Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987-2013

Abstract

More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant-placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r=0.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p=0.42) and the magnitude of antidepressant-placebo differences (10.5% vs. 10.3%, p=0.37) have remained statistically equivalent. Furthermore, the frequency of positive trial arms has gone up in the past 15 years (from 47.8% to 63.8%), but this difference in frequency has not reached statistical significance. Trial design features that were previously associated with a possible lower magnitude of placebo response were not implemented, and their relationship to the magnitude of placebo response could not be replicated. Of the 34 recent trials, two implemented enhanced interview techniques, but both of them were unsuccessful. The results of this study suggest that the relationship between the magnitude of placebo response and the outcome of antidepressant clinical trials is weak at best. These data further indicate that antidepressant-placebo differences are about the same for all of the sixteen antidepressants approved by the FDA in the past thirty years.

Keywords: Antidepressants; antidepressant-placebo difference; clinical trials; effect size; enhanced interview techniques; placebo response; success rate.

Figure 1

Percent symptom reduction in 74 placebo and 92 antidepressant treatment arms from 85 clinical trials for 16 antidepressant approval programs plotted with time. The correlation between year of new drug approval and percent symptom reduction was significant in both the placebo (r=0.46, p<0.001) and the antidepressant group (r=0.37, p<0.001).

Figure 2

Mean effect size (Hedges’ g) of antidepressant clinical trials based on year of approval. There was no significant relationship between year of new drug approval and mean program effect size (r=−0.06, p=0.85).