Ethical concerns in schizophrenia research: looking back and moving forward.

Over the past two decades, the debate over the ethical issues involved in schizophrenia research has evolved considerably in some, but not all, respects. In general, discussions about the most important of these issues have been propelled by developments both in our understanding of schizophrenia and within the field of psychiatry itself, as well as in tandem with the evolution of standards for the protection of human research participants. Although new scientific developments, particularly those having occurred over the last decade, have required researchers to consider new and increasingly complicated ethical conundrums, there are also many issues from years past that remain only partially resolved. The larger debate on the ethics of experimentation with human subjects essentially began during the post–World War II period with the Nuremburg trials, as the world learned about the experimentation committed by the Nazis on unwilling human subjects. The Nuremburg Code, issued in 1947, was perhaps the first official document that called for the consent of individuals participating in research.1 Here, the basic principles of ethical research were stipulated, including the importance of voluntary consent, the protection of research participants from harm, and the freedom to withdraw from participation. This was followed by the Declaration of Helsinki, adopted by the 18th World Medical Assembly in 1964,2 which added provisions on the importance of research protocols, protection of confidentiality, and professional integrity in the conduct of research and publication of results. Although organizations like the American Medical Association,3 and later the American Psychiatric Association,4 began to amend their ethics codes to address issues concerning research with human subjects, the first federal regulations on research, described in the National Research Act, were not enacted until 1974. This act required the Department of Health, Education, and Welfare to codify regulations for human research. The first broad set of federal guidelines was enacted in 1981 and was based on the principles outlined in the Belmont Report.5 This report identified three major principles in evaluating research: respect for persons; beneficence; and justice. In addition, it delineated the distinction between research and treatment, the assessment of risks and benefits, and the importance of informed consent. Several populations were also identified as needing special protections: children, pregnant women and fetuses, prisoners and, most relevant to schizophrenia research, the institutionalized mentally disabled. Regulations for all but the institutionalized mentally disabled were enacted. Objections to the proposed regulations for the mentally disabled were plentiful and strenuous, and were focused on the fact that the regulations assumed equivalence between incapacity to give an informed consent and mental illness, while neglecting the fact that non-psychiatric conditions can also produce impaired capacity. These recommendations were initially set aside, but were later revisited by several Presidential Commissions.6 Ultimately, no regulations resulted, and their helpfulness was questioned.7–8 Finally, in 1991, the Federal Policy for the Protection of Human Subjects (Title 45, Code of Federal Regulations, Part 46) was adopted across federal agencies and created a uniform approach to human research in the United States. Ethical concerns about schizophrenia research have been raised, for the most part, because of concerns about the decision-making capacity of the potential research participants. Schizophrenia is a disorder of disturbed thinking, and so it was reasoned that if thinking is disturbed, then capacity to consent is likely to be compromised. As a result, individuals with schizophrenia have long been considered a vulnerable population in the research setting. In this article, we address five main areas where ethical issues have been, and continue to be, particularly prominent in schizophrenia research: 1. competency of participants and informed consent; 2. exclusion of suicidal patients from research on schizophrenia; 3. early intervention with prodromal patients; 4. medication withdrawal and medication-free protocols; and 5. genetic research on schizophrenia. In this brief review of the developments that have occurred over the past several decades, our intention is to highlight the progress that has been made in each of these areas, as well as several issues that in our view require additional consideration.