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Psychiatric symptom-provoking studies: An ethical appraisal
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COMMENTARY
Psychiatric Symptom-Provoking Studies: An Ethical Appraisal Franklin G. Miller and Donald L. Rosenstein Key Words: Bioethics, biological psychiatry, challenge studies, institutional review board, informed consent BIOL PSYCHIATRY 1997;42:403--409
Introduction Biological psychiatry is dedicated to improving the diagnosis and treatment of psychiatric disorders by means of expanding scientific understanding of their underlying neurobiological mechanisms. Achieving this goal requires nontherapeutic experimentation with patients who volunteer to participate in the enterprise of seeking knowledge about mental disorders. Recently the conduct of psychiatric research has come under increasing ethical and regulatory scrutiny (Office for Protection from Research Risks 1994; The Journal of the California Alliance for the Mentally Ill 1994; Katz 1993; Applebaum 1996; Dresser 1996). The ability of severely ill psychiatric patients to give informed consent to participate in research, in general, and treatment studies requiring a drug withdrawal phase, in particular, have been called into question. Concerns have focused both on the decision-making capacity of psychiatric patients, especially those suffering from schizophrenia, and the adequacy of disclosure of risks and discomforts of research by investigators. We believe that an open discussion of potentially problematic psychiatric From the Center for Biomedical Ethics, University of Virginia, Charlottesville, Virginia (FGM); and the Psychiatry Consultation-Liaison Service, National Institutes of Health, Bethesda, Maryland (DLR). The opinions expressed in this paper are those of the authors and do not necessarily represent the position of any institutions with which the authors are affiliated. Address reprint requests to Donald L. Rosenstein, MD, National Institute of Mental Health, Bldg. 10 Room 3N238, 10 Center Dr MSC 1276, Bethesda, MD 20892-1276. Received July 15, 1996; revised February 10, 1997.
© 1997 Society of Biological Psychiatry.
research coupled with refinement of research guidelines may obviate excessive regulatory restrictions that could hamper valuable research and its promise of contributing to improved patient care. In this article we identify and discuss ethical concerns posed by one form of psychiatric research--the "challenge study." In this paradigm investigators administer a psychopharmacologic agent or psychological challenge procedure to patients under controlled conditions to probe psychiatric symptoms and other neurobiological responses. The principal scientific rationale behind this approach is to learn more about the underlying pathophysiological mechanisms responsible for the symptomatic expression of psychiatric illnesses. In addition, the knowledge gained from this type of study might lead to better predictors of treatment response or the identification of novel therapeutic interventions. This approach might develop eventually to the point that it yields clinical benefits analogous to the use of electrophysiological stimulation for symptomatic cardiology patients, designed to provoke arrhythmias and thus to inform the rational and individualized selection of antiarrhythmic medications. In psychiatric research the term "challenge study" encompasses a wide range of pharmacologic and psychologic provocations, such as intravenous amphetamine, inhaled carbon dioxide, and the presentation of a phobic stimulus, and an equally diverse set of outcome measures: e.g., hormonal responses, cerebral blood flow, and behavioral or mood ratings. We restrict our discussion in this 0006-3223/97/S 17.00 Pn S0006-3223(97 )00189-3
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paper to research that is designed to gain knowledge about psychiatric disorders by experimentally inducing characteristic symptoms in psychiatric patients. Accordingly, we refer to this type of investigation as a "psychiatric symptom-provoking study." Examples of such studies include attempts to provoke panic attacks with infusions of sodium lactate (Liebowitz et al 1984) or pentagastrin (Abelson and Nesse 1994), to induce temporary depressive symptoms by tryptophan depletion in patients who have responded to antidepressant medication (Delgado et al 1991), and to elicit obsessive-compulsive symptoms in response to administration of m-chlorophenylpiperazine (Zohar et al 1987). It should be stressed that symptom provocation represents one part of the design of these studies, which also includes measurement of physiological and biochemical responses to challenge agents or procedures. Psychiatric symptom-provoking studies offer considerable scientific and clinical promise (Hollander 1995). For example, challenge experiments with obsessive-compulsive disorder (OCD) patients have contributed to understanding the role of brain serotonin in the pathophysiology of this illness and the mechanism of action of effective drug treatments, such as clomipramine, fluoxetine, and fluvoxamine (Zohar et al 1990). The differential effects of anxiogenic challenge agents on patients with panic disorder and OCD indicate that these are neurobiologically distinct disorders (Goodman et al 1991). Gorman et al forecast the potential clinical benefits of the pharmacologic challenge model in panic disorder as follows: It is conceivable that in the not too distant future, pharmacologically induced panic attack models will be used to screen new putative antipanic medications and to track a patient's progress through treatment. Ultimately, if one of the models meets the specificity test, pharmacologically induced panic could even serve the clinician as a diagnostic tool. (Gorman et al 1987) As technologies to study brain physiology continue to evolve at a rapid pace, it is likely that future research will rely increasingly on methods designed to study psychiatric patients under conditions that provoke the symptoms of their illness. Nonetheless, these studies raise ethical questions, which have not been adequately discussed in either the psychiatric or bioethics literature. Our purpose in appraising psychiatric symptom-provoking studies from an ethical perspective is threefold: first, to increase awareness among investigators and members of institutional review boards ORBs) about the ethical dimensions of these studies; second, to analyze critically the ethical considerations relevant to this research paradigm; and third, to propose specific practical recommendations for the ethical use of this promising approach to psychiatric research. In focusing on psychiatric symptom-pro-
yoking studies, we do not claim that the ethical issues that we examine are unique to, or more serious in, psychiatric research. Nontherapeutic investigation in other domains of medical research presents similar ethical issues and also warrants careful review and safeguards comparable to what we recommend for this method of psychiatric experimentation.
