Washouts/Relapses in Patients Participating in Neurobiological Research Studies in Schizophrentia

Dianne N. Irving
and Adil E. Shamoo, Ph.D. First National Conference
Ethics in Neurobiological Research With Human Subjects
Baltimore-Marriott Inner Harbor
Baltimore, Maryland
January 7-9, 1995
[Background Paper: in Program at Conference]
Reproduced with Permission

I. Introduction

Neural biological disorders (NBD) (mental illnesses) are common widespread afflictions of brain functions manifested in modifications of behavior, ranging from socially unacceptable behavior to psychosis and delusions. Schizophrenia, one of the most serious forms of NBD, afflicts over two million persons in the United States (Andreasen and Carpenter 1993)1 and tens of millions of persons worldwide. About 10% of these persons commit suicide. Since the 1950's pharmacologic agents (e.g., neuroleptics) have become the primary tool in treating schizophrenia (Kane and Marder 1993).2 However, the pharmacological treatment for schizophrenia is accompanied by large numbers of serious side effects (such as tardive dyskinesia) and large variations of patients' responses to drug treatments. Further, schizophrenic patients can have periods of "wellness" even without any medications before a relapse can occur.

This situation has encouraged the scientific community to explore research on new drugs, using patients with schizophrenia as human research subjects, with increasing success. In reviewing the literature, some of these studies included the withdrawal of medications (washouts) for periods ranging from one day to over one year. Some studies involved the use of placebos or double-blind protocols; others involved the use of "challenge" doses of drugs, e.g., amphetamines or L-dopa (to induce relapse-like symptoms in patients). Many of these studies resulted in patient relapses (considered high-risk consequences to the patients).

The purpose of this paper is to familiarize those inside and outside the field with a brief background on: (1) medical research studies in schizophrenia in which washouts/relapses occurred; and, (2) some of the ethical issues which have been raised concerning such research studies.

II. Washouts/Relapses in Patients Participating in Neurobiological Research Studies

Very few systematic studies on the incidence of relapses in patients with schizophrenia participating in neurobiological research protocols have been reported in the scientific literature. The issue of whether or not relapse may cause irreversible brain damage is controversial (Wyatt 1991; Miller 1989),3 4 as is the issue of whether or not relapse may cause severe worsening of the patients' conditions (Wistedt 1981; Johnson et al 1983; Hass, Keshavan and Sweeney 1994).5 6 7

The most exhaustive study on the incidence of relapses in research studies is by Shamoo and Keay.8 They conducted a literature search on the National Library of Medicine MEDLINE for the years 1966-1993 (August), using the subject index "schizophrenia", "relapse", "human", and "English language". 142 studies were identified, 141 of which were obtained. In these 141 studies, only 66 studies used patients directly [see references 9-78]. Of these, 41 were of U.S. origin, and 25 were of non-U.S. origin. Shamoo and Keay proceeded to analyze the U.S.-only studies according to several scientific and ethical parameters (the ethical parameters are addressed below).

Some of the important results of this literature study indicate a need to address the incidence of washouts and relapses experienced by the patients who participated in these research protocols. For example, in the 41 U.S.-only studies (involving 2471 patients), 936 patients (37.9%) relapsed; and in the 25 non-U.S. studies (involving 1259 patients), 46% relapsed. Another important result concerned the dropping out of patients from the research protocols. 245 patients in the U.S.-only studies dropped out (9.9%), with no known or noted whereabouts of 98.3% of these patients. 95 patients in the non-U.S. studies dropped out (7.6%), with no known or noted whereabouts of 97.4% of these patients. Of further concern to the authors is the use of placebos, double-blind protocols and "challenge" drugs in some of these studies, which also result in relapses in the patients participating in these protocols.

