Chemotherapy in Psychiatry

Transcription

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2 Chemotherapy in Psychiatry

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4 Ross J. Baldessarini Chemotherapy in Psychiatry Pharmacologic Basis of Treatments for Major Mental Illness

5 Ross J. Baldessarini Harvard Medical School McLean Hospital Psychopharmacology Program Belmont, MA, USA ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, speci fi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

6 For Frances, who thrice encouraged and supported the writing of this book

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8 Preface This third edition of Chemotherapy in Psychiatry (CTP-III ) has been extensively updated since the second edition of 1985, and is being produced by a new, international publisher. As in the fi rst editions, the monograph addresses the basic aspects of modern psychopharmacology and the clinical applications of drugs that are useful for the treatment of many major psychiatric disorders, including psychoses, major mood disorders, and many anxiety disorders. The presentation covers descriptions of the main classes of psychotropic drugs, selected information concerning their known action mechanisms and metabolic disposition, and their clinical applications for acute illnesses and for prevention of recurrences or long-term morbidity, which are all too common among psychiatric disorders. In addition, limitations and adverse effects of each type of agent are covered. The title of the book, by analogy to treatments used for cancer, was selected to emphasize the point that all psychotropic agents have adverse effects, ranging from annoying to potentially lethal. The art of clinical application of psychotropic medicines centers on the need to balance bene fi ts and risks at the level of individual persons. Moreover, it is increasingly appreciated that use of psychotropic drugs has come to dominate clinical practice in psychiatry worldwide perhaps owing largely to perceived simplicity, ease of use, and apparent ef fi ciency, as well as apparent cost-effectiveness of such treatments. Nevertheless, it is important to emphasize that medicinal treatments for almost all psychiatric patients are but one component of comprehensive clinical care of complex human problems. Effective application of psychiatric chemotherapy requires more than rapid recognition of a syndrome and selection of an appropriate medicine and dose aimed at suppressing selected target symptoms. The now nearly universal domination of clinical psychiatry by a relatively narrow medicinal approach underscores the thesis that premature devaluing or abandonment of traditional psychological and social aspects of clinical psychiatry would be a grave error. In addition to its profound impact on clinical practice since the 1950s, modern psychopharmacology has had a fundamental effect on contemporary academic and theoretical psychiatry. Despite limited advances in fundamental understanding of basic neurobiological and behavioral processes that may underlie major psychiatric vii

9 viii Preface disorders, the availability of effective medicinal treatments and partial understanding of their neuropharmacology have strongly stimulated a generation of research strategies that have moved modern psychiatry closer to the mainstream of general medicine. In part, as a contribution to more precise applications of speci fi c treatments to particular disorders and individual patients, there is also a renewed interest in psychiatric nosology and in psychopathology after decades of neglect, particularly by American academic psychiatry. This monograph developed initially from several years of seminars on psychopharmacology for psychiatric residents, medical students, and postgraduate training programs, and many additional years of consultative clinical practice and case conferences for inpatients and outpatients based at Massachusetts General and McLean Hospitals in Boston. It has also been informed by more than four decades of leading a laboratory program in preclinical neuropharmacology at the Mailman Research Center of McLean Hospital, aimed at better understanding of known psychotropic drugs and in developing improved agents. Additional insights have come from many years of industrial consulting to the pharmaceutical and biotechnology industries, as well as from authoring the chapters on psychopharmacology for a leading textbook of general pharmacology ( Goodman and Gilman s The Pharmacological Basis of Therapeutics; New York: McGraw-Hill) from 1980 to Particularly valuable information has arisen from interactions with patients, trainees, and especially from experiences shared in a series of continuing medical education seminars for a broad range of mental health professionals in Boston, Cape Cod, Santa Fe and elsewhere, and from ongoing international research collaborations with academic and clinical colleagues throughout the world. Since the fi rst edition of the book appeared in 1977, at a time when textbooks in this fi eld were uncommon, many specialized reviews and excellent comprehensive textbooks on various aspects of psychopharmacology have appeared. In the face of the growing complexity and specialization of the fi eld, this monograph has attempted to provide a relatively brief, consistent, and hopefully readable text aimed at communicating basic principles as well as facts, and at contributing to safe and effective clinical application of chemotherapy in psychiatry. It may be limited in representing largely American, and possibly somewhat regional, perspectives and practices, but attempts to balance the risk of parochialism with the principles and major research fi ndings that underlie modern theories and practices. Now that the fi eld has been in existence for more than six decades, it also seemed timely to consider the current state of psychopharmacology, its evolution and promise, but also its theoretical and practical limitations, as the rate of innovation and of fundamentally new drug-products is declining, and its negative as well as many positive effects on clinical care of the mentally ill have become more apparent. Many colleagues in psychiatry, pharmacology, and industry have shared expertise, scienti fi c insights, and clinical experiences that have contributed importantly to this book. Special thanks is also given to Mrs. Rita Burke, for her tireless assistance in gathering research literature on which the book is based. Belmont, MA, USA Ross J. Baldessarini

