Psychoneuroendocrinology: The Scientific Basis of Clinical Practice

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PSYCHONEUROENDOCRINOLOGY The Scientific Basis of Clinical Practice

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PSYCHONEUROENDOCRINOLOGY The Scientific Basis of Clinical Practice Edited by

Owen M. Wolkowitz, M.D. Anthony J. Rothschild, M.D.

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U. S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. Copyright © 2003 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 07 06 05 04 6 5 4 3 2 First Edition Typeset in Adobe’s Berling Roman and Galahad Regular American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Psychoneuroendocrinology : the scientific basis of clinical practice / edited by Owen M. Wolkowitz, Anthony J. Rothschild. p. cm. Includes bibliographical references and index. ISBN 0-88048-857-3 (alk. paper) 1. Psychoneuroendocrinology. 2. Mental illness—Endocrine aspects. I. Wolkowitz, Owen M., 1952– II. Rothschild, Anthony J. QP356.45 .P795 2003 616.89—dc21 2002028228 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

To Janet, Gavin, and Mikaela and to the memory of my parents O.M.W.

To Judy, Rachel, and Amanda; to my mother and the memory of my father A.J.R.

This book is also dedicated to our dear colleague and contributor to this volume, Dr. Martin Szuba, who passed away. Marty was a generous and gentle colleague, a thoughtful and compassionate man, and a psychiatrist who worked hard for his patients and taught his students well.


Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi

Part I

Introduction Chapter 1 Introduction and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Owen M. Wolkowitz, M.D., and Anthony J. Rothschild, M.D.

Chapter 2 Historical Roots of Psychoneuroendocrinology . . . . . . . . . . . . . . . . . . 9

Steven E. Lindley, M.D., Ph.D., and Alan F. Schatzberg, M.D.

Part II

Peptide Hormones Chapter 3 Neuropeptides and Hypothalamic Releasing Factors in Psychiatric Illness . . . . . . . . . . . . . . . . . . . . . . . 29

Dominique L. Musselman, M.D., M.S., and Charles B. Nemeroff, M.D., Ph.D.

Chapter 4 Chronobiology and Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Robert L. Sack, M.D., Alfred J. Lewy, M.D., Ph.D., Magda Rittenbaum, M.D., and Rod J. Hughes, Ph.D.

Chapter 5 Prolactin, Growth Hormone, Insulin, Glucagon, and Parathyroid Hormone: Psychobiological and Clinical Implications . . . . . . . . . . . 107

Mady Hornig, M.D., and Jay D. Amsterdam, M.D.

Part III

Adrenocortical Hormones Chapter 6 The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness . . 139

Anthony J. Rothschild, M.D.

Chapter 7 Psychiatric Manifestations of Hyperadrenocorticism and Hypoadrenocorticism (Cushing’s and Addison’s Diseases). . . . . . . 165

Monica N. Starkman, M.D., M.S.

Chapter 8 Psychiatric Effects of Glucocorticoid Hormone Medications . . . . . . 189

Victor I. Reus, M.D., and Owen M. Wolkowitz, M.D.

Chapter 9 Dehydroepiandrosterone in Psychoneuroendocrinology . . . . . . . . . 205

Owen M. Wolkowitz, M.D., and Victor I. Reus, M.D.

Part IV

Gonadal Hormones Chapter 10 Menstrual Cycle–Related and PerimenopauseRelated Affective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

David R. Rubinow, M.D., and Peter J. Schmidt, M.D.

Chapter 11 Endogenous Gonadal Hormones in Postpartum Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Lisa S. Weinstock, M.D., and Lee S. Cohen, M.D.

Chapter 12 Clinical Psychotropic Effects of Gonadal Hormone Medications in Women . . . . . . . . . . . . . . . . . . . . . . . . . . 303

Uriel Halbreich, M.D., Steven J. Wamback, B.S., and Linda S. Kahn, Ph.D.

Chapter 13 Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids . . . 331

Harrison G. Pope Jr., M.D., and David L. Katz, M.D., J.D.

Part V

Thyroid Hormones Chapter 14 Thyroid Function in Psychiatric Disorders . . . . . . . . . . . . . . . . . . . 361

David O’Connor, M.D., Harry Gwirtsman, M.D., and Peter T. Loosen, M.D., Ph.D.

Chapter 15 Psychiatric and Behavioral Manifestations of Hyperthyroidism and Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . 419

Michael Bauer, M.D., Ph.D., Martin P. Szuba, M.D., and Peter C. Whybrow, M.D.

Chapter 16 Thyroid Hormone Treatment of Psychiatric Disorders . . . . . . . . . . 445

Stephen Sokolov, M.D., F.R.C.P.C., and Russell Joffe, M.D.

Part VI

Laboratory Testing Chapter 17 Laboratory Evaluation of Neuroendocrine Systems . . . . . . . . . . . . . 469

David Michelson, M.D., and Philip W. Gold, M.D.

Chapter 18 Endocrine Imaging in Depression . . . . . . . . . . . . . . . . . . . . . . . . . . 499

Kishore M. Gadde, M.D., and K. Ranga R. Krishnan, M.D.

Part VII

Stress Chapter 19 Stress and Neuroendocrine Function: Individual Differences and Mechanisms Leading to Disease. . . . . . . . . . . . . . . 513

Bruce S. McEwen, Ph.D. Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547

Contributors

Jay D. Amsterdam, M.D. Professor of Psychiatry, University of Pennsylvania School of Medicine, and Director, Depression Research Unit, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania Michael Bauer, M.D., Ph.D. Head, Department of Psychiatry and Psychotherapy, Humboldt University at Berlin, Berlin, Germany; Visiting Professor of Psychiatry, Neuropsychiatric Institute and Hospital, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, California Lee S. Cohen, M.D. Director, Perinatal and Reproductive Psychiatry Clinical Research Program, Massachusetts General Hospital; Associate Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts Kishore M. Gadde, M.D. Assistant Clinical Professor, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Philip W. Gold, M.D. Chief, Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

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PSYCHONEUROENDOCRINOLOGY

Harry Gwirtsman, M.D. Associate Professor, Department of Psychiatry, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee Uriel Halbreich, M.D. Professor of Psychiatry and Research Professor of Gynecology/Obstetrics, Director of BioBehavioral Research, State University of New York at Buffalo, BioBehavioral Program, Buffalo, New York Mady Hornig, M.D. Director of Translational Research, Center for Immunopathogenesis and Infectious Diseases, and Associate Professor, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York Rod J. Hughes, Ph.D. Circadian, Neuroendocrine and Sleep Disorders Section, Endocrine Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Russell Joffe, M.D. Dean and Professor of Psychiatry, UMDNJ–New Jersey Medical School, Newark, New Jersey Linda S. Kahn, Ph.D. Research Assistant Professor, BioBehavioral Research Program, State University of New York, Buffalo, New York David L. Katz, M.D., J.D. Senior Director of Medical Affairs, The Advisory Board Company, Washington, D.C. K. Ranga R. Krishnan, M.D. Professor and Chair, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Alfred J. Lewy, M.D., Ph.D. Professor of Psychiatry and Associate Chairman, Department of Psychiatry, and Director, Sleep and Mood Disorders Laboratory, Oregon Health and Science University, Portland, Oregon

Contributors

xiii

Steven E. Lindley, M.D., Ph.D. Clinical Faculty, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Associate Director for Research, National Center for PTSD, Palo Alto VA Health Care System, Palo Alto, California Peter T. Loosen, M.D., Ph.D. Professor, Departments of Psychiatry and Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee Bruce S. McEwen, Ph.D. Professor and Head, Laboratory of Neuroendocrinology, Rockefeller University, New York, New York David Michelson, M.D. Medical Director, Lilly Research Laboratories, Indianapolis, Indiana; Associate Professor of Psychiatry, Indiana University Dominique L. Musselman, M.D., M.S. Associate Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia Charles B. Nemeroff, M.D., Ph.D. Reunette W. Harris Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia David O’Connor, M.D. Department of Psychiatry, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee Harrison G. Pope Jr., M.D. Professor of Psychiatry, Harvard Medical School; Chief, Biological Psychiatry Laboratory, McLean Hospital, Belmont, Massachusetts Victor I. Reus, M.D. Professor of Psychiatry, University of California School of Medicine, San Francisco, California

xiv


Magda Rittenbaum, M.D. Resident in Neurology, Oregon Health and Science University, Portland, Oregon Anthony J. Rothschild, M.D. Irving S. and Betty Brudnick Professor of Psychiatry and Director of Clinical Research, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts David R. Rubinow, M.D. Clinical Director and Chief, Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland Robert L. Sack, M.D. Professor of Psychiatry and Medical Director, Sleep Disorders Medicine Service, Oregon Health and Science University, Portland, Oregon Alan F. Schatzberg, M.D. Kenneth T. Norris Jr. Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California Peter J. Schmidt, M.D. Chief, Unit on Reproductive Endocrinology, Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland Stephen Sokolov, M.D., F.R.C.P.C. Assistant Professor, Department of Psychiatry, University of Toronto; Staff Psychiatrist, Mood Disorders Clinic, Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada Monica N. Starkman, M.D., M.S. Associate Professor, Department of Psychiatry, University of Michigan Medical Center, Ann Arbor, Michigan Martin P. Szuba, M.D.† Assistant Professor of Psychiatry, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

†

Deceased.

Contributors

xv

Steven J. Wamback, B.S. State University of New York, Buffalo, New York Lisa S. Weinstock, M.D. Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Peter C. Whybrow, M.D. Professor and Executive Chairman, Department of Psychiatry and Biobehavioral Sciences; Director, Neuropsychiatric Institute and Hospital, University of California at Los Angeles, Los Angeles, California Owen M. Wolkowitz, M.D. Professor of Psychiatry and Director, Psychopharmacology Assessment Clinic, University of California School of Medicine, San Francisco, California


Part I Introduction


Chapter 1 Introduction and Overview Owen M. Wolkowitz, M.D. Anthony J. Rothschild, M.D.

T

he importance of endocrinology for psychiatric practice has never been stronger than it is now. We are currently witnessing a paradigm shift in understanding endocrinologic aspects of psychiatric illness. Hormonal aberrations (and even so-called normal changes that occur with aging and in response to physical or emotional stress) are increasingly viewed less as epiphenomena, diagnostic tests, or “windows into the brain” and more as vital pathophysiological changes and as potential targets for novel hormonally based pharmacotherapies. The recent discovery of neurosteroids, which indicates that the brain itself is a steroidogenic organ, further blurs the boundaries between endocrinology and neuropsychiatry. An enormous amount of information has now been gathered regarding hormone effects on the brain and behavior. Excellent textbooks of psychoneuroendocrinology, some encyclopedic in their coverage, have already been published. The goal of this volume is to be no less authoritative but to fill an important niche: to show how the principles and emerging findings of psychoneuroendocrinology can inform modern clinical practice and lead to new breakthroughs in future practice. With that goal in mind, leading authorities, all of whom are internationally renowned researchers and most of whom are active clinicians themselves, were invited to contribute the individual chapters. They were asked to review not only the latest empirical scientific findings in their areas of expertise but to highlight the clinical significance of these findings and to provide, wherever appropriate, clinical guidelines for the management of patients. This book, then, was designed with the clinician, as well as the researcher-scientist, in mind, and we hope that it will prove useful to psychi-

3

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atrists, neurologists, endocrinologists, obstetrician-gynecologists, internists, family and general practitioners, psychologists, nurses, and advanced students. More broadly, we hope that it will be of interest to anyone seeking to learn more about the bidirectional interaction of the mind and the body and of the psyche and the soma. Psychoneuroendocrinologic investigation has generally followed three paths, each of which is discussed in this volume: 1) alterations in endogenous hormone levels observed in primary psychiatric illness; 2) psychiatric concomitants or sequelae of hormonal dysregulation in primary endocrinologic illness; and 3) behavioral effects of exogenously administered hormones or hormone antagonists (both the study of the side effects of hormonal medications and the use of hormones and hormone antagonists as psychotropic medications). In this volume, each of these paths is explored in turn for each hormonal system presented (e.g., the hypothalamic-pituitary-adrenal axis hormones, gonadal hormones, and thyroid hormones). In addition, special topics of interest are included, such as the role of neuropeptides and hypothalamic releasing factors in psychiatric illness, the use of laboratory tests and imaging procedures in evaluating hormonal function in psychiatric patients, the place of newer alternative hormonal medications such as melatonin and dehydroepiandrosterone (DHEA) in therapeutics, and consideration of the particular role of stress in precipitating illness. Drs. Lindley and Schatzberg begin this volume with a lively history of psychoneuroendocrinology, recounting the many false starts in this field, pointing optimistically to more promising recent advances, and emphasizing where the field is now headed. This account of the development of the field sets the stage for the chapters that follow. In particular, their account of the earliest conceptualizations of the role of stress in mental and physical illness nicely complements the final chapter of the volume (by Dr. McEwen), which points to very newly developed conceptualizations. Drs. Musselman and Nemeroff then review the work of their own group and that of others in elucidating the role of neuropeptides and hypothalamic releasing factors in neuroendocrine regulation and in psychiatric illness. Moving from the historical contexts of the neuroendocrine window and the pharmacologic bridge approaches, they consider whether neuropeptide changes are secondary to or are causal of aspects of psychiatric illness, and they point the way to the development of novel psychopharmacologic agents. Drs. Sack, Lewy, Rittenbaum, and Hughes review the physiological roles and therapeutic potential of melatonin, distinguishing fact from current fad. They emphasize the potential of melatonin and melatonin

Introduction and Overview

5

analogs as chronobiotic drugs (i.e., they reset circadian rhythms) in conditions such as jet lag, shiftwork maladaptation, and other sleep disorders, as well as their (separate) hypnotic properties. Drs. Hornig and Amsterdam review the psychiatric manifestations of the most common endocrinopathy, diabetes mellitus, along with those of the least common ones—such as those affecting secretion of prolactin, parathyroid hormone, glucagon, and growth hormone and those associated with panhypopituitarism. In addition to reviewing the behavioral correlates of disturbances in each of these systems, they concisely review the use of several of these hormones as “windows into the brain” in pharmacologic challenge studies. Dr. Rothschild summarizes and synthesizes data pertaining to the best-studied of psychoneuroendocrine topics: corticosteroids in psychiatric illness. It has been estimated that well over 8,000 scientific articles have appeared in the medical literature regarding the utility (or lack thereof) of the dexamethasone suppression test in psychiatric patients. Dr. Rothschild comments on the proper (and improper) use of tests of the hypothalamic-pituitary-adrenal (HPA) axis and discusses the incidence and significance of HPA axis aberrations in psychiatric illnesses. He concludes with suggestions for novel therapies aimed at normalizing HPA axis secretion. Dr. Starkman reviews the particular endocrine disease that has both historically and currently stimulated the greatest discussion about the dependence of behavior, mood, and memory on hormonal activity. In her review of Cushing’s syndrome and its counterpart, Addison’s disease, Dr. Starkman considers the relative roles of corticotropin-releasing hormone and adrenocorticotropic hormone versus cortisol (and other less wellstudied hormones) in determining behavioral outcome in these conditions, as well as their relative utility in differential diagnosis and treatment planning. She also reviews studies of behavioral response after treatment of these disorders and summarizes data from her own group on certain intriguing neuroanatomical changes seen in Cushing’s syndrome. Drs. Reus and Wolkowitz examine exogenous corticosteroid effects on mood and cognition in their chapter on steroid psychosis. Behavioral effects of steroid medications have been recognized since the time of their introduction into clinical practice, but few controlled trials have studied their incidence, character, etiology, and response to treatment. Drs. Reus and Wolkowitz review the latest developments in understanding these side effects (which affect literally thousands of patients yearly), and they review currently available prophylactic and treatment strategies. Drs. Wolkowitz and Reus then review the rapidly expanding database concerning the role of DHEA in memory, mood, and neuropsychiatric ill-

6


ness. DHEA and its metabolite, DHEA sulfate, are the most plentiful adrenal corticosteroids in humans, yet their functions remain uncertain. Moderating between claims of a youth-enhancing super-hormone and therapeutic nihilism, the authors put the current DHEA hype into scientific perspective and point to possible novel treatments involving this interesting hormone. Drs. Rubinow and Schmidt review the prevalent psychiatric disorders associated with the menstrual cycle and the perimenopausal years in women. In addition to reviewing the normal physiology of these occurrences and posing questions regarding hormonal causality of these behavioral disturbances, they highlight current approaches to diagnosis and treatment. Drs. Weinstock and Cohen review postpartum behavioral changes, distinguishing between postpartum “blues,” depression, and psychosis. In addition to reviewing what is known about the endocrine and nonendocrine causes of these disorders, they suggest prophylactic and therapeutic approaches for patients who are experiencing or are at risk for contracting these conditions. Dr. Halbreich, Mr. Wamback, and Dr. Kahn review the mood and cognitive effects of exogenously administered female gonadal hormones (e.g., oral contraceptives and estrogen replacement therapy), paying particular attention to the specific behavioral effects of estrogen alone versus estrogen-progestin combinations. The chapter includes abundant clinical recommendations, often derived from the authors’ clinical experience, in areas where controlled data are not yet available. Drs. Pope and Katz extensively review the literature on use of anabolic and androgenic steroids, including studies from their own laboratory. Although they acknowledge that much remains to be discovered regarding vulnerability to anabolic steroid–induced behavioral changes, the authors provide general conclusions, treatment recommendations, and forensic guidelines. Drs. O’Connor, Gwirtsman, and Loosen provide a thorough review of thyroid function in psychiatric disorders. Included are delineations of different levels of thyroid dysfunction (e.g., peripheral thyroid hormone levels, thyroid-stimulating hormone levels, and antithyroid antibodies) in disorders as diverse as mood disorders, alcoholism, anxiety disorders, premenstrual dysphoric disorder, eating disorders, and schizophrenia. Important, but often overlooked, effects of somatic treatments on thyroid function are also reviewed. Drs. Bauer, Szuba, and Whybrow delineate psychiatric syndromes seen in patients with hyperthyroidism or hypothyroidism. Examination of the psychiatric sequelae of such endocrinologic diseases illuminates

Introduction and Overview

7

the importance of hormonal homeostasis for proper central nervous system functioning. In addition to describing the psychiatric comorbidities of thyroid disease, the authors comment on laboratory evaluations of such diseases and emphasize psychiatric responses to therapeutic endocrine correction. The observed relationships between thyroid disease states and psychiatric symptomatology led to a sizable number of studies evaluating exogenously administered thyroid hormones as psychopharmacologic agents. These trials are reviewed and synthesized by Drs. Sokolov and Joffe, whose own research group has conducted much of this research. Of special interest to clinicians is the authors’ comparison of the efficacy of different thyroid hormones (e.g., T3 versus T4) as well as T3 versus lithium in augmenting antidepressant response. Drs. Michelson and Gold provide a detailed overview of laboratory testing in clinical psychoneuroendocrinology. With proper attention to methodology and to the correct use and interpretation of these tests, accurate diagnosis and treatment are greatly facilitated. Clinicians involved in the evaluation and care of psychiatric, endocrine, and general medical patients will find this chapter both practical and thorough. Drs. Gadde and Krishnan describe another approach to diagnosing and investigating neuroendocrine alterations in psychiatric illnesses: radiographic imaging of endocrine tissues and other organs. Although computed tomographic or magnetic resonance imaging of organs such as the pituitary and the adrenal gland may not be routinely indicated in evaluating psychiatric illness, abnormalities in volumetric measurements of these and other structures speak directly to endocrine-associated physical alterations that relate to major behavioral disturbances. Dr. McEwen closes the volume with a provocative and compelling chapter examining the relationship between stress and illness. An assumption underlying much of this volume is that changes in the body’s internal milieu can significantly alter behavioral and affective experience. In a complementary way, changes in the individual’s external milieu often provoke hormonal adaptations. Drawing on a wide body of experimental data, Dr. McEwen distinguishes between the protective and destructive effects of hormonal responses to stress and introduces the concept of allostatic load to explain some of the health consequences of chronic stress.