Ethical Concerns Posed by Psychiatric Symptom-Provoking Studies The two main ethical concerns with psychiatric symptomprovoking studies are related to informed consent and risk/benefit determinations. Are patients recruited for participation in psychiatric symptom-provoking studies able to give adequate informed consent, and do the potential scientific and future clinical benefits of these studies justify exposing these patients to some degree of psychic distress? Undoubtedly, psychiatric illness--e.g., severe depression and profound thought disorder--can interfere with the understanding, judgment, and volition required to give informed consent. Although the capacity of psychiatric patients to give inlbrmed consent to research has not been studied systematically, a recent study of the capacity of psychiatric patients to make treatment decisions found that the majority of the sampled patients with schizophrenia and major depression displayed decision-making capacity (Grisso and Appelbaum 1995). We see no reason to presume that psychiatric patients are incapable of giving informed consent for participation in research or that diagnostic categories are reliable indicators of decisionmaking capacity. As in all clinical research, psychiatric investigators must carefully assess the mental capacity of prospective subjects and ensure their understanding of the nature of the research, its risks and potential benefits, available alternatives, and their ability to decline participation at any time. Although we see no cause for general concern about informed consent to psychiatric research, including symptom-provoking studies, we do think that legitimate questions about informed consent may be raised with respect to the context and timing of symptom-provoking studies involving severely ill psychiatric patients. Such patients are often invited to participate in these nontherapeutic experiments either before or after receiving treatment. For example, in a number of studies amphetamine and methylphenidate have been administered to schizophrenic patients shortly after psychiatric hospitalization, during a period when they were acutely psychotic and before receiving treatment (Levy et al 1993; Sharma et al 1991; Jody et al 1990). We believe that this linkage between treatment and symptom-provoking studies has the potential to interfere with informed consent in two respects:
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first, the patient-subjects who are seeking treatment may not fully appreciate the nontherapeutic nature of the symptom-provoking experiment; second, the offer of treatment may operate as an undue inducement to patients to agree to participate in symptom-provoking studies. The problem of psychic distress caused by symptomprovoking studies merits careful attention. It might be objected that competent adults, including psychiatric patients, who are adequately informed about symptomprovoking studies and voluntarily consent to participate in them should be free to do so. This argument oversimplifies the ethical assessment of clinical research. Scrupulous attention to informed consent is necessary to justify human subjects research; however, it is not sufficient. The norms of research ethics and federal regulations prescribe riskbenefit assessment by investigators and IRBs as an independent ethical standard (Levine 1986a; The 1978 Code of Federal Regulations, 45 CFR 46). To be ethically appropriate, symptom-provoking experiments, like all research involving human subjects, must pass two tests. First, they must present a favorable or acceptable "risk-benefit ratio"; in the words of the federal regulations, "Risks to subjects are reasonable in relation to anticipated benefits, if any to subjects, and the importance of the knowledge that may reasonably be expected to result" [45 CFR 46.111 (a) (2)]. Second, they must comply with the norms of informed consent. Risk-benefit assessment is ethically prior to informed consent in that potential research subjects should only be invited to participate in experiments that have been determined by IRB review to present the prospect of benefits, including scientific knowledge, that outweigh the risks of harm and discomfort. IRBs are responsible for assessing the risks to human subjects presented by proposed studies, including psychic distress that can be predicted to result from the research procedures (Levine 1986b). In addition, IRBs are charged with assuring that in the design and conduct of research "Risks to subjects are minimized" [45 CFR 46.111 (a) (1)]. For most symptom-provoking studies the level of risk is relatively low, since the psychic distress that they produce is typically brief and of mild to moderate intensity: e.g., a panic attack lasting a few minutes, comparable to those often experienced by panic disorder patients; temporary increase in anxiety and obsessive thoughts in OCD patients; short-lived depressive symptoms, etc.; however, some subjects experience more pronounced symptomatic responses. The psychic distress caused by symptom-provoking studies should be assessed against the background of distressing symptoms typical of the psychiatric disorders from which the research subjects suffer. It is the additional, immediately provoked distress resulting
from challenge procedures, and any more lasting sequelae, that prompt ethical concern with this type of research. We present below some examples, derived from published articles, of relatively intense reactions to symptomprovoking experiments. Although not representative of typical reactions, they do illustrate the potential of these studies to cause psychic distress. 1. A study of metergoline administered to OCD patients: The magnitude of the change during the metergoline study period was within the subclinical category as assessed by the NIMH Global Anxiety Scale (4 to 6) for all but two patients. Over the four-day metergoline period, one patient (patient 5) developed gradually mounting anxiety, which remained unabated for three days after the study was terminated. Another patient (patient 7), who was well-controlled with relatively low doses of clomipramine, reported a similar experience peaking in the evening of day 3 of metergoline administration. She reported being "frantic," "agitated," and very fearful and noted a dramatic increase in compulsive checking. On the evening of day 3, she reported three hours of moving repeatedly in and out of her house during a severe thunderstorm to check on a specific item in her backyard. This sudden attack of anxiety and compulsive behavior was very unusual and distressing for her, as she had not experienced similar symptoms for months. (Benkelfat et al 1989) 2. A study of tryptophan depletion following treatment for depression: She began to cry inconsolably and described her emotions as being "out of control." She said that she did not know why she was crying but could not stop. She also described psychic anxiety, difficulty concentrating, loss of energy, loss of self-confidence, and a sense that nothing was worthwhile. She felt as if all the gains she had made over the past few weeks had "evaporated," and her HDRS increased to 34... By the following morning she said that she felt "back to herself," with an HDRS score of 9. She commented that the previous day had been a "nightmare" but that she had learned that the depression was not her "fault." She also noted that, although she would not want to repeat the test, it had been worthwhile because of what she had learned about her illness. (Delgado et al 1990) 3. A study of lactate infusion of Vietnam veterans with posttraumatic stress disorder: Except for patient 6, all the men became depressed and felt guilty during flashbacks... Patient 7 burst into tears during a lactate flashback as he saw his best friend blown up by a booby-trapped grenade. (Rainey et al 1987) 4. A study of methylphenidate infusion in patients with borderline personality disorder: The placebo infusion produced no subjective or objective changes. The methylphenidate response was dramatic; within
