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% (r50.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r50.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p50.42) and the magnitude of antidepressant-placebo differences (10.5% vs. 10.3%, p50.37) 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.

RationaleThe last systematic analysis of suicidality in antidepressant clinical trials submitted for approval by the US Food and Drug Administration was in 2000. Given the attention to suicide and antidepressants in the early 2000s, the authors aimed to evaluate if there have been any changes in suicide rates in antidepressant clinical trials following 2000.Objective and MethodsThe Integrated Safety Summary data from approval packets for 14 investigational antidepressant programs (1991–2013, 40,857 patients, 10,890.5 exposure years) were used to calculate suicides and suicide attempts per 100,000 patient exposure years (standardized rates) for antidepressant and placebo treatment groups separately. Suicides/suicide attempt rates, mean age, and percent female were compared between 1991 and 1998 (pre-2000) and 2002–2013 (post-2000). Drug-placebo differences in suicide/suicide attempt rates were explored.ResultsAmong antidepressant-treated patients, the standardized suicide rate decreased significantly from pre- to post-2000 (643.6 to 25.8, p < 0.0001) as did the standardized suicide attempt rate (3975.7 to 645.4, p < 0.0001). For placebo-treated patients, the decrease was not significant for suicide rate (471.1 to 174.2, p = 0.66) but was significant for suicide attempt rate (from 3538.3 to 522.6, p < 0.001). Regression analysis showed a similar pattern with suicide/suicide attempt rates decreasing over time. None of the drug-placebo comparisons in suicide or suicide attempt rates were statistically significant. There was no change in percent female or mean age of patients in trials pre- and post-2000.ConclusionsDeaths by suicide and suicide attempts have decreased significantly in antidepressant clinical trials following 2000 compared to the decade before 2000. Basic demographic features of the patients have remained consistent and medication treatment effects on suicidality were not apparent. These findings may reflect enhanced screening procedures and effective exclusion of suicidal patients in clinical trials for depression.

In a study of recent antidepressant clinical trial data, it was found placebo response had grown significantly over time and that contrary to expectations, trial outcome measures and success rate were not impacted. The aim of this paper was to evaluate if this trend of increasing placebo response and stable outcome measures could be seen in clinical trial data for Attention-Deficit Hyperactivity Disorder, a different psychiatric condition with susceptibility to placebo response. For this reason, we evaluated efficacy data reported in the FDA Medical and Statistical reviews for 10 ADHD medication programs (4917 patients, 17 trials, 29 treatment arms). Placebo and medication response were measured as percent symptom reduction and effect sizes and drug-placebo differences were calculated for each treatment arm and analyzed in relation to year of approval. We also investigated the potential role of age and medication class on trends and outcomes. Results showed a similar pattern to antidepressants wherein the placebo response is rising significantly over time (r = 0.636, p = 0.006) and effect size (r < 0.0001, p = 1.0), drug-placebo difference (r = -0.238, p = 0.214), and success rate (28/29 97%) have remained unaffected, likely due to a parallel, although not statistically significant increase in medication response (r = 0.326, p = 0.085). Age and medication class did not alter these observed time trends but pediatric trials and stimulants were found to have more robust treatment effects than adult trials and non-stimulants. The results of this study suggest that like antidepressants, the relationship between placebo response and the outcomes of ADHD clinical trials is weak at best.