Sudden Death in Psychiatric Patients: the Role of Neuroleptic Drugs

TABLE OF CONTENTS Introduction …………………………………………………………………….. 1 Definitions ……………………………………………………………………… 2 Incidence of Sudden Death …………………………………………………... 3 A Critical Review of Case Reports of Sudden Death ………………….….. 3 Antiarrhythmic Effects of Antipsychotic Drugs ……………………………... 5 Cardiotoxicity and Sudden Death with Psychotropic Drugs ……………… 5 Hypotension ………………………………………………………………….... 6 Postictal Death …………………………………………………………….….. 6 Aspiration and Asphyxiation …………………………………………….…… 6 Megacolon and Paralytic Ileus ………………………………………………. 7 27 Heat Stroke …………………………………………………………………….. 7 Malignant Hyperthermia ………………………………………………………. 7 Neuroleptic Malignant Syndrome ………………………………………….… 7 Physical Exhaustion ……………………………………………………..….… 7 SUDDEN DEATH IN Other Explanations of Sudden Apparent Cardiac Death ………………….. 8 Stress Factors and Sudden Death ………………………………………..… 8 PSYCHIATRIC PATIENTS: Conclusions ……………………………………………………………………. 8 Recommendations …………………………………………………………,… 9 References …………………………………………………………………..… 10 THE ROLE OF NEUROLEPTIC DRUGS INTRODUCTION An American Psychiatric Association Task Force Report Sudden, unexpected death may occur in apparently healthy individuals. Its occurrence in psychiatric patients has raised the concern George M. Simpson, M.D. that the use of psychotropics, especially antipsychotics, may be associated John Davis, M.D. with an increased risk for sudden death. This concern is maintained even James W. Jefferson, M.D. though not all psychiatric patients who have succumbed to sudden death Jorge F. Perez-Cruet, M.D. have been on psychotropics. Early reports presented the concern that the use of chlorpromazine Publication authorized by the Board of Trustees, December 1987 and thioridazine were associated with sudden death. More recently, the focus shifted to the more potent agents. Indeed, the FDA Advisory This is the twenty-seventh report in a monograph series authorized by the Committee discussed the possibility of a connection between sudden Board of Trustees of the American Psychiatric Association to give wider death and haloperidol. No decision could be reached by the FDA dissemination to the findings of the Association's many commissions, Committee because of the enormous complexity of the problem. committees, and task forces that are called upon from time to time to Nonetheless, since sudden death continues catastrophically to complicate evaluate the state of the art in a problem area of current concern to the the course of some patients, the Task Force on Sudden Death was formed profession, to related disciplines, and to the public. to investigate further the relationship of antipsychotic agents and sudden Manifestly, the findings, opinions, and conclusions of the Task Force death. Reports do not necessarily represent the views of the officers, trustees, or This is a difficult issue to explore for many reasons. It demands a all members of the Association. Each report, however, does represent the knowledge of incidence of sudden death in the normal population thoughtful judgment and consensus of the task force of experts who compared to the psychiatric population both before and after psychotropics formulated it. These reports are considered a substantive contribution to were introduced. Obtaining these data is complicated by the fact that the the ongoing analysis and evaluation of problems, issues, and practices in term "sudden death" has been given widely varying definitions. Thus, the a given area of concern. use of standardized definitions and comparison of age, sex and otherwise George H. Pollock, M.D. matched population is necessary to determine if, in fact, a relationship President, APA 1987-1988 between antipsychotic administration and sudden death exists. In addition, the issue of stress and sudden death needs to be ISBN 0-88048-313X examined. Stress itself is difficult to define, but folklore and, indeed, data Library of Congress Catalogue Card No. 88- 70132 suggest that sudden bad or good news can produce sudden death. Copyright 1988 by the American Psychiatric Association Similarly, excessive physical exercise, e.g., the annual opening of football 1400 K Street, N.W., D.C. 20005 camps, results in sudden death in apparently healthy athletes, Adding the Printed in the U.S.A. consideration of stress to the examination of the relationship between antipsychotics and sudden death in psychiatric patients makes matters ACKNOWLEDGMENTS even more complex. If there is an association between neuroleptics and sudden death, these patients would comprise a high risk population. On The authors wish to thank Dr. Paul Leber, Dr. William H. Wilson, Dr. Paul the other hand, they may also be at high risk for stress-induced sudden Silver, Dr. Hardeep Singh, Dr. Douglas Levinson, M.Y. Zhang, and