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a few minutes after the infusion Mr. A experienced nausea and motor agitation. Soon thereafter he began thrashing about uncontrollably and appeared to be very angry, displaying facial grimacing, grunting, and shouting...Fifteen minutes after the infusion he shouted, "It's coming at me again--like getting out of control--it's stronger than I am." He slammed his fists into the bed and table and implored us not to touch him, warning that he might become assaultive. Gradually over the next half-hour Mr. A calmed down and began to talk about his experience...He described the episode as identical to those he had experienced at home. (Lucas et al 1987) In the fourth case the authors evinced some ethical qualms about the effects of the challenge agent, since they reported that they decided to discontinue the protocol. They concluded their article with the following observation: The induction of characteristic dysphoric responses in two borderline patients by methylphenidate infusion suggests that the pharmacologic challenge model used in other episodic disorders may also help delineate the biochemical substrates of episodic dysphorias in borderline individuals. However, the severity of psychiatric symptoms and cardiovascular response produced by methylphenidate may limit its use as a pharmacologic probe in borderline personality disorder. (Lucas et al 1987) One potential indicator of severity of distress caused by challenge studies is the need for treatment to manage the symptoms caused by the experimental provocation. We found only one published article that reported counteractive treatment. This article described a study of 16 patients diagnosed with borderline personality disorder who were administered orally 30 mg of amphetamine: "Two patients had a significant psychotic experience following amphetamine on the first day and were treated with neuroleptic" (Schulz et al 1987). Based on published articles it is impossible to determine how frequently symptomatic responses to challenge studies are considered by investigators to warrant counteractive treatment. Another potential indicator of severity of effects produced by symptom-provoking studies is whether experimental administration of the challenge agent can precipitate relapse of psychiatric illness among patients in remission. Davidson et al administered levodopa (L-dopa) for 7 days as a challenge to schizophrenic patients in remission following withdrawal of neuroleptic treatment (Davidson et al 1987). The investigators determined correlations between symptom exacerbation in response to L-dopa and the time between the challenge experiment and schizophrenic relapse. The possible causal connection between receiving the challenge agent and the occurrence of relapse was discussed by the investigators as follows: The vast majority of patients returned to baseline levels of psychopathology, assessed by the BPRS scale, after the
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discontinuation of L-dopa. However, a few patients did not, and indeed their relapse could be said to have begun concomitant with L-dopa administration and continued with the discontinuation of the drug. It seems likely that L-dopa played a role in bringing on relapse in these few patients or caused some form of sensitization to psychosis. However, without a placebo L-dopa group it is impossible to know how many patients would have relapsed during this time period had L-dopa not been administered. (Davidson et al 1987) These case reports constitute anecdotal evidence that symptom-provoking studies can cause considerable psychic distress. For most studies the negative effects are short-lived, lasting from minutes to hours. In some instances the symptomatic responses have lasted for a few or more days (Benkelfat et al 1989); and in some cases psychoactive drug treatment has been administered to counteract the effects of challenge agents (Schulz et al 1987). There is no evidence that these studies produce disease, but they frequently elicit or exacerbate symptoms of the diseases from which the patients suffer. The results of at least one study suggest that challenge experiments have the potential to cause or accelerate relapse of illness (Davidson et al 1987).
The Justifiability of Psychiatric SymptomProvoking Studies The identification of ethical concerns posed by symptomprovoking studies by no means implies that this mode of research is ethically inappropriate. The potential for psychic distress needs to be evaluated in the context of the benefits that these studies may produce and the process of obtaining informed consent from patient-subjects. The possible benefits of symptom-provoking studies consist of generating valuable scientific knowledge and contributing to future improvements in diagnosis and treatment of psychiatric disorders. More specifically, these studies may produce the following benefits: 1. Help generate and test hypotheses concerning pathophysiology of psychiatric disorders 2. Identify and discriminate between neurobiologically distinct disorders 3. Elucidate the mechanism of action of treatments 4. Aid in predicting treatment response or risk of relapse after discontinuation of treatment 5. Lead to the development of clinically useful diagnostic tests 6. Contribute to the design of new treatments (Goodman et al 1991). The motivations of patients to participate in psychiatric research are diverse and have not been investigated. Although symptom-provoking studies usually offer no
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direct medical benefits to subjects, they may produce some psychological benefits. Participation in these studies may help patients gain a better understanding of the disorders from which they suffer; and recognition of the biological basis of the disorder may help counteract patients' negative self-image. Some patients may volunteer for altruistic reasons and thus derive personal benefit from contributing to scientific knowledge. We hold that symptom-provoking studies are ethically justifiable if three conditions are met: 1) they have genuine scientific merit; 2) the effects of administering challenge agents or procedures are not anticipated to be severe or long-lasting (any discomfort should be relievable by supportive care, reassurance, or brief pharmacologic treatment); and 3) recruitment, screening, contracting, and the process of obtaining informed consent engage subjects who are knowing, voluntary partners in the research enterprise. In the following section we offer guidelines for the design and review of ethically acceptable symptomprovoking studies. These guidelines consist of specifications of existing federal regulations, which are intended to be responsive to the ethical concerns posed by symptomprovoking studies.
Recommended Guidelines for Design and IRB Review of Symptom-Provoking Studies Scientific Design Determination of scientific merit is a basic component of risk-benefit assessment, since the risks posed by an experiment cannot be justified if there is no prospect that the experiment can generate valuable scientific knowledge (Freedman 1987). Protocols for symptom-provoking studies should either present a reasonable opportunity of making an original contribution to knowledge concerning the etiology, pathophysiology, diagnosis, or treatment of psychiatric disorders, or they should be capable of providing a useful test of hypotheses and findings reported in significant prior research.
Exclusionary Criteria Risks of serious harm produced by symptom-provoking experiments may be reduced by excluding subjects with certain clinical vulnerabilities. Since suicide is a risk in various psychiatric disorders (Appleby 1992), and these studies can elicit or exacerbate distressing symptoms, screening of prospective subjects to assess the risk of suicide is imperative. In general, those subjects at considerable risk for suicide should be excluded from challenge studies that are likely to produce distressing symptoms. In addition, evidence of a propensity to violent behavior should be considered as a potential exclusionary criterion.