In his 1956 book, The Stress of Life, Hans Selye (the father of stress physiology) wrote

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PSYCHONEUROENDOCRINOLOGY We are on our guard against external intoxicants, but hormones are parts of our bodies; it takes more wisdom to recognize and overcome the foe who fights from within.... What can we do about this? Hormones are probably not the only regulators of our emotional level. Besides, we do not yet know enough about their workings to justify any attempt at regulating our emotional key by taking hormones.

Now, more than 45 years after Selye wrote these words and with the cumulative benefit of the observations reviewed in this volume, we are in a much stronger position to “regulate our emotional key” by recognizing and correcting hormonal imbalances that may result in behavioral disturbances.

Chapter 2 Historical Roots of Psychoneuroendocrinology Steven E. Lindley, M.D., Ph.D. Alan F. Schatzberg, M.D.

C

linical psychoneuroendocrinology is a relatively young area of research, but its historical roots go back to antiquity. Psychoneuroendocrinology is grounded in advances in basic scientific knowledge, evolving from developments in endocrinology, neurochemistry, and behavioral pharmacology and from clinical observations. The subsequent chapters of this book contain reviews of the exciting recent advances in the field of psychoneuroendocrinology, emphasizing areas of possible direct clinical utility. The purpose of this chapter is to take a step back and examine some of the early scientific and social developments that shaped the development of the field from the beginning of history to the 1960s (Table 2–1). Specifically, we examine 1) how it was first appreciated that endocrine abnormalities can affect behavior; 2) how the nature of endocrine communication was discovered, which led to the discovery of chemical neurotransmission; 3) what observations indicated that endocrine secretions are regulated by the brain; and finally 4) the development of the modern understanding of how psychological states can alter endocrine systems. In reviewing these developments, we focus on the hypothalamic-pituitaryadrenal (HPA) axis, in part because it is one of our interests, but also because the HPA axis has been the most intensely studied neuroendocrine system in psychiatry. We emphasize past missteps and dead ends to pro-

Work for this chapter was supported by NIMH Grant MH50604, a NARSAD Young Investigator Award, and a DANA Research Fellowship.

9

10 TABLE 2–1.

469–399 B.C. 130–200 1628 1719 1811 1849 1849 1855 1855 1856 1884 1889 1891 1894 1899 1905 1907 1921 1926 1932 1936 1940s 1946 1954

A.D.

PSYCHONEUROENDOCRINOLOGY Early conceptual advances in the psychoneuroendocrinology of the hypothalamicpituitary-adrenal axis: antiquity to 1950s Hippocrates on black bile and melancholia Galen of Pergamum—anatomy of humors Harvey’s description of the circulation First chemical analysis of brain by Hensing Vauquelin’s chemical composition of the brain Berthold’s description of testicular replacement Pavlov’s neural reflexes Bernard’s observation of internal secretions from the liver Addison’s description of adrenal atrophy Brown-Séquard’s description of effects of adrenalectomy Thudichum’s work on brain chemical constitution Brown-Séquard’s advocacy of organotherapy Murray injects thyroid extracts into myxedema patient Oliver and Schäfer’s vasoconstrictor effects of adrenal extracts Abel and Crawford isolate epinephrine Bayliss and Starling discover secretin; coin the term hormone Langley hypothesizes receptors Loewi demonstrates release on chemical neurotransmitters Cannon’s concept of homeostasis Cushing’s syndrome described Selye’s concept of stress as general adaptation syndrome Harris’s work on hypothalamic neurohumoral pituitary control von Euler demonstrates norepinephrine neuronally released Vogt demonstrates norepinephrine unevenly distributed in central nervous system

vide clues for avoiding future mistakes in this very exciting and expanding field. This review is not meant to be exhaustive, and it relies mostly on the insight and material provided by other authors (Bleuler 1982; Hughes 1977; McCann 1992a; Money 1983; Peart 1979; Sawyer 1988; Tattersall 1994; Tourney 1969; Tower 1981; Welbourn 1992; Wilson 1984), but its goal is to try to set the historical stage for the chapters that follow.

Ancient Concepts The beginnings of psychoneuroendocrinology can be traced to black bile and phlegm. The concepts of the four humors and the brain as the source of intelligence and mental illness were described in the writings of Alc-

Historical Roots of Psychoneuroendocrinology

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maeon of Croton (a pupil of Pythagoras, around 500 B.C.), Hippocrates of Cos (469–399 B.C.), and other ancient philosophers. These ideas were developed, in part, based on data derived from animal experimentation. It was believed at that time that the four bodily humors—yellow and black bile, blood, and phlegm—could cause mental illness by influencing the brain. For instance, phlegm, which was believed to cool the brain, could accumulate in sites throughout the body, such as in joints and semen. Treatment for an excess of phlegm included removal from the body by ejaculation (Peart 1979). A less enjoyable therapy involved black bile. Black bile, a product of the spleen, was thought to be the cause of melancholia. The treatment for melancholia involved black hellebore, the Christmas rose, a cathartic and diuretic herb (Mora 1975). Roman physicians expanded on these theories. The writings of Galen (A.D. 130–200) contributed significantly to the advancement of anatomy and pathology, but they also solidified the belief in humoral causes of disease. Galen’s philosophy, which became known as Galenism, had a strong influence on the practice of psychiatry until the middle of the nineteenth century (Mora 1975). Galen described intraarterial “vital spirits” that were converted by the brain into “animal spirits.” The waste products of this reaction were funneled down the infundibular stalk to the pituitary gland, through ducts in the sphenoid and ethmoid bones to the nasopharynx, where they appeared as nasal mucus or “pituita” (from Harris, quoted in Sawyer 1988, p. 23). Galen’s treatments included phlebotomy for melancholia, a practice that continued for the next one and a half millennia, and sexual activity for hysterical symptoms, which he hypothesized to be the result of a lack of sexual relations (Mora 1975).

Early Modern Endocrinology During the Renaissance period, scientists described the anatomy of most of the endocrine glands, but their function was unknown until the late eighteenth century. In 1716, the Academia des Sciences de Bordeaux offered a prize for an answer to the question “what is the role of the adrenals?” The judge did not award the prize to any of the conflicting theories offered and closed his criticism with the words “perhaps some day chance will reveal what all of this work was unable to do” (Nelson 1988, p. 87). To understand the role of endocrine glands in general, one needed to appreciate their lack of a direct physical connection to the rest of the body, an idea that did not develop until the eighteenth century (Bleuler 1982). In 1742, Théophile de Bordeu, a medical practitioner in Paris,

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noted that glands, as well other tissues, influence each other by releasing products into the bloodstream (Peart 1979, p. 274), and Albert von Haller in 1766 hypothesized that glands without ducts, such as the thyroid, pour special substances into the circulation (Welbourn 1992, p. 138). By 1844, a recognizable modern concept of endocrine glands was described by the physiologist Johannes Mueller, who wrote, “Glands without ducts exercise their plastic influences on the fluids within them and those which circulate through them and return to the general circulatory system” (see Bleuler 1982, p. 2). Clues to the chemical nature of endocrine products were first obtained from the most externally accessible gland, the testes (Money 1983). The physiological and behavioral effects of the testes had been observed with the first castrations of domesticated animals and in eunuchs. Aristotle (384–322 B.C.) wrote about the effects of castration in both animals and humans, and Galen concluded, “Is it then astonishing that a certain power is communicated from the testicles to the whole body?... This faculty is the cause in man of masculinity” (quoted in Peart 1979, p. 272). However, these early investigators and philosophers attributed the loss of testicular functioning to semen, not hormones. Evidence to the contrary was provided by the experiments of John Hunter, an English anatomist and surgeon, in the mid-eighteenth century. In experiments with cockerels, he noted that testicular replacement produces secondary sex characteristics in castrated animals. However, because he was mainly interested in organ transplantation, he published only a few brief reports on his observations (reviewed in Money 1983; Welbourn 1992). Not until 1849 did Arnold Adolph Berthold describe evidence for what are now known as hormones. Berthold observed that transplantation of testes reversed the effects of castration on sexual and aggressive behaviors and physical characteristics in chickens, confirming Hunter’s findings. But Berthold attributed this effect to internal secretions from the gland. Furthermore, he commented that the effects of testicular secretions must influence “the whole organism of which, it must be admitted, the nervous system forms a very substantial part,” foreshowing our understanding of the effect of androgens on the central nervous system (CNS) (Sawyer 1988). Because his experiments involved problems with immune rejection associated with organ transplantation, they were difficult to replicate and were largely ignored until the early twentieth century (Peart 1979; Welbourn 1992). In 1855 Claude Bernard, professor of physiology at the Collége de France, Paris, coined the term internal secretion to describe the secretion of newly synthesized glucose from the liver. In the same year, Thomas Addison correctly ascribed a role to the adrenal glands in his descriptions


13

of a syndrome in patients with gross adrenal disease (Addison’s disease). The next year, Charles-Edouard Brown-Séquard, more famous for his description of the syndrome associated with spinal cord hemisection, reported that bilateral adrenalectomy was fatal in many animals, usually within 24 hours. He concluded that the syndrome was similar to that found in patients dying from Addison’s disease (Tattersall 1994). The first endocrine therapy was developed as a treatment for thyroid disease. Goiters were described throughout recorded history and were attributed to iodine deficiency. Because of the similarities between patients with cretinism and myxedema and patients who had undergone thyroidectomy, Felix Semon proposed in 1883 that both cretinism and myxedema resulted from a degeneration of the thyroid gland. A “myxedema committee” that was set up at St. Thomas’ Hospital in London investigated his theory. Five years later, after obtaining further clinical and animal data, this committee agreed with Semon that myxedema was indeed caused by loss of thyroid secretions. Three years later, George Murray, a medical resident, successfully treated a myxedematous patient with glycerinated sheep thyroid extract with the help of the myxedema committee. This was the first successful endocrinologic replacement treatment, and it understandably generated a great deal of enthusiasm (see accounts in Peart 1979; Welbourn 1992).

The Era of Organotherapy The enthusiasm generated by the advances described above was soon dampened by a peculiar setback, which was set into motion by a scientist who had made tremendous contributions to both neurology and endocrinology, Charles-Edouard Brown-Séquard (Beach 1981; Tattersall 1994; Welbourn 1992; Wilson 1984). On June 1, 1889, at age 72, Dr. BrownSéquard announced to the Société de Biologie in Paris the results of an endocrine experiment. Serving as his own experimental subject, he had injected himself subcutaneously with dog and guinea pig testicular extracts. He stated that he had conducted these experiments because “it is well known that seminal losses from any cause produce a mental and physical disability which is in proportion to their frequency” (Tattersall 1994, p. 729). He reported that this treatment had remarkable effects on his physiology, including his being able to move 7 kg more weight, greater regularity of his bowel function, a decrease in mental fatigue, and a 25% increase in the jet of his urine. He asked the elder members of the society to make an effort to replicate his findings (Tattersall 1994; Welbourn 1992).

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The initial reaction of the scientific community and the public in general was skepticism and ridicule. For example, an editorial in Wiener Medizinische Wochenschrift stated, “Professor Brown-Séquard’s audience appears to have received an impression of the intellectual capacity of the aged scientist very different from the one which he, in his elevated frame of mind, evidently expected to produce. This lecture must be regarded as further proof of the necessity of retiring professors who have attained their threescore years and ten” (Beach 1981, p. 332). Despite this initial reaction, by the end of 1889, 12,000 physicians had tested his extract and had reported remarkable cures for a wide variety of illnesses. Besides senile disability, efficacy for this treatment was reported for glycosuria, neurasthenia, tabes dorsalis (314 cures out of 415 trials), pulmonary tuberculosis, heart disease, leprosy, malaria, Addison’s disease, and cancer (Tattersall 1994). Dr. Brown-Séquard reportedly believed that the extract increased the “nervous force” in the body, allowing one to better fight disease. A number of pharmaceutical companies, including Burroughs, Wellcome, began to manufacture various organ extracts, a craze that continued into the 1920s (Tattersall 1994). The bad reputation that these organ extract therapies—generally called organotherapy—received in the general medical community resulted in a loss of respectability for endocrinology. It was said that “any young physician who dared embark on a career in the field of internal secretions was looked [at] askance, [was] considered naive and gullible[,] or [was] suspected of straying into the realm of quackery and heading for the endocrine gold fields” (Tattersall 1994, p. 730). Even the reported efficacy of thyroid replacement for myxedema was viewed with skepticism because of the similarities to organotherapy (Peart 1979). Furthermore, because of the remarkable psychological effects reported, many endocrinologists doubted whether scientific methods could be applied to investigating the psychological effects of hormones (from Beach 1981).

Birth of Modern Endocrinology Despite its negative impact, organotherapy did generate advances in endocrinology that eventually led to the development of neurochemistry and modern biological psychiatry. In 1893, an English general practitioner named George Oliver began experimenting with extracts of various tissues. During these investigations, he is reported to have fed an adrenal extract to his son and observed evidence of vasoconstriction—an experiment that would not pass even the most lenient human subjects commit-


15

tee today. Dr. Oliver approached Edward A. Schäfer, a professor of physiology at his former medical school, with his findings. Using an experimental dog that he had already prepared for the measurement of arterial blood pressure, a skeptical Dr. Schäfer was surprised at the large increase in blood pressure produced by the extract (Peart 1979; Welbourn 1992; Wilson 1984). Oliver and Schäfer concluded that they had found the secretion that was missing in Addison’s disease patients. Investigations conducted the following winter revealed that the substance was restricted to the adrenal medulla and was missing at autopsy in two patients with Addison’s disease (Peart 1979; Welbourn 1992; Wilson 1984). The general scientific community was excited by these findings, and several researchers turned their attention to identifying this substance. Within 5 years, John Jacob Abel and Albert Crawford, both of Johns Hopkins University, had isolated the extract and named it epinephrine. A Japanese chemist named Jokichi Takamine later purified the substance in crystalline form and gave it the name adrenaline, producing the first purified hormone. This accomplishment set off a race to isolate other hormones (Peart 1979; Welbourn 1992; Wilson 1984). Although it could not be known then, the isolation of epinephrine also marked the beginning of the modern era of neurochemistry by illustrating the interrelationship between endocrine secretions and neural transmission. During this period, chemical messengers were being investigated at another level in a separate line of research. In 1902, William Bayliss and Ernst Starling began an investigation of the regulation of pancreatic secretions in dogs. They discovered that extracts of the intestinal mucosa stimulated pancreatic secretions in the absence of neuronal input. They named this hypothetical chemical messenger in the extract secretin and proposed a new classification for this extract: a hormone, meaning “I arouse to activate” (Peart 1979; Welbourn 1992; Wilson 1984). They defined a hormone as “being produced in particular organs, carried in the blood current, acting as chemical messengers, and influencing cell processes in distant organs.… They provide chemical coordination of the organism, working side by side with that of the nervous system” (Welbourn 1992, p. 146).

