Foundations of Biochemical Psychiatry David S. Segal, PhD Associate Professor Department of Psychiatry School of Medicine University of California, San Diego La Jolla, California Joel Yager, MD Assistant Professor Department of Psychiatry School of Medicine University of California Los Angeles, California John L. Sullivan, MD Assistant Professor Department of Psychiatry School of Medicine Duke University Durham, North Carolina BUTTERWORTHS Boston London The Butterworth Group United States Canada Butterworth (Publishers) Ine Butterworth & Co. (Canada) Ltd 19 Cummings Park 2265 Midland Avenue Woburn, MA 01801 Scarborough, Ontario M1P 4SI England New Zealand Butterworth & Go. (Publishers) Ltd Butterworths of New Zealand Ltd Borough Green 26-28 Waring Taylor Street Sevenoaks, Kent TN15 8PH Wellington 1 Australia South Africa Butterworth Pty Ltd Butterworth & Co. (South Africa) 586 Pacific Highway (Pty) Ltd Chatswood, NSW 2067 152-154 Gale Street, Durham Copyright © 1976 by Butterworth (Publishers) Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Printed in the United States of America Library of Congress Catalog Card Number: 76-18765 ISBN: 0-409-95001-7 Library of Congress Cataloging in Publication Data Main entry under title : Introduction to biochemical psychiatry. Bibliography: p. Includes index. 1. Mental illness—Physiological aspects. 2. Mental illness—Genetic aspects. 3. Psy- chopharmacology. 4. Psychobiology. I. Segal, David S. II. Yager, Joel. III. Sullivan, John Lawrence, 1943- RC455.4.B5I57 616.8'9 76-18765 ISBN 0-409-95001-7 Preface Although most of the psychiatric world has not yet acknowledged it, the age of clinical application of behavioral biology is upon us. Basic discoveries in the laboratories of neu- ropharmacologists and neurobiologists are now being taken to research wards for appli­ cation to humans in a brief matter of months or years. Complex human traits such as sensitivity, passivity, aggressiveness, and sexuality, previously conceived of as metaphysi­ cal, are now being examined by behavioral biologists and suitably oriented psychiatrists as the influence of their chemical understanding of the human body expands. There are reasons this trend is being resisted by many schools of human behavior. First is the fact that previous scientific promises to the psychiatrically ill have been disap­ pointing. Lobotomy produced a patient who was shallow and irresponsible. High doses of sedatives proved toxic and ineffective in the treatment of psychoses. Electroshock was predictably useful only for a subgroup of depressives. Recently, even the phenothiazines have been shown to produce severe toxic side effects. Perhaps only in the area of the affective disorders are we gaining some everyday clinical credibility, through the use of tricyclic antidepressants, monoamine oxidase inhibitors, and lithium. A second factor that has led to resistance among clinically or behaviorally oriented theorists and practitioners has been the gap between the dependent variables of experi­ ments (eg, leucine incorporation, inhibitory postsynaptic potential, amine turnover) and the phenomenology of humans (eg, desire, envy, love, contempt). I've heard it said that successful efforts to close this gap will lead humans to lose their specialness, the soul. It is particularly frightening to the older generation to have human traits described as genet­ ically and chemically determined. "What will the world be coming to when I can take a pill to alter my personness? Who am I, then, after all?" The historical sequence in psychiatry has been almost circular with regard to re- ductionism. When psychodynamic and psychoanalytic thinkers began to derive the high­ est forms of human functioning from "baser" instincts, they were accused of denying the person's unique self-determination and choice. Now, when behavioral biologists name and characterize the central mechanisms underlying instinctual life (the music behind the words of living), they are seen as still worse offenders of the idea of human special­ ness. Interestingly, the strongest formal objections came from neo-Freudian philosophers who focus on the human being's cognitive ability as having originated from "neutralized" instinctual energy. As a group they have moved as far as possible from biological deter­ minants of behavior. They feel that human nature is beyond comprehension in biological terms. The psychoanalyst who saw the animal in all of us is uneasy about seeing the ani­ mal's brain in all of us. Hopefully, like all resistance to valid scientific advance, the present cultural and intellectual inertia in psychiatry will pass. From an epistemological point of view, textbooks represent organized defenses of the status quo. They arrive relatively late during periods of scientific transition, and are fre­ quently