III. Ethical Issues in Neurobiological Research Resulting in Washouts/Relapses

A review of the bioethics literature by Irving and Shamoo on the ethical issues concerning research in schizophrenia was conducted on BIOETHICSLINE (Kennedy Institute of Ethics Library, Georgetown University, Washington, D.C.), generated by MEDLARS II, National Library of Medicine, for the years 1973-1994 (October). The term searched was "schizophrenia" (all citations). 149 citations were identified. Only five citations were found which specifically addressed the issues of washouts/relapses and the use of placebos and/or double-blind protocols. While two of these citations expressed concern about the worsening of the patients conditions during these studies (Klerman 1986; Abrams 1986)9 10 the third argued that there were no consistent or important clinical or social differences between the patients in the drug and the control groups after a 7-year follow-up study (Curson et al 1986).11 This was the only citation found to systematically address any follow-up studies on these patients in view of their relapse conditions. Additionally, two citations were articles which were published in The New York Times (Hilts 1994; Editorial 1994)12 13 concerning problems associated with recent U.C.L.A. experiments involving patients who had relapsed.

Why so few citations addressing schizophrenia in general, and the issues of washouts/relapses, the use of placebos, double-blind protocols, or "challenge" drugs were identified in this search is unknown. This could be a question of a lack of interest or knowledge within the bioethics or ethics communities, or the range of journals, books, media sources, etc., which are indexed in the BIOETHICSLINE or MEDLAR II computer programs. Perhaps these issues are addressed more often within the context of the strictly scientific literature.

Some other citations independently identified are included here. For example, Shamoo and Irving (1993) addressed their concerns about possible harms caused to relapsing patients in their article on accountability in research using persons with mental illness.14 Rothman and Michels (Aug. 1994) expressed similar concern for patients with schizophrenia participating in experiments using placebo controls.15 Hass, Keshavan and Sweeney (Dec. 1994) recently indicated that failure to treat psychosis in patients with schizophrenia may be associated with worse treatment responses and a more severe course of illness.16 Articles by Davidson et al (1987)17, and Angrist et al (1973)18 report the effects of using "challenge" doses of L-dopa on patients with schizophrenia during their research studies. In a recent book by Maris (1986),19 Biology of Suicide, an article by van Praag20 discusses the importance of the use of "challenge" drugs in experiments in schizophrenia; and Tanney's article21 in the same book argues for the use of electroconvulsive therapy (ECT) in patients with schizophrenia who are suicidal.

There were several articles specifically relevant to washouts/relapses in the Spring 1994 volume of The Journal of the California Alliance For The Mentally Ill.22 In that journal volume articles by Hassner,23 Shamoo,24 Becker,25 Caplan,26 Irving,27 and the Journal's "Postscript"28 express specific concerns for the harmful effects of relapses, washouts or the use of placebos or double-blind protocols with patients who have schizophrenia because of the harmful effects often experienced by these patients. Also included was the reprint of the New York Times editorial (above) identifying some of the harmful effects of washouts and relapses on patients with schizophrenia in a recent U.C.L.A. study.29 In other articles Levine,30 Smith,31 Kane,32 Angrist,33 Lieberman and Sloan,34 Goodwin,35 Shore et al,36 acknowledge similar concerns, but argue generally that some research of this type, under appropriate conditions, is required in order to develop new drugs for treatments for patients with schizophrenia. [Articles by Annas,37 Barchas and Barchas,38 Lazarus,39 Rubenstein,40 Wirshing,41 Opler,42 Schell,43 Ghaemi and Hundert,44 Destro,45 Thomasma,46 Frese,47 Kaminski,48 Moline and Aisen,49 Meiback,50 Zarin and West51 address more specifically other ethical issues involved in research using patients with schizophrenia in general].