Growth of an Appreciation for Psychiatric Aspects of Endocrinologic Disorders With the expansion of knowledge in hormones came a greater appreciation for the psychiatric aspects of endocrine disease. But, as noted by

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Bleuler (1982, p. 6), “most early descriptive studies of the behavioral consequences of endocrine disorders based their findings on single observations and therefore often over-generalized their findings, sometimes with unfortunate results.” For example, Benjamin Rush is quoted as stating that the larger size of the thyroid gland in women “was necessary to guard against the female system from the influence of the more numerous causes of irritation and vexation of the mind to which they are exposed than the male sex” (Kathol 1992, p. 400). Sometimes these simplistic generalizations led to invasive therapies. In 1872, Robert Battery, a Georgia surgeon, advocated ovariectomy for dysmenorrhea. Over time the clinical indications for ovariectomy were broadened to include psychiatric conditions such as neurosis (Welbourn 1992). A theory that schizophrenia resulted from a defect in adrenal hormone production led to adrenalectomies in a number of schizophrenic patients (Bleuler 1982). Despite these clinical misadventures, the availability of efficacious treatments for endocrine disorders produced many real dramatic psychiatric cures, as illustrated in the following 1892 description by Drs. Shaw and Stansfield of the treatment a female patient with myxedema (see Kathol 1992, p. 403): Following the birth of her second child she had an attack of lactational melancholia and inflicted a wound on her throat....Symptoms of myxedema were first noticed when she was pregnant with her third child. The principal mental symptoms were mental confusion and inability to concentrate or employ herself. She had considerable insight into her mental state and became languid and disinterested in her occupation and her children....The mental condition became worse and she was certified and sent to the Banstead Asylum in April 1891....To the ordinary symptoms of myxedema were added occasional stupor, aphonia, rigidity, and erotomania. She would periodically get into other patients’ beds and when being bathed, unless the nurses were careful, would seize and almost strangle them in excess of her sexual desire. All sorts of remedies were tried to no avail: hot baths, massage, injections of pilocarpine (until, indeed, profuse salivations resulted), tonics and electricity....Finally it was decided to treat the patient with glycerine extract of the thyroid of the sheep. The committee purchased the sheep, killed them, and dissected out the thyroid. A 20% glycerine extract was made by pounding and macerating the gland for forty-eight hours and then straining it through several layers of very fine muslin. The patient was given an injection every second day. The reaction was remarkable. In ten weeks’ time, Mrs. H was out on trial and at the expiration of her trial she was discharged and recovered.

Such successes with hormonal therapy generated curiosity as to whether hormones were involved in the pathophysiology of psychiatric disorders


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in general. Emil Kraepelin theorized about endocrine etiologies for dementia praecox, and Sigmund Freud wondered if the damaging effects of hormones on the psyche could be the basis of the “actual neurosis” (Bleuler 1982). Endocrinologists also shared this enthusiasm. In the first edition of the journal Endocrinology in January 1917, Charles E. De Medicis Sajous, commenting on recent evidence suggesting adrenalin was located in neurons, wrote In the great field of neurology and psychiatry, to which work beyond compution and praise has been devoted, discouragement has remained the dominant note precisely where efforts on behalf of sufferers should have proved more telling. Nowhere has therapeutics remained less efficient....And yet, no single line of medical thought offers greater opportunity for development through the intermediary of the ductless glands. (Sajous 1917, p. 1)

Growth of Modern Neurochemistry From Roots in Endocrinology The link between psychology and endocrinology is exemplified by the growth of neurochemistry out of endocrinology. An appreciation for the chemical nature of neural transmission started with the discovery of epinephrine at the turn of the century, although the first chemical investigations of the brain began with the first recorded chemical analysis of the brain in 1719 (Tower 1981). However, when it came to the mechanism of how neurons communicated, most of the attention remained focused on the electrical nature of neuronal transmission. There was evidence in the late nineteenth century suggestive of chemical neurotransmission, from investigations of neuroactive compounds such as nitrous oxide, ether, bromide, and phenobarbital. Claude Bernard demonstrated that curare blocked nerve transmission at the nerve-muscle junction (Tower 1981). In 1877, the electrophysiologist Du Bois-Reymond suggested that nerves might act chemically as well as electrically (Brooks 1988). It was Oliver and Schäfer’s isolation of adrenal extract that sparked the modern development of neurochemistry. Starting in 1905, Thomas Renton Elliott began publishing papers noting the similarities between the effects of adrenaline and those produced by stimulation of the sympathetic nervous system. He suggested that adrenaline might be acting as a chemical neural transmitter (Fleming 1984). In 1914, Sir Henry Dale noted similarities with acetylcholine and parasympathetic stimulation and described the “muscarinic” and “nicotinic” actions of acetylcholine. Then,

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in a series of simple experiments in 1921, Otto Loewi demonstrated that a chemical signal released on stimulation of the vagus nerve, which he termed vagustoff, could mimic vagus stimulation when placed on a denervated heart, an effect that was blocked by atropine. Dale and Loewi won the Nobel Prize for their work on the chemical nature of neural transmission (Fleming 1984; Peart 1979; Welbourn 1992; Wilson 1984). Despite this conceptual breakthrough, technical limitations would slow further advances on chemical neurotransmission until after World War II. In 1946, the Swedish physiologist Ulf von Euler (and later in Germany) demonstrated that mammalian sympathetic nerves release norepinephrine as a transmitter. In 1954, Vogt observed that norepinephrine is distributed unevenly in the CNS, a finding that strongly suggested its function as central neurotransmitter rather than an artifact from sympathetic nerve endings (Cooper et al. 1991). Since that time, the field has expanded at a tremendous rate, with the discovery of increasing numbers of transmitter substances and receptors, and has served as the cornerstone of modern biological psychiatry.

Development of Neuroendocrinology Another set of developments was taking place during the first half of the twentieth century that would further link hormones with brain function: the discoveries of endocrine secretions from the pituitary and of CNS control of these secretions. These developments have been outlined in detail by a number of investigators in the field (Brooks 1988; Hughes 1977; McCann 1975, 1992a, 1992b; Sawyer 1988). Although its anatomy had been investigated, the function of the pituitary remained a mystery until the description of two cases of acromegaly by Pierre Marie in 1886. In 1927 Philip Smith demonstrated that the pituitary gland produced hormones that stimulated the adrenal cortex, thyroid, and gonads and also stimulated growth. By the early 1930s, the remaining pituitary hormones had been discovered (reviewed in McCann 1992b). The role of the hypothalamus in control of the pituitary was also first suggested from clinical observations of patients with endocrine disorders as early as the beginning of the twentieth century. In 1901, Alfred Fröhlich in Vienna diagnosed the adiposogenital syndrome in a 14-year-old obese boy with arrested sexual development that Fröhlich attributed to damage in the hypothalamus (Sawyer 1988). In 1921, Percival Bailey and Frédéric Bremer confirmed and extended early findings that lesions of discrete areas of the hypothalamus in dogs induced the adiposogenital


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syndrome, experimentally demonstrating hypothalamic control over the pituitary. This and other work led to Harvey Cushing’s 1929 description of the hypothalamus: “Here in this well-concealed spot, almost to be covered by a thumb nail, lies the very main-spring of primitive existence” (see Brooks 1988, p. 657). The way the hypothalamus directs the pituitary was postulated by Hinsey and Markee in 1933, when they suggested that hypothalamic neurohypophyseal hormones might control the secretions of the anterior pituitary. In the late 1940s, in a series of experiments involving pituitary stalk lesions, Geoffrey W. Harris provided experimental evidence that factors released into the portal blood from the hypothalamus exerted control over pituitary secretion (McCann 1992b). By the 1950s, the search turned to the identification of these hypothalamic releasing and inhibiting factors. Some of these factors proved more difficult to isolate then others; the chemical identity of corticotropin-releasing hormone was not discovered until 1981 (Vale et al. 1981). As the hypothalamic neurohumoral factors were isolated and were also found to be present, along with their receptors, in brain regions outside the medial basal hypothalamus, the line separating endocrine and neuronal control became blurred even further.

Homeostasis and Stress The growth of knowledge about hormones and chemical neural transmission led to the development of two important concepts for modern psychoneuroendocrinology: homeostasis and stress. The Harvard University physiologist Walter Bradford Cannon began to develop the concept of homeostasis from work that he began while a medical student in 1896. At that time, he observed the impact of emotional states on physiology while working on a research project on the digestive system. As reviewed by Fleming (1984), he brought together contemporary knowledge of the functioning of the adrenal gland with the work he began as a medical student on the autonomic nervous system to formulate a theory of psychoendocrine relationships. In his book Bodily Changes in Pain, Hunger, Fear and Rage (Cannon 1915), he postulated that strong emotions influenced physiology through the “sympathico-adrenal medullary system” and described the fight-or-flight response. Expanding on Claude Bernard’s concept of a “milieu interior” that was held in balance, Cannon theorized that the purpose of a fight-or-flight response was to maintain the body’s physiological balance. He coined the term homeostasis to describe this

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process, which he defined as the process by which the body’s regulatory mechanisms allow it to maintain physiological stability despite environmental changes. He thereby linked the impact of emotional states on the endocrine systems with a normal physiological function (Fleming 1984). Cannon referred to “stresses and strains” as the physical and psychological forces that could disturb homeostatic processes (Cannon 1935). This concept of stress was greatly expanded a decade and a half later in the work of the physician-physiologist Hans Selye from the Université de Montréal. Selye developed his theories from work he began in the 1930s. During failed attempts to isolate a new sex hormone, Selye observed that the toxic, nonspecific effects of his extract often included adrenal cortical hypertrophy, atrophy of the thymus, and gastrointestinal ulcers (Mason 1975). By examining the effects of a variety of stressors—including bacteria inoculation, toxins, physical trauma, and exposure to heat and cold— on the responses of the anterior pituitary and adrenal cortex, he developed his theory of the organism’s “general adaptation syndrome” to stress (Selye 1950). The popularization of his work on the stress response continues to have a lasting effect on all areas of medical science (reviewed in Mason 1975) .

HPA Axis Activity and Depression The seminal studies of Cannon and Selye sparked a great deal of interest in psychiatry, because since antiquity many psychiatric disorders— depressive disorders in particular—had been linked to “stress” (Board and Persky 1957). Early studies were limited methodologically and relied on indirect measures of adrenal function, such as changes in lymphocyte and eosinophil levels, alterations in levels of inorganic phosphates, and variations in urinary concentrations of potassium, sodium, and uric acid. In retrospect, it is not surprising that many of these early studies generated conflicting results. In the 1950s, as more direct measures of urinary and plasma cortisol levels became available, a number of researchers demonstrated that stressful life situations, states of arousal, and various states of emotional distress in humans were linked with these indices of increased adrenal activity (Bliss et al. 1955, 1956; Bryson and Mertin 1954; Cleghorn and Graham 1950; Friedman et al. 1963; Price et al. 1957; Renold et al. 1951; Rubin and Mandell 1966). In these early HPA axis studies, clinical depression was a focus of inquiry because it was viewed as a common, time-limited state of profound emotional distress and therefore should have an influence on adrenal


21

activity (Board and Persky 1957; Bryson and Mertin 1954; Rizzo et al. 1954). In 1956, using a direct measure of adrenal activity, plasma concentration of 17-hydroxycorticosteroid, a group of researchers from Michael Reese Hospital demonstrated increased levels of this substance in patients with severe depression (Board and Persky 1957; Board et al. 1956). This finding has been widely replicated since that time, using various direct measures of adrenal activity (Carpenter and Bunney 1971; Gibbons 1964; Gibbons and McHugh 1966; Gibbons et al. 1960; Kocsis et al. 1984; McClure 1966; Rothschild et al. 1993; Sachar 1967; Sachar et al. 1973; Stokes et al. 1984). In the study of depression, through the application of increasingly sophisticated measurements of HPA activity—such as the dexamethasone suppression test (DST), described by Carroll and co-workers in 1981—increasingly consistent observations have been reported. The DST has since become one of the most widely studied measurements in biological psychiatry (reviewed by Arana et al. 1985). As a result of the isolation of corticotropin-releasing hormone (Vale et al. 1981), investigators have been able to examine more directly the state of CNS control of adrenal activity in depressed subjects (reviewed by Gold and Chrousos 1985; Nemeroff 1993). With the appreciation of HPA hyperactivity in depression, interest has been focused on how this hypersecretion affects CNS functioning (reviewed by Rothschild et al. 1989; Wolkowitz 1994; Wolkowitz et al. 1985, 1987, 1989, 1993a, 1993b); this finding may contribute to the pathophysiology of the symptoms of depression, particularly in patients with psychotic depression (reviewed in Schatzberg and Rothschild 1988; Schatzberg et al. 1985). It has also has led to attempts to manipulate the HPA axis for therapeutic benefit in depressed patients (O’Dwyer et al. 1995; Rothschild and Schatzberg 1992; Ur et al. 1992; Wolkowitz et al. 1992), which could possibly fulfill the hopes of the early researchers in psychoneuroendocrinology.

The Present and the Future Much has happened in the field of psychoneuroendocrinology since the 1960s, as reviewed in the other chapters of this book. The number of investigators in the field has increased at an exponential rate. Technical advances have increased the understanding of psychoneuroendocrine interactions to the molecular level; the level of complexity has also increased, with discovery of an ever-expanding number of neurotransmitters, peptides, hormones, and receptors. The promises for therapeutic

22


breakthroughs have never been greater. However, as Ralph Gerard is quoted in Tower’s review of neurochemistry, “the bright area of knowledge ever spreads and, although the dark surface of ignorance is presumably decreasing, the perimeter of contact with the unknown also increases” (Tower 1981).

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Price DB, Thaler M, Mason JW: Preoperative emotional states and adrenal cortical activity. Archives of Neurology and Psychiatry 77:656–656, 1957 Renold AE, Quigley TB, Kennard HE, et al: Reaction of the adrenal cortex to physical and emotional stress in college oarsman. N Engl J Med 244:744– 757, 1951 Rizzo ND, Fox HM, Laidlaw JC, et al: Concurrent observations of behavioral changes and of adrenocortical variations in a cyclothymic patient during a period of 12 months. Ann Intern Med 41:798–815, 1954 Rothschild AJ, Schatzberg AF: Theoretical basis for response to steroid suppression in major depression (letter; comment). J Clin Psychopharmacol 12(2): 142–144, 1992 Rothschild AJ, Benes F, Hebben N, et al: Relationships between brain CT scan findings and cortisol in psychotic and nonpsychotic depressed patients. Biol Psychiatry 26(6):565–575, 1989 Rothschild AJ, Samson JA, Bond TC, et al: Hypothalamic-pituitary-adrenal axis activity and 1-year outcome in depression. Biol Psychiatry 34(6):392–400, 1993 Rubin RT, Mandell AJ: Adrenal cortical activity in pathological emotional state: a review. Am J Psychiatry 123(4):387–400, 1966 Sachar EJ: Corticosteroids in depressive illness. Arch Gen Psychiatry 17:544–553, 1967 Sachar EJ, Hellman L, Roffwarg HP, et al: Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 28:19–24, 1973 Sajous CED: The future of internal secretions. Endocrinology 1(1):1–11, 1917 Sawyer CH: Anterior pituitary neuronal control concepts, in Endocrinology: People and Ideas. Edited by McCann SM. Bethesda, MD, American Physiological Society, 1988, pp 23–40 Schatzberg AF, Rothschild AJ: The roles of glucocorticoid and dopaminergic systems in delusional (psychotic) depression. Ann N Y Acad Sci 537:462–471, 1988 Schatzberg AF, Rothschild AJ, Langlais PJ, et al: A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 19(1): 57–64, 1985 Selye H: Stress and the general adaptation syndrome. Br Med J, June 17, 1950, pp 1383–1392 Stokes PE, Stoll PM, Koslow SH, et al: Pretreatment DST and hypothalamicpituitary-adrenocortical function in depressed patients and comparison groups: a multicenter study. Arch Gen Psychiatry 41(3):257–267, 1984 Tattersall RB: Charles-Edouard Brown-Sequard: double-hyphenated neurologist and forgotten father of endocrinology. Diabet Med 11(8):728–731, 1994 Tourney G: History of biological psychiatry in America. Am J Psychiatry 126:29– 42, 1969 Tower DB: Neurochemistry in historical perspective, in Basic Neurochemistry, 3rd Edition. Edited by Siegel GJ, Albers RW, Agranoff BW, et al. Boston, MA, Little, Brown, 1981, pp 1–16


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Ur E, Dinan TG, O’Keane V, et al: Effect of metyrapone on the pituitary-adrenal axis in depression: relation to dexamethasone suppressor status. Neuroendocrinology 56(4):533–538, 1992 Vale W, Spiess J, Rivier C, et al: Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397, 1981 Welbourn RB: The emergence of endocrinology. Gesnerus 49(Pt 2):137–150, 1992 Wilson LG: Internal secretions in disease: the historical relations of clinical medicine and scientific physiology. J Hist Med Allied Sci 39:263–302, 1984 Wolkowitz OM: Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids. Psychoneuroendocrinology 19(3):233– 255, 1994 Wolkowitz OM, Sutton ME, Doran AR, et al: Dexamethasone increases plasma HVA but not MHPG in normal humans. Psychiatry Res 16(2):101–109, 1985 Wolkowitz OM, Doran AR, Breier A, et al: The effects of dexamethasone on plasma homovanillic acid and 3-methoxy-4-hydroxyphenylglycol: evidence for abnormal corticosteroid-catecholamine interactions in major depression. Arch Gen Psychiatry 44(9):782–789, 1987 Wolkowitz OM, Doran A, Breier A, et al: Specificity of plasma HVA response to dexamethasone in psychotic depression. Psychiatry Res 29(2):177–186, 1989 Wolkowitz OM, Reus VI, Manfredi F, et al: Antiglucocorticoid strategies in hypercortisolemic states. Psychopharmacol Bull 28(3):247–251, 1992 Wolkowitz OM, Reus VI, Manfredi F, et al: Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 150(5):810–812, 1993a Wolkowitz OM, Weingartner H, Rubinow DR, et al: Steroid modulation of human memory: biochemical correlates. Biol Psychiatry 33(10):744–746, 1993b


Part II Peptide Hormones


Chapter 3 Neuropeptides and Hypothalamic Releasing Factors in Psychiatric Illness Dominique L. Musselman, M.D., M.S. Charles B. Nemeroff, M.D., Ph.D.

I

n the search for the underlying pathophysiology of the major psychiatric disorders, neuropeptides in general, and hypothalamic releasing factors in particular, have been scrutinized closely. Undoubtedly one rationale for such intensive study in patients with primary psychiatric disorders is the higher-than-expected psychiatric morbidity in patients with primary endocrine disorders such as Addison’s disease or Cushing’s syndrome. However, a core assumption, the neuroendocrine window strategy, remains the essential impetus for continuing investigation of the major endocrine axes in psychiatric disorders. This strategy is based on a large body of literature that indicates that the secretion of the target endocrine organ (e.g., the adrenal cortex or thyroid) is largely controlled by the organ’s pituitary trophic hormone, which in turn is controlled primarily by the secretion of its hypothalamic release and release-inhibiting hormones (Figure 3–1). There is now considerable evidence that the secretion of these hypothalamic hypophysiotropic hormones is controlled by the classic neurotransmitters, including serotonin (5-hydroxytryptamine [5-HT]), acetylcholine, and norepinephrine, all previously posited to play a preeminent role in the pathophysiology of affective, anxiety, and psychotic disorders.

