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Detecting Women at Risk for Postnatal Depression Using the Edinburgh Postnatal Depression Scale at 2 to 3 Days Postpartum
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Review Paper
Ethics in Psychiatric Research: Study Design Issues

Gordon DuVal

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Treatment Planning in Psychotherapy: Taking the Guesswork Out of Clinical Care.
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Pharmacogenetics of Psychotropic Drugs.
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Modafinil Treatment of Excessive Sedation Associated With Divalproex Sodium

Ziprasidone in Parkinson’s Disease Psychosis

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Doxepin Increases Serum Cholesterol Levels

Re: Suicide: The Persisting Challenge

Reply: Suicide: The Persisting Challenge

Depression and a History of Alcoholism

Gains in Speeded Information Processing Following Clozapine Treatment of Schizophrenia

Problems With Crystallizing Phenomenology and Nosology in Adolescent Psychiatry

Serotonin Syndrome With Prolonged Dysphagia

Review Paper

Ethics in Psychiatric Research: Study Design Issues

Gordon DuVal, SJD1

 

Objective: To identify and discuss ethical aspects of study design issues in psychiatric research.

Method: We conducted a literature review and conceptual analysis of study design in psychiatric research focusing on placebo, medication tapering and withdrawal (washout), and symptom provocation (challenge) designs.

Results: While advances in the care and treatment of persons with psychiatric disorders are crucial to the improved well-being of this stigmatized and often forgotten population, past abuses demonstrate the importance of the thoughtful application of ethical principles in the conduct of research. Some ethical issues have particular relevance to psychiatric research arising primarily from the specific vulnerabilities of those with mental illness and the risks posed by some research methodologies. Accordingly, sensitivity is required in the design of psychiatric research.

Conclusions:Placebo, challenge, and washout study designs can present particular risks in the population of persons with mental illness. These issues are described and suggestions offered to promote the ethical design of psychiatric research.

(Can J Psychiatry 2004;49:55–59)

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Clinical Implications

  • Psychiatric research raises ethical issues that require specific sensitivity in its design.

  • Placebo, washout, and challenge study methodologies, while not unique to psychiatric research, may pose particular risks when used in a psychiatric population.

Limitations

  • Special ethical rules governing the involvement of human subjects are not unique to psychiatric research.

  • The extent to which persons with mental disorders require special protections in research remains controversial.

  • This paper is not exhaustive. There may be other design issues of significance for research involving subjects with psychiatric conditions.


Key Words
: research ethics, mental health research ethics, psychiatric research, mental health research, vulnerable research subjects, placebos, challenge studies, washout studies

Résumé : L’éthique en recherche psychiatrique : questions de méthodologie

The 1980s and 1990s saw an acceleration of clinical research into mental illness and important advances have been made in the treatment of mental disorders. However, the situation facing researchers in psychiatry today is serious: by some estimates, 20% to 30% of the population will suffer some form of diagnosable mental illness during their lifetime. Collectively, the social economic burden of mental disorders is exceeded only by that of ischemic heart disease and is greater than cancer, stroke, and HIV–AIDS (1,2).

Much of this important research requires the participation of subjects who themselves suffer from mental illness. The history of psychiatric research is littered with public and private sector studies that have exploited the vulnerability of mentally ill, neurologically impaired, and developmentally disabled research subjects (3–7). However, advances in mental health science promise great benefits for those who suffer, or will come to suffer, from mental illness and, in some cases, for research subjects themselves. While persons with mental illness may be vulnerable in several ways, research regulations that focus primarily on their vulnerabilities and deficits could encourage and possibly exacerbate the stigmatization already felt by this population (8,9). Further, it may be unjust to exclude, by overly restrictive regulation, those people with mental illness who could benefit from research participation. An ethically appropriate framework for psychiatric research ethics balances rigourous protections for human subjects with a recognition of the enormous social and individual benefits arising from well-designed and ethically conducted scientific research (10–12). How this balance is struck has important implications for research ethics generally, particularly for research involving vulnerable persons. This paper identifies specific issues surrounding study design and explores their implications for the ethics of psychiatric research.

Persons with mental illness often face vulnerabilities arising from stigma, dependence, fractured relationships, the fear and discomfort displayed by others, unemployment, homelessness, poverty, loneliness, and other factors, all primarily brought on by their illness (13–15). While all subjects of clinical research are vulnerable to some degree, persons participating in clinical psychiatric research may be vulnerable by reason of compromised cognitive and emotional functioning, widespread social stigma and discrimination, and the erosive effect of some psychiatric conditions on awareness and insight into illness (16). Further, some common psychiatric symptoms such as ambivalence, apathy, paranoia, self- destructiveness, and impulsivity may prevent those with mental illness from participating meaningfully in the consent process or otherwise adequately protecting themselves from harm (17). Accordingly, persons with mental illness, as a research subject population, are in need of protections especially suited and targeted to their particular vulnerabilities.

