Estimating heterogeneity of treatment effect in psychiatric clinical trials

Currently, placebo-controlled clinical trials report mean change and effect sizes, which masks information about heterogeneity of treatment effects (HTE). Here, we present a method to estimate HTE and evaluate the null hypothesis (H 0 ) that a drug has equal benefit for all participants (HTE=0). We developed measure termed ‘estimated heterogeneity of treatment effect’ or eHTE , which estimates variability in drug response by comparing distributions between study arms. This approach was tested across numerous large placebo-controlled clinical trials. In contrast with variance-based methods which have not identified heterogeneity in psychiatric trials, reproducible instances of treatment heterogeneity were found. For example, heterogeneous response was found in a trial of venlafaxine for depression (p eHTE =0.034), and two trials of dasotraline for binge eating disorder (Phase 2, p eHTE =0.002; Phase 3, 4mg p eHTE =0.011; Phase 3, 6mg p eHTE =0.003). Significant response heterogeneity was detected in other datasets as well, often despite no difference in variance between placebo and drug arms. The implications of eHTE as a clinical trial outcomes independent from central tendency of the group is considered and the important of the eHTE method and results for drug developers, providers, and patients is discussed.