The authors are supported by NIH Grants DK-17298, MH-42088, MH-49523, MH-39415, MH-40524, and 1P50MH-58922.

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Relations between brain neurotransmitter systems, hypothalamic peptidergic (releasing-factor) neurons, anterior pituitary, and peripheral endocrine organs, illustrating feedback loops.

FIGURE 3–1.

Note. Dark black line represents inhibitory signal. TRH=thyroid-stimulating hormone; LHRH=luteinizing hormone–releasing hormone; SRIF=somatotropin release inhibitory factor (somatostatin); MIF=melanocyte stimulating hormone release–inhibiting hormone; CRH= corticotropin-releasing hormone; GRF= gonadotropin-releasing factor; TSH=thyroidstimulating hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; PRL=prolactin; GH=growth hormone; ACTH= adrenocorticotropic hormone. Source. Reprinted from Nemeroff CB: Psychoneuroendocrinology: Current Concepts. Kalamazoo, MI, The Upjohn Company, 1990, p. 22. Used with permission.

However, the hypothesis that information about higher central nervous system (CNS) neuronal activity (for example, the activity of serotonergic neurons) in a particular disease state can be obtained simply by measuring the activity of a specific endocrine axis is far from proven and is fraught with difficulty. The differing behavioral and neurobiological effects of antidepressants, anxiolytics, and antipsychotics—as well as drugs that induce or worsen depression (such as reserpine), anxiety (cholecystokinin), and psychosis (psychostimulants, phencyclidine)—have provided yet another impetus for scrutiny of neuroendocrine pathophysiology in the major psychiatric

Neuropeptides and Hypothalamic Releasing Factors

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illnesses. This second core assumption, the psychopharmacologic bridge technique, posits that if a drug produces therapeutic effects and has specific biochemical actions, an etiologic relationship between the therapeutic effects, the biochemical changes, and the cause of the syndrome may exist (Janowsky et al. 1993). For example, tricyclic antidepressants block reuptake of norepinephrine and serotonin, monoamine oxidase inhibitors inhibit the metabolism of catecholamines, and downregulation or decrease in the number of b-adrenergic receptors (associated with most antidepressant treatments) occurs in association with the clinically successful treatment of depression. Therefore, what the pharmacologic bridge technique and the neuroendocrine window strategy provide is 1) clear evidence that alterations of a variety of endocrine axes exist within patients with major psychiatric disorders, and 2) an appreciation of the complexity of neuropeptide circuits in the CNS. The pharmacologic bridge technique also provides evidence of altered neurotransmitter transporter or receptor-mediated signal transduction in depression and other psychiatric disorders. Whether alterations in peripheral endocrine organ hormone secretion contribute primarily to the pathogenesis of psychiatric disorders and whether altered secretion of pituitary and hypothalamic hormones primarily contribute to the signs and symptoms of a specific mental illness remain subjects of considerable controversy. In this chapter we briefly outline the major findings concerning neuropeptides and hypothalamic releasing factors in psychiatric diseases.

Corticotropin-Releasing Hormone The neuroendocrine axis that has been most intensively scrutinized in psychiatric disorders is the hypothalamic-pituitary-adrenal (HPA) axis (Figure 3–2 and Table 3–1). There are literally hundreds of reports documenting HPA axis hyperactivity in drug-free depressed patients. In this section we briefly review evidence for CNS (i.e., corticotropin-releasing hormone [CRH]) involvement, pituitary (i.e., adrenocorticotropic hormone [ACTH]) involvement, and adrenal (i.e., glucocorticoid) involvement in the pathophysiology of the HPA axis in depression and anorexia nervosa. CRH, which is composed of 41 amino acids, is the primary physiological mediator of secretion of ACTH and b-endorphin from the anterior pituitary (Vale et al. 1981). Within the hypothalamus, CRH-containing neurons project from the paraventricular nucleus to the median eminence (Swanson et al. 1983). Activation of this CRH-containing neural circuit

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FIGURE 3–2.


The hypothalamic-pituitary-adrenal axis.

Note. Dark black line represents inhibitory signal. CRH=corticotropin-releasing hormone; ACTH=adrenocorticotropic hormone; MSH = melanocyte stimulating hormone. Source. Reprinted from Nemeroff CB: Psychoneuroendocrinology: Current Concepts. Kalamazoo, MI, The Upjohn Company, 1990, p. 29. Used with permission.

occurs in response to stress, resulting in an increase in synthesis and release of ACTH, b-endorphin, and other pro-opiomelanocortin (POMC) products. Convergent findings suggest that dysregulation of hypothalamic or extrahypothalamic CRH neurons are involved in the pathophysiology of major depression. Multiple studies of drug-free patients with major depression have revealed elevated CRH concentrations in cerebrospinal fluid (Arato et al. 1986; Banki et al. 1987, 1992b; France et al. 1988; Nemeroff et al. 1984; Risch et al. 1992), although not all studies agree (Geracioti et al. 1997). Postmortem CRH concentrations in cerebrospinal fluid collected from the intracisternal space of depressed persons who had committed suicide and control subjects who had died suddenly were also revealed to be markedly greater in the depressed group than in the control subjects (Arato et al. 1989). Elevated cerebrospinal fluid concen-

Neuropeptides and Hypothalamic Releasing Factors TABLE 3–1.

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Alterations in the activity of the limbic-hypothalamicpituitary-adrenal axis in depression

Increased corticotropin-releasing hormone (CRH) in cerebrospinal fluida,b Blunted adrenocorticotropic hormone (ACTH) and b-endorphin response to CRH stimulationa Decreased density of CRH receptors in frontal cortex of suicide victims Diminished hippocampal volume Pituitary gland enlargement in depressed patientsb Adrenal gland enlargement in depressed patientsb and suicide victims Increased ACTH production during depression Increased cortisol production during depressiona Plasma glucocorticoid, ACTH, and b-endorphin nonsuppression after dexamethasone administrationa Increased urinary free cortisol concentrations a

State dependent. Significantly correlated to postdexamethasone cortisol concentrations.

b

trations of CRH are believed to be a reflection of increased synaptic concentrations of the peptide, likely due to central CRH hypersecretion (Post et al. 1982). The increase in cerebrospinal fluid CRH concentrations that occurs during depression normalizes on recovery. In patients with major depression with psychotic features and elevated cerebrospinal fluid CRH concentrations, clinical recovery after electroconvulsive therapy is associated with significant reductions in cerebrospinal fluid CRH concentrations (Nemeroff et al. 1991). Treatment with antidepressants also results in reduction in cerebrospinal fluid CRH concentrations in healthy volunteers after administration of desipramine (Veith et al. 1992) and in depressed patients after treatment with fluoxetine (DeBellis et al. 1993) or amitriptyline (Heuser et al. 1998). Therefore, elevated cerebrospinal fluid CRH concentrations may represent a state, rather than a trait, marker of depression—that is, a marker of the state of depression rather than a marker of vulnerability to depression (Nemeroff et al. 1991). Furthermore, high or increasing cerebrospinal fluid CRH concentrations despite symptomatic improvement of major depression during antidepressant treatment may be the harbinger of early relapse (Banki et al. 1992b), as Nemeroff and Evans (1984) have previously reported (see below) for dexamethasone suppression test (DST) nonsuppression (Arana et al. 1985). In the standard DST paradigm, patients ingest 1 mg of dexamethasone, a synthetic glucocorticoid, at 2100. Blood samples are obtained at 1600 and 2100 the next day for measurement of plasma cortisol concentrations. Individuals without major depression generally “suppress” or diminish

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endogenous production of cortisol as demonstrated by plasma cortisol concentrations of less than 5.0 mg/dL. Another method for assessing the activity of the HPA axis is the CRH stimulation test, in which CRH (usually 100 mg or 1 mg/kg) is administered intravenously and the ensuing ACTH (or b-endorphin) and cortisol responses are measured (Hermus et al. 1984; S.J. Watson et al. 1988). In drug-free depressed patients, the ACTH and b-endorphin response to exogenously administered ovine CRH is blunted compared with nondepressed subjects (Amsterdam et al. 1988; Gold et al. 1984, 1986b; Holsboer et al. 1984; Kathol et al. 1989; Young et al. 1990). Krishnan et al. (1993) also reported that the blunted ACTH response to CRH occurs in depressed DST nonsuppressors but not in DST suppressors. This neuroendocrine abnormality, like the elevation in cerebrospinal fluid CRH concentration, is state dependent, returning to normal after successful treatment of depression (Amsterdam et al. 1988). (See also Chapter 17 for a more detailed description of CRH testing.) The blunted ACTH response to exogenously administered CRH in depressed patients is likely due (at least in part) to chronic hypersecretion of CRH from the nerve terminals in the median eminence, resulting in downregulation of anterior pituitary CRH receptors with resultant decreased pituitary responsiveness to CRH. Direct evidence for hypersecretion of CRH was provided by Raadsheer and colleagues (1994, 1995), who demonstrated a marked increase in the number of paraventricular nucleus CRH neurons and CRH mRNA expression in postmortem hypothalamic tissue from depressed patients compared with nondepressed control subjects. Such downregulation of CRH receptors in the pituitary in response to excessive CRH secretion was previously documented in laboratory animals (Aguilera et al. 1986; Holmes et al. 1987; Wynn et al. 1983, 1984, 1988). Moreover, in postmortem tissue from those who have committed suicide a decrease in the density of CRH receptors was observed in the frontal cortex (Nemeroff et al. 1988), although a discrepant report does exist (Hucks et al. 1997). On the basis of laboratory animal studies documenting corticotroph cell hypertrophy and hyperplasia in response to CRH, as well as other neuroendocrine alterations in depression (see below), Krishnan et al. (1991) sought to determine whether depressed patients exhibited pituitary gland enlargement. Using magnetic resonance imaging, these authors demonstrated pituitary gland enlargement in depressed patients in comparison to age- and sex-matched control subjects. In a second study, the magnitude of pituitary gland enlargement was significantly correlated to postdexamethasone cortisol concentrations, a measure of HPA axis hyperactivity (Axelson et al. 1992) (see Chapter 18).


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Cortisol hypersecretion in depression has been documented by elevated plasma corticosteroid concentrations (Carpenter and Bunney 1971; Gibbons and McHugh 1962), increased levels of cortisol metabolites (Sachar et al. 1970), and elevated 24-hour urinary free cortisol concentrations. Sachar and colleagues (1970) also reported that cortisol production is increased during depression and returns to normal in most subjects after recovery. Hypercortisolemia appears to be state dependent, like the hypersecretion of CRH and the blunting of the ACTH response to CRH in patients with major depression. Surprisingly, such elevations of plasma cortisol concentrations are not proportional to increases in ACTH concentrations (Linkowski et al. 1985). Moreover, patients exhibit a heightened cortisol response to pharmacologic doses of ACTH, which appears to be due to adrenocortical hypertrophy, not to increased adrenocortical sensitivity (Amsterdam et al. 1983; Kalin et al. 1982; Krishnan et al. 1990) (see below). Based on postmortem reports of enlarged adrenal glands in suicide victims (Zis and Zis 1987) and similar findings from a computed tomographic pilot study of depressed patients (Amsterdam et al. 1987), we conducted a computed tomographic study of 38 depressed patients and confirmed the findings of increased adrenal gland size (Nemeroff et al. 1992). This adrenal hypertrophy likely explains the fact that unlike the blunted ACTH and b-endorphin response to CRH, the plasma cortisol response is not different between depressed patients and healthy control subjects (Amsterdam et al. 1987; Gold et al. 1984, 1986b; Holsboer et al. 1984; Kathol et al. 1989; Young et al. 1990). Enlargement of adrenal glands in depressed patients has now been confirmed using magnetic resonance imaging. It is state dependent (Rubin et al. 1995), waxing and waning in parallel with exacerbation and denouement of clinical depressive symptoms. Such hypertrophy of the adrenal gland in patients with major depression may reflect current adrenocortical capacity (Nemeroff et al. 1993), because one study has reported that adrenal gland size is not correlated with plasma cortisol concentration, lifetime number of depressive episodes, severity of depression, or presence of melancholia (Rubin et al. 1996) (see Chapter 18). DST nonsuppression—like hypercortisolemia, hypersecretion of CRH, blunting of the ACTH response to CRH, and adrenal gland hypertrophy—appears to be state dependent (see Chapter 6). Hypersecretion of CRH during and immediately preceding a depressive episode with secondary pituitary and adrenal gland hypertrophy likely contributes to the multitude of studies reporting that patients with depression manifest HPA axis hyperactivity. Impairment of the normal negative feedback of cortisol on HPA axis activity may exist in the particular subset of depressed patients who exhibit DST nonsuppression. Indeed, elevated

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cerebrospinal fluid CRH concentrations have specifically been shown to occur in depressed patients who are DST nonsuppressors (Pitts et al. 1990; Roy et al. 1987). In healthy volunteers, however, there is evidence that a negative correlation exists between cerebrospinal fluid CRH and simultaneous cortisol plasma concentrations (Kling et al. 1994). Moreover, diminished cerebrospinal fluid CRH concentrations have been documented in depressed patients with normal plasma cortisol concentrations (Geracioti et al. 1997). The recent refinement of the DST is the combined dexamethasoneCRH test. Generally used within clinical research settings, this test is believed to be the most sensitive method of examining HPA axis activity. (See Chapter 17 for details on administration of the dexamethasoneCRH test.) If patients with depression who have been pretreated with dexamethasone are challenged with CRH, a paradoxical increase in ACTH and cortisol release is observed in comparison with control subjects. In nondepressed individuals, pretreatment with dexamethasone suppresses any major elevations of ACTH and cortisol plasma concentrations in response to CRH stimulation. Initial reports indicate the sensitivity of the dexamethasone-CRH test for major depression (about 80%) greatly exceeds that of either the DST (an average of 44%) or the CRH stimulation test (Heuser et al. 1994). The dexamethasone-CRH test is thought to reveal subtle alterations of the negative feedback regulation of the HPA axis (Holsboer-Trachsler et al. 1991). Unlike with the traditional DST, the failure of dexamethasone to prevent CRH stimulation of the HPA axis is not dependent on plasma concentrations of dexamethasone (Holsboer et al. 1987; Ritchie et al. 1990). In contrast to the CRH stimulation test, increases in ACTH plasma concentrations during the dexamethasone-CRH test may demonstrate the secretory stimulus of vasopressin on pituitary ACTH release. Nevertheless, the abnormally increased HPA response to a combined dexamethasoneCRH test gradually diminishes after successful antidepressant treatment (Holsboer-Trachsler et al. 1991) and predicts risk for relapse within 6 months of antidepressant treatment (Zobel et al. 1999). Of particular interest are the findings of Holsboer et al. (1995), who reported that asymptomatic first-degree relatives of patients with major depression exhibit abnormalities in the dexamethasone-CRH test compared with healthy control subjects but not as severe as patients with major depression. Future investigations will undoubtedly study relationships between cerebrospinal fluid CRH and plasma glucocorticoid concentrations; symptom profile studies; and volumetric measures of hippocampal, pituitary, and adrenal glands in depressed patients to further elucidate the relationship among these findings.


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Cerebrospinal fluid CRH concentrations have been measured in a variety of other psychiatric disorders, including the anxiety disorders, schizophrenia, somatization disorders, and Alzheimer’s disease (Table 3–2).

TABLE 3–2.

