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April 16, 1999
By Mark Moran
What is the physiology that underlies symptoms of an illness? And what happens to symptoms when you withdraw an established therapy?
Those questions have long been studied by clinical researchers, and the tools they use to answer them-challenge studies and medication "washout" trials-have furthered scientific knowledge.
Yet the nature of such studies, involving the purposeful production of symptoms, has always flirted with the boundaries of ethical propriety. And today some challenge studies of mental illness have come under scrutiny-even under attack-following a report in January by the National Bioethics Advisory Commission (NBAC) calling for greater oversight to guarantee protection of human subjects involved in those and other psychiatric trials.
Last month Steven Hyman, M.D., director of the National Institute of Mental Health, established a formal, explicit process of review at NIMH for studies involving human subjects.
The commission's report, "Research Involving Persons With Mental Disorders That May Affect Decisionmaking Capacity," and subsequent lay press accounts that have been sharply critical of certain challenge studies have engendered debate among psychiatrists and mental health advocates. Converging in this debate are questions about informed consent, the scientific validity of some research, and the public image of psychiatry and psychiatric research.
"The short-term impact of these controversies is unfortunately to raise questions in the minds of the public about the intentions of psychiatrists," said Paul Appelbaum, M.D., chair of the department of psychiatry at the University of Massachusetts and APA secretary. "The articles that have appeared in the general media have made psychiatrists out to be uncaring Dr. Frankensteins who manipulate the minds of human beings for their own purposes."
He added, "It is grossly unfair to psychiatric research and gives psychiatry a black eye that affects all of us in our clinical roles."
In a letter to President Bill Clinton accompanying the NBAC report, commission chair Harold Shapiro, Ph.D., said current standards for protecting human subjects in clinical psychiatric research are inadequate.
"Although existing federal regulations for research involving human subjects have provided special protections for certain populations that are regarded as particularly vulnerable, persons with mental disorders who may have impaired capacity to make decisions and therefore to give voluntary informed consent have not received any such special protections," Shapiro wrote. "We believe that this current state of affairs is not satisfactory, and that additional federal protections are needed."
Some in the research community say, however, that the commission's work could have disastrous consequences. William Carpenter, M.D., director of the Maryland Psychiatric Research Center, called the report "a tremendous stigma document" that unfairly singles out psychiatric research.
He commented that recent press accounts have wantonly questioned the value of challenge studies vital to understanding psychiatric illness.
"The question should not be whether challenge studies are good or bad," said Carpenter. "Rather, for any kind of study, the questions should be, What is the scientific purpose? What is the safety profile? What is the decisional capacity of patients? And what are the procedures for informed consent?"
Carpenter is among a group of researchers at the Maryland Psychiatric Research Center and elsewhere who have been using the drug ketamine in challenge studies to mimic the symptoms of schizophrenia, a protocol that has received considerable attention in the lay press.
He acknowledged that throughout clinical research and in all areas of medicine, the procedures for obtaining informed consent are not uniform; some institutions may do better than others, and some processes may need improvement. But he denied reports that subjects have been given ketamine in any challenge studies that he was aware of without being adequately informed of the effects of the drug. He also emphasized the scientific validity of the trials.
In the studies, ketamine is used to activate schizophrenic-like symptoms in subjects, who then receive a PET scan to track affected areas in the brain. So far the trials have yielded evidence of the involvement in schizophrenia of the "glutamate system" of neurotransmitters, a finding that holds significance for medication development. Currently, medications used to treat schizophrenia are designed to act on certain dopamine and serotonin receptors, and not all of them are successful for all patients. In this way, Carpenter said, pharmacotherapy for schizophrenia has "been stuck in one mechanism of action" for years.
Development of agents that block the effect of ketamine, by working on a different system of neurotransmitters, would "open up an entirely new avenue of drug development," he said. He added that findings reported in the January Archives of General Psychiatry showed that one drug that acts on the glutamate system is successful in treating certain negative symptoms of schizophrenia.
Carpenter added that highly publicized assaults on research activity have the potential for slowing down progress, not only in the short term through oversight regulations not imposed on other kinds of research, but also over the long term by discouraging young psychiatrists from entering research.
Appelbaum noted that among the commission's recommendations is one that would require researchers conducting studies deemed to be of "greater than minimal risk" to obtain an independent assessment of the competence of every subject by someone not involved in the project. "That is potentially enormously burdensome given that greater-than-minimal-risk studies might include those that ask about sexual behavior or other behavior that might be considered embarrassing or illegal, or any studies involving medication," said Appelbaum. "You are talking about a huge volume of psychiatric research, much of it very low risk. It seems more reasonable to save the 'big gun' of independent competence evaluation for high-risk studies."
But Laurie Flynn, executive director of the National Alliance on Mental Illness and a member of the NBAC, reiterated the commission's findings that some research protocols, including studies using ketamine, have significant problems with informed consent.
"We on the commission reviewed the protocols and had the opportunity to look at some of the informed-consent documents," she said. "We did not think the risks of the research were adequately spelled out in all the documents."
Moreover, researchers have an obligation to go beyond merely getting a signature on a piece of paper, Flynn said, noting that "informed consent is more than a document."
She applauded Hyman for establishing a review process to look at studies involving human subjects. But she suggested that some in the research community have been slow to appreciate concerns about treatment of human subjects in psychiatric research.
Might the concerns raised by the commission and subsequent publicity in the lay press slow down development of treatments for people with serious mental illness?
Yes, she acknowledged. "But we need to be sure when we ask people to participate in research, that the research question is an important one. . . . We need to take the time to get it right and restore confidence, even if that slows things down."
Flynn also suggested that ketamine studies, while exploring an important avenue of medication development, have yet to produce results that justify continuation of such a controversial and "risky study" design.
"It may be that they are looking for some important understandings, but in the 10 years they have been going on, I don't know that we have made any great scientific advance," she said. "If we are not really learning anything, we may want to think about another type of effort."
Ultimately, Flynn said, psychiatric research will benefit from honest and fair scrutiny. "Good research and good researchers should feel confident that at the end of this period of questioning and challenging, the research will be stronger and [public] confidence will be stronger."
Appelbaum suggests that there may be a middle ground between what he characterized as the excesses of the commission report and turning a blind eye to weaknesses in the protection of human subjects in clinical research.
"I think it is important for us as psychiatrists to not let the unfair attacks on psychiatric research go unanswered, because the consequences could be severe," said Appelbaum. "But it is equally important not to be defensive. Failure to acknowledge problems where they exist could be equally disastrous."
An executive summary of the NBAC report and the 21 recommendations put forward by the commission can be viewed at the Web site