Mary death in which case antipsychotics may be protective. To complicate Tluczek for their assistance in the preparation of this report. things further, the stress that psychotic patients endure is quite difficult to assess and quantify. The charge to the Task Force was to evaluate the REPRODUCTION NOTE relative weight and interactions of these factors against the background of an acceptable definition of sudden death. This involved consideration of This document differs in pagination from the originally published Task the various causes of sudden death together with potential drug-induced Force Report. To verify a citation or quote, search this document by word mechanisms and risk factors. Finally, the Task Force considered or phrase for the statement of interest. recommendations that might favorably affect the risk/benefit ratio and the possible ways of obtaining more information on the subject. DEFINITIONS 3. "Non-violent death occurring unexpectedly within six hours in an apparently healthy subject, or in a sick person whose condition was either The subject of sudden death has been of concern to and studied by steady or improving" (in Pisa, 1980). the medical profession for many years. The term "sudden death" sounds 4. "An individual who died due to natural causes and who was not rather unambiguous -- an apparently healthy person rather abruptly restricted to his home, a hospital, or an institution, or unable to function in collapses and rapidly expires. For epidemiological purposes, however, a the community for more than 24 hours prior to death and which 1he time more precise definition is necessary. Unfortunately, there is no widely interval from the onset of the fatal event was less than 24 hours." [Based accepted, standardized definition that would permit reliable cross-study on this definition, one can appreciate that this study, "An Epidemiological comparisons of the type essential to evaluating a specific area such as Study of Sudden and Unexpected Death in Adults," (Kuller, et al., 1967) psychotropic drug-related sudden death. would involve a population quite different from the population in which The prototypic psychotropic drug-related sudden death might be a most psychotropic drug associated sudden deaths have been described.] hospitalized psychiatric patient with no known medical illness who, early in Kuller (1966) points out that it is often difficult to establish time of the course of parenteral treatment with an antipsychotic drug and while onset of symptoms, especially if death occurs unobserved. He also under close observation, is found dead minutes after being last seen and reviews a number of studies in which the term "sudden" was defined by in whom, after a meticulous post-mortem examination, no cause of death intervals from onset of symptoms to death of less than one hour, one hour, can be established; hence, an unexplained, unexpected, sudden, natural two hours, twelve hours, and twenty-four hours. death. If psychotropic drugs could be unequivocally implicated in causing One of the better studies of neuroleptic drug-related sudden death such deaths, the term "unexplained" would no longer be appropriate. Often used as a definition "an apparently healthy person's death occurring in the absence of an alternative explanation, the relationship between the literally instantaneously or within one hour of the onset of the symptoms, medication and the death is assumed to be causal rather than excluding suicide, homicide, and accident" (Ungvairi, 1980). coincidental. An analogy can be made with the patient with puzzling The definition of the term "sudden death" has also been handled by symptoms in whom a physical evaluation is unrevealing and who is, avoiding a definition and, instead, suggesting that each case be dealt with therefore, assumed to have a psychological illness. Such an assumption by recording time elapsed between onset of symptoms and death {Pisa, mayor may not be correct, for a nonpsychiatric medical illness may still be 1980) . causal yet remain undetected for lack of appropriate diagnostic procedures In.summary, definitional issues abound. Myerberg concludes: "Thus, it (Jefferson and Marshall, 1981). is not possible to give a single best definition for the syndrome. However, a broad definition of sudden death might be stated as natural death, Death occurring instantaneously, or within one hour of the onset of symptoms, in In recent years, a considerable amount of medical and legal effort has a patient who may or may not have known pre-existing disease but in gone into establishing a precise definition of death. While controversy whom the time and mode of death come unexpectedly. The three terms remains with regard to the finer points, an uncomplicated definition could that should

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