 189, 193 treatment 214 see also agoraphobia; school phobia; social phobia phosphocreatine 50 phospholipase C 49 pimozide 277 anorexia nervosa treatment 413 pervasive developmental disorder treatment 287 tic suppression 177, 393, 395 pindolol 177 ADHD treatment 246 adverse effects 246 depression treatment 96–7 plasmapheresis 22, 399 plasticity, developmental 39–40 platelet-derived growth factor 49 polycystic ovary disease 17, 120, 123 polypharmacy 15–16 Positive and Negative Symptom Scale for Schizophrenia (PANSS) 146, 266 postpartum depression 124 post-traumatic stress disorder 193–4 aggression in 305, 320 comorbidity 202–3 diagnosis 190 differential diagnosis 138 prevalence 194 treatment 200, 212, 214 adults 202–3 Prader–Willi syndrome 281 prefrontal cortex, and pervasive developmental disorder 274 pregnancy, and bipolar mood disorder 123–4 PRN (pro re nata) medications 318–19 procyclidine 148, 149 propranolol 6, 149, 235, 277 ADHD treatment 246 adverse effects 235 anxiety disorder treatment 204, 212 dosage 204 pervasive developmental disorder treatment 282, 289–90 post-traumatic stress disorder treatment 214 substance abuse treatment 352 protein phosphorylation, and substance abuse 346–7 protriptyline 240

psychoeducation anxiety disorder 216 bipolar mood disorder 117, 126–7 tic disorders 392–3, 399–400 psychosis aggression in 305 behavioral variables amenable to pharmacotherapy 82 in intellectually disabled children/adolescents 136 psychostimulants 4, 6–7 abuse of 239 ADHD treatment 1–3, 58, 232–40 combined pharmacotherapy 250 adverse effects 17, 237–8 growth deficits 238–9 tic disorders 239, 400 aggression treatment 317–18 pervasive developmental disorder treatment 290 psychotherapy bipolar mood disorder 117–18, 126–7 bulimia nervosa 422–4 obsessive–compulsive disorder 170 quantitative trait loci (QTL) genetic mapping 339 rapid cycling 118, 121 rash 17 reboxetine 53 receptors blockade 143–5 development 44–7, 61–2 referral bias 432 relaxation training 399 remaron, depression treatment 101 research, academic 13–14, 21 reserpine 4, 41 induction of depression 95 respiratory illness 439–40, 441–2, 449 asthma 439–40, 442 restless leg syndrome 398 Restricted Academic Playroom observation 73 Rett’s syndrome 22, 268, 271 Revised Children’s Manifest Anxiety Scale (RCMAS) 215 reward pathways, and substance abuse 340–1 rhythm stability hypothesis 117 risperidone 144, 277, 278, 286 adverse effects 119, 288 aggression treatment 317 mania treatment 119 obsessive–compulsive disorder treatment 177 pervasive developmental disorder treatment 276, 278, 288, 293 schizophrenia treatment 152 tic suppression 393 ritanserin 282 alcohol abuse treatment 344, 354

465

Index

Scale for the Assessment of Negative Symptoms (SANS) 266 Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS) 93–5, 107, 118, 141 schizoaffective disorder 137 schizoid personality 165 schizophrenia 55, 61, 134–57 behavioral variables amenable to pharmacotherapy 82 characteristics 135–6 comorbidity 366 diagnosis 134, 135, 140–1 differential diagnosis 107, 113, 136–40, 265–6 mental status chart 79 misdiagnosis 109–10 early-onset schizophrenia (EOS) 135–6 etiologic theories 142–3 genetics 143 neurodegenerative theories 142 neurodevelopmental theories 142 negative symptoms 135, 153, 266, 267 positive symptoms 135, 266, 267 treatment 52, 85, 146–56 acute or initial presentation 146–8, 153–4 adults 143–5 atypical neuroleptics 151–3 electroconvulsive therapy 153–4 intermediate and long-term management 154–6 involuntary treatment 146 relapses 155–6 very early-onset schizophrenia (VEOS) 135–6 schizotypal personality disorder 134 differential diagnosis 138–9 school phobia/refusal 5, 189, 215 treatment 207, 209, 211, 213 seasonal affective disorder, light therapy 21 second messenger systems 49 and Tourette’s syndrome 391 seizures 140, 152, 448 selective mutism 188, 191, 193 treatment 203, 213 selective serotonin reuptake inhibitors see specific serotonin reuptake inhibitors selegiline 234 ADHD treatment 243 adverse effects 234 self-harm 118, 311–12 treatment 282–3, 312–13, 314 see also suicide Self-Injurious Behavior Questionnaire 317 sensitisation 332 sensitive periods, developmental 39–40 separation anxiety disorder (SAD) 6, 192, 198, 442 diagnosis 190 mental status chart 80–1 epidemiology 189 treatment 5, 7, 208, 209, 213 seroquel 144, 282

