Placebo in clinical trials for depression: complexity and necessity.

Abstract

WITHIN THE LAST SEVERAL YEARS, THE LONGsimmering debate about the ethical issues surrounding placebo administration in randomized clinical trials has reached new levels of intensity. The report of the National Bioethics Advisory Commission included specific recommendations for studies involving more than minimal risk, including the use of placebo controls in clinical trials. At a time of increased interest in drug discovery in medicine and the potential need for definitive randomized clinical trials, the controversy over the ethical issues places an appropriate burden on the scientific community to justify the use of placebo controls. One argument is that placebo administration is not appropriate if effective treatment for a condition exists and that assessment of efficacy can be conducted with active controls. Another view is that placebo controls may be necessary to determine the assay sensitivity of a trial and are ethical if patients provide informed consent and are not harmed. Treatment of depression, a well-recognized and worldwide public health problem, represents a special opportunity to highlight several key issues in the “placebo controversy” and to demonstrate why for the foreseeable future placebo-controlled trials will be necessary. While the treatment of depression has been marked by major successes with the introduction of new classes of antidepressants and their “uptake” by clinicians and patients, newer antidepressants will continue to be developed. These new products may target specific subtypes of depression, may provide more complete recovery and sustained remission, and may have reduced adverse effects and faster onset of action. These products will require proof of efficacy and Food and Drug Administration approval. A better understanding of the many alternative or complementary treatments for depression, such as nonprescription herbal compounds, also contributes to the need to determine when placebo controls are appropriate. Two articles in this issue of THE JOURNAL, one from the Hypericum Depression Trial Study Group and another from Walsh et al on placebo response, focus attention on the key issues. The first report examines the efficacy of St John’s wort (Hypericum perforatum) in major depressive disorder (MDD) in a 3-arm clinical trial. This study provides an opportunity to comment on the role of placebo and whether placebo efficacy rates “interfere” with the establishment of the efficacy of new treatments. The second report addresses the problems of placebo in depression trials using a 20-year perspective. Walsh and colleagues describe how placebo characteristics and clinical response levels have changed. The current study on the use of St John’s wort in the treatment of MDD is the second one within a year to conclude that St John’s wort is not effective. These trials were conducted because, even though St John’s wort is widely used for the treatment of major depression and depressive symptoms, its efficacy has not been clearly established, despite more than 20 randomized trials, most of which are considered to have had serious methodological flaws. Both of the recent trials were multicenter randomized, doubleblind, placebo-controlled trials with a standardized extract of St John’s wort. The previous 8-week trial by Shelton et al showed no significant difference between St John’s wort extract and placebo on any of the depression outcome measures. Response rates in the intention-to-treat analysis were also not significantly different (26.5% for St John’s wort vs 18.6% for placebo). The second study, reported in this issue, also included a large multicenter population of outpatients with MDD, but differed in that a selective serotonin reuptake inhibitor (SSRI), sertraline, was included as an active control in addition to testing St John’s wort extract (hypericum) and placebo. From this 8-week clinical trial, the authors conclude that neither sertraline nor hypericum was significantly different from placebo on the 2 primary outcome measures, the Hamilton Depression Scale (HAM-D) and the Clinical Global Impression Scale (CGI-I). The overall response rates (including partial and full response) were 38.1% for hypericum, 43.1% for placebo, and 48.6% for sertraline. As the authors point out, their study represents an excellent example of why it is critical to include both placebo and active comparators in trials of agents for which efficacy is unproven. Without a placebo control, one might pre-