Psychiatric Research: Doing the Right Thing

May you be cursed to live in interesting times.
--Old Chinese Proverb

Rarely has there been a period in which such important and powerful forces of change have been juxtaposed in mental illness research. Since World War II, modern medical science has evolved to a point where its capacity to unravel the mysteries of human disease and discover new treatments seems limitless. Technological advances, combined with our country's economic prosperity and consequent increases in the National Institutes of Health research budget allocations, have created the potential for a virtual golden age of biomedical research. With the ascendance of the new field of neuroscience, research in mental illnesses has advanced like the rest of medicine.

An important part of this process has been the evolution of the lay advocacy movement with its ability to raise public awareness of mental illness and influence the budget-allocation process and the research agenda. The National Alliance for the Mentally Ill has figured prominently in the development of the mental health care and research fields.

At the same time, however, dark clouds of suspicion and concern hang over the biomedical research enterprise concerning studies with human subjects. Highly publicized instances of scientific fraud and allegations of abuse of patients have led to increased scrutiny of the ethics of biomedical research. Although this scrutiny has extended across all branches of medicine, it has been most intensely focused recently on psychiatric research. Perhaps this is because mental illness is less well understood by scientists and the general public, or perhaps individuals with mental illness are perceived to be more vulnerable to exploitation. Whatever the reasons, the effect has been to focus public attention and official inquiry primarily on research into mental illnesses. One form that this scrutiny has taken is the President's appointment of a National Bioethics Advisory Commission (NBAC), which recently issued its report and recommendations for research in decisionally impaired populations with mental disorders.

The draft of the report has generated intense debate among professionals and consumers alike because its prescriptions-taken literally-would substantially alter the nature and process of psychiatric research.

The psychiatric research community and the National Institute of Mental Health (NIMH) have responded and continue to respond to the expressions of concern in numerous ways. Among these responses has been a series of workshops and consensus meetings sponsored by the NIMH (as well as other professional organizations, including the Institute of Medicine of the National Academy of Science, the American Psychiatric Association, and the American College of Neuropsychopharmacology) on ethics and research practices to raise the awareness of investigators and improve the policies and standards governing clinical research.

Recently, NIMH Director Dr. Steven Hyman proposed the establishment of a Human Subject Research Workgroup of the National Advisory Mental Health Council to examine all "high risk" studies that the NIMH is considering supporting to ensure that they are scientifically and ethically sound. There have also been numerous publications and articles in scientific and professional journals on ethical dilemmas in psychiatric research, including the recent volume, Ethical Issues in Psychiatric Research: A Resource Manual on Human Subjects Protection, published by the American Psychiatric Press (1998).

At the same time clinical investigators like me, despite our concern for the safety of patients and desire to improve the safeguards in the research process, have felt we are under siege and unfairly criticised. Although there may have been some procedural mistakes in which researchers did not properly follow the rules, these were isolated and by no means widespread cases. By and large, researchers are people who are dedicated to the search for the causes and cures for mental illnesses, and they care deeply about the patients whose illnesses they study. Contrary to assertions-such as those made in the series of articles in The Boston Globe in November 1998-we are not motivated by the search for fame or financial gain, but by the desire to help people through the advance of medical science and our interest in solving the mysteries of the human brain and curing mental illness. We are also concerned that the increased restrictions that could result from this criticism and adverse publicity will make it more difficult to carry out mental illness research and discourage young scientists and physicians from entering careers in psychiatry. (When students are choosing among areas of medicine, why choose psychiatric research where role models are embattled and in which they might have to work under burdensome restrictions?) Therefore, although researchers hear the message and find much merit in the numerous expressions of concern, we also find the perspectives of our critics to be challenging and worry that their actions could lead to unintended consequences that could be detrimental to those individuals they are trying to protect.

To paraphrase an old advertising slogan, if the knowledgeable patient/advocate is the best consumer, then it is important for consumers, providers, and researchers all to understand each other's perspectives. It is beyond the scope of this article to discuss all of the issues relevant to the re-examination of ethical policies and practices in psychiatric research. However, I would like to summarize some of the central issues and findings that have come out of the recent workshops and consensus meetings in the hope of furthering mutual understanding. My perspective is that of a clinician and a psychiatric researcher.

Issue # 1: Is there systematic and widespread ethical abuse of patients in psychiatric research? The biggest question raised over the past few years has been whether there are system-wide and pervasive breaches of what would be considered safe and ethical research. In spite of the claims of a small number of vocal extremists, the consensus is that there is not widespread and systematic abuse of patients who are subjects in psychiatric research. There is certainly no evidence to justify the exaggerated comparisons that have been made to Nazi medical experimentation and the Tuskegee syphilis study. While it must be acknowledged that there may have been isolated studies that were not carried out in strict accordance with ethical guidelines, there is no indication that this occurs in psychiatric research any more than in other types of medical research. Simultaneously, it is widely accepted that more can be done to systematically ensure the safety of all subjects in psychiatric research.