Various ethical concerns are particularly acute or worrisome in psychiatric research and give rise to the need for special sensitivity and insight (18–20). Certain study designs, when used in psychiatric research, may create unique risks to subjects with mental illness and raise special concerns (21,22). These include research involving placebos, medication tapering and withdrawal (washout designs), and symptom provocation (challenge designs).

Some caution, however, is indicated. There is no consensus that the ethical issues arising in mental health research are qualitatively distinct from those in other areas of research. Research designs including those involving placebos, washout, and symptom provocation are not unique to mental health research and present risks to any research subject (8). Treating persons suffering from mental illness as especially vulnerable, or in need of special protections, may further stigmatize an already tragically stigmatized population (23,24). Although estimates of incidence of mental illness are high (with a lifetime incidence of 20% to 30%), diagnoses of mental illness are often equivocal, and conceptions of mental health and illness remain controversial. Most people suffering from mental illness function reasonably well. Too great a focus on special regulations for research involving this population may be unnecessary and stigmatizing. Nevertheless, ethical principles clearly must be applied with sensitivity to the particular vulnerabilities of people with mental illness.

Psychiatric Research Designs

Some study methodologies have drawn particular ethical scrutiny when used in psychiatric research, both because of their inherent risks, and because of the subject population of persons with mental illness (25). Three types of study design have raised ethical concerns.

Placebo-Controlled Studies
The randomized controlled trial is generally accepted as the gold standard experimental design for assessing the efficacy and toxicity of proposed new medications. In studies of new drugs, a placebo study arm allows the investigator to control for factors that may confound a valid assessment of a drug’s effectiveness and toxicity. However, the use of a placebo control design has been criticized where an effective treatment exists for the disease being studied, and such criticisms have been conspicuously aimed at research in psychiatry (13,26,28).

The concern is that, when a placebo is used, research subjects in the control arm are deprived of access to treatment proven to be effective (29). This violates the ethical requirement of equipoise (30) that there must be a genuine uncertainty on the part of the expert medical community about the comparative therapeutic merits of each arm of a clinical trial (31,32). Clearly, the placebo control cannot be hypothesized to be of equal merit when compared with a proven effective treatment. It also violates the general ethical rule, codified in the World Medical Association Declaration of Helsinki, requiring that no research subject, including those in a control group, be deprived of the best-proven diagnostic and therapeutic methods (33). The general ethical principle is that researchers may not ask prospective subjects to forego clinically effective treatment to contribute to their research.

Further, placebos in such studies are said to be unnecessary, since the objective of the experiment should be to learn whether an experimental medication is better than what already exists, not whether it is better than nothing (34,35). Leaving persons with mental illness untreated is especially risky, even for the duration of the placebo control period, because of the possibility of harmful long-term and short-term effects (36,37), including depression, anxiety, delusion (38,39), suicide (40), homicide, and other violent behaviour.

Methodological objections to the use of placebos are also raised (20,35). Inclusion of a placebo group may systematically bias the patient sample to less-responsive patients. Treating physicians will typically want to ensure that study participation would not be an inappropriate clinical option for their patients. If the patient is acutely ill and has a history of responding well to previous trials of medication, then the physician may be hesitant to suggest that the patient enrol in a study that might result in receiving placebo. Inviting a patient to participate in a study involving an active control is less problematic. In addition, physicians commonly regard the level of capacity required to consent to a placebo-controlled study to be higher than that for a study involving an active comparison drug. The net effect is that patient selection for placebo studies will tend to be biased toward relatively treatment-refractory patients who possess a high degree of insight. Such patients may not be representative of most patients with the illness being studied, and generalization of the results is questionable. Further, the dropout rate in a placebo group may be high, since only those patients who are managing well on placebo will remain in the placebo group. Experience shows that others are likely to drop out. As a result, it may be more difficult to demonstrate that a new medication is effective.

Others have argued, however, that a placebo design in mental health research is scientifically necessary or desirable in some circumstances, even when an effective treatment exists for the condition being studied. For example, where a new drug is thought to be no more effective but less toxic than standard therapy, or more effective for some subgroup of patients, only a placebo trial can establish the efficacy of the new drug (20,41,43). Because of the variable and often high placebo response rate associated with psychiatric medications (an average of 30% in a recently published metaanalysis; 44), the fact that an experimental drug does as well as an existing one may not be adequate proof that the new drug is itself effective. Also, because sample sizes can be smaller in placebo studies, with fewer research subjects enrolled, the cumulative risk may be reduced. Finally, where truly informed and voluntary consent is given, where risks are appropriately minimized, and procedures are in place to deal with untoward events, patients should be permitted to take part in such studies for altruistic or other reasons (45). This accords respect to the autonomy and decision making of individuals (46).