In terms of media coverage of the issues of washouts/relapses, aside from the above-mentioned editorial, and article by Phil Hilts (both published in The New York Times), little has been written. Phil Hilts discussed the problems of the same U.C.L.A. experiment in an article in The New York Times.52 The Los Angeles Times Magazine (1994) published an extensive article on the suicide of one of the patients with schizophrenia who had participated in a U.C.L.A. research program.53 Additionally, a T.V. program in Minneapolis (1994) produced a piece entitled "Fatal Experiment", exploring the circumstances surrounding the suicide of a patient with schizophrenia shortly after taking part in a drug protocol at a local hospital in Minneapolis.54

In the medical research literature study mentioned above (Shamoo and Keay 1994), several ethical issues specifically associated with washouts/relapses were addressed. The focus of their concerns was on ethical issues such as:


1 Andreasen NC, Carpenter WT. Diagnosis and classification of schizophrenia. Schiz Bull 1993; 19:25-40. [Back]

2 Kane JM, Marder SR. Psychopharmacologic treatment of schizophrenia. Schiz Bull 1993; 19:113-128. [Back]

3 Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schiz Bull 1991; 17:325-347. [Back]

4 Miller R. Schizophrenia as a progressive disorder: relations to EEG, CT, neuropathological and other evidence. Progress Neurobiology 1989; 33:17-44. [Back]

5 Wistedt B. A depot neuroleptic withdrawal study: a controlled study of the clinical effects of the withdrawal of depot fluphenazine decanoate and depot flupenthixol deconoate in chronic schizophrenic patients. Acta Psychiat Scand 1981; 64:65-84. [Back]

6 Johnson DAW, Pasterski G, Ludlow JM, Street K, Taylor RDW. The discontinuance of maintenance neuroleptic therapy in chronic schizophrenic patients: drug and social consequences. Acta Psychiatr Scand 1983; 67:339-352. [Back]

7 Hass GL, Keshavan MS, Sweeney JA. Delay to first medication in schizophrenia: evidence for a possible negative impact of exposure to psychosis. Abstracts of Panels and Posters (Poster Session II), 33rd Annual Meeting, American College of Neuropsychopharmacology, San Juan, Puerto Rico, Dec. 12-16, 1994; 171. [Back]

8 Shamoo AE, Keay TJ. Ethical concerns about relapse studies. 1994; unpublished. [Back]

9 Klerman GL. Scientific and ethical considerations in the use of placebo controls in clinical trials in psychopharmacology. Psychopharmocol Bull 1986; 22(1):25-29. [Back]

10 Abrams RA. Ethical questions raised by a proposed randomized, double-blind study involving placebo, standard drug therapy and experimental antipsychotic drug therapy for patients with schizophrenia. Clin Res 1986 Jan.; 34(1):6-9. [Back]

11 Curson DA, Hirsch SR, Platt SD, Bamber RW, Barnes TRE. Does short term placebo treatment of chronic schizophrenia produce long term harm? Brit Med J 1986 Sep.20; 293(6549):726-728. [Back]

12 Hilts P. Agency faults a U.C.L.A. study for suffering of mental patients. New York Times 1994 Mar 10; A1, B10. [Back]

13 Editorial. Medical ethics in the dock. The New York Times Mon., Mar 14, 1994. [Back]

14 Shamoo AE, Irving DN. Accountability in research using persons with mental illness. Accountability in Research 1993; 3:1-17. [Back]

15 Rothman KJ, Michels KB. Sounding Board: The continuing unethical use of placebo controls. NEJM Aug. 1994; 331(6):394-398. [Back]

16 Haas G, Keshavan MS, Sweeney JA. Delay to first medication in schizophrenia: evidence for a possible negative impact of exposure to psychoses. Abstracts of Panels and Posters (Poster Session II), 33rd annual Meeting, American College of Neuropsychopharmacology, San Juan, Puerto Rico, Dec. 12-16, 1994; 171. [Back]

17 Davidson M, et al. L-dopa challenge and relapse in schizophrenia. Am J Psychiatry 1987 July; 144(7):934-938. [Back]

18 Angrist B, Sathananthan G, Gershon S. Behavioral effects of L-dopa in schizophrenic patients. Psychopharmacologia (Berl.) 1979; 31:1-12. [Back]