Hypothalamic-pituitary-adrenal axis activity in anxiety and other psychiatric disorders

Posttraumatic stress disorder Increased cerebrospinal fluid corticotropin-releasing hormone (CRH) concentrations Diminished adrenocorticotropic hormone (ACTH) response to CRH stimulation Plasma cortisol nonsuppression after low-dose (i.e., 0.5 mg) dexamethasone administration Normal or decreased 24-hour urinary free cortisol concentrations Diminished hippocampal volume Panic disorder Normal cerebrospinal fluid CRH concentrations Diminished ACTH response to CRH administration Obsessive-compulsive disorder Normal or increased cerebrospinal fluid CRH concentrations Alcohol dependence Increased cerebrospinal fluid CRH concentrations in acute alcohol withdrawal Anorexia nervosa Increased cerebrospinal fluid CRH concentrations Plasma cortisol nonsuppression after dexamethasone administration Increased plasma cortisol concentrations Increased urinary free cortisol Alzheimer’s disease Increased cerebrospinal fluid CRH concentrations early in the disease Normal cerebrospinal fluid CRH concentration as the disease progresses Diminished cerebrospinal fluid CRH concentration in the later stages of the illness Reduced cerebrospinal fluid CRH concentrations Huntington’s disease Parkinson’s disease Spinocerebellar degeneration Normal cerebrospinal fluid CRH concentrations Generalized anxiety disorder Schizophrenia Somatization disorders Abstinent patients with alcohol dependence

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Involvement of CRH in anxiety disorders has been well documented from both animal and human studies. As reviewed by Arborelius and colleagues (1999), patients with posttraumatic stress disorder (i.e., Vietnam combat veterans) exhibit significantly elevated cerebrospinal fluid CRH concentrations (Baker et al. 1999; Bremner et al. 1997) as well as a diminished response to CRH challenge (M.A. Smith et al. 1989). Unlike patients with major depression, patients with posttraumatic stress disorder exhibit normal 24-hour urinary free cortisol concentrations (Baker et al. 1999) or even reduced plasma concentrations of cortisol, especially after dexamethasone administration (Heim et al. 1997; Yehuda 1997). Although cerebrospinal fluid CRH concentrations are not increased in patients with panic disorder (Fossey et al. 1996; Jolkkonen et al. 1993), a diminished ACTH response to CRH administration has been observed (Roy-Byrne et al. 1986). Increased (Altemus et al. 1992) or normal concentrations (Chappell et al. 1996; Fossey et al. 1996) of cerebrospinal fluid CRH have been documented in patients with obsessive-compulsive disorder, although significant decreases in cerebrospinal fluid CRH concentrations occur with a therapeutic response to clomipramine (Altemus et al. 1994). Patients with generalized anxiety disorder, however, exhibit similar cerebrospinal fluid CRH concentrations in comparison to psychiatrically healthy control subjects (Banki et al. 1992a; Fossey et al. 1996). Not surprisingly, increased concentrations of cerebrospinal fluid CRH occur in alcohol withdrawal, a condition of sympathetic arousal and increased anxiety (Adinoff et al. 1996; Hawley et al. 1994). In contrast, cerebrospinal fluid CRH concentrations are reduced (Geracioti et al. 1994) or normal (Roy et al. 1990) in abstinent individuals with chronic alcoholism who have normal cortisol plasma concentrations. In sum, although HPA-axis hyperactivity exists in patients with certain anxiety disorders, such perturbations do not exist in the patterns suggestive of CRH hypersecretion as documented in patients with major depression (Arborelius et al. 1999). Normal cerebrospinal fluid CRH concentrations are usually found in schizophrenic patients (Banki et al. 1987, 1992c; Nemeroff et al. 1984; Nishino et al. 1998), and these patients exhibit normal ACTH and cortisol responses to CRH (Roy et al. 1986). However, after maintenance haloperidol was replaced by placebo, cerebrospinal fluid CRH plasma concentrations significantly increased in male schizophrenic patients and was unrelated to psychotic, depression, or anxiety symptoms (Forman et al. 1994). Reductions in cerebrospinal fluid CRH concentrations are generally reported in patients with neurodegenerative brain disorders, such as Huntington’s disease, Parkinson’s disease, end-stage Alzheimer’s disease (Edvinsson et al. 1993; Heilig et al. 1995; Suemaru et al. 1993), or


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spinocerebellar degeneration (Suemaru et al. 1995). However, increased cerebrospinal fluid CRH concentrations have been documented in patients with Alzheimer’s disease who exhibit DST nonsuppression (Martignoni et al. 1990) and in patients with dementia and depression (Banki et al. 1992a). Elevated cerebrospinal fluid CRH concentrations have also been reported in patients with Tourette’s syndrome in comparison to control subjects (Chappell et al. 1996). Unfortunately, most of these studies have failed to carefully measure dimensional indices of comorbid depressive symptoms that would be expected to be associated with elevations of cerebrospinal fluid CRH concentrations across these seemingly disparate psychiatric and neurological disorders. Another psychiatric syndrome with evidence of HPA axis hyperactivity and CRH hypersecretion is anorexia nervosa. In fact, many patients with anorexia nervosa also exhibit comorbid depressive symptoms. Elevated cerebrospinal fluid CRH concentrations have been reported in patients with anorexia nervosa (Hotta et al. 1986; Kaye et al. 1987). As in individuals with depression, patients with anorexia nervosa exhibit elevated plasma cortisol levels, increased secretion of urinary free cortisol, and DST nonsuppression (Brambilla et al. 1985). Kaye and colleagues (1987) reported that cerebrospinal fluid concentrations of CRH are significantly correlated with depression severity ratings in patients with weight correction. Moreover, normalized pituitaryadrenal function and cerebrospinal fluid CRH concentrations occur on weight recovery. As in major depression, underweight anorexic patients exhibited a blunted ACTH response after intravenous CRH administration (Gold et al. 1986a; Hotta et al. 1986). ACTH responses to CRH normalize after weight gain. Hotta and colleagues (1986) report that this normalization occurs immediately after correction of weight loss. However, the ACTH response to CRH has also been reported to normalize only after 6 months following weight gain. In summary, underweight patients with anorexia nervosa have been observed to exhibit elevated cerebrospinal fluid CRH concentrations and a blunted ACTH response to CRH, and normalization of both perturbations occurs on recovery of weight. Further research will seek to elucidate the role of CRH in anorexia nervosa and to determine whether it is associated only with the frequent comorbid major depression. Given the putative role of CRH in the stress response and the disease state of major depression, multiple pharmacologic treatment strategies have been considered, including inhibition of CRH synthesis, secretion, and metabolism, and neutralization of CRH by antibodies (Chalmers et al. 1996). Currently in development in multiple laboratories is another exciting strategy, the use of small-molecule, nonpeptide CRH receptor

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antagonists capable of crossing the blood-brain barrier (Deak et al. 1999). A CRH receptor antagonist could be targeted to either of the two subtypes of CRH receptors: the CRH1 or CRH2 receptors. CRH1 receptors exist within the pituitary, cerebellum, neocortex, and sensory structures. The CRH2 receptor, whose role is less well defined, is localized within subcortical areas such as the amygdala and hypothalamus, or peripheral organs such as cardiac and skeletal muscle, lung, and intestine (Chalmers et al. 1995; Lovenberg et al. 1995; Perrin et al. 1995). The distinctive distribution of CRH1 receptor subserves its function as the primary neuroendocrine pituitary receptor responsible for the CRH-stimulated ACTH release and its importance in cortical, cerebellar, and sensory functions. The localization of the CRH2 receptor is considered to relay not only the neuroendocrine actions but also autonomic and behavioral actions of CRH (Chalmers et al. 1995; Dieterich et al. 1997). Furthermore, with the discovery of urocortin (Vaughan et al. 1995), the preferred ligand for the CRH2 receptor, a series of experiments must now be undertaken concerning a role for this novel peptide in mood and anxiety disorders. Certain CRH receptor antagonists diminish fear (Deak et al. 1999; Schultz et al. 1996) or learned helplessness responses (Mansbach et al. 1997) in animals. These are in the last stages of drug development for human use and will likely produce a novel class of antidepressants or anxiolytics (Arborelius et al. 1999).

Endogenous Opioid Peptides The isolation of the endogenous opioid–like neuropeptides methionineenkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin) by Hughes and colleagues in 1975 and the discovery of b-endorphin in 1976 by Li and Chung were followed by determination of a third endogenous opioid peptide system, the dynorphins (Goldstein et al. 1979). In the approximately 20 years since their discovery, intensive examination of these peptides has provided evidence for their involvement in a variety of physiological processes, including regulation of pain, mood, respiration, cardiovascular function, gastrointestinal activity, satiety, and sexual behavior. Now recognized as brain neurotransmitters, endogenous opioid peptides exist within a variety of organs such as the pituitary, thyroid, adrenal gland, gastrointestinal tract, placenta, and peripheral nervous system (see review by A.I. Smith and Funder 1988). At the genomic level, three genes are responsible for the precursors of opioid peptides: POMC,


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proenkephalin, and prodynorphin. Consequently, there are at least three classes of opioid peptides with different biosynthetic and neuronal pathways: the b-endorphins, the enkephalins, and the dynorphins. In the adenohypophysis (Bloom et al. 1976), POMC is processed to yield only ACTH and b-lipotropin. b-Lipotropin is then processed to yield at least three compounds, including b-, g-, and a-endorphin. The second endogenous opioid system is composed of the enkephalins whose precursor is proenkephalin. This enkephalin family contains among its opioid compounds met-enkephalin and leu-enkephalin. Derived from prodynorphin is the third group of endogenous opioid peptides, including dynorphin A, dynorphin B, and neoendorphin, which is located almost exclusively in the posterior pituitary. Investigation of the role of endogenous opioid peptides in psychiatric illness has largely focused on schizophrenia, the major mood disorders, the eating disorders, and childhood autism and self-injurious behavior (Frecska and Davis 1991). Clinical investigations have used various approaches, including measurement of endogenous opioid concentrations in cerebrospinal fluid and plasma, neuroendocrine challenge tests with determination of opioid responses, administration of opioid receptor agonists or antagonists in clinical trials, postmortem regional brain measurements, and even removal of opioid peptides from plasma of schizophrenic patients via hemodialysis or peritoneal dialysis. Intensive research conducted over two decades has produced no evidence that endogenous opioid peptides play an important role in either the pathophysiology or treatment of schizophrenia (see below). However, the investigations of patients with affective illness indicate that alterations of certain endogenous opioid peptides (e.g., b-endorphin) occur in conjunction with HPA axis hyperactivity in patients with major depression. These findings are not surprising, because b-endorphin and ACTH share a common precursor, POMC, within the anterior pituitary, and both are concomitantly released during stress (Guillemin et al. 1977). Most investigators (Black et al. 1986; Gerner and Sharp 1982; Inturrisi et al. 1982; Naber et al. 1981; Pickar et al. 1982), but not all (Risch 1982), have reported normal concentrations of cerebrospinal fluid b-endorphin in patients with major depression. Because of these negative findings and a lack of other evidence, extensive scrutiny of cerebrospinal fluid enkephalin and dynorphin concentrations in patients with affective disorder has not been conducted. In contrast, increased concentrations of basal plasma b-endorphin in patients with major depression are usually observed (Brambilla et al. 1986; Breier 1989; Gispen-de-Wied et al. 1987; Risch 1982), although there is one discrepant report of no significant alterations of basal plasma b-endorphin in depressed patients (Young et al.

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1990). However, depressed patients with increased urinary free cortisol concentrations exhibit positive correlations between their urinary free cortisol and cerebrospinal fluid opioid concentrations compared with healthy individuals (Rubinow et al. 1981). Such a correlation between plasma cortisol and b-endorphin concentrations has also been observed in depressed patients (Cohen et al. 1984). Similar to the ACTH response to intravenous CRH challenge (see above), the b-endorphin response to exogenously administered ovine CRH is blunted in depressed patients compared with nondepressed subjects (Young et al. 1990). Moreover, nonsuppression of plasma b-endorphin occurs in depressed patients in a manner similar to cortisol nonsuppression after dexamethasone administration. b-Endorphin nonsuppression to dexamethasone has been observed even in patients whose baseline b-endorphin levels were similar to those of healthy control subjects (Maes et al. 1990; Meador-Woodruff et al. 1987; Rupprecht et al. 1988). In these patients, postdexamethasone levels of cortisol and b-endorphin were strongly correlated (Maes et al. 1990; Rupprecht et al. 1988). In contrast, depressed patients have been reported to exhibit increased secretion of b-endorphin in response to cholinergic stimulation (Risch et al. 1982), thyrotropin-releasing hormone (TRH), and luteinizing hormone– releasing hormone (LHRH) in comparison with control subjects (Brambilla et al. 1986). Unfortunately, neither opioid agonists nor opioid antagonists have been found to be effective in the treatment of unipolar disorder, bipolar disorder, or schizophrenia. The short-acting opiate antagonist naloxone can prevent the induction of hallucination and thought disorganization after administration of exogenous opiates (such as b-endorphin) ( Jasinski et al. 1967; Pickar et al. 1984). Used as single agents, opioid antagonists were ineffective in patients with schizophrenia but were initially thought to be effective as an adjuvant treatment (Bissette et al. 1986a; Pickar et al. 1981a, 1981b, 1982a). In the international collaborative World Health Organization trial, neuroleptic augmentation with repeated doses of naloxone was comparable to placebo in reducing psychotic symptoms of schizophrenia patients (Pickar et al. 1989). A single report does exist in which long-term administration (for more than 30 days) of the highly potent opioid receptor antagonist nalmefene was more effective than placebo in decreasing psychotic symptoms (Rapaport et al. 1993). Several case reports document reductions in self-injurious behavior in patients with autism and mental retardation after administration of one of the opioid receptor antagonists naloxone (Barrett et al. 1980; Bernstein et al. 1984; Davidson et al. 1983; Gillman and Sandyk 1985; Richardson and Zaleski 1983; Sandman et al. 1983, 1987; Sandyk 1985) and naltrex-


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one (Campbell et al. 1989; Casner et al. 1996; Herman et al. 1987). However, there are some negative reports (Beckwith et al. 1986; Szymanski et al. 1987). A few reports document the efficacy of naltrexone in diminishing self-injurious behaviors in patients with borderline personality disorder as well (Roth et al. 1996). With minor exception, these reports are generally limited by open-label design, a relatively brief duration of treatment, small numbers of patients, characterization of patients by behavior rather than etiology, or a retrospective perspective (Casner et al. 1996). It has been hypothesized that such self-injury results in pain-induced endorphin release with continued stereotyped behaviors by the patient in an attempt to maintain increased endogenous opioid levels. In concordance with this hypothesis, investigators have reported increased cerebrospinal fluid endorphin concentrations in self-injurious autistic children compared with autistic patients without such behaviors (Gillberg et al. 1985). In fact, increased plasma concentrations of b-endorphin (Sandman 1988) and met-enkephalin (Coid et al. 1983) have been detected in self-injurious, developmentally disabled individuals in comparison with control subjects. Although the aforementioned results are very preliminary, they certainly serve as an impetus for further scrutiny.

Vasopressin Arginine vasopressin (AVP), the antidiuretic hormone, is one of the two posterior pituitary hormones. The most well-known AVP pathway consists of AVP-containing neurons whose cell bodies lie within the lateral magnocellular subdivision of the hypothalamic paraventricular and supraoptic nuclei. These AVP-containing neurons terminate in the neurohypophysis and secrete AVP into the systemic circulation, although they have collaterals to the hypothalamo-hypophyseal portal system as well (Chrousos 1992). Another group of AVP-containing neurons project from the medial parvocellular subdivision of the paraventricular nucleus to the median eminence. Within the median eminence, the parvocellularderived AVP is released from axon terminals, secreted into the hypothalamo-hypophyseal portal circulation, and carried to the anterior lobe of the pituitary gland (Swanson et al. 1983). Moreover, extrahypothalamic AVP-containing neurons lie within limbic structures such as the septum and amygdala, as well as the brainstem and spinal cord (Sawchenko and Swanson 1982; Swanson 1987). AVP-containing neurons also receive afferent innervation from many different neuronal cell groups and send axonal projections from the cerebral cortex throughout the CNS.

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It is thought that AVP and the other well-known posterior pituitary hormone, the nonapeptide oxytocin, play a role in modulating neural activity in hypothalamic, limbic, and autonomic circuits. Osmotic and chemoreceptor stimulation, hemorrhage, and hypotension activate the magnocellular neurons of the paraventricular nucleus and increase secretion of AVP from the neurohypophysis and extrahypothalamic brain regions (Cunningham and Sawchenko 1991). AVP allows the reabsorption of water back into the body by increasing the permeability of the distal and collecting ducts of the kidney tubules. The normal, narrow reference range of osmolality in humans is 280–295 mOsm/kg. To protect the body from a hyperosmolar state, maximal stimulation of AVP occurs at 295 mOsm/kg; antidiuretic hormone is not secreted as hypo-osmolarity approaches (i.e., near 280 mOsm/kg). In humans an increase in plasma osmolality as minute as 2% stimulates a twofold to threefold surge in plasma levels of AVP. When plasma osmolality is normal, AVP is secreted in large amounts during hypovolemia and hypotension. However, approximately 40 times more AVP is required to increase blood pressure compared with antidiuresis. Chronic stress or adrenalectomy increases the activity of the parvocellular AVP system (DeGoeij et al. 1992; Whitnall 1989). Interestingly, AVP and CRH are the major hypothalamic secretagogues for ACTH release. AVP administered together with CRH produces a synergistic release of pituitary POMC-derived peptides, that is, ACTH and b-endorphin in humans (DeBold et al. 1984) and animals (Plotsky 1991). CRH and AVP are co-localized in the parvocellular cells of the human hypothalamus and may be secreted together into the human hypothalamic-hypophyseal portal circulation (Mouri et al. 1993). The ratio of AVP to CRH in the hypothalamic-hypophyseal portal circulation varies in different species (Plotsky 1991) and according to the nature of the stress (Canny et al. 1989; Caraty et al. 1990). Similar to the clinical investigations regarding CRH, a variety of patient groups have been studied. Alterations of cerebrospinal fluid AVP have been reported in patients with major depression, bipolar disorder, schizophrenia, anorexia, obesity, alcoholism, Alzheimer’s disease, and Parkinson’s disease (Demitrack et al. 1989; Legros et al. 1993). Cerebrospinal fluid AVP concentrations in patients with major depression are reportedly reduced in comparison with control subjects, although the source of cerebrospinal fluid AVP is likely extrahypothalamic and not, in contrast to its purported hypersecretion, from the paraventricular nucleus in major depression (Gjerris et al. 1984, 1985; Linkowski et al. 1984). Basal plasma concentrations of AVP (secreted from the magnocellular neurons of the paraventricular nucleus after osmotic or barorecep-