To the extent that existing knowledge can be used to predict severe responses to challenge agents, this should be employed in developing exclusionary criteria.
Selection of Challenge Procedures In designing challenge experiments, investigators face the task of attempting to achieve a satisfactory balance between the prospects of obtaining scientifically useful information concerning symptomatic responses and protection of human subjects. For pharmacologic challenge studies, this calls for careful attention to the dose of the challenge agent, its route of administration (e.g., intravenous versus oral), the frequency of administration, and invasiveness of challenge procedures. For a scientifically successful and ethically appropriate experiment, the challenge procedures must be potent enough to elicit transient symptoms, but not so strongly provocative as to cause severe or long-lasting distress. Review of the literature and communication with other investigators may help determine an appropriate challenge stimulus. When adequate information is lacking, investigators should err on the side of caution by experimenting with less potent challenge procedures before attempting more strongly provocative interventions.
Subject Monitoring Investigators should design and implement appropriate procedures for monitoring the physical and psychological condition of research subjects in view of the anticipated severity of responses to administered challenge agents. Reasonable decisions must be made about whether, after receiving challenge agents, subjects should be hospitalized for the likely duration of adverse reactions, or whether it is safe to conduct the experiment with outpatients. In the latter case, careful planning is needed to determine the appropriate frequency and quality of contact to assess the condition of subjects who have received challenge agents. Effective treatments should be available and used as clinically indicated to counteract severe reactions. To the extent practicable, investigators should specify in advance criteria for discontinuing challenge procedures and offering effective symptomatic treatment. To protect subjects and assess the risks of symptom-provoking studies, IRBs should clarify the conditions under which investigators must file incident reports concerning severe symptom exacerbations that may have been caused by challenge experiments.
Process of Informed Consent Individual protocols are assessed by IRBs as separate research projects, yet patients enter into research programs
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in which they are invited to participate in a variety of studies. When psychiatric patients are offered treatment in a research setting, informed consent depends on an understanding of the differences between standard clinical care and research (Appelbaum et al 1987). In initial conversations with potential subjects, investigators should clarify that participation in the challenge study is intended to produce scientific knowledge by eliciting and studying potentially distressing symptoms under experimental conditions and will rarely have direct medical benefits for the subjects. It is vital that research subjects understand the alternatives for treatment and care in clinical practice outside the research program. The process of obtaining informed consent for symptom-provoking studies, including consent forms, should give particular attention to full, accurate, and concrete disclosure of the purpose of the study, the procedures to be employed, the anticipated and possible psychiatric symptoms elicited by the challenge agents, the plan for monitoring the condition of subjects during and after administration of the challenge agent, and the availability of counteractive treatment in the event of severe reactions. The adequacy of informed consent depends on a careful assessment of potential subjects' capacity to consent to research, particularly for subjects with conditions that may impair understanding, judgment, or volition. Subjects of symptom-provoking studies must be capable of understanding the lack of therapeutic intent and the design to elicit symptoms that may be distressing. Also, there must be no undue inducement to volunteer for the challenge study in exchange for treatment. Prospective subjects should clearly understand that the availability of treatment to counteract excessive reactions to challenge procedures is not an offer of treatment for the patient's condition. Independent assessment of decision-making capacity is recommended if investigators or other members of the research or clinical care teams have any serious doubts about the capability of a patient to give informed consent. Scientific articles reporting the results of psychiatric symptom-provoking studies routinely state that the investigators obtained informed consent; however, they rarely provide any description of how investigators assess subjects' decision-making capacity, convey relevant information about the research, and determine adequate understanding. We suggest that more attention to these issues in the methods section of published articles would help dispel doubts about whether valid informed consent is being obtained for psychiatric research.
Rationale and Justification for Study The responsibility to demonstrate the ethical justification of specific symptom-provoking studies rests with investi-
gators. Protocols involving symptom-provoking studies should explicitly discuss the risk-benefit ratio of the proposed research, including a detailed rationale for conducting the study with respect to scientific merit and potential benefits for improving the diagnosis and treatment of psychiatric disorders. IRBs must assess each protocol on its own merits, weighing the benefits in potential scientific knowledge and possible future clinical applications against the severity of both symptomatic responses and side effects that the symptom-provoking experiment is likely to produce.
Follow-up with Subjects To protect human subjects it is important to develop systematic information on the effects of participation in symptom-provoking studies. It is desirable that follow-up studies be conducted to collect data from research subjects on their reasons for participation, their reactions to participation (including assessment of the degree of psychic distress experienced), evidence of any lasting adverse effects (Harrington et al 1996), and their willingness to repeat the challenge procedure or participate in other challenge studies. Lingering doubts concerning the ethical propriety of these studies, as well as other forms of psychiatric research, are likely to continue in the absence of systematic follow-up data concerning the experiences of participants.
Conclusions Scientific understanding of the pathophysiology of psychiatric disorders and the mechanism of action of pharmacologic treatments has been enhanced by symptom-provoking studies. Valuable knowledge of potential clinical benefit for the diagnosis and treatment of disabling psychiatric disorders is anticipated from the future use of this method of research. Nevertheless, like other forms of nontherapeutic experimentation, symptom-provoking studies present ethical issues. These studies typically produce transient symptoms in the subclinical spectrum; however, the discomfort and distress caused by these experiments may be intense. Published reports do not indicate whether symptom-provoking studies have produced any lasting or irreversible harm. The conditions under which some symptom-provoking studies are conducted--e.g., administering challenge agents to acutely ill schizophrenic patients before treatment trials--raise particular concerns about informed consent. Awareness by investigators and IRB members of the ethical issues posed by symptom-provoking studies, careful efforts to design and monitor challenge experiments, and scrupulous atten-
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tion to obtaining informed consent can help promote the ethically appropriate use of this promising approach to psychiatric research. To this end, we have recommended a
series of practical guidelines for the design, review, and conduct of symptom-provoking studies of psychiatric patients.