19 Maris R (ed.). Biology of Suicide (New York: The Guilford Press, 1986); 21-50. [Back]

20 Van Praag HM. Affective disorders and aggression disorders: evidence for a common biological mechanism. in Maris 1986; 21-50. [Back]

21 Tanney BL. Electroconvulsive therapy and suicide. in Maris 1986; 116-140. [Back]

22 Weisburd D (ed.). The Journal of the California Alliance for the Mentally Ill Spring 1994; 5(1). [Back]

23 Hassner V. What is ethical? what is not? where do you draw the line? ibid., 4-5. [Back]

24 Shamoo AE. Our responsibilities toward persons with mental illness as human subjects in research. ibid., 14-16. [Back]

25 Becker JC. A mother's testimony, ibid., 17. [Back]

26 [xxvi]. Caplan AL. Are existing safeguards adequate? ibid., 36-38. [Back]

27 Irving DN. Psychiatric research: reality check. ibid., 42-44. [Back]

28 Editor. A disturbing postscript. ibid., 69. [Back]

29 Editorial. Medical ethics in the dock. The New York Times (Mon., Mar.14, 1994); ibid., 12. [Back]

30 Levine RH. A researcher's concern with ethics in human research. ibid., 6-8. [Back]

31 Smith ML. Power, advocacy, and informed consent. ibid., 25-27. [Back]

32 Kane JM. Enormous ethical challenges. ibid., 28-29. [Back]

33 Angrist B. Ethical issues regarding prospective studies of amphetamine psychosis. ibid., 32-35. [Back]

34 Lieberman JA, Sloan J. The moral imperatives of medical research in human subjects. ibid., 40-42. [Back]

35 Goodwin FK. Questions and answers. ibid., 45-47. [Back]

36 Shore D, Berg K, Mullican C. Ethical issues in clinical neurological research. ibid., 61-62. [Back]

37 Annas GJ. Experimentation and research. ibid., 9-11. [Back]

38 Barchas JD, Barchas ID. The imperative for research on severe mental disorders. ibid., 18-19. [Back]

39 Lazarus J. Critical ethical issues and conflicts. ibid., 20-21. [Back]

40 Rubenstein LS. Psychiatric experimentation: the lessons of history. ibid., 22-24. [Back]

41 Wirshing WC. In a perfect world none of this would concern us. ibid., 30. [Back]

42 Opler LA. Conducting clinical psychiatric research in "non-research" settings. ibid., 30-31. [Back]

43 Schell, BH. The ominous shadow of the CIA has imprinted itself on the brain research community. ibid., 38-40. [Back]

44 Ghaemi SN, Hundert EM. The ethics of research in mental illness. ibid., 47-49. [Back]

45 Destro RA. Law, professionalism, and bad attitude. ibid., 50-53. [Back]

46 Thomasma, DC. Obtaining consent for research in the neurobiologically impaired. ibid., 54-55. [Back]

47 Frese FJ. Informed consent and the right to refuse or participate. ibid., 56-57. [Back]

48 Kaminski R. The importance of maintaining patient's continued and informed consent. ibid., 57-58. [Back]

49 Moline ML, Aisen MW. Perspectives of protocol reviewers. ibid., 59-60. [Back]

50 Meiback RC. Why does it take so long now for drugs to get to the marketplace? ibid., 63-65. [Back]

51 Zarin DA, West J. ACORN: APA clinical outcomes research network. ibid., 66-67. [Back]

52 Hilts P. Agency faults a U.C.L.A. study for suffering of mental patients. New York Times 1994 Mar 10; A1, B10. [Back]

53 Horowitz J. For the sake of science. Los Angeles Times Magazine Sept. 11, 1994; 16 (cover story). [Back]

54 Leer R. A fatal experiment. Nov. 3, 1994; Station KSET, Minneapolis, MN (Unit Five Investigation). [Back]