At a minimum, ethically acceptable placebo-controlled research requires the following: clear scientific and methodological justification; low risk of harm to self and others; adequate safeguards to minimize risks; exacting assessment of capacity to consent; procedural safeguards to ensure adequate information and voluntariness; and transparent procedures to avoid conflict of interest. As with all studies, the research must address a scientifically valuable question and methodologically be reasonably likely to answer that question (47). Investigators must employ the methodology that poses the least risk to human subjects and is consistent with achieving their research goals (48).

Washout Studies
A washout study is one in which researchers discontinue the medication of a subject to study the patient in an unmedicated state or to initiate another therapy, often an experimental one (42). Accordingly, the existing medication is discontinued, usually following a gradual reduction in dosage (49). The withdrawal period typically must be long enough for the drug to have cleared from the patient’s system so that residual effects from the withdrawn medication do not confound the study results or result in unwanted drug interactions. Depending on the particular study design and the medication involved, the washout can last indefinitely or until acute symptoms return (25).

Washout is used in psychiatric research for several reasons. An initial medication withdrawal period is intended to reduce the risk of adverse drug interactions as an experimental drug is introduced and to minimize any effects of the prestudy drug in confounding the effects of the experimental intervention. In patients being treated, it allows new compounds to be compared with placebo to establish effectiveness and determine adverse events. Washing out existing medication permits the establishment of baseline clinical data against which subsequent events may be measured. Drug discontinuation is also valuable to distinguish behavioural effects associated with the discontinued medication from those manifesting from the illness and to identify patients who may no longer require medication (42).

Challenge Studies
In a challenge study, a psychopharmaceutical agent or psychological challenge is administered to research subjects under controlled conditions to measure or observe the results (50,51). Researchers may wish to observe a behavioural response, a neurobiological response using brain imaging, or both. In psychiatry, these designs have proven to be extremely valuable in testing hypotheses and in characterizing various neurochemical and pathophysiological processes (48). Research of this kind may lead to improved predictions of treatment response and effective new therapies (50). In research studies throughout Canada and the US, research subjects diagnosed with schizophrenia and other mental illnesses have had psychotic symptoms provoked using ketamine, amphetamines, and other drugs—sometimes with harmful consequences.

The primary concern in using this design is that persons who are already sick, or who are vulnerable to a negative response to the challenge, may have harmful symptoms provoked or exacerbated or may suffer relapse (52). The duration and intensity of symptoms are important considerations. It is unclear whether the balance of risks and potential benefits can ever justify enrolling individuals in studies in which potentially harmful responses are intentionally induced. Short-term risks include discomfort and emotional pain caused by the provocation of symptoms associated with mental disorders (53,54). Long-term risks include the exacerbation of illness, relapse, or an increase in the time to cure or substantially control the disease in question (50). Challenge study designs often involve a washout element as well, heightening ethical concern (50). Finally, for practical reasons, challenge studies often require that subjects be deceived, or at best partially informed, about the details of the study (55).

In reviewing challenge studies, particular care must be taken in assessing the risks posed by the agent to be administered. The researcher should have a high level of confidence that the symptoms provoked will be mild and transient (56). Subjects should be closely screened for susceptibility; healthy patients may have less risk. If patients must be used, severity of illness, history of harm to self or others, and time to recovery after relapse are relevant considerations in ensuring that subjects with the least risk are recruited (48). Subjects must be closely monitored to ensure safety and a prompt response to adverse effects (57).

Conclusion

Despite a history that has included serious abuses, psychiatric research is important—not least to those who suffer from mental illness. Clinical psychiatric research creates challenging ethical dilemmas. The choice of research design can have significant implications for subject safety and must be carefully considered. While these issues are not necessarily unique to this context, the particular vulnerabilities attending psychiatric illness merit close attention in the design of research involving persons with psychiatric disorders.


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Author(s)

Manuscript received August 2002, revised, and accepted May 2003.

1. Bioethicist, Centre for Addiction and Mental Health, Joint Centre for Bioethics and Faculty of Law, Department of Psychiatry, University of Toronto, Toronto, Ontario.

Address for correspondence: Dr G DuVal, Centre for Addiction and Mental Health, Joint Centre for Bioethics, University of Toronto, 88 College Street, Toronto, ON M5G 1L4

e-mail: gordon.duval@utoronto.ca

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