serotonin 43–4, 442–3 and aggression 307, 308 and anxiety 195 and bulimia nervosa 420 and pervasive developmental disorder 276 receptors 45–6 and social phobia 201 and substance abuse 343–4 and Tourette’s syndrome 390 serotonin reuptake inhibitors (SRIs) obsessive–compulsive disorder treatment 166–7, 172 augmentation strategies 177 withdrawal syndrome 174–5 see also specific serotonin reuptake inhibitors (SSRIs) serotonin syndrome 175–6, 206, 210, 211, 313 sertindole 282 sertraline 96, 235, 244, 278, 283 ADHD treatment 250 adverse effects 205, 235 dosage 176, 207 metabolism 99, 174 obsessive–compulsive disorder treatment 172, 173, 174 panic disorder treatment 199, 207 pervasive developmental disorder treatment 276, 278, 281, 285, 286 social phobia treatment 201 sexual dysfunction neuroleptic side effects 151 SSRI adverse effects 100 side effects see adverse effects sleep disturbance 121 treatment 209–10, 214 smoking see cigarette smoking; substance use disorder (SUD) social learning disorders 236 social phobia 187, 188 comorbidity 125, 192 diagnosis 190 mental status chart 80–1 epidemiology 193 treatment 200, 201, 218 social rhythm therapy, bipolar mood disorder 117 specific serotonin reuptake inhibitors (SSRIs) 61, 87, 235 ADHD treatment 244 combined pharmacotherapy 250 adverse effects 99–100, 174, 205–6, 207, 235 aggression treatment 312–13, 321 anorexia nervosa treatment 413–14, 417 anxiety disorder treatment 125, 200, 203–7, 218, 356–7 generalized anxiety disorder 189, 201–2, 203–5, 214 bulimia nervosa treatment 421, 425 depression treatment 98, 99–100, 101, 122 adults 96–7 developmentally determined drug response 59

466

Index

specific serotonin reuptake inhibitors (cont.) drug interactions 175, 206, 244 history of use 7, 8–9, 16, 19 metabolism 175, 206 obsessive–compulsive disorder treatment 172–6, 203, 205 augmentation strategies 177 panic disorder treatment 189, 199, 203, 205, 213 pervasive developmental disorder treatment 281 post-traumatic stress disorder treatment 202, 214 selective mutism 203 social phobia treatment 201 SSRI-induced frontal release 16, 17 withdrawal syndrome 99–100, 174–5, 206 see also specific drugs State-Trait Anxiety Inventory 215 Steven–Johnson syndrome 17, 122 stimulants see psychostimulants streptococcal infections 168–9, 438, 440–1 and Tourette’s syndrome 391, 398 stress, developmental effects 53–4 substance abuse 329–30 see also substance use disorder (SUD) substance dependence 330–2 substance P 48 substance use disorder (SUD) 141, 215, 328–68 comorbidity 125, 153, 334–7 in adults 335 explanatory models 336–7 implications for research and clinical practice 336 treatment 351, 356–7, 361, 364–5, 366–7 differential diagnosis 108, 137–8 epidemiology 333–4 etiology 337 genetic factors 339–40, 348 neurobiology 337–49 brain circuits involved in 340–2 neurotransmitters/neuropeptides 342–5 risk factors 338 tolerance 332 treatment 125, 349–67 acute intoxication 350 agonist substitution therapy 351, 359–61 alcohol withdrawal 352–7 cocaine withdrawal 361–3 comorbid disorders 351, 356–7, 361, 364–5, 366–7 decreasing reinforcing effects 350–1, 353–4, 358–9, 362 nicotine withdrawal 363–4 opiates withdrawal 357–61 pharmacologic deterrents 351, 355 withdrawal states 350, 352–3, 357–8, 361–2, 363–4 sudden death 17–18, 241–2 suicide 92, 99, 215, 328 sulpiride anorexia nervosa treatment 413

