Task Force Reports This is the eighteenth in a series of reports approved by the Board of Trustees of the American Psychiatric Association to give wider dissemination to the findings of APA's many commissions, committees, and task forces that are called upon to evaluate the state of the art in a problem area of current concern to the profession, to related disciplines, and to the public. The findings, opinions, and conclusions of the report do not necessarily represent the views of the officers, trustees, or all members of the Association. Each report, however, does represent the thoughtful judgment and findings of the task force of experts who composed it. These reports are considered a substantive contribution to the ongoing analysis and evaluation of problems, programs, issues, and practices in a given area of concern. Alan A. Stone, M.D. President, APA, 1979-80 Library of Congress Catalogue No. 80-65372 Copyright 1980 by the American Psychiatric Association 1400 K Street, N.W., Washington, D.C. 20005 Printed in U.S.A. 2nd Printing October, 1983 TARDIVE DYSKINESIA Report of the American Psychiatric Association Task Force on Late Neurological Effects of Antipsychotic Drugs Ross J. Baldessarini, M.D., Chairperson Jonathan O. Cole, M.D. John M. Davis, M.D. George Gardos, M.D., Consultant Sheldon H. Preskorn, M.D., Falk Fellow George M. Simpson, M.D. Daniel Tarsy, M.D., Invited Neurologist Approved for Publication by the Council on Research and Development John M. Davis, M.D., Chairperson Charles Gaitz, M.D. Edward Joel Sachar, M.D. George Winokur, M.D. Peter Wolff, M.D. Joyce Lowinson, M.D., Observer-Consultant Leigh M. Roberts, M.D., Assembly Liaison H. Keith H. Brodie, M.D., Board Liaison Henry H. Work, M.D., Staff Liaison Publication authorized by the Board of Trustees December 1979 AMERICAN PSYCHIATRIC ASSOCIATION 1400 K Street, N.W. Washington, D.C. 20005 ACKNOWLEDGMENTS The work of this Task Force was initiated and supported by the Ameri- can Psychiatric Association but was also given indirect support by a National Institute of Mental Health (NIMH) Career Award to Dr. Baldessarini (MH-47370). Dr. Preskorn was supported by the Falk Fellowship Program of APA. Mrs. Mila Cason provided invaluable assistance in the administration of the Task Force and preparation of its report. Margaret C. McDonald assisted in the editing of this report. The members of the Task Force would also like to thank the many colleagues in America and abroad who generously provided informa- tion, opinions, and unpublished data. CONTENTS Preface .................................... v Chapter I. Introduction ...................................................... 1 Chapter II. Clinical Description, Differential Diagnosis, and Methods of Evaluation .................................. 23 Chapter III. Epidemiology of Tardive Dyskinesia...........43 Chapter IV. Pathophysiology and Etiology of Tardive Dyskinesia................................................ 57 Chapter V. Clinical Indications for Prolonged Neuro- leptic Treatment.................................. 98 Chapter VI. Prevention and Treatment......................... Chapter VII. Summary, Conclusions, and Recom- mendations.......................................... 160 Appendices I. Clinical Rating Scales for Tardive Dys- kinesia 177 II. Summary of International Survey on Neuroleptic Drug Therapy................ 200 III. Glossary .................................... 204 This page intentionally left blank PREFACE The past two decades have produced almost revolutionary changes in the pattern of care of psychiatric patients. Important features of this revolution are a strikingly decreased prevalence of psychiatric hos- pitalization, the phasing out of many public mental institutions, the early return of psychotic patients to home and work, the development of open psychiatric units in general hospitals, and an increased reli- ance on local community and outpatient treatment facilities even for patients with severe or psychotic illnesses such as schizophrenia and manic or depressive disorders, many of whom are treated effectively by physicians without specialized training in psychiatry as well as by psychiatrists. These changes almost certainly are the result of a com- plex interplay among new forms of medical treatment of psychiatric patients, administrative decisions, social and philosophic changes in medicine, and cultural and historical factors that are still poorly un- derstood. Among these factors, the introduction of effective and relatively safe new antipsychotic medications that are useful in schizophrenia, paranoid disorders, mania and some severe forms of depression, and certain neuropsychiatric disorders, and the rise of the new discipline of psychopharmacology since the early 1950s