10 Macbeth: Doctor: Macbeth: Doctor: How does your patient, doctor? Not so sick, my lord, as she is troubled with thick-coming fantasies, that keep her from her rest. Cure her of that: Canst thou not minister to a mind diseas d: pluck from the memory a rooted sorrow; raze out the written troubles of the brain; and with some sweet oblivious antidote cleanse the stuff d boson of that perilous stuff which weighs up on the heart? Therein the patient must minister to himself. William Shakespeare, Macbeth (67 )

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12 Contents Chapter 1. Modern Psychopharmacology and Psychiatric Treatment... 1 Chapter 2. Antipsychotic Agents Chapter 3. Mood-Stabilizing Agents Chapter 4. Antidepressant-Antianxiety Agents Chapter 5. Status and Prospects for Psychopharmacology Index xi

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14 Chapter 1 Modern Psychopharmacology and Psychiatric Treatment In the fi elds of observation chance favors only the prepared mind Louis Pasteur The need for effective treatments of psychiatric disorders is indicated by the high prevalence of many of these disorders [ 47 ], particularly substance-use, anxiety, and mood disorders, as well as their high burden of direct and indirect costs to society (Tables 1.1 and 1.2 ). Psychiatric, substance-abuse, and primary brain disorders account for approximately 13% of the global disease burden (years of healthy life lost due to early death or disability). Depression alone, even excluding bipolar disorders, is the third leading contributor to the worldwide disability. Associated suicides number 1.5 million/year, and attempts are estimated at over 20 million/year [ 24 ]. Throughout the recorded history of medicine, efforts have been made to utilize chemical or medicinal means to modify abnormal behavior and emotional pain. Alcohol and opiates have been used for centuries not only by physicians and healers but also spontaneously for their soothing or mind-altering effects. Stimulant and hallucinogenic plant products also have been a part of folk practices for centuries. More recently, man has applied modern technology, fi rst to rediscovering and purifying many natural products, later to synthesizing and manufacturing their active principles or structural variants with desired properties. Throughout the discussion that follows, the classes of chemicals used for their psychotropic effects (altering feelings, thinking, or behavior) are referred to by the somewhat arbitrary terms antipsychotic, antimanic or mood-stabilizing, antidepressant, and antianxiety agents. This system of terminology grows out of the allopathic tradition of modern scienti fi c medicine, which treats with drugs producing effects opposite, or antagonistic to the signs and symptoms of a given illness. The modern era of psychopharmacology can be dated from 1949, when the antimanic effects of the lithium ion were discovered, or 1952, when the psychotropic and antiadrenergic effects of reserpine were investigated, and when the special properties of chlorpromazine began to be recognized. The antidepressant monoamineoxidase (MAO) inhibitor iproniazid also was introduced in the early 1950s, and in the R.J. Baldessarini, Chemotherapy in Psychiatry: Pharmacologic Basis of Treatments for Major Mental Illness, DOI / _1, Springer Science+Business Media New York

15 2 1 Modern Psychopharmacology and Psychiatric Treatment Table 1.1 Needs and markets for psychotropic drugs Prevalence of psychiatric illnesses (United States) Substance abuse (alcohol and drug) (27%) Anxiety disorders (25%) Major depression and dysthymia (24%) Bipolar disorders (5%) Antisocial personality (3.5%) Schizophrenia and related psychoses (1%) Two or more disorders (27%) Professionally treated (42%) Illness costs Mental illness + dementias (30%) Cardiovascular (18%) Brain + spinal injuries (13%) Cancers (12%) Mood disorders (11%) Acquired immunodeficiency (HIV/AIDS) (8%) Arthritis (5%) Schizophrenia (4%) Ranking by sales income 1. Psychotropics 2. Cancer chemotherapies 3. Anticholesterol agents 4. Diabetes drugs 5. Gastric proton-pump inhibitors 6. Antihypertensives 7. Analgesics late 1950s, the tricyclic antidepressant imipramine was introduced. Use of the anxiolytic-sedative meprobamate began in 1954, and the fi rst benzodiazepine, chlordiazepoxide, was being developed before 1960 as an antianxiety agent. By the end of the 1950s, general medicine and psychiatry had therapeutic agents available for the psychotic and major mood disorders including schizophrenia, mania, and severe depression and the anxiety disorders (formerly neuroses ). Remarkably few fundamentally new kinds of psychiatrically therapeutic agents have been developed since that time. Instead, the past half- century has been marked by an accumulation of structural analogues of earlier agents or chemically dissimilar drugs with similar actions and clinical effects all with adverse effects, some similar and others new. Nevertheless, there have been important advances in understanding the biological and clinical actions of the available psychotropic drugs and their appropriate clinical use. Currently available psychotropic drugs are the leading pharmaceutical products of all kinds, based on their annual sales (Table 1.1 ). Psychotropic drugs that are currently available are summarized by generic and corresponding original or prominent brand names in Table 1.3. A recent market analysis of leading psychotropic drugs based on annual sales in the United States [ 30 ] indicated the following ranking: (1) alprazolam ( Xanax ), (2) zolpidem ( Ambien ), (3) S -citalopram ( Lexapro ), (4) lorazapam ( Ativan ), (5) gabapentin