Should Placebos Continue to be Used in Depression Trials? Two New Studies Answer the Question

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Within the psychiatric profession, there has been a long-simmering controversy over the ethics of giving sugar pills (placebos) to study participants who are suffering major depression. Many psychiatrists believe it is unethical to give a treatment that is less effective than antidepressant drugs. Furthermore, many people with severe depression are also suicidal; therefore administering an inactive treatment is dangerous. Others, usually research psychiatrists, point out that study participants given placebos often do as well as--and sometimes, better than--the study participants taking the active drug. This has been shown in numerous clinical trials.

In an effort to settle the controversy, a team of researchers in New York City, searched the database of all published clinical trials in which participants with major depression had been randomly assigned to take either an antidepressant drug or a placebo. Seventy-five such trials, published between 1981 and 2000, were retrieved by the research team led by R. Timothy Walsh, MD, Department of Psychiatry, College of Physicians and Surgeons of Columbia University. They found that the percentage of people with major depression who got better on placebos varied considerably. The range was "approximately 10% to more than 50%, and frequently was substantial; in approximately half of the studies, 30% or more of the patients assigned to placebo exhibited a clinically significant improvement."

As for the people taking the antidepressant drugs in these trials, the rates of those who found them to be effective were 31% to 70%, with an average of 50%. Oddly enough, Dr. Walsh and colleagues discovered that study participants did increasingly better over the years whether they were taking a placebo or an active drug. They were not able to determine why this happened, but in an interview last month for The Washington Post, Dr. Walsh mentioned that there has been a reduction in the stigma attached to mental illness. Widespread advertising and media attention given the newer antidepressant drugs could also heighten people's expectations.

A clinical trial exploring the use of the popular herb, St. John's wort, was published in the same issue of the Journal of the American Medical Association (JAMA, 4/10/02). This trial included not only the placebo, but also something called an "active placebo," which means that the pill has some activity, such as the ability to cause dry mouth (a common side effect of antidepressant drugs), but no antidepressant effects. Antidepressant drug trial participants are often people who have taken other antidepressants and are therefore familiar with their side effects.

The 340 adults with major depression(*) were randomly assigned to take daily doses of St. John's wort, the active placebo, or the standard placebo. Neither the participants, nor the investigators knew who was taking the St. John's wort. At the end of this eight-week study, the response rate for the people who had taken St. John's wort was no different from that of the people taking the two types of placebo.

The investigators concluded that their study shows why the continued use of placebos in clinical trials is imperative. Had they not been included in their St. John's wort study, people might have prematurely concluded that St. John's wort is effective because its response rate in this new trial was similar to that shown for Prozac in other clinical trials.

The danger of suicide among study participants given placebos, cited at the beginning of this article, was not addressed by either of the two new studies. This was, however, the sole concern of an analysis of the relevant trials in the database of the Food and Drug Administration conducted over two years ago. (The FDA requires that new antidepressant drugs be compared to placebos.) Altogether 19,639 depressed people participated in the FDA-required trials. The rates of suicide and suicide attempts did not differ between the placebo- and drug-treated people, according to Arif Khan, MD, and colleagues at the Northwest Clinical Research Center in Bellevue, Washington. (Archives of General Psychiatry, 4/02).

(*) An earlier analysis of all the best trials of people with mild to moderate depression found that St. John's wort is not only more effective than a placebo, the herb was shown in some trials to be more effective than the old, as well as the newer antidepressant drugs like Prozac.

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By Maryann Napoli

Maryann Napoli is the associate director of the Center for Medical Consumers in New York City.

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