have surely had an im- portant effect. This era was opened by the introduction of reserpine and chlorpromazine (Thorazine) into the treatment of severely dis- turbed psychiatric patients in 1952. The new antipsychotic psycho- pharmaceuticals lead to rapid control of psychotic symptoms and behavior and have profound preventive effects, both of a direct phar- macologic type and by prevention of some untoward complications of prolonged institutionalization. While the present report deals only with an important toxic neuro- logical side-effect associated with prolonged use of the antipsychotic, or so-called neuroleptic, agents, it is important to emphasize at the outset that the use of neuroleptic drugs has had extremely beneficial direct effects on patient care. In addition, it has also helped to draw psychiatry even closer to the rest of medicine, has encouraged more careful differential diagnosis, and has gained support for biomedical approaches in psychiatry which complement psychosocial theories and therapies. This page intentionally left blank CHAPTER I INTRODUCTION Tardive dyskinesia This Task Force Report deals with the late dyskinetic neurologic dis- orders, commonly referred to as "tardive dyskinesia," which are asso- ciated with the prolonged use of the presently available antipsychotic drugs. We will review the clinical features, evaluation, differential diagnosis, epidemiology, neuropathology, pathophysiology and phar- macology, prevention, and management of this condition. Antipsychotic drugs produce several distinctive transient and more prolonged or even irreversible extrapyramidal neurologic syn- dromes. Acute dyskinesias, akathisia, and parkinsonism were all rec- ognized soon following the introduction of phenothiazines into clin- ical practice in the 1950s. The neurological effects of these agents in animals and man justified the term neuroleptic, which was coined in Europe to describe them—a term that meant "affecting the nervous system," but that also implied "mimicking neurologic disorders." Transient extrapyramidal reactions occurred early in treatment, sub- sided with reduction in drug dosage, and were often regarded as desir- able aims or indications of effective antipsychotic therapy (1, 2). The first clinical reports recognizing the occurrence of persistent dyskinesias following prolonged treatment with phenothiazines were published in the late 1950s (3, 4). Thereafter, a number of reports appeared describing the occurrence of similar persistent dyskinesias, nearly always among chronic psychiatric patients, in the course of treatment with phenothiazine antipsychotic drugs (5-9). Initial reports emphasized the orofacial distribution of the dyskinesia and referred to it as a "bucco-linguo-masticatory syndrome" (4,5); it was later referred to as "terminal extrapyramidal insufficiency syndrome" (10). The now commonly used term, "tardive dyskinesia" (late and persistent dyskinesia), was introduced by Faurbye and his colleagues in 1964 (11). The subject has been extensively reviewed (12-14) with regard to clinical description (11, 15-17), pathophysiology (18-20), pharmacol- ogy (13, 14, 19, 21), and management (13, 14, 22). Tardive dyskinesia (TD) was initially regarded as a complication of antipsychotic drug therapy largely restricted to elderly, chronically 1 Task Force Report 18 institutionalized, frequently brain-damaged patients receiving pro- longed drug treatment. In recent years, however, the status of tardive dyskinesia as a more general public health problem of major propor- tions, which may interfere with the ultimate rehabilitation of the patient in the community, has been given strong emphasis (23, 24). Prior to more detailed discussions of specific aspects of tardive dyskinesia, it may be helpful to provide a brief overview of the current understanding of the major actions of the neuroleptic drugs on the nervous system and to outline the several other extrapyramidal dis- orders associated with their use. Introductory comments on the antipsychotic drugs Antipsychotic agents include compounds proven effective in the management of a broad range of psychotic symptoms and particularly useful in the treatment of schizophrenia and mania. Nearly all produce neurological effects in animals and in humans. The evidence that this class of substances has real and selective antipsychotic effects in schizophrenia and other disorders marked by abnormalities of thought associations, perceptions, and beliefs is now overwhelming (25). Anti- psychotic drugs are rarely, if ever, curative, although they are highly effective in hastening remissions of acute psychotic illnesses and also seem to prevent later exacerbations of psychotic symptoms. Since their effects in truly chronic and relentless psychoses