Issue # 2: Are psychiatric patients unable to give informed consent? Informed consent is a fundamental element of ensuring that medical research is ethical and just. People may submit themselves to possible risk or inconvenience or forego the certainty of specific treatments to participate in a study as an expression of their personal autonomy, individual rights, and humanitarian interest. However, this is only ethical if the research participants have been fully informed about the study and have entered into it voluntarily. There is often an inference or assumption that mental health consumers by virtue of their illness are not competent enough to understand the issues and to give informed consent. However, research has shown (and it is generally agreed) that this assumption is not true. Indeed, many if not the majority of mental health consumers are able to provide informed consent. Moreover, to say that persons with mental illness are incompetent and deprive them as a group of the opportunity to participate in research would be unfair and ultimately would be to their disadvantage.

Issue # 3: Does research mean better treatment? Often people equate participating in a research study with getting a new and better treatment. The belief that being in a study means that a patient will receive new and better treatments is commonly referred to as the "therapeutic fallacy." In some cases, when the study is of a new treatment that does indeed prove to be better or safer, this belief may prove true. However, most studies are not treatment studies, so there is no potential for getting a newer and better treatment. At the same time, it is the impression of many professionals and consumers that participation in research provides patients with better care than they might otherwise receive. Unfortunately, this principally reflects the reality that the level of care of patients with severe and chronic mental illnesses is not what it should be, not that research will always confer special benefits.

Issue # 4: Are there certain forms of research that should not be permitted? The most controversial types of psychiatric studies are those involving placebo-controlled trials, discontinuation of treatment, or provocative testing with pharmacologic agents that can transiently induce symptoms. There have been many extensive analyses of the pros and cons of these types of studies. Without attempting to explain their logic and complexities, let me say that it is generally agreed that these studies have provided and can continue to provide very valuable information about the causes of disease and new treatments. However, to justify them, there must be absolute assurance that two critical conditions are met. First, the study must be capable of producing important and clear-cut scientific benefits, and second, maximum safeguards must be taken to protect patients. The NIMH's proposed Human Subjects Research Workgroup to examine all such "high risk" studies could be an important way to ensure that they are of sufficient scientific importance and safe for patients.

Principles for patients: In the process of medical research, a clinical investigator must balance the responsibility of the physician always to act benevolently and in the best interests of the patient with the scientific need to acquire new knowledge for the benefit of future patients. Because in some instances these may be conflicting obligations, there must be mechanisms by which to examine any proposed study and determine whether it is scientifically sound, safe, and appropriate. In this article I have tried to articulate some of the mechanisms that guide researchers, care providers, and policy-makers. However, I hope that it is also clear that research participants-patients and volunteers alike-have a critical role in making this process on which the future of medical progress depends work effectively, safely, and humanely. The following principles are fundamental and should always be considered by patients in evaluating a study.

• In general the knowledge to be gained by a study must outweigh the risks to which it could potentially expose a patient. Any study that cannot provide new information is therefore unethical.
• Efforts must be made to minimize the risk to which any study exposes a patient.
• Individual autonomy of subjects must be respected. Participation of subjects must be voluntary. Participants must be able to drop out of the study whenever they wish.
• The principles of informed consent must be followed fully. A patient, or his legal representative, should consent to participate in a study only after risks and benefits have been effectively communicated to him or her.
• Research is not treatment. Although treatment can be a part of studies, subjects should clearly understand that the purpose of research is to produce information that can be generalized to benefit future science, society, and patients with similar conditions. Patients should not believe that there is a guarantee they will receive any direct benefit other than possible payments.
• Researchers and personal physicians may not have the same opinion about the study and an individual's participation in it. Participants may ask researchers and physicians whether they think it is in their personal best interest to participate.
• Information learned from a study, whether general or specific to a patient, whether positive or negative, should be made available to the patient and to the medical community in a timely fashion as long as making it available does not compromise the study.

*About the author: Jeffrey A. Lieberman, M.D., is professor of psychiatry, pharmacology, and radiology and director of the Mental Health and Neuroscience Clinical Research Center at the University of North Carolina at Chapel Hill. A graduate of The George Washington University, he is a member of numerous professional societies, including the American College of Neuropsychopharma- cology, Collegium Internationale Neuropsychopharmacologicum, and the Psychiatric Research Society. Dr. Lieberman is associate editor or on the editorial board of the American Journal of Psychiatry, Biological Psychiatry, Psychiatry Research, and Schizophrenia Bulletin and has co-authored more than 100 published scientific papers and several books, primarily on schizophrenia and psychotropic drugs.

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