oversimplified (and therefore inaccurate) summaries of how things were. When a field is in a state of rapid flux, textbook writing is almost impossible. In its place come collections of papers, which have the advantage of freshness. There have recently been a few such compendiums in biological psychiatry. However, all of them, although of good quality, lack continuity. They lack the informal discussions that create holistic impres­ sions. It seems to me that Drs. Segal, Yager, and Sullivan have taken on the challenge of creating a textbook in a field of rapid flux with the best possible result. From an active, ever-changing, and currently revolutionary field, they have chosen representative and im­ portant original work. Their discussions provide continuity. They have fleshed out the chemical bones of biological psychiatry with well-chosen clinical material, and they have done all this without assuming a political posture. Most importantly, they have made available to a wide range of readers the kind of material that certainly will be part of the liberal arts education of the future. They are to be congratulated on a difficult job well done. I hope the reader will enjoy the book as much as I have. ARNOLD J. MANDELL Reading Selections and Contributors 18 Leonard L. Heston, MD: The Genetics of Schizophrenic and Schizoid Disease. Sci ence 167:249-256, 1970. 33 Richard J. Wyatt, MD, Benedict A. Termini, MD, and John Davis, MD: Biochem­ ical and Sleep Studies of Schizophrenia: A Review of the Literature—1960-1970. Schizophrenia Bull 4:10-66, 1971. 87 E. H. Ellinwood, Jr., MD: Amphetamine Psychosis: A Multi-dimensional Process. Sem Psychiat 1:208-226, 1969. 103 Solomon H. Snyder, MD, Shailesh P. Banerjee, PhD, Henry I. Yamamura, PhD, and David Greenberg, PhD: Drugs, Neurotransmitters and Schizophrenia. Science 184: 1243-1253, 1974. 125 Larry Stein, PhD, and C. David Wise, PhD: Possible Etiology of Schizophrenia: Pro­ gressive Damage to the Nonadrenergic Reward System by 6-Hydroxydopamine. Science 171:1032-1036, 1971. 146 Elliot S. Gershon, MD, David L. Dunner, MD, and Frederick K. Goodwin, MD: Toward a Biology of Affective Disorders. Arch Gen Psychiat 25:1-15, 1971. 167 Joseph J. Schildkraut, MD: The Catecholamine Hypothesis of Affective Disorders: A Review of Supporting Evidence. Amer J Psychiat 122:509-522, 1965. 181 Frederick K. Goodwin, MD, Dennis L. Murphy, MD, H. Keith H. Brodie, MD, and William E. Bunney, Jr., PhD: L-DOPA, Catecholamines, and Behavior: A Clinical and Biochemical Study in Depressed Patients. Biol Psychiat 2:341-366, 1970. 206 Baron Shopsin, MD, Sherman Wilk, PhD, Gregory Sathananthan, MD, Samuel Gershon, MD, and Kenneth Davis, MD: Catecholamines and Affective Disorders Revised: A Critical Assessment. / Nerv Ment Dis 158:369-383, 1974. 222 Alec Coppen, MD, DPM: Indoleamines and Affective Disorders. / Psychiat Res 9: 163-197, 1972. 230 David S. Janowsky, MD, John M. Davis, MD, M. Khaled El-Yousef, MD, and H. Joseph Sekerke, PhD : A Cholinergic-Adrenergic Hypothesis of Mania and De­ pression. The Lancet, September 22:632-635, 1972. 241 Gary D. Miner, PhD: Evidence for Genetic Components in the Neuroses. Arch Gen Psychiat 29:111-118, 1973. 254 D. M. Warburton, PhD: Modern Biochemical Concepts of Anxiety. Int Pharmaco- psychiat 9:189-205, 1974. 272 Solomon H. Snyder, MD, and James L. Meyerhoff, MD: How Amphetamine Acts in Minimal Brain Dysfunction. Anns NY Acad Sci 205:310-320, 1973. x READING SELECTIONS AND CONTRIBUTORS XI Page 283 L. Eugene Arnold, MD, Paul H. Wender, MD, Keith McCloskey, MD, and Solomon H. Snyder, MD: Levoamphetamine and Dextroamphetamine: Comparative Effi­ cacy in the Hyperkinetic Syndrome. Arch Gen Psychiat 27:816-822, 1972. 298 Donald W. Goodwin, MD, Fini Schulsinger, MD, Leif Hermansen, MD, Samuel B. Guze, MD, and George Winokur, MD: Alcohol Problems in Adoptees Raised Apart from Alcoholic Biological Parents. Arch Gen Psychiat 28:238-243, 1973. 312 Edward J. Sachar, MD: Hormonal Change in Stress and Mental Illness. Hospital Practice 10:49-56, 1975. Acknowledgments We cannot adequately thank all those who made this book possible. First, the authors and original publishers of the articles were kind enough to permit us to include their work. Second, we extend thanks to the many friends and colleagues who read and commented on the manuscript in various stages of preparation: Drs. Samuel H. Barondes, Ronald T. Kuczenski, Arnold J. Mandell, Marc A. Schuckit, and Eileen Yager, and Mrs. Bar­ bara Blomgren, who in particular made our efforts readable. Mrs. Pat Hermann deserves special thanks for editing and typing our many drafts and for her invaluable assistance in attending to the many details which made prepara­ tion of this book possible. Our thanks, too, to Mr. Thomas V. Kelley, our editor, who provided us with en­ couragement