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COMMENTARY
Psychiatric Symptom-Provoking Studies: An Ethical Appraisal Franklin G. Miller and Donald L. Rosenstein Key Words: Bioethics, biological psychiatry, challenge studies, institutional review board, informed consent BIOL PSYCHIATRY 1997;42:403--409
Introduction Biological psychiatry is dedicated to improving the diagnosis and treatment of psychiatric disorders by means of expanding scientific understanding of their underlying neurobiological mechanisms. Achieving this goal requires nontherapeutic experimentation with patients who volunteer to participate in the enterprise of seeking knowledge about mental disorders. Recently the conduct of psychiatric research has come under increasing ethical and regulatory scrutiny (Office for Protection from Research Risks 1994; The Journal of the California Alliance for the Mentally Ill 1994; Katz 1993; Applebaum 1996; Dresser 1996). The ability of severely ill psychiatric patients to give informed consent to participate in research, in general, and treatment studies requiring a drug withdrawal phase, in particular, have been called into question. Concerns have focused both on the decision-making capacity of psychiatric patients, especially those suffering from schizophrenia, and the adequacy of disclosure of risks and discomforts of research by investigators. We believe that an open discussion of potentially problematic psychiatric From the Center for Biomedical Ethics, University of Virginia, Charlottesville, Virginia (FGM); and the Psychiatry Consultation-Liaison Service, National Institutes of Health, Bethesda, Maryland (DLR). The opinions expressed in this paper are those of the authors and do not necessarily represent the position of any institutions with which the authors are affiliated. Address reprint requests to Donald L. Rosenstein, MD, National Institute of Mental Health, Bldg. 10 Room 3N238, 10 Center Dr MSC 1276, Bethesda, MD 20892-1276. Received July 15, 1996; revised February 10, 1997.
© 1997 Society of Biological Psychiatry.
research coupled with refinement of research guidelines may obviate excessive regulatory restrictions that could hamper valuable research and its promise of contributing to improved patient care. In this article we identify and discuss ethical concerns posed by one form of psychiatric research--the "challenge study." In this paradigm investigators administer a psychopharmacologic agent or psychological challenge procedure to patients under controlled conditions to probe psychiatric symptoms and other neurobiological responses. The principal scientific rationale behind this approach is to learn more about the underlying pathophysiological mechanisms responsible for the symptomatic expression of psychiatric illnesses. In addition, the knowledge gained from this type of study might lead to better predictors of treatment response or the identification of novel therapeutic interventions. This approach might develop eventually to the point that it yields clinical benefits analogous to the use of electrophysiological stimulation for symptomatic cardiology patients, designed to provoke arrhythmias and thus to inform the rational and individualized selection of antiarrhythmic medications. In psychiatric research the term "challenge study" encompasses a wide range of pharmacologic and psychologic provocations, such as intravenous amphetamine, inhaled carbon dioxide, and the presentation of a phobic stimulus, and an equally diverse set of outcome measures: e.g., hormonal responses, cerebral blood flow, and behavioral or mood ratings. We restrict our discussion in this 0006-3223/97/S 17.00 Pn S0006-3223(97 )00189-3
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paper to research that is designed to gain knowledge about psychiatric disorders by experimentally inducing characteristic symptoms in psychiatric patients. Accordingly, we refer to this type of investigation as a "psychiatric symptom-provoking study." Examples of such studies include attempts to provoke panic attacks with infusions of sodium lactate (Liebowitz et al 1984) or pentagastrin (Abelson and Nesse 1994), to induce temporary depressive symptoms by tryptophan depletion in patients who have responded to antidepressant medication (Delgado et al 1991), and to elicit obsessive-compulsive symptoms in response to administration of m-chlorophenylpiperazine (Zohar et al 1987). It should be stressed that symptom provocation represents one part of the design of these studies, which also includes measurement of physiological and biochemical responses to challenge agents or procedures. Psychiatric symptom-provoking studies offer considerable scientific and clinical promise (Hollander 1995). For example, challenge experiments with obsessive-compulsive disorder (OCD) patients have contributed to understanding the role of brain serotonin in the pathophysiology of this illness and the mechanism of action of effective drug treatments, such as clomipramine, fluoxetine, and fluvoxamine (Zohar et al 1990). The differential effects of anxiogenic challenge agents on patients with panic disorder and OCD indicate that these are neurobiologically distinct disorders (Goodman et al 1991). Gorman et al forecast the potential clinical benefits of the pharmacologic challenge model in panic disorder as follows: It is conceivable that in the not too distant future, pharmacologically induced panic attack models will be used to screen new putative antipanic medications and to track a patient's progress through treatment. Ultimately, if one of the models meets the specificity test, pharmacologically induced panic could even serve the clinician as a diagnostic tool. (Gorman et al 1987) As technologies to study brain physiology continue to evolve at a rapid pace, it is likely that future research will rely increasingly on methods designed to study psychiatric patients under conditions that provoke the symptoms of their illness. Nonetheless, these studies raise ethical questions, which have not been adequately discussed in either the psychiatric or bioethics literature. Our purpose in appraising psychiatric symptom-provoking studies from an ethical perspective is threefold: first, to increase awareness among investigators and members of institutional review boards ORBs) about the ethical dimensions of these studies; second, to analyze critically the ethical considerations relevant to this research paradigm; and third, to propose specific practical recommendations for the ethical use of this promising approach to psychiatric research. In focusing on psychiatric symptom-pro-
yoking studies, we do not claim that the ethical issues that we examine are unique to, or more serious in, psychiatric research. Nontherapeutic investigation in other domains of medical research presents similar ethical issues and also warrants careful review and safeguards comparable to what we recommend for this method of psychiatric experimentation.