tic suppression 393, 396 Sydenham’s chorea 168, 391, 398, 438, 441 talipexole, tic suppression 398 tardive dyskinesia 151, 152, 205–6, 287–8, 395 temperament research 197 temporal lobe, and pervasive developmental disorder 274 testosterone, and aggression 307 tetrabenzine, tic suppression 389, 393 tetrahydrocannabinol, anorexia nervosa treatment 415 thalamus, and pervasive developmental disorder 275 thioridazine 144 thrombocytopenia 120 thyroid hormone 49 depression treatment 96 thyrotrophin-releasing hormone (TRH) 345 tiapride alcohol abuse treatment 343, 357 tic suppression 393, 396 tics 87, 174, 318, 384 assessment strategies 392 complex motor tics 384 complex vocal tics 384 differential diagnosis 164 with obsessive–compulsive disorder 161, 162–3, 167 psychostimulant effects 239 simple motor tics 384 simple vocal tics 384 treatment 177, 316, 392–401 alpha-adrenergic agonists 396–7 dopamine antagonists 394–6 nonpharmacologic treatment 399 see also Tourette’s syndrome (TS) tobacco smoking see cigarette smoking; substance use disorder (SUD) tolerance 332 tomoxetine, ADHD treatment 251 Tourette’s syndrome (TS) 62, 382–402 central nervous system mechanisms 387–91 neuroanatomic location 387–8 neurotransmitters 388–91 streptococcal infection 391, 398 comorbidity 162–3, 167–8, 383, 384–6 ADHD 385, 400 learning disorders 386 obsessive–compulsive symptoms 385–6, 401 treatment 400–1 diagnosis 384 genetic basis 383 treatment 5, 6, 7, 9, 22, 382–4 comorbid conditions 400–1 psychosocial treatment 399–400 see also tics Tourette’s Syndrome Severity scale (TSSS) 392 training programs 12–13

467

Index

transcranial magnetic stimulation 22 transcription factors, and substance abuse 347–8 transforming growth factor 49 tranylcypromine 234, 243 ADHD treatment 243 adverse effects 234 trazodone anxiety treatment 356 depression treatment 96 pervasive developmental disorder treatment 282 substance abuse treatment 362 treatment duration 87–8 trichotillomania 164 tricyclic antidepressants (TCAs) 61, 95, 234 ADHD treatment 3, 240–2, 249 combined pharmacotherapy 249–50 and manic symptoms 249 adverse effects 17, 99, 209, 234, 240 anorexia nervosa treatment 413 anxiety disorder treatment 199, 200, 208–10, 218 depression treatment 16, 97–100, 356 adults 95–6 developmentally determined drug response 59 drug interactions 210, 244 history of use 4, 7, 19 post-traumatic stress disorder treatment 202 substance abuse treatment 356, 362 withdrawal effects 210 see also specific drugs trifluperazine, pervasive developmental disorder treatment 287 trimipramine 240 triplet repeat expansion disorders 54–5, 107, 111

pervasive developmental disorder treatment 289 and polycystic ovary disease 17, 123 venlafaxine 235 ADHD treatment 245 adverse effects 212, 235 anxiety disorder treatment 200, 204, 212 generalized anxiety disorder 202, 212, 214 depression treatment 97, 98, 101 dosage 204 social phobia treatment 201 ventricular enlargement 112, 113 vigabatrin 314 Vineland Scale 317 viqualine, substance abuse treatment 354 Visual Analog Scale (VAS) 294

valproate 314 bipolar disorder maintenance treatment 126

zinc, anorexia nervosa treatment 416–17 ziprasidone 282

Ward scale of impulsivity 316 weight gain, and neuroleptics 151 Wide Range Achievement Test (WRAT) 114 Wisconsin Card Sorting Test (WISC) 114, 273 withdrawal syndromes 332, 343 treatment 350 alcohol 352–3 cocaine 361–2 opiates 357–8 see also specific drugs; substance use disorder (SUD) Wolfram syndrome 22 Yale–Brown Obsessive–Compulsive Scale (Y–BOCS) 165, 317 Yale Global Tic Severity Scale (TGTSS) 392