45

tor stimulation) within depressed patients have also been reported to be decreased in comparison with age-matched control subjects (Laruelle et al. 1990), although other researchers have found no difference (Gold et al. 1981). Interestingly, AVP secretion in response to an infusion of hypertonic saline is diminished in depressed patients compared with control subjects (Gold et al. 1981). A blunted ACTH response to exogenous AVP administration in depressed patients was reported by Kathol et al. (1989), but the finding was not replicated by two other studies (Carroll et al. 1993; Meller et al. 1987). Remarkably, an increase in the number of paraventricular nucleus AVP neurons co-localized with CRH cells has been reported in depressed patients compared with control subjects (Purba et al. 1996; Raadsheer et al. 1994). This is of interest in view of the ability of AVP to potentiate the actions of CRH at the corticotroph. In contrast to the findings suggestive of diminished hypothalamic-vasopressinergic activity in depressed patients are the findings suggestive of hypersecretion of AVP observed in bipolar patients in the manic phase. Elevations in cerebrospinal fluid AVP concentrations have been documented in manic patients (Legros et al. 1983), as have significant increases in plasma AVP concentrations in relation to patients with unipolar depression and control subjects (Legros and Ansseau 1989). AVP dysregulation has also been demonstrated in anorexia nervosa. Underweight anorexia nervosa patients exhibit osmotic dysregulation characterized by AVP release dissociated from gradual increases in plasma osmolality (Gold et al. 1983) in comparison with control subjects, in whom increases in plasma osmolality are accompanied by a linear rise in plasma AVP (Robertson et al. 1976). Although the AVP response to increased plasma osmolality may normalize with weight recovery, some anorexia nervosa patients demonstrate persisting defects in osmoregulation after weight stabilization for more than 6 months. Furthermore, patients with anorexia nervosa exhibit a cerebrospinal fluid to plasma AVP ratio greater than 1, in contrast to healthy control subjects, who exhibit a cerebrospinal fluid to plasma AVP ratio less than 1. This reversal of the cerebrospinal fluid to plasma AVP ratio persists well after weight recovery for some anorexia nervosa patients. Disturbances of AVP function have been thought to exist in aging individuals, particularly those with neurodegenerative syndromes (e.g., Parkinson’s disease), due to their cognitive dysfunction and associated perturbations of fluid and electrolyte homeostasis (Leake et al. 1991). Patients with Alzheimer’s disease were initially reported to exhibit CNS AVP hyposecretion as evidenced by reduced AVP brain concentrations (Fujiyoshi et al. 1987), diminished AVP cerebrospinal fluid concentrations (Bevilacqua et al. 1986; Mazurek et al. 1986a, 1986b; Raskind et

46


al. 1986), a blunted AVP and b-endorphin response to cholinergic challenge with intravenous physostigmine (Raskind et al. 1989), and a diminished ACTH and cortisol response to a combined intravenous CRH/AVP stimulation test (Dodt et al. 1991). However, further investigation of AVP-producing neurons within the paraventricular nucleus and supraoptic nucleus of the hypothalamus revealed that the neurons expressing AVP in the paraventricular nucleus and supraoptic nucleus do not decline in number (and may even increase) during aging or in Alzheimer’s disease (Van der Woude et al. 1995). During aging or in Alzheimer’s disease, there may be increased (“activated”) peptide synthesis within the AVPproducing neurons, as evidenced by increased plasma concentrations of AVP and hypertrophy of AVP neurons (Vogels et al. 1990) with enlarged nuclei and Golgi apparatus (Lucassen et al. 1993). Other investigators have even observed that cerebrospinal fluid AVP concentrations in patients with Alzheimer’s disease are similar to concentrations seen in control subjects (Jolkkonen et al. 1989), as are postmortem brain AVP concentrations (Leake et al. 1991; van Zwieten et al. 1996) and AVPmRNA levels (Lucassen et al. 1997). Another challenge study also documented that patients with Alzheimer’s disease exhibit plasma AVP responses to osmotic stimulation induced by hypertonic saline infusion that are quite similar to those seen in healthy control subjects (Peskind et al. 1995). The discordant results within the extant literature of AVP perturbations in patients with Alzheimer’s disease are no doubt due to multiple studies with small sample sizes, assay variability, and the inherent difficulties of postmortem brain studies (e.g., fixation time, postmortem delay). Moreover, despite early hopes for AVP as a cognitive enhancing agent, neither vasopressin nor its analogs have been effective in the treatment of patients with memory disorders such as Alzheimer’s disease or Korsakoff’s syndrome (Legros and Timsit-Berthier 1988). Multiple groups have investigated whether alterations of cerebrospinal fluid AVP concentrations exist in patients with schizophrenia. Schizophrenic patients have been observed to exhibit increased (Linkowski et al. 1984), diminished (Linkowski et al. 1984; Van Kammen al. 1981), or similar (Beckmann et al. 1985) cerebrospinal fluid concentrations of AVP in comparison with healthy control subjects. However, two so-called challenge studies—one utilizing apomorphine (a dopamine receptor agonist) and the other methylphenidate (a dopamine releasing agent)—have provided tantalizing clues regarding alterations of AVP secretion in patients with schizophrenia. Legros and colleagues (1992) observed that, in comparison with healthy control subjects, schizophrenic patients exhibit a blunted vasopressin (and oxytocin) response following an apomorphine challenge. Moreover, after methylphenidate administra-


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tion, schizophrenic patients with psychogenic polydipsia exhibit significant increases in vasopressin plasma concentrations despite concomitant hyponatremia compared with patients with polydipsia but not hyponatremia. Clearly, hypothalamic and extrahypothalamic AVP circuits are regulated independently. Whether the perturbations of AVP secretion in patients with neuropsychiatric disorders are state dependent or trait dependent requires further elucidation.

Growth Hormone and Somatostatin Growth hormone is synthesized and secreted from the somatotroph cells of the anterior pituitary. Its secretion is modulated primarily by two hypothalamic hypophysiotropic hormones—growth hormone–releasing hormone (GHRH) and somatostatin—and secondarily by classic neurotransmitters such as dopamine, norepinephrine, and 5-HT that innervate the releasing factor–containing neurons (Table 3–3). Located primarily in the arcuate nucleus of the hypothalamus, GHRH stimulates the synthesis and release of growth hormone. Inhibition of growth hormone release is mediated primarily by somatostatin, a tetradecapeptide, which is found primarily in the periventricular nucleus of the hypothalamus. Somatostatin, unlike GHRH, is widely distributed in extrahypothalamic brain regions, including the cerebral cortex, hippocampus, and amygdala. Both GHRH and somatostatin are released from nerve terminals in the median eminence and are transported via the hypothalamohypophyseal portal system to act on the growth hormone–producing somatotrophs of the anterior pituitary. Release of growth hormone is stimulated by levodopa (Boyd et al. 1970), a catecholamine precursor, and by apomorphine, a dopamine receptor agonist (Lal et al. 1973). Growth hormone release also occurs after the administration of the serotonin precursors L-tryptophan and 5-hydroxytryptophan (5-HTP) (Imura et al. 1973; Muller et al. 1974). Serotonin receptor antagonists methysergide and cyproheptadine interfere with the growth hormone response to hypoglycemia (Toivola et al. 1972). Clonidine, a central a2-adrenergic receptor agonist (Lal et al. 1975), and norepinephrine (Toivola et al. 1972) also stimulate the release of growth hormone. In contrast, phentolamine, a nonspecific a-adrenergic receptor antagonist, inhibits growth hormone secretion (Toivola et al. 1972). Growth hormone secretion varies in a daily circadian pattern that decreases in magnitude as one ages. Under normal basal conditions, growth hormone is secreted in pulses that are highest during the initial hours of the night (Finkelstein et al. 1972).

48 TABLE 3–3.

PSYCHONEUROENDOCRINOLOGY Releasing and inhibiting factors for growth hormone

Growth hormone–releasing factors Growth hormone–releasing hormone Dopamine Levodopa Apomorphine (dopamine receptor agonist) Norepinephrine Clonidine (nonspecific a-adrenergic receptor agonist) Serotonin L-Tryptophan 5-Hydroxytryptophan Factors that inhibit growth hormone release Somatostatin Phentolamine (nonspecific a-adrenergic receptor antagonist) Methysergide (serotonin receptor antagonist) Cyproheptadine (serotonin receptor antagonist)

The growth hormone response to exogenously administered GHRH has been studied in drug-free depressed patients. At present, this test has not been standardized to body weight, which significantly correlates with the growth hormone response to GHRH in healthy subjects (Krishnan et al. 1988). Further confounding factors include the influence of sex, age, and menstrual cycle on the growth hormone response to GHRH. The existing data on responses to GHRH in subjects with depression is discordant, possibly because of the factors listed above (Nemeroff and Krishnan 1992). However, the vast majority of studies have reported a marked attenuation of the growth hormone response to noradrenergic agents (e.g., clonidine, desipramine) (Charney et al. 1982; Checkley et al. 1981; Dinan and Barry 1990; Matussek et al. 1980; Siever 1987; Siever et al. 1982) and, to a lesser extent, dopaminergic agonists (apomorphine) (Ansseau et al. 1988) in depressed patients. In depressed patients, dysregulation of the secretion of growth hormone is also indicated by other findings (Table 3–4). Not only is nocturnal growth hormone secretion diminished in depressed patients (Schilkrut et al. 1975), but hypersecretion of growth hormone during the waking hours has been reported in unipolar and bipolar patients compared with nondepressed control subjects (Mendlewicz et al. 1985). With the characterization of the genes encoding GHRH and its receptor, alterations in the CNS of depressed patients that underlie the diminished growth hormone response to norepinephrine and dopamine agonists can now be studied in postmortem tissue.


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Growth hormone disturbances associated with major depression

Blunted growth hormone response to noradrenergic or dopaminergic agents Reduction of nocturnal growth hormone secretion Hypersecretion of growth hormone during waking hours

A substantial body of literature also exists regarding alterations of somatostatin in patients with major depression and other neuropsychiatric disorders such as Alzheimer’s disease and multiple sclerosis (see the extensive review by Rubinow and colleagues 1995). Somatostatin not only inhibits growth hormone release, but it also has multiple inhibitory effects on various neuroendocrine systems, including reducing secretion of thyroid-stimulating hormone (TSH) and CRH. Although somatostatin does not alter ACTH concentrations in nondepressed control subjects (Ambrosi et al. 1990; Patel 1992), somatostatin infusion diminishes hypoglycemia-induced increases of cortisol concentration (Rubinow et al. 1992). In preclinical studies, somatostatin influences a variety of vegetative functions (including appetite and locomotor activity), as well as analgesia and learning (Rubinow et al. 1995; Vecsei and Widerlov 1990; Walsh et al. 1985) There are at least seven studies documenting diminished cerebrospinal fluid concentrations of somatostatin in patients with major depression (Agren and Lundqvist 1984; Bissette et al. 1986b; Gerner and Yamada 1982; Kling et al. 1993; Molchan et al. 1991; Rubinow et al. 1983, 1984, 1995). Indeed, hypercortisolemia and diminished cerebrospinal fluid somatostatin-like immunoreactivity (SLI) have often been observed in patients with psychiatric disorders (Wolkowitz et al. 1987). Reduced cerebrospinal fluid somatostatin concentrations have been reported in patients exhibiting dexamethasone nonsuppression (whether schizophrenic or depressed) and are negatively correlated with the maximum postdexamethasone cortisol plasma concentration in patients with major depression (Doran et al. 1986). In fact, administration of supraphysiological doses of prednisone to healthy volunteers is accompanied by significant reductions of cerebrospinal fluid SLI (Wolkowitz et al. 1987). Although there is some evidence of normalization of cerebrospinal fluid somatostatin concentration after recovery from depression (Agren and Lundqvist 1984; Post et al. 1988; Rubinow et al. 1984), other studies have noted no significant changes in cerebrospinal fluid somatostatin concentrations of depressed patients despite clinical improvement with antidepressant (Banki et al. 1992b) or electroconvulsive therapy treatment (Nemeroff et al. 1991). Interestingly, administration of certain psychotropic medi-

50


cations is known to 1) decrease cerebrospinal fluid somatostatin concentrations (e.g., carbamazepine [Rubinow et al. 1992], diphenylhydantoin, and fluphenazine [Doran et al. 1989]); 2) increase cerebrospinal fluid somatostatin concentrations (e.g., haloperidol [Gattaz et al. 1986]; or 3) have no effect (e.g., desmethylimipramine or lithium carbonate [Rubinow et al. 1992]). Reductions of cerebrospinal fluid somatostatin concentrations have also been consistently observed in patients with Alzheimer’s disease (Bissette et al. 1986b; Oram et al. 1981; Soininen et al. 1984; Wood et al. 1983), as have reductions in somatostatin in brain—particularly in the frontal, parietal, and temporal cortices—on postmortem examination (Lowe et al. 1988). Obvious alterations of CNS growth hormone and somatostatin concentrations and function exist in major depression, although whether these changes represent fundamental contributors to this syndrome or are merely epiphenomena remains to be determined. Diminished concentrations of the inhibitory neuropeptide somatostatin might plausibly allow CRH hypersecretion and increased HPA axis activity. Further elucidation of somatostatin receptor function and the effects and utility of somatostatin receptor agonists and antagonists will provide important information regarding the pathophysiology of major depression and neurodegenerative disorders such as Alzheimer’s disease.

Cholecystokinin First identified in the gastrointestinal tract as a 33–amino acid peptide, cholecystokinin (CCK) (Mutt and Jorpes 1968) was discovered in the mammalian CNS in 1975. Utilizing a gastrin antiserum that avidly crossreacts with CCK, Vanderhaeghen and colleagues (1975) found abundant gastrin-like material in the brains of many vertebrate species, including humans. Amino acid sequence analysis determined this substance to be the carboxyl-terminal amidated peptide CCK 8 (Dockray et al. 1978). In the gut, CCK exists predominantly in its larger forms of CCK 22, 33, 39, and 58, with smaller quantities of CCK 8. In the brain, its major amidated form is CCK 8. Interestingly, CCK is found in higher concentrations in the brain than in the gastrointestinal tract. In the brain, only neuropeptide Y exists in higher concentrations than CCK. CCK and high densities of its receptors exist in areas of the mammalian brain associated with emotion, motivation, and sensory processing, such as the cortex, striatum, hypothalamus,


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hippocampus, and amygdala (Dietl and Palacios 1989; Hokfelt et al. 1980; Innis and Snyder 1980; Saito et al. 1980; Tang and Man 1991). CCK is often co-localized with dopamine in the mesolimbic and mesocortical areas. Of the two major subtypes of CCK receptors that exist, the CCKA receptor is primarily found in the bowel, pancreas, and gallbladder, whereas the CCKB receptor predominates in the brain. Cholecystokinin has been reported to reduce the release of dopamine (Fuxe et al. 1980; Lane et al. 1986; Voigt et al. 1986); conversely, the release of CCK is modulated by dopamine (Meyer and Krauss 1983; Meyer et al. 1984). Moreover, preclinical studies indicated that dopaminergic neuronal activity may be either facilitated or inhibited by CCK (Crawley et al. 1985; Hommer and Skirboll 1983; Vaccarino and Rankin 1989; Van Ree et al. 1983). Therefore, initial investigation of a putative role for CCK in the pathophysiology of neuropsychiatric disorders focused on the potential involvement of the peptide in schizophrenia. Concentrations of CCK in cerebrospinal fluid of medication-free schizophrenic patients were reported to be decreased (Garver et al. 1991a; Lotstra et al. 1985; Verbanck et al. 1984), increased (Gerner et al. 1985), or unchanged (Gerner and Yamada 1982; Gjerris et al. 1984; Rafaelsen and Gjerris 1985) compared with control subjects. Unfortunately, the CCK analog cerulein produced no therapeutic benefit to medication-free schizophrenic patients (Hommer et al. 1985), and the efficacy of ongoing antipsychotic drug treatment of schizophrenic patients was not improved with co-administration of a decapeptide closely related to CCK, ceruletide (Hommer et al. 1985), or the CCK antagonist proglumide (Hicks et al. 1989; Innis et al. 1986). Investigation of possible perturbations of CCK function in patients with mood disorders has also demonstrated rather disappointing findings. There is a single report of diminished concentrations of cerebrospinal fluid CCK in patients with bipolar disorder (Verbanck et al. 1984), but similar findings have not been made in unipolar depression (Gerner and Yamada 1982; Gjerris et al. 1984; Lotstra et al. 1985; Rafaelsen and Gjerris 1985). Impetus for study of the role of CCK in the pathophysiology of panic disorder and other anxiety disorders was provided by the finding that intravenous injection of cholecystokinin tetrapeptide (CCK 4) induced panic symptoms in healthy individuals (De Montigny 1989). In a subsequent double-blind study, patients with panic disorder experienced panic attacks after intravenous administration of CCK but not after saline challenge (Bradwejn et al. 1990). Furthermore, compared with healthy control subjects, patients with panic disorder exhibit an increased sensitivity to CCK 4, a preferential CCKB receptor agonist (Bradwejn et al. 1991a, 1991b, 1992), although both panic disorder patients and control subjects

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experience panic attacks with increasing doses of CCK-4 (Bradwejn et al. 1991a, 1991b). These findings were extended in investigations in which pentagastrin (another CCKB receptor agonist) provoked panic attacks in patients with panic disorder and, to a lesser extent, in patients with generalized anxiety disorder (Brawman-Mintzer et al. 1997) and healthy control subjects (Abelson and Nesse 1990; van Megen et al. 1994). Of note is that patients with panic disorder exhibit diminished cerebrospinal fluid CCK concentrations in comparison with control subjects (Lydiard et al. 1992). The development of CCKB receptor antagonists may be a potentially novel treatment for panic disorder and other anxiety disorders. Certain CCKA or CCKB receptor antagonists have demonstrable anxiolytic (Hendrie and Dourish 1990; Hughes et al. 1990; Ravard and Dourish 1990; Ravard et al. 1990), antidepressant (Kelly and Leonard 1992), or memoryenhancing (Lemaire et al. 1992) effects in animals. Moreover, in patients with panic disorder, administration of L-365,260, a benzodiazepine-derived CCKB receptor antagonist, blocks CCK 4–induced panic (Bradwejn et al. 1994). In control subjects without panic disorder, L-365,260 did not exhibit an anxiolytic effect but did not induce adverse changes in mood, appetite, or memory (Grasing et al. 1996). Another compound, CI-988, has been studied in patients with generalized anxiety disorder but was not more effective than placebo as an anxiolytic (Adams et al. 1995). Nevertheless, efforts continue toward the development of an alternative, effective anxiolytic that does not have the adverse sedative and cognitive effects of benzodiazepines.