Ethical Concerns Posed by Psychiatric Symptom-Provoking Studies The two main ethical concerns with psychiatric symptomprovoking studies are related to informed consent and risk/benefit determinations. Are patients recruited for participation in psychiatric symptom-provoking studies able to give adequate informed consent, and do the potential scientific and future clinical benefits of these studies justify exposing these patients to some degree of psychic distress? Undoubtedly, psychiatric illness--e.g., severe depression and profound thought disorder--can interfere with the understanding, judgment, and volition required to give informed consent. Although the capacity of psychiatric patients to give inlbrmed consent to research has not been studied systematically, a recent study of the capacity of psychiatric patients to make treatment decisions found that the majority of the sampled patients with schizophrenia and major depression displayed decision-making capacity (Grisso and Appelbaum 1995). We see no reason to presume that psychiatric patients are incapable of giving informed consent for participation in research or that diagnostic categories are reliable indicators of decisionmaking capacity. As in all clinical research, psychiatric investigators must carefully assess the mental capacity of prospective subjects and ensure their understanding of the nature of the research, its risks and potential benefits, available alternatives, and their ability to decline participation at any time. Although we see no cause for general concern about informed consent to psychiatric research, including symptom-provoking studies, we do think that legitimate questions about informed consent may be raised with respect to the context and timing of symptom-provoking studies involving severely ill psychiatric patients. Such patients are often invited to participate in these nontherapeutic experiments either before or after receiving treatment. For example, in a number of studies amphetamine and methylphenidate have been administered to schizophrenic patients shortly after psychiatric hospitalization, during a period when they were acutely psychotic and before receiving treatment (Levy et al 1993; Sharma et al 1991; Jody et al 1990). We believe that this linkage between treatment and symptom-provoking studies has the potential to interfere with informed consent in two respects:
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first, the patient-subjects who are seeking treatment may not fully appreciate the nontherapeutic nature of the symptom-provoking experiment; second, the offer of treatment may operate as an undue inducement to patients to agree to participate in symptom-provoking studies. The problem of psychic distress caused by symptomprovoking studies merits careful attention. It might be objected that competent adults, including psychiatric patients, who are adequately informed about symptomprovoking studies and voluntarily consent to participate in them should be free to do so. This argument oversimplifies the ethical assessment of clinical research. Scrupulous attention to informed consent is necessary to justify human subjects research; however, it is not sufficient. The norms of research ethics and federal regulations prescribe riskbenefit assessment by investigators and IRBs as an independent ethical standard (Levine 1986a; The 1978 Code of Federal Regulations, 45 CFR 46). To be ethically appropriate, symptom-provoking experiments, like all research involving human subjects, must pass two tests. First, they must present a favorable or acceptable "risk-benefit ratio"; in the words of the federal regulations, "Risks to subjects are reasonable in relation to anticipated benefits, if any to subjects, and the importance of the knowledge that may reasonably be expected to result" [45 CFR 46.111 (a) (2)]. Second, they must comply with the norms of informed consent. Risk-benefit assessment is ethically prior to informed consent in that potential research subjects should only be invited to participate in experiments that have been determined by IRB review to present the prospect of benefits, including scientific knowledge, that outweigh the risks of harm and discomfort. IRBs are responsible for assessing the risks to human subjects presented by proposed studies, including psychic distress that can be predicted to result from the research procedures (Levine 1986b). In addition, IRBs are charged with assuring that in the design and conduct of research "Risks to subjects are minimized" [45 CFR 46.111 (a) (1)]. For most symptom-provoking studies the level of risk is relatively low, since the psychic distress that they produce is typically brief and of mild to moderate intensity: e.g., a panic attack lasting a few minutes, comparable to those often experienced by panic disorder patients; temporary increase in anxiety and obsessive thoughts in OCD patients; short-lived depressive symptoms, etc.; however, some subjects experience more pronounced symptomatic responses. The psychic distress caused by symptom-provoking studies should be assessed against the background of distressing symptoms typical of the psychiatric disorders from which the research subjects suffer. It is the additional, immediately provoked distress resulting
from challenge procedures, and any more lasting sequelae, that prompt ethical concern with this type of research. We present below some examples, derived from published articles, of relatively intense reactions to symptomprovoking experiments. Although not representative of typical reactions, they do illustrate the potential of these studies to cause psychic distress. 1. A study of metergoline administered to OCD patients: The magnitude of the change during the metergoline study period was within the subclinical category as assessed by the NIMH Global Anxiety Scale (4 to 6) for all but two patients. Over the four-day metergoline period, one patient (patient 5) developed gradually mounting anxiety, which remained unabated for three days after the study was terminated. Another patient (patient 7), who was well-controlled with relatively low doses of clomipramine, reported a similar experience peaking in the evening of day 3 of metergoline administration. She reported being "frantic," "agitated," and very fearful and noted a dramatic increase in compulsive checking. On the evening of day 3, she reported three hours of moving repeatedly in and out of her house during a severe thunderstorm to check on a specific item in her backyard. This sudden attack of anxiety and compulsive behavior was very unusual and distressing for her, as she had not experienced similar symptoms for months. (Benkelfat et al 1989) 2. A study of tryptophan depletion following treatment for depression: She began to cry inconsolably and described her emotions as being "out of control." She said that she did not know why she was crying but could not stop. She also described psychic anxiety, difficulty concentrating, loss of energy, loss of self-confidence, and a sense that nothing was worthwhile. She felt as if all the gains she had made over the past few weeks had "evaporated," and her HDRS increased to 34... By the following morning she said that she felt "back to herself," with an HDRS score of 9. She commented that the previous day had been a "nightmare" but that she had learned that the depression was not her "fault." She also noted that, although she would not want to repeat the test, it had been worthwhile because of what she had learned about her illness. (Delgado et al 1990) 3. A study of lactate infusion of Vietnam veterans with posttraumatic stress disorder: Except for patient 6, all the men became depressed and felt guilty during flashbacks... Patient 7 burst into tears during a lactate flashback as he saw his best friend blown up by a booby-trapped grenade. (Rainey et al 1987) 4. A study of methylphenidate infusion in patients with borderline personality disorder: The placebo infusion produced no subjective or objective changes. The methylphenidate response was dramatic; within