Practical Child and Adolescent Psychopharmacology

Child and Adolescent Clinical Psychopharmacology

Child and Adolescent Clinical Psychopharmacology

Clinical Manual of Child and Adolescent Psychopharmacology

Child and Adolescent Psychiatry: A Practical Guide

Child and Adolescent Psychiatry

Child and Adolescent Psychopathology

Lewis's Child and Adolescent Psychiatry

The depressed child and adolescent

Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (Essential Psychopharmacology Series)

Essential Psychopharmacology. Neuroscientific Basis and Practical Applns

Treating Child and Adolescent Aggression Through Bibliotherapy

Technique in Child and Adolescent Analysis

Handbook of Child and Adolescent Psychopathy

Child and Adolescent Psychopathology, 2nd edition

Child and Adolescent Development for Educators

Handbook of Child and Adolescent Psychotherapy

Handbook of Child and Adolescent Anxiety Disorders

Child and Adolescent Development: An Advanced Course

Child and Adolescent Psychiatry: The Essentials

Child and Adolescent Development: An Advanced Course

Child and Adolescent Therapy Cognitive. Behavioral Procedures

International Perspectives on Child & Adolescent Mental Health (International Perspectives on Child and Adolescent Mental Health)

Pediatric and Adolescent Psychopharmacology: A Practical Manual for Pediatricians (Cambridge Clinical Guides)

Psychopharmacology and Child Psychiatry Review: With 1200 Board-Style Questions

Complementary and Alternative Medicine for Child and Adolescent Care: A Practical Guide for Healthcare Professionals

Child and Adolescent Obesity: Causes and Consequences, Prevention and Management

Clinical Assessment of Child and Adolescent Personality and Behavior

Suicide in Children and Adolescents (Cambridge Child and Adolescent Psychiatry)

Child and Adolescent Mental Health Policies and Plans

Practical Child and Adolescent Psychopharmacology

Child and Adolescent Clinical Psychopharmacology

Child and Adolescent Clinical Psychopharmacology

Clinical Manual of Child and Adolescent Psychopharmacology

Child and Adolescent Psychiatry: A Practical Guide

Child and Adolescent Psychiatry

Child and Adolescent Psychopathology

Lewis's Child and Adolescent Psychiatry

The depressed child and adolescent

Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (Essential Psychopharmacology Series)

Essential Psychopharmacology. Neuroscientific Basis and Practical Applns

Treating Child and Adolescent Aggression Through Bibliotherapy

Technique in Child and Adolescent Analysis

Handbook of Child and Adolescent Psychopathy

Child and Adolescent Psychopathology, 2nd edition

Child and Adolescent Development for Educators

Handbook of Child and Adolescent Psychotherapy

Handbook of Child and Adolescent Anxiety Disorders

Child and Adolescent Development: An Advanced Course

Child and Adolescent Psychiatry: The Essentials

Child and Adolescent Development: An Advanced Course

Child and Adolescent Therapy Cognitive. Behavioral Procedures

International Perspectives on Child & Adolescent Mental Health (International Perspectives on Child and Adolescent Mental Health)

Pediatric and Adolescent Psychopharmacology: A Practical Manual for Pediatricians (Cambridge Clinical Guides)

Psychopharmacology and Child Psychiatry Review: With 1200 Board-Style Questions

Complementary and Alternative Medicine for Child and Adolescent Care: A Practical Guide for Healthcare Professionals

Child and Adolescent Obesity: Causes and Consequences, Prevention and Management

Clinical Assessment of Child and Adolescent Personality and Behavior

Suicide in Children and Adolescents (Cambridge Child and Adolescent Psychiatry)

Child and Adolescent Mental Health Policies and Plans

Recommend Documents