Neurotensin Discovered in 1973 by Carraway and Leeman in bovine hypothalamus, the tridecapeptide neurotensin exerts a variety of actions on endocrine and gastrointestinal systems, in addition to its function within the CNS. The highest concentrations of neurotensin are within the hypothalamus, particularly the posterior hypothalamus and mammillary bodies. Significant concentrations of neurotensin are also found within the substantia nigra, ventral tegmental area, and central nucleus of the amygdala, as well as the dorsal hippocampus, septum, dorsal pallidum, and nucleus accumbens (Jennes et al. 1982; Manberg et al. 1982). Although a discussion of the anatomical localization of neurotensin is beyond the scope of this chapter (see Bissette and Nemeroff 1995 for review), the most extensively characterized neurotensin pathway is the mesolimbic-cortical projection


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of neurotensin-containing neurons from the ventral tegmental area to the frontal cortex and nucleus accumbens (Kalivas and Miller 1984). Partly because of the extensive co-localization of neurotensin and dopamine in the rat brain and the neuroleptic-like effects of neurotensin, intensive investigation of the hypothesis that this peptide is an endogenous neuroleptic continues (Binder et al. 2001). Decreased neurotensin concentrations in the cerebrospinal fluid of drug-free schizophrenic patients in comparison with healthy sex- and age-matched control subjects have been observed in several studies (Garver et al. 1991b; Lindstrom et al. 1988; Widerlov et al. 1982). Although one study determined no significant difference in cerebrospinal fluid neurotensin concentrations between drug-free schizophrenic patients and control subjects (Breslin et al. 1994), even these researchers observed a bimodal distribution of cerebrospinal fluid neurotensin in their cohort of schizophrenic patients. Indeed, reductions in cerebrospinal fluid neurotensin concentrations have not been observed in other psychiatric syndromes, notably major depression, anorexia-bulimia, or premenstrual syndrome (Nemeroff et al. 1989a). Preclinical studies have demonstrated that administration of typical antipsychotic drugs such as haloperidol and chlorpromazine is associated with increases in neurotensin concentrations and neurotensin mRNA expression in both the caudate nucleus and nucleus accumbens. The atypical antipsychotic clozapine increases neurotensin concentrations in the nucleus accumbens but not in the striatum, which likely contributes to the lower incidence of extrapyramidal side effects observed with clozapine treatment (Govoni et al. 1980; Kinkead and Nemeroff 1994; Levant and Nemeroff 1992). Microdialysis studies have revealed that these increases in tissue concentrations are mirrored by increases in extracellular fluid concentrations of neurotensin (Radke et al. 1996). Moreover, concentrations of neurotensin in the aforementioned brain regions are not altered by tricyclic antidepressants, antihistamines, or benzodiazepines. Antipsychotic drug treatment of schizophrenic patients is also followed by significant increases in cerebrospinal fluid neurotensin concentrations (Breslin et al. 1994; Widerlov et al. 1982). Another technique that has been used to study neurotensin alterations associated with psychopathology is postmortem brain investigation, although it can be confounded by antipsychotic treatment administered during the patient’s life, which may alter concentrations of neurotensin in the brain. Postmortem examinations of seven subcortical brain regions of schizophrenic patients, including nucleus accumbens and caudate nucleus tissue, have not demonstrated significant alterations of neurotensin concentrations (Kleinman et al. 1983; Nemeroff et al. 1983). In the studies examining seven areas of cortical tissue, only Brodmann’s area 32 of

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the schizophrenic brain exhibited a significant group mean increase in neurotensin concentration relative to the control group (Nemeroff et al. 1983). Bean and colleagues (1992) found no difference between schizophrenic patients and control subjects in concentrations of neurotensin mRNA or in its genomic sequence in ventral midbrain neurons. Interestingly, polymorphisms have been detected in the neurotensin receptor mRNA sequences from human brain tissue (M. Watson et al. 1993). Whether such mRNA polymorphisms are associated with functional alterations of the neurotensin receptor (and in turn are associated with the clinical psychopathology of schizophrenia) remains to be determined. Postmortem regional CNS investigations of other neuropsychiatric diseases, however, have revealed alterations in neurotensin concentrations in brain tissue. Diminished concentrations of neurotensin in the amygdala of Alzheimer’s disease patients have been documented (Benzing et al. 1990; Nemeroff et al. 1989b). In contrast, increased neurotensin concentrations have been observed in the caudate nucleus and globus pallidus of Huntington’s disease patients (Nemeroff et al. 1983). Although the number of neurotensin receptors on dopamine neurons in the substantia nigra decreases as these neurons degenerate (Sadoul et al. 1984; Uhl et al. 1984), postmortem neurotensin concentrations in various brain regions (including the caudate nucleus, nucleus accumbens, and ventral tegmental area) in subjects with Parkinson’s disease are remarkably similar to those found in age- and sex-matched control subjects (Bissette et al. 1985). This may be due to the finding that neurotensin and dopamine, though co-localized in the mesolimbic system of rodents, is not co-localized in primates. Development of specific neurotensin receptor agonists and antagonists may allow further determination of the physiological effects of altered neurotensin receptor activity. A specific neurotensin receptor agonist affords the tantalizing possibility of antipsychotic activity, whereas a neurotensin antagonist might disrupt the actions of endogenous neurotensin, thus providing even greater information of the role of this peptide in dopamine neurotransmission and hormonal regulation within the CNS.

Neuropeptide Y Originally cloned from a pheochromocytoma by Minth and colleagues in 1984, neuropeptide Y is a 36–amino acid peptide whose gene is expressed in cells derived from neural crest (Allen and Balbi 1993). Neurons dis-


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playing neuropeptide Y immunoreactivity are abundant within the limbic areas of the CNS (De Quidt and Emson 1986; Hendry 1993). Neuropeptide Y is also present within neurons of the hypothalamus, brainstem, and spinal cord. Present in most sympathetic nerve fibers, neuropeptide Y can be detected in vascular beds throughout the body and occurs in parasympathetic nerves as well (Sundler et al. 1993). Receptors for neuropeptide Y are also widely distributed. Not only do neuropeptide Y–containing neurons innervate CRH-containing cells of the paraventricular nucleus (Liposits et al. 1988), but administration of neuropeptide Y increases hypothalamic CRH levels (Haas and George 1987, 1989) as well as its release (Tsagarakis et al. 1989). The relationship of neuropeptide Y to CRH is further substantiated by the partial blockade of the neuropeptide Y–stimulated ACTH response by a CRH receptor antagonist. Moreover, neuropeptide Y potentiates the effects of exogenously administered CRH in animals (Inoue et al. 1989). Although an initial investigation (Berrettini et al. 1987) did not find significantly diminished cerebrospinal fluid neuropeptide Y concentrations in depressed patients, Widerlov and colleagues (1988) subsequently reported that patients with major depression do exhibit decreased cerebrospinal fluid neuropeptide Y concentrations compared with sex- and age-matched control subjects. Negative correlations have been also observed between dimensional anxiety ratings and cerebrospinal fluid neuropeptide Y levels in depressed patients (Heilig and Widerlov 1990). Furthermore, marked reductions in brain tissue concentrations of neuropeptide Y were subsequently reported in suicide victims, with the most dramatic decreases occurring in patients diagnosed with major depression (Widdowson et al. 1992). Preclinical investigations demonstrate the effect of neuropeptide Y in appetitive behaviors. After intracerebroventricular injections, neuropeptide Y provokes excessive eating in mammals (Stanley 1993). After starvation, the hypothalamic paraventricular nucleus concentrations of neuropeptide Y increase; they diminish rapidly to prestarvation levels after food ingestion (Sahu et al. 1988). In humans, increased cerebrospinal fluid concentrations of neuropeptide Y have been detected in underweight amenorrheal anorexic patients and in the same amenorrheal patients within 6 weeks after weight restoration. Furthermore, an inverse relationship between cerebrospinal fluid neuropeptide Y concentration and caloric intake is observed in healthy female volunteers (Kaye et al. 1989, 1990). Whether the symptoms of anorexia are induced by increased neuropeptide Y secretion or whether increased cerebrospinal fluid concentrations of neuropeptide Y result from starvation remains to be determined.

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Efforts toward development of neuropeptide Y receptor–specific agonists and antagonists continue. Neuropeptide Y–ergic medications may have significant benefit in the treatment of affective illness or eating disorders.

Substance P In mammals, members of the rapidly acting peptide tachykinin family are known as neurokinins (Guard and Watson 1991) and include neurokinin A, neurokinin B, and substance P. The most abundant of the neurokinins, the undecapeptide substance P, was discovered in 1931 by von Euler and Gaddum but was not isolated in pure form until 1970 by Chang and Leeman (1970). Substance P binds to the neurokinin 1 receptor, neurokinin A binds to the neurokinin 2 receptor, and neurokinin B binds to the neurokinin 3 receptor. Within the CNS, substance P is localized within in the limbic and stress response areas (amygdala, hypothalamus, periaqueductal gray matter, locus coeruleus, and parabrachial nucleus) (Ku et al. 1998) and exists within norepinephrine- and serotonin-containing cell bodies as well (Bittencourt et al. 1991; Helke and Yang 1996; Magoul et al. 1993; Pelletier et al. 1981). Furthermore, substance P and other tachykinins serve as pain neurotransmitters in primary afferent neurons (J. Culman and Unger 1995) and exert a variety of other peripheral actions, including bronchoconstriction, vasodilatation, salivation, and smooth muscle contraction in the gut (Payan et al. 1984; Pernow 1983). Preclinical studies have provided much of the impetus to continue investigation of the efficacy of substance P receptor antagonism, although these agents have not been effective as analgesics (Nutt 1998). Administration of substance P (or substance P agonist) to animals elicits behavioral and cardiovascular effects resembling the stress response and socalled defense reaction (Helke et al. 1990). Moreover, preclinical studies documented reduction of behavioral and cardiovascular stress responses by administration of substance P receptor antagonists (C. Culman et al. 1997; Kramer et al. 1998). An exciting initial study indicated that the substance P receptor antagonist MK-869 is more effective than placebo and is as effective as paroxetine in patients with moderate to severe symptoms of major depression (Kramer et al. 1998). Future clinical investigations will determine whether brain and cerebrospinal fluid substance P concentrations are altered in patients with major depression (Berrettini et al. 1985; Rimon et al. 1984) and whether there are significant changes in cerebrospinal fluid concentrations of substance P after treatment (Martensson et al. 1989).


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Other Peptides Another neuropeptide that is possibly involved in the pathophysiology of anxiety disorders is diazepam-binding inhibitor (DBI). There has been a great deal of interest in the isolation of endogenous ligands for benzodiazepine recognition sites in the CNS. DBI, an 11-kDa polypeptide, was identified not only in animal brain tissue (Guidotti et al. 1983) but also in human brain tissue (Ferrero et al. 1986; Shoyab et al. 1986). This endogenous peptide, which avidly inhibits the binding of benzodiazepines to brain synaptosomes, is present in high concentrations in the amygdala and hippocampus. DBI is thought to be important in responses to stress, particularly in regulating steroid production in both the CNS and adrenal glands, and it may therefore play a role in modulation of depressive and anxiety symptoms (Ferrarese et al. 1993). Indeed, intracerebroventricular injections of human DBI into animals facilitates behavioral inhibition (Ferrero et al. 1986). Moreover, elevation of cerebrospinal fluid DBI concentrations has been documented in patients with major depression (Barbaccia et al. 1987) and has been positively correlated with cerebrospinal fluid concentrations of CRH (Roy et al. 1989). Clinical investigations will undoubtedly further determine the physiological function of DBI and whether this neuropeptide can be utilized as a biochemical marker indicative of anxiety or affective illness. Delta sleep–inducing peptide (DSIP) may have a role in the pathophysiology of sleep disorders. Isolated in 1977, the nonapeptide DSIP was identified in animals after electrical stimulation of the thalamus to induce sleep (Monnier and Hoesli 1965; Schoenenberger et al. 1978). Circulating forms of DSIP were subsequently recognized by antisera and were referred to as DSIP-LI for DSIP-like immunoreactivity. DSIP-LI has been detected in various brain areas and body fluids, including adenohypophyseal corticotroph/melanotropin cells, where it is co-localized with ACTH (Bjartell et al. 1987; Vallet et al. 1988). DSIP was originally proposed to be a sleep-inducing hormone because of its sleep-inducing qualities after intravenous administration in animals and humans (Schneider-Helmert and Schoenenberger 1983; Schneider-Helmert et al. 1981). DSIP has been utilized in clinical trials with patients with chronic insomnia and narcolepsy, with both positive (Schneider-Helmert 1984a, 1984b) and negative results (Graf and Kastin 1986). In patients with major depression, diminished cerebrospinal fluid DSIP levels have been detected (Lindstrom et al. 1985; Walleus et al. 1985). In depressed patients, CRH stimulation reduces plasma DSIP-LI concentration, in contrast to nondepressed volunteers, in whom intrave-

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nous CRH administration induces increased plasma DSIP-LI concentration (Lesch et al. 1988). Decreased levels of cerebrospinal fluid DSIP have also been detected in drug-free schizophrenic patients in comparison with healthy control subjects (Lindstrom et al. 1985; Van Kammen et al. 1992). Interestingly, prophylactic lithium treatment of patients with mood disorders increases cerebrospinal fluid and plasma concentrations of DSIP (Regnell et al. 1988; Walleus et al. 1985). Obviously, the literature on DBI and DSIP in psychiatric disorders will be further developed and extended. Future efforts will undoubtedly reveal whether agents altering the function of these peptides can be therapeutically effective in patients with anxiety, mood, and sleep disorders.

Clinical Implications The last three decades of neuropsychophysiologic exploration have yielded a plethora of new findings regarding the alterations of CNS neuropeptides and hypothalamic releasing factors in certain psychiatric disorders (Table 3–5). Not only does understanding of these findings require a sophisticated level of psychoneuroendocrine knowledge, but integration of the seemingly disparate data into a conceptual schema must be postponed until further information is gathered. Although the balance of evidence indicates that multiple neuropeptide systems within the CNS are altered in major depression and anorexia nervosa, determination of the activity or dysfunction of these systems within the brain remains relatively difficult. Not only may there be differences between hypothalamic and extrahypothalamic secretion within the brain, but disagreement continues as to which compartment cerebrospinal fluid sampling accesses (or whether it access both compartments). Furthermore, there is discordance between CNS and more peripheral sources of a neuropeptide, such as neurotensin and cholecystokinin. Peripheral plasma concentrations of a neuropeptide or hypothalamic releasing factor are determined not only by the rate of release but also by local metabolic degradation and by redistribution into other extravascular spaces (Linares et al. 1988). For example, plasma CRH concentrations can be measured but may not truly represent CNS secretion because of the CRH contribution by the adrenal medulla and spleen. Nevertheless, the importance of hypothalamic releasing factors in the pathophysiology of psychiatric illness is most evident in the large body of literature indicative of CRH hypersecretion in patients with major depression, although not all studies are in agreement (Geracioti et al.


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Alterations of neuropeptides and hypothalamic releasing factors in various psychiatric disorders

Major depression Hyperactivity of the hypothalamic-pituitary-adrenal axis Dysregulation of growth hormone secretion Diminished somatostatin activity Diminished neuropeptide Y secretion Diminished delta sleep–inducing peptide secretion Bipolar disorder—manic phase Hypersecretion of arginine vasopressin Anxiety disorders Increased sensitivity to CCK-4, a preferential CCKB receptor agonist Anorexia nervosa Hyperactivity of the hypothalamic-pituitary-adrenal axis Hypersecretion of neuropeptide Y Schizophrenia Decreased neurotensin secretion Alzheimer’s disease Somatostatin hypoactivity Note.

CCK=cholecystokinin.

1992). Virtually all of the neuropeptide and neuroendocrine axis alterations in patients with major depression thus far studied are state dependent. However, nearly all the studies noted in this chapter are “crosssectional” in design—that is, the psychiatric disorder and the alterations of neuropeptide or hypothalamic releasing factors are determined at approximately the same time. Clinical investigators of the twenty-first century will extend understanding of whether certain neurobiological alterations provide fundamental pathophysiological contributions to the behavioral manifestation of particular psychiatric disorders or are merely epiphenomena, for example, diminished cerebrospinal fluid concentrations of somatostatin in patients with Alzheimer’s dementia. Nevertheless, further cross-sectional studies are necessary to confirm whether DBI peptide systems in depression and endogenous opioid peptide systems in psychiatric disorders with self-mutilatory behaviors are truly disordered. Furthermore, present efforts guided by the neuroendocrine window strategy and the pharmacologic bridge technique may provide information as to whether the secretion of neuropeptides and hypothalamic releasing factors are associated with alterations in the activity of putative neurotransmitters—such as 5-HT, dopamine, and acetylcholine—in particular disease states. More likely, functional brain

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imaging methods, such as positron emission tomography, will provide direct data of alterations in neuropeptide circuits in psychiatric disorders. A clearer understanding of the neuroendocrinology of depression, anxiety, and schizophrenia may well lead to the development of novel pharmacologic agents for the treatment of these major mental disorders. We await confirmation of an initial report documenting the effectiveness of the substance P receptor antagonist, MK-869, in patients with major depression. Early studies of novel CRH receptor antagonists suggest efficacy in the treatment of depression. A selective CCKB antagonist with anxiolytic activity may offer a new psychotropic modality in the treatment of panic disorder. Progress during the last three decades has been nothing short of remarkable, and the future is likely to bring further progress in treating these disorders.

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Chapter 4 Chronobiology and Melatonin Robert L. Sack, M.D. Alfred J. Lewy, M.D., Ph.D. Magda Rittenbaum, M.D. Rod J. Hughes, Ph.D.

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elatonin is a hormone produced at night by the pineal gland. When administered exogenously, its actions are prototypical of a new class of drugs termed chronobiotics (Dawson and Armstrong 1996). Chronobiotics are substances that can therapeutically adjust the timing of circadian rhythms (Simpson 1980); in other words, they can “reset” the biological clock. The prime targets for chronobiotic treatment are the circadian rhythm sleep disorders (American Sleep Disorders Association 1997), which include jet lag and shiftwork maladaptation, as well as some other less common sleep disorders. Certain mood disorders, including winter depression, may also involve circadian rhythm disturbances (Lewy et al. 1987). All of these disorders have a common underlying pathophysiology; that is, a desynchrony between the timing of endogenous circadian rhythms and the timing of the environmental day-night cycle or the timing of the desired sleep-wake schedule (in some cases sleep is desired at an atypical time; for example, during the day in night workers). Chronobiotic drug activity should be distinguished from hypnotic activity. Hypnotic drugs directly induce drowsiness or sleep but do not

An earlier version of this chapter (Sack RL, Lewy AJ, Hughes RJ, et al.: “Melatonin as a Chronobiotic Drug”) was originally published in Drug News and Perspectives 9(6):325–332, 1996. Copyright 1996, Prous Science Publishers. Used with permission.