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a few minutes after the infusion Mr. A experienced nausea and motor agitation. Soon thereafter he began thrashing about uncontrollably and appeared to be very angry, displaying facial grimacing, grunting, and shouting...Fifteen minutes after the infusion he shouted, "It's coming at me again--like getting out of control--it's stronger than I am." He slammed his fists into the bed and table and implored us not to touch him, warning that he might become assaultive. Gradually over the next half-hour Mr. A calmed down and began to talk about his experience...He described the episode as identical to those he had experienced at home. (Lucas et al 1987) In the fourth case the authors evinced some ethical qualms about the effects of the challenge agent, since they reported that they decided to discontinue the protocol. They concluded their article with the following observation: The induction of characteristic dysphoric responses in two borderline patients by methylphenidate infusion suggests that the pharmacologic challenge model used in other episodic disorders may also help delineate the biochemical substrates of episodic dysphorias in borderline individuals. However, the severity of psychiatric symptoms and cardiovascular response produced by methylphenidate may limit its use as a pharmacologic probe in borderline personality disorder. (Lucas et al 1987) One potential indicator of severity of distress caused by challenge studies is the need for treatment to manage the symptoms caused by the experimental provocation. We found only one published article that reported counteractive treatment. This article described a study of 16 patients diagnosed with borderline personality disorder who were administered orally 30 mg of amphetamine: "Two patients had a significant psychotic experience following amphetamine on the first day and were treated with neuroleptic" (Schulz et al 1987). Based on published articles it is impossible to determine how frequently symptomatic responses to challenge studies are considered by investigators to warrant counteractive treatment. Another potential indicator of severity of effects produced by symptom-provoking studies is whether experimental administration of the challenge agent can precipitate relapse of psychiatric illness among patients in remission. Davidson et al administered levodopa (L-dopa) for 7 days as a challenge to schizophrenic patients in remission following withdrawal of neuroleptic treatment (Davidson et al 1987). The investigators determined correlations between symptom exacerbation in response to L-dopa and the time between the challenge experiment and schizophrenic relapse. The possible causal connection between receiving the challenge agent and the occurrence of relapse was discussed by the investigators as follows: The vast majority of patients returned to baseline levels of psychopathology, assessed by the BPRS scale, after the
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discontinuation of L-dopa. However, a few patients did not, and indeed their relapse could be said to have begun concomitant with L-dopa administration and continued with the discontinuation of the drug. It seems likely that L-dopa played a role in bringing on relapse in these few patients or caused some form of sensitization to psychosis. However, without a placebo L-dopa group it is impossible to know how many patients would have relapsed during this time period had L-dopa not been administered. (Davidson et al 1987) These case reports constitute anecdotal evidence that symptom-provoking studies can cause considerable psychic distress. For most studies the negative effects are short-lived, lasting from minutes to hours. In some instances the symptomatic responses have lasted for a few or more days (Benkelfat et al 1989); and in some cases psychoactive drug treatment has been administered to counteract the effects of challenge agents (Schulz et al 1987). There is no evidence that these studies produce disease, but they frequently elicit or exacerbate symptoms of the diseases from which the patients suffer. The results of at least one study suggest that challenge experiments have the potential to cause or accelerate relapse of illness (Davidson et al 1987).
The Justifiability of Psychiatric SymptomProvoking Studies The identification of ethical concerns posed by symptomprovoking studies by no means implies that this mode of research is ethically inappropriate. The potential for psychic distress needs to be evaluated in the context of the benefits that these studies may produce and the process of obtaining informed consent from patient-subjects. The possible benefits of symptom-provoking studies consist of generating valuable scientific knowledge and contributing to future improvements in diagnosis and treatment of psychiatric disorders. More specifically, these studies may produce the following benefits: 1. Help generate and test hypotheses concerning pathophysiology of psychiatric disorders 2. Identify and discriminate between neurobiologically distinct disorders 3. Elucidate the mechanism of action of treatments 4. Aid in predicting treatment response or risk of relapse after discontinuation of treatment 5. Lead to the development of clinically useful diagnostic tests 6. Contribute to the design of new treatments (Goodman et al 1991). The motivations of patients to participate in psychiatric research are diverse and have not been investigated. Although symptom-provoking studies usually offer no
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direct medical benefits to subjects, they may produce some psychological benefits. Participation in these studies may help patients gain a better understanding of the disorders from which they suffer; and recognition of the biological basis of the disorder may help counteract patients' negative self-image. Some patients may volunteer for altruistic reasons and thus derive personal benefit from contributing to scientific knowledge. We hold that symptom-provoking studies are ethically justifiable if three conditions are met: 1) they have genuine scientific merit; 2) the effects of administering challenge agents or procedures are not anticipated to be severe or long-lasting (any discomfort should be relievable by supportive care, reassurance, or brief pharmacologic treatment); and 3) recruitment, screening, contracting, and the process of obtaining informed consent engage subjects who are knowing, voluntary partners in the research enterprise. In the following section we offer guidelines for the design and review of ethically acceptable symptomprovoking studies. These guidelines consist of specifications of existing federal regulations, which are intended to be responsive to the ethical concerns posed by symptomprovoking studies.
Recommended Guidelines for Design and IRB Review of Symptom-Provoking Studies Scientific Design Determination of scientific merit is a basic component of risk-benefit assessment, since the risks posed by an experiment cannot be justified if there is no prospect that the experiment can generate valuable scientific knowledge (Freedman 1987). Protocols for symptom-provoking studies should either present a reasonable opportunity of making an original contribution to knowledge concerning the etiology, pathophysiology, diagnosis, or treatment of psychiatric disorders, or they should be capable of providing a useful test of hypotheses and findings reported in significant prior research.
Exclusionary Criteria Risks of serious harm produced by symptom-provoking experiments may be reduced by excluding subjects with certain clinical vulnerabilities. Since suicide is a risk in various psychiatric disorders (Appleby 1992), and these studies can elicit or exacerbate distressing symptoms, screening of prospective subjects to assess the risk of suicide is imperative. In general, those subjects at considerable risk for suicide should be excluded from challenge studies that are likely to produce distressing symptoms. In addition, evidence of a propensity to violent behavior should be considered as a potential exclusionary criterion.
