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Using placebos in trials of new antidepressants
Researcher defends placebo controls
The U.S. Food and Drug Administration requires that new psychiatric drugs be tested against placebo to ensure that they are effective. Despite that fact, some ethicists criticize the use of placebo in these trials, saying all psychiatric patients who volunteer for studies deserve the best-proven existing treatment.
Researchers also can encounter that opinion in IRB reviews, says Boadie Dunlop, MD, director of the Mood and Anxieties Disorder Program at the Emory University School of Medicine in Atlanta.
Dunlop recently authored an article in the Journal of Medical Ethics defending the ethics of placebo use in clinical trials for major depression and anxiety disorders. He says his interest in the topic was based in part on his experience fielding questions in IRB reviews.
"I think a big motivation for writing this was to try to make more clear to members of IRB committees how as a researcher I see the ethics of placebo use," he says. "Rather than getting into a back-and-forth with the IRB asking for clarifications of why a placebo is justified, it would be nice to have a document to refer to, to say 'The arguments are enclosed in this paper.'"
Questioning safety, effectiveness
Dunlop notes that recent meta-analyses of research into psychiatric medications have raised questions about both the efficacy and safety of existing antidepressants:
-In a 2008 article in the Public Library of Science Medicine, a meta-analysis of data submitted to the FDA found that efficacy of newer antidepressants only was found to be clinically significant in the most severely depressed patients.
"It suggested that for mild to moderate depression, existing antidepressants were no better than placebos," Dunlop says. "There are concerns about the way that meta-analysis was conducted and people have critiqued it, but nevertheless, there have been other (studies) that have raised similar concerns."
-In 2004, the FDA issued a public health advisory for antidepressants, warning that they could increase the risk of suicidal thoughts or behavior. The warning was based on an analysis of placebo-controlled studies that showed that children taking the antidepressants had a small but statistically significant increased risk of these behaviors, compared to children taking placebos.
Dunlop points out that such an analysis would not even have been possible without the use of placebos. If experimental antidepressants had been compared to existing ones, and the risk increased for both drugs, it would not have been discerned in the study.
"You would think it's just part of the course of depression for people to develop suicidal ideation," he says. "It never would have been found that in a small number of young people there is an increase in suicidal or self-directed harm thoughts."
Even if future studies downgrade that risk, Dunlop says the placebo controls are necessary to properly investigate it.
"Without placebo control, we'd never know whether we should be looking or not," he says. "It's easy to fall into the assumption these are antidepressants, how could people get worse? And that's the hubris about our knowledge. We just don't know — we're always in the state of accumulating more knowledge."
It isn't just a "placebo effect" per se; it is the response rate in subjects assigned to a placebo, says Mark S. Schreiner, MD, chairman of the Committee for the Protection of Human Subjects at the Children's Hospital of Philadelphia. "Mild to moderate depression is a waxing and waning condition," he says. "Numerous studies have found the response rate in placebo-treated patients to be about 40%. This reflects the natural history of depression as much as it reflects the response to placebo."
Dunlop says one reason placebo controls are necessary in research involving treatment of mood and anxiety disorders is that those conditions have a high placebo response rate — a certain percentage of people who take a placebo for these disorders report improvement.
So, the only way to tell if a drug is truly effective is to see whether its effectiveness trumps the placebo's effectiveness. Otherwise, Dunlop says, you run risk of helping to approve a drug that isn't any better for patients than placebo.
"It is an ethical obligation of the researcher to make sure that the research they're conducting is valid, otherwise we're dishonoring the contribution of the volunteers for the study," he says. "Yes, they're in the study to feel better but they're also in the study to contribute to the advancement of knowledge.
"And if the data that emerges from the study is not something that can be interpreted with confidence, there's enormous ethical consequences to that."
Dunlop also notes that it's easier to achieve statistical significance in a placebo-controlled trial, meaning that fewer participants must be exposed to an experimental drug.
"If you eliminate placebo controls and go with equivalence designs, you need many more subjects," he says. "From the get-go, you're exposing many more people to the unknown and potentially harmful effects of an experimental medication."
Dunlop says he remains optimistic that researchers someday will discover biomarkers that show the biological changes proving that a drug has an antidepressant or anti-anxiety effect, eventually making placebo-controlled trials unnecessary.
"Right now, we haven't got that, so we have to maintain a humble approach to the brain," he says.