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necessarily shift circadian rhythms. Chronobiotics are not necessarily hypnotic; instead, they improve sleep by optimizing the alignment between endogenous circadian sleep drive and the desired sleep time. Melatonin may have both chronobiotic and hypnotic actions, especially in higher doses, but it may be possible to tease apart the two actions at lower doses. Perhaps the easiest circadian rhythm disorder to understand is jet lag. After rapid transmeridian travel, there is a period lasting for several days in which endogenous rhythms are out of phase with local time. This state of circadian desynchrony generates symptoms of daytime sleepiness and nighttime insomnia. In addition, there may be intense fatigue, gastrointestinal disturbance, and difficulty maintaining concentration. The symptoms gradually resolve as the internal body clock “catches up” and circadian harmony is restored. A more persistent form of circadian desynchrony underlies night-shift work maladaptation. If the night worker does not reset his or her clock, circadian rhythms will remain desynchronized indefinitely. The night worker’s daytime sleep may be short and unrefreshing. Consequently, a “sleep debt” builds up, and maintaining alertness at night is a struggle. Disorders that may involve misalignment of circadian rhythms are listed in Table 4–1.

TABLE 4–1.

Circadian rhythm disorders

Time zone change syndrome (jet lag) Shift work sleep disorder Irregular sleep-wake pattern Delayed sleep-phase pattern Advanced sleep-phase pattern Non-24-hour sleep-wake disorder

The potential benefits of circadian phase correction have been recognized for some time. Appropriately timed bright light exposure was the first practical treatment method for circadian phase resetting (Lewy et al. 1984) and is currently being applied in a variety of settings. Although bright light exposure is quite potent, it is a relatively inconvenient and timeconsuming treatment compared with a safe and effective drug. Nevertheless, even if chronobiotic drugs are developed, planned light exposure could be used synergistically with pharmacotherapy for the treatment of circadian rhythm disorders. The phase-resetting action of exogenous melatonin administration was discovered quite recently, and the parameters for treatment, such as

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optimal timing and dosage, are currently being worked out. Meanwhile, scientific research on melatonin has been overshadowed by a melatonin fad in the United States, where it is sold in health food stores as a dietary supplement. Although melatonin is not classified as a drug, those who produce it for the health food market make implied claims that it is an effective treatment for insomnia. Proponents of the fad also extend the highly speculative hopes that melatonin has anti-aging effects, bolsters the immune system, and can augment cancer therapy. We do not attempt to review these claims in this chapter; instead we concentrate on the circadian phase-resetting and hypnotic actions of melatonin. The principles discussed will presumably also apply to melatonin analogs and perhaps to other chronobiotics that are under active development.

Circadian Rhythm Physiology The word circadian is derived from the Greek roots circa, meaning “about,” and dies, meaning “day.” Circadian rhythms have evolved as an adaptation to the alternating light-dark cycle caused by the rotation of the earth (for a very readable overview of circadian rhythm physiology, see Moore-Ede et al. 1982). Circadian rhythms are not passive responses but are actively generated by an internal pacemaker that operates to maintain synchrony with the light-dark cycle. The endogenous nature of these rhythms can be demonstrated by placing an organism in an isolated environment and then observing variations in behavior or physiology that continue to oscillate about every 24 hours, even in the absence of any external time cues (zeitgebers, from the German for “time-givers”). The circadian system provides a mechanism for anticipatory adaptation to predictable changes in the environment; for example, core body temperature rises in the second half of the night, presumably preparing an individual for activity on awakening in the morning. In mammals, the circadian clock is located in the hypothalamus within the suprachiasmatic nucleus (SCN) (Klein et al. 1991) (Figure 4–1). The SCN acts as the master circadian pacemaker and controls the timing of most circadian rhythms, including melatonin secretion, sleepiness, core body temperature, and cortisol secretion. If this tiny area of the brain is destroyed in laboratory animals, circadian rhythms in body temperature and hormonal secretion are lost, and sleep occurs in short bouts evenly distributed throughout the 24-hour day. Circadian rhythms can be restored in SCN-lesioned animals by transplanting fetal SCN tissue into the third ventricle of the brain (Ralph 1991). The intrinsic rhythm of the

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FIGURE 4–1. Diagram of the major elements of the pineal interactions with the circadian system. The suprachiasmatic nucleus (SCN) in the hypothalamus receives photic input from the retina via the specialized retinohypothalamic tract (RHT). This pathway is critical for lightmediated entrainment of the circadian pacemaker located in the SCN. Multisynaptic efferents descend from the SCN to the superior cervical ganglion (SCG), and postganglionic b-adrenergic fibers ascend to terminate on the pineal gland. On receiving a signal from the SCN, the pineal gland secretes melatonin. Circulating melatonin interacts with receptors in the SCN, forming a feedback loop. The phase-shifting effects of melatonin administration are most likely mediated by mimicking this arm of the loop. Source. Reprinted from Sack RL, Blood ML, Hughes RJ, et al.: “Circadian Rhythm Sleep Disorders in the Totally Blind.” Journal of Visual Impairment and Blindness 92:145–161, 1998. Used with permission.

SCN is not exactly a 24-hour cycle but ranges from about 23 to 25 hours (in humans, about 24.5 hours). When subjects are isolated from all time cues, circadian rhythms express a cycle that is slightly longer (or shorter) than 24 hours. For circadian rhythms to be synchronized to a precise 24hour day, the circadian clock must be regularly adjusted (reset) by exposure to 24-hour time cues. Thus, circadian phase resetting is a normal, ongoing process; the resynchronization that occurs after a challenge to the system such as transmeridian flight is an extension of an intrinsic process that occurs normally every day in nontravelers. The process of adjustment through interaction with time cues in the environment is called entrainment. In nature the primary time cue is the solar light-dark cycle, although other timing signals may play a role. Light information is delivered directly to the SCN via the retinohypothalamic tract, which is anatomically distinct from the visual imaging circuitry (see Figure 4–1).


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The SCN stimulates the pineal gland to secrete melatonin during the nighttime hours. A functional feedback loop between the pineal and the SCN (see Figure 4–1) is mediated by highly specific melatonin receptors (Reppert et al. 1994, 1995) concentrated in the SCN. This feedback loop appears to regulate the timing, but not the amplitude, of melatonin secretion. Melatonin receptors in the SCN are the probable target for the clock-resetting effects of exogenously administered melatonin.

Melatonin: Basic Biology Melatonin is a phylogenically ancient hormone that is almost ubiquitous in the animal kingdom, including some single-celled organisms (Poeggeler et al. 1991). It is synthesized in the pineal gland from tryptophan via serotonin as an intermediate precursor (Arendt 1995). Melatonin is always produced at night, regardless of whether an animal is active during the day or during the night. Therefore, it is always concomitant with darkness (Arendt 1995) but not necessarily with sleep—nocturnal species are active at night. In nature, melatonin secretion is suppressed by light at dusk and dawn; consequently, the duration of secretion varies with the seasonal changes in the length of the day. It is useful to think of melatonin as a hormonal signal for nocturnal darkness; the message may be used by different species in different ways. For example, the best-established role for melatonin is the regulation of seasonal breeding cycles in some animals (Tamarkin et al. 1985). When melatonin is administered exogenously, it can mimic the effects of the short days and long nights of winter. In hamsters, short days are antigonadal, but in sheep they are progonadal. Thus, the effects of melatonin on reproductive biology are species specific and are mediated through its role as a transducer of day length. It is likely that the phase-resetting effect of exogenous melatonin administration is derived from its role as a signal for nighttime darkness; that is, exogenous melatonin administration is interpreted by melatoninreceptive areas in the hypothalamus as an early dusk or a late dawn, depending on the time it is given, and the circadian pacemaker responds by adjusting its phase accordingly.

Melatonin Phase Response Curves Both the potency and the direction of environmental time cues are dependent on the time of day they are presented. In chronobiology, this

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relationship is described by a phase response curve (PRC) (Moore-Ede et al. 1982). For example, light in the morning (early subjective day) shifts rhythms earlier, whereas light in the afternoon (late subjective day) shifts rhythms later. Light in the middle of the day has no effect. The landmark experiment documenting the entraining effects of melatonin was conducted by Redman, Armstrong, and Ng (1983). They tested the effects of exogenous melatonin administration on rats that were maintained in a constant dim-light environment and that expressed non24-hour, free-running rhythms. Daily injections of melatonin late in the subjective day (1–3 hours before onset of activity) entrained the animals to a normal 24-hour cycle, but placebo treatment at the same time of the day had no effect. The mechanism for entrainment was a daily phase advance (15–45 minutes) sufficient to counteract the free-running rhythms, which were longer than 24 hours. In rodents, melatonin caused advances but not delays. McArthur et al. (1991) provided the first evidence of direct SCN resetting by melatonin using an in vitro brain slice preparation. The dependent measures included the rate of firing in SCN neurons, which typically peaks during midday (8–14 Hz), with slowest rates occurring throughout the night (typically 2–4 Hz). Bath application of physiological melatonin solution applied to rat SCN brain slices induced a phase advance of up to 4 hours in the peak firing rate when delivered late in the day. By monitoring the brain slice for multiple cycles, a permanent resetting of the circadian clock was documented. This observation was remarkably consistent with the behavioral studies of Redman and Armstrong (Armstrong and Chesworth 1987; Redman et al. 1983). There appear to be considerable species differences in the phase-shifting effects of melatonin. For example, in lizards, melatonin injections cause larger shifts than in rodents and can delay as well as advance circadian rhythms, depending on the time of administration (Underwood 1986). On the other hand, hamsters are relatively immune to phase-shifting effects (Hastings et al. 1992). In summary, animal studies have clearly documented the ability of melatonin administration to influence the mammalian circadian system. Presumably, this effect is related to the physiological role of endogenous melatonin.

Melatonin Phase Resetting in Humans In 1987, we reported our initial study of melatonin administration to totally blind subjects (Sack et al. 1987), with additional data reported over


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the next few years (Sack and Lewy 1988; Sack et al. 1990, 1991). The strategy of treatment was based on the animal experiments of Armstrong and co-workers (Armstrong and Chesworth 1987; Redman and Armstrong 1988; Redman et al. 1983). Five totally blind males with consistent free-running (non-24-hour) melatonin rhythms were given exogenous melatonin (5 mg by mouth at bedtime) for up to 3 weeks. Four of the five subjects showed significant cumulative advances (7–16 hours) in the phase of melatonin rhythm compared with phase projections derived from their pretreatment rhythms (Sack et al. 1991). Cortisol rhythms were advanced in parallel with the melatonin rhythms. In blind subjects, the treatment-induced phase advances were unconstrained by the light-dark cycle and therefore accumulated over the 3-week period. In these early studies, we were not able to entrain the subjects’ circadian rhythms to a 24-hour cycle, perhaps because the duration of treatment was limited to 3 weeks. We have readdressed the issue of melatonin treatment of blind people. Using a higher dose (10 mg), we have been able to entrain six of seven subjects treated (Sack et al. 1999, 2000). Placebo treatment had no effect. Figure 4–2 shows representative data from one of the blind subjects. Entrainment of free-running rhythms in blind people is a clear-cut demonstration of the clock-resetting potency of melatonin. Recently, we found that 0.5 mg can be effective in these individuals (Lewy et al. 2001). After our initial demonstration of phase resetting in blind people with free-running rhythms, we proceeded with studies in sighted people. We administered melatonin at all phases of the circadian cycle, evaluating delaying as well as advancing effects, and derived a PRC (Lewy et al. 1992). For each trial, subjects were given a daily 0.5-mg dose of melatonin or placebo at the same time each day for 4 days, and circadian phase was assessed on the fifth day by measuring the timing of endogenous melatonin rhythm (dim light melatonin onset [DLMO]). Sleep times were held relatively constant. The difference in DLMO between active treatment and placebo was used as the measure of phase shift. Figure 4–3 presents the melatonin PRC developed by this strategy. Advance responses (shifts to an earlier time) are most likely to occur after melatonin administration in the late afternoon and evening (just before the onset of endogenous melatonin secretion), whereas delay responses (shifts to a later time) are most likely to occur after melatonin administration in the morning (coincident with the decline in endogenous secretion). The strategy for using melatonin and light to shift circadian rhythms according to their respective PRCs is summarized schematically in Figure 4–4. As shown in the upper panel, melatonin administration in

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Data from entrainment of a totally blind man with freerunning rhythms by melatonin 10 mg given nightly at bedtime.

FIGURE 4–2.

Total blindness is associated with circadian rhythms that run on a non-24-hour, “free-running” cycle (see text). Recurrent insomnia and daytime sleepiness result when endogenous circadian rhythms are out of phase with the desired sleep-wake cycle. The subject is a 57-yearold man who was totally blinded at age 26 from trauma. His 24-hour melatonin profiles were assessed at 2- to 4-week intervals to detect his melatonin onset (MO), the time when concentrations rose above 10 pg/mL. His circadian period (tau) was determined by fitting the MOs to a linear regression. MOs assessed during a diagnostic assessment (open circles) revealed a free-running melatonin rhythm with a tau of 24.6 hours. The tau was unchanged by placebo treatment (open squares). MOs assessed on melatonin treatment days 42 and 52 (closed squares) were at a slightly delayed but consistent phase of 1:00 and 12:45 A.M., 6.8 hours and 13.2 hours (respectively) earlier than predicted by extrapolation of the freerunning rhythm (shown as the dotted line). Source. Reprinted from Sack RL, Brandes RL, deJongh L, et al.: “Melatonin Entrains FreeRunning Circadian Rhythms in a Totally Blind Person.” Sleep 22(suppl):S138–S139, 1999. Used with permission.

the evening (or light in the morning ) will shift circadian rhythms earlier (i.e., cause a phase advance). As shown in the lower panel, melatonin administration in the morning (or light in the evening) will shift the circadian rhythms later (i.e., cause a phase delay). The most critical times for


FIGURE 4–3.

Melatonin phase response curve (PRC) derived from repeated trials of melatonin administration.

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Advance responses are most likely in the late afternoon and evening (just before the onset of endogenous melatonin secretion), whereas delay responses are most likely to occur in the morning (coincident with the decline in endogenous secretion). Source. Reprinted from Lewy et al. 1998. Used with permission.

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The strategy for using melatonin and light to shift circadian rhythms according to their respective phase response curves (PRCs), shown schematically (see text for details).

FIGURE 4–4.

Source. Reprinted from Lewy AJ, Sack RL: “The Role of Melatonin and Light in the Human Circadian System.” Progress in Brain Research 111(205):205–216, 1996. Copyright 1996, with permission from Elsevier Science.

phase shifting in nature are dawn and dusk. Melatonin given in the middle of the night and light exposure in the middle of the day (so-called dead zones of the PRCs) have minimal phase-shifting effects.

Melatonin Treatment of Night-Shift Workers— Some Research Findings To test the phase-shifting actions of melatonin in the field, we conducted a double-blind clinical trial of melatonin in night-shift workers and have obtained some data indicating therapeutic efficacy (Sack and Lewy 1997). Our subjects were night-shift workers on a “7-70” rotating schedule involving seven consecutive 10-hour shifts (9:30 P.M. to 7:30 A.M) alternating with 7 days off. This schedule is advantageous for circadian rhythm research because subjects have a lengthy opportunity (seven days) to adapt to both their work and off-work schedules, and thus the dynamics of adaptation to the alternating schedules can be investigated. Also, subjects work precisely the same schedule every other week, so that


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repeated measures can be made and the effects of treatments evaluated in a repeated-measures design. The subjects (nurses and hospital clerical personnel) were between ages 21 and 55 and had worked on the 7-70 shift for at least 6 months. All of the subjects participated in a double-blind, crossover study of melatonin administration. For one 2-week block they received melatonin (0.5 mg), and for the other 2-week block they received placebo (cornstarch) formulated in identical gelatin capsules. Subjects were given melatonin (0.5 mg) at their usual bedtimes—that is, between 9:00 and 11:00 P.M. during the off-work weeks and between 8:00 and 10:00 A.M. during work weeks. Subjects were blind to the treatment condition, and the order of treatment was randomized. To monitor circadian phase, weekly assessments of the melatonin profile were obtained so that estimates of the direction and rate of phase shifting could be made. Just before beginning a run of night work, and just after, subjects were admitted to the clinical research center, where blood samples were obtained every hour for 24 hours for determination of the DLMO, which was used as the marker of circadian phase. We have collected data on 24 subjects to date and have formed some conclusions. At the end of their week off, the night workers were in about the same circadian phase as a comparison group of day-active subjects participating in another study. A major question of this study was the magnitude and direction of the circadian phase shifts between the beginning and the end of the 7-night work week without treatment (placebo condition). In brief, we found substantial variability in both the magnitude and the direction of phase shifting (Figure 4–5). Eight subjects showed no shift, four advanced their DLMO, five had partial delays, and eight were delayed 6 hours or more. Laboratory studies indicate that the congruence of sleep with the circadian sleep propensity rhythm is a critical determinant of sleep duration and that correction of an abnormal phase relationship by a variety of strategies can improve sleep. To address this issue, we divided the group into definite “shifters” (more than a 6-hour phase shift) (n=10) and “nonshifters” (less than a 3-hour phase shift) (n=7) and compared wrist actigraphic estimates of sleep during the placebo work and off-work weeks. Between-group comparisons showed that time in bed was an average of 70 minutes longer per day during the work week for shifters than for nonshifters (511±72 minutes vs. 441±83 minutes; P

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