and ample time to complete this book. 1. Introduction to Fundamental Concepts Biochemical psychiatry has emerged over the past 25 years as an important conceptual and experimental approach to understanding mental illness. Although various physical techniques used in the treatment of mental illness since the 19th century reflect an early biological orientation in psychiatry, the major impetus to the development of biochemi­ cal psychiatry came in the early 1950s with the introduction of pharmacological agents that proved effective in the treatment of schizophrenia and depression. The past 25 years have also been characterized by rapid technological growth in ex­ perimental psychopharmacology, neurochemistry, neurophysiology, and genetics. Antide- pressant and antipsychotic drug effects and familial patterns of mental illness have become focal points of experimental investigation into the biological foundations of psychiatric disease. Neurochemical, neurophysiological, and behavioral data from animal studies have provided insight into the mechanisms of action of drugs that affect the functioning of the central nervous system and understanding of the dynamics of synaptic transmission. Carefully controlled genetic studies of psychiatric populations have afforded provocative evidence regarding genetic transmission of psychiatric illness, particularly schizophrenia and disorders of mood. The primary objective of this text is to provide, through discussion and readings, an overview of the contributions made by biochemical psychiatry to the understanding of mental illness. The readings selected bear directly and indirectly on biochemistry; they include biochemical studies of psychiatric patients before and after pharmacological in­ tervention and genetic studies which imply that yet largely unknown but critically impor­ tant biochemical events play a major role in these disorders. The readings include both review articles that provide broad overviews of several areas of research, as well as orig­ inal studies that demonstrate specific research methods in high-power focus. Since many of the selections assume that the reader is familiar with basic concepts of abnormal be­ havior and brain function, we will introduce and define those that are most fundamental. In addition, some of the more frequently used research strategies are presented to acquaint the reader with the values and limitations of current experimental procedures. 1 2 FOUNDATIONS OF BIOCHEMICAL PSYCHIATRY Abnormal Behavior We all have a common sense idea of what kinds of behavior we consider normal. These ideas usually stem from the mores and values that we have learned to accept as appropriate in our society. However, mores and values may differ not only among in­ dividuals, but for the same individual at different times in his or her life. It should not be surprising, therefore, that there is great difficulty finding definitions of normality and abnormality that have universal agreement. Most attempts at defining normal and ab­ normal behavior have involved either a statistical or a relativistic approach. According to the statistical view, any behavior that deviates from the mean may be considered abnormal. Although at first glance this definition might appear adequate, there are several difficulties with it. First, how extreme or divergent must the behavior be before it is considered pathological? The length of time that behavior must remain di­ vergent for the individual to be classified as abnormal is also arbitrary : should the person who infrequently exhibits divergent behavior be considered abnormal? Finally, which divergent behaviors should be considered pathological? For example, individuals who are continuously depressed depart from the mean, but so do those who are exceptionally intelligent or creative. It is not possible to find universal agreement as to which behav­ ioral dimensions are relevant for the diagnosis of psychopathology. According to the relativistic approach, the behavior of an individual should be evaluated on the basis of the culture or group with which he or she is associated (the ref­ erence group). The proponents of this view point to the fact, for example, that aggressive behavior is quite normal in some cultures, but frowned upon in others; thus it is neces­ sary to avoid the untenable conclusion that all the members of a particular culture are abnormal because they differ from the mean of the total population. However, this def­ inition is subject to most of the difficulties that limit the statistical definition of abnor­ mality; it also deals with deviance from a mean, in this case the mean of the reference group. In addition, there is the problem of determining the appropriate group to use as a reference. Such a choice could be made on the basis of any of a