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.

The conundrum of depression clinical trials: one size does not fit all.

In this paper we review the history of antidepressant (AD) development, since the discovery of imipramine in 1957 to the present day. Through this exploration we will show that the increasing placebo response is likely a red herring and that a higher magnitude of placebo response is not an adequate explanation for AD trials' high failure rates. As a better explanation for their lack of success, we will examine some of the fundamental flaws of AD clinical trials and their origins in historical forces. We focus on underpowering, which occurs as a consequence of unrealistic expectations for AD performance. In addition, we describe the lack of precision in the depression outcome measurements for the past 40 years and show how these measures contrast with those used in clinical trials of other chronic diseases, which use simpler outcome measures. Finally, we describe the role of regulatory agencies in influencing clinical trial design and how the assumption that 'one size fits all' for the past 60 years has led to flawed design of AD clinical trials.