Discussion
MDD, depression
SECONDARY
We conducted a secondary analysis of pooled IPD from 232 randomized clinical trials submitted to the FDA for antidepressant monotherapy for MDD to characterize the distribution of antidepressant response by depression severity. We observed that the population distribution of depression responses was strictly superior in the treatment arm vs the placebo arm in this filtered data set of participants with severe baseline depression. All studied portions of the depression response distribution were at least as favorable in the treatment arm as in the placebo arm. The participants with the worst response receiving antidepressant treatment responded at least as favorably (in terms of percentage improvement in HAMD-17 scores) as the participants with the worst response receiving placebo. Likewise, the participants with the best response receiving antidepressant treatment responded at least as favorably as the participants with the best response receiving placebo, and similarly for everyone in between. The response was most pronounced in the center of the distribution. These observations do not depend on any special assumptions; they are a simple consequence of the raw quantile distributions of antidepressant treatment response.We did not observe violations of rank similarity in our data when using the percentage definition of depression response. In contrast, when we defined depression response in terms of absolute improvement from baseline, there was a formal violation of rank similarity, although the magnitude of that observed violation was small. Our ability to test for rank similarity was limited. For instance, we only had the data to test for the potentially rank-distorting influence of a single potential moderator of treatment effect and not several other potential moderators that have been reported in the literature, such as brain network and perfusion patterns.How should we interpret the fact that the middle of the quantile distribution is where the drug and placebo curves separate the most? Rank similarity permits the following interpretation: participants who would have had a typical, middling response to placebo (ie. a percentage change of HAMD-17 score from baseline to final response at or near the median of the distribution of placebo responses) stand to gain the most from active drug. In contrast, patients who would have had a robust response with placebo receive little additional benefit from active drug. Perhaps this is because those with a robust response to placebo need no further treatment. Similarly, nonresponders to placebo would have received little additional benefit from active drug. Perhaps this is because individuals who do not respond to placebo experience a particularly entrenched form of depression that also responds poorly to drugs.These findings are exploratory and would need to be confirmed through specialized placebo run-in trials with a prolonged run-in duration (eg, the 6 weeks of placebo tested herein) followed by randomization of all run-in period participants, in contrast to common placebo run-in practices.Our analysis does not directly contradict that of Stone et alAnalyses based on rank similarity tend to estimate response distributions as the broadest possible values that are consistent with the data. If rank similarity is only partly or approximately true, then the true distribution of antidepressant response would be more concentrated than the responses estimated herein. It would take a very large violation of rank similarity to arrive at responses as concentrated as those reported by Stone et al.