To the extent that existing knowledge can be used to predict severe responses to challenge agents, this should be employed in developing exclusionary criteria.
Selection of Challenge Procedures In designing challenge experiments, investigators face the task of attempting to achieve a satisfactory balance between the prospects of obtaining scientifically useful information concerning symptomatic responses and protection of human subjects. For pharmacologic challenge studies, this calls for careful attention to the dose of the challenge agent, its route of administration (e.g., intravenous versus oral), the frequency of administration, and invasiveness of challenge procedures. For a scientifically successful and ethically appropriate experiment, the challenge procedures must be potent enough to elicit transient symptoms, but not so strongly provocative as to cause severe or long-lasting distress. Review of the literature and communication with other investigators may help determine an appropriate challenge stimulus. When adequate information is lacking, investigators should err on the side of caution by experimenting with less potent challenge procedures before attempting more strongly provocative interventions.
Subject Monitoring Investigators should design and implement appropriate procedures for monitoring the physical and psychological condition of research subjects in view of the anticipated severity of responses to administered challenge agents. Reasonable decisions must be made about whether, after receiving challenge agents, subjects should be hospitalized for the likely duration of adverse reactions, or whether it is safe to conduct the experiment with outpatients. In the latter case, careful planning is needed to determine the appropriate frequency and quality of contact to assess the condition of subjects who have received challenge agents. Effective treatments should be available and used as clinically indicated to counteract severe reactions. To the extent practicable, investigators should specify in advance criteria for discontinuing challenge procedures and offering effective symptomatic treatment. To protect subjects and assess the risks of symptom-provoking studies, IRBs should clarify the conditions under which investigators must file incident reports concerning severe symptom exacerbations that may have been caused by challenge experiments.
Process of Informed Consent Individual protocols are assessed by IRBs as separate research projects, yet patients enter into research programs
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in which they are invited to participate in a variety of studies. When psychiatric patients are offered treatment in a research setting, informed consent depends on an understanding of the differences between standard clinical care and research (Appelbaum et al 1987). In initial conversations with potential subjects, investigators should clarify that participation in the challenge study is intended to produce scientific knowledge by eliciting and studying potentially distressing symptoms under experimental conditions and will rarely have direct medical benefits for the subjects. It is vital that research subjects understand the alternatives for treatment and care in clinical practice outside the research program. The process of obtaining informed consent for symptom-provoking studies, including consent forms, should give particular attention to full, accurate, and concrete disclosure of the purpose of the study, the procedures to be employed, the anticipated and possible psychiatric symptoms elicited by the challenge agents, the plan for monitoring the condition of subjects during and after administration of the challenge agent, and the availability of counteractive treatment in the event of severe reactions. The adequacy of informed consent depends on a careful assessment of potential subjects' capacity to consent to research, particularly for subjects with conditions that may impair understanding, judgment, or volition. Subjects of symptom-provoking studies must be capable of understanding the lack of therapeutic intent and the design to elicit symptoms that may be distressing. Also, there must be no undue inducement to volunteer for the challenge study in exchange for treatment. Prospective subjects should clearly understand that the availability of treatment to counteract excessive reactions to challenge procedures is not an offer of treatment for the patient's condition. Independent assessment of decision-making capacity is recommended if investigators or other members of the research or clinical care teams have any serious doubts about the capability of a patient to give informed consent. Scientific articles reporting the results of psychiatric symptom-provoking studies routinely state that the investigators obtained informed consent; however, they rarely provide any description of how investigators assess subjects' decision-making capacity, convey relevant information about the research, and determine adequate understanding. We suggest that more attention to these issues in the methods section of published articles would help dispel doubts about whether valid informed consent is being obtained for psychiatric research.
Rationale and Justification for Study The responsibility to demonstrate the ethical justification of specific symptom-provoking studies rests with investi-
gators. Protocols involving symptom-provoking studies should explicitly discuss the risk-benefit ratio of the proposed research, including a detailed rationale for conducting the study with respect to scientific merit and potential benefits for improving the diagnosis and treatment of psychiatric disorders. IRBs must assess each protocol on its own merits, weighing the benefits in potential scientific knowledge and possible future clinical applications against the severity of both symptomatic responses and side effects that the symptom-provoking experiment is likely to produce.
Follow-up with Subjects To protect human subjects it is important to develop systematic information on the effects of participation in symptom-provoking studies. It is desirable that follow-up studies be conducted to collect data from research subjects on their reasons for participation, their reactions to participation (including assessment of the degree of psychic distress experienced), evidence of any lasting adverse effects (Harrington et al 1996), and their willingness to repeat the challenge procedure or participate in other challenge studies. Lingering doubts concerning the ethical propriety of these studies, as well as other forms of psychiatric research, are likely to continue in the absence of systematic follow-up data concerning the experiences of participants.
Conclusions Scientific understanding of the pathophysiology of psychiatric disorders and the mechanism of action of pharmacologic treatments has been enhanced by symptom-provoking studies. Valuable knowledge of potential clinical benefit for the diagnosis and treatment of disabling psychiatric disorders is anticipated from the future use of this method of research. Nevertheless, like other forms of nontherapeutic experimentation, symptom-provoking studies present ethical issues. These studies typically produce transient symptoms in the subclinical spectrum; however, the discomfort and distress caused by these experiments may be intense. Published reports do not indicate whether symptom-provoking studies have produced any lasting or irreversible harm. The conditions under which some symptom-provoking studies are conducted--e.g., administering challenge agents to acutely ill schizophrenic patients before treatment trials--raise particular concerns about informed consent. Awareness by investigators and IRB members of the ethical issues posed by symptom-provoking studies, careful efforts to design and monitor challenge experiments, and scrupulous atten-
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tion to obtaining informed consent can help promote the ethically appropriate use of this promising approach to psychiatric research. To this end, we have recommended a
series of practical guidelines for the design, review, and conduct of symptom-provoking studies of psychiatric patients.
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