number of criteria, in­ cluding culture, sex, age, or socioeconomic level. In fact, the issue of normality is not necessarily relevant to research dealing with the biochemical basis of behavior. That is, the appropriateness of a behavior and whether or not it requires alteration is not essential to the question of what biochemical mecha­ nisms subserve that behavior. Rather, the primary focus is on what neurochemical pro­ cesses are involved in the elaboration of a behavior and the extent to which alterations in those processes are responsible for behavioral differences. Within the content of bio­ chemical psychiatry the specific behaviors of interest are those that represent the distin­ guishing characteristics of syndromes such as schizophrenia and depression. Psychiatric Classification. Attempts at classification are in general subject to a num­ ber of difficulties. Often there is greater variability between individuals within the same diagnostic category than there is between individuals in different diagnostic categories. Symptoms exhibited by an individual may depend on experiential and situational fac­ tors. Moreover, individuals placed in a particular category might be only superficially similar; that is, comparable symptoms might have very different causes. In spite of these and other limitations, most behavioral scientists agree that a distinc- Introduction to Fundamental Concepts 3 tion between neurosis and psychosis is useful. While a protracted neurosis can be more debilitating to an individual than a temporary psychotic state, in general the neuroses in­ terfere less with social functioning than the psychoses do. An individual having some form of neurosis is usually able to function at least moderately well in many social situations. In fact, neurosis might be undetectable, particularly by casual acquaintances. On the other hand, psychoses, even if transient, often affect behavior to such an extent that social func­ tioning is markedly impaired. The differences between neuroses and psychoses are not always apparent ; in patients classified as severe neurotics some symptoms may be quite similar to those usually attributed to the psychotic. It is, however, generally believed that neuroses do not usually develop into "true" psychoses. Neurosis. The term neurosis commonly refers to any one of a group of conditions in which there is a chronic or repetitive pattern of thoughts, moods, or behaviors usually seen as undesirable by the afflicted individual. The onset of significant symptoms is usually abrupt and frequently associated with a stressful event. Anxiety is so frequently a part of neurosis that many believe it to be central to these conditions. The ability to distinguish reality from fantasy is usually preserved, and the person may recognize that the troubling symptoms are of irrational origin. Biochemical factors may play an important role in de­ termining the susceptibility of an individual to neurotic disorders, but few biochemical theories of neurosis have been formulated. In spite of the emphasis on experiential or psychodynamic factors, several families of drugs, especially the so-called antianxiety agents, have been used with some degree of success in the treatment of neuroses. For example, chlordiazepoxide (Librium®) and di- azepam (Valium®) have both proved to be clinically effective in the reduction of anxi­ ety.1 Although the mechanisms by which these drugs exert their clinical effects are unclear, knowledge of these mechanisms may eventually provide us with insight into biochemical factors that influence neurotic behavior. Psychosis. The term psychosis refers to any one of a group of conditions in which reality testing is impaired. Reality testing refers to the ability of the individual to discrimi­ nate the source and significance of perceptions, thoughts, and feelings and to validate these with external experiences. As a consequence of impaired reality testing, the behavior of psychotics often appears inappropriate and bizarre. Two of the main classifications of psychoses are schizophrenia, in which the promi­ nent disorder involves an impairment of thinking or cognition, and affective disease, in which the prominent disorder involves extremes of mood or affect. It should be recognized that, although either thinking or mood disorder may be prominent, both are usually present to some extent in all psychotics, and that differentiations between schizophrenia and affective disorder are sometimes ambiguous. More complete descriptions of schizo­ phrenia and affective disorders are presented in the introduction to Sections 2 and 3, respectively. Biochemical Considerations A growing body of evidence indicates that biochemical factors play an important role in the etiology of at least some forms of psychotic behavior. The evidence includes