Consistently Modest Antidepressant Effects in Clinical Trials: the Role of Regulatory Requirements

Despite being widely heralded following their discovery, the effectiveness and clinical utility of antidepressants has been questioned, in part due to the release of several decades of regulatory trial data. Upon investigation, contemporary regulatory trials of antidepressants have demonstrated a nearly identical effect size (0.3) for the past 40 years, regardless of placebo response or attempts to improve trial design. In this review, we examine the historical methods of antidepressant trials and re-evaluate regulatory trial data over time and according to drug class (SSRIs, SNRIs, and atypicals) with the addition of two classes of antidepressants not previously analyzed: tricyclics used as active comparators and the recently-approved NMDA receptor antagonist, esketamine. We show that among these five classes of antidepressants there were no significant differences between effect sizes or percent symptom reduction. We suggest that within the context of a regulatory trial of antidepressants, effect sizes will remain modest (~0.3) regardless of class or novel drug mechanism, possibly due to regulatory changes to trial design and conduct following the Kefauver-Harris Act of 1962. We comment that the regulatory double-blind, parallel, placebo-controlled trial model is an artificial creation for a narrow purpose-designed to demonstrate simple superiority over placebo and to determine basic safety. We should be cautious of stretching trial results beyond their limited capacity to inform clinical practice as trials are not representative of real-world patients or medication management practices. There is a substantial need to develop more realistic models to evaluate the clinical utility of antidepressants.