A Bayesian Reanalysis of a Trial of Psilocybin Versus Escitalopram for Depression

A Bayesian reanalysis of a trial comparing psilocybin (25 mg) to escitalopram (20 mg) over 6 weeks in 59 patients with major depressive disorder found that psilocybin outperformed escitalopram on three of four depression scales, though evidence was not uniformly clinically meaningful. Using skeptical priors that bias results toward zero, the analysis showed strong to extremely strong evidence favoring psilocybin on the BDI-1A, MADRS, and HAMD-17, while evidence on the primary outcome (QIDS SR-16) was indeterminate. For clinically meaningful superiority, evidence was moderate against it for the QIDS SR-16 but moderate to strong for the MADRS and HAMD-17. Psilocybin showed extremely strong evidence of noninferiority to escitalopram across all scales. The findings support further research on psilocybin's relative efficacy.

Study at a glance

Abstract

Background: A trial of psilocybin (COMP360) versus escitalopram for major depressive disorder (MDD) was reported as negative, as there was no significant difference in the primary outcome, mean change in the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS SR-16). However, analyses using three other depression scales (17-item Hamilton Depression Rating Scale [HAMD-17], Montgomery and Åsberg Depression Rating Scale [MADRS], and Beck Depression Inventory 1A [BDI-1A]) all significantly favored psilocybin, although without a prespecified plan for multiple comparisons correction. Methods: Bayesian reanalysis of a trial of two doses of psilocybin (25 mg) versus 6 weeks of escitalopram (20 mg) was done in 59 patients with MDD. We used skeptical priors, which bias estimates toward zero, and Bayes factors, which quantify evidence for or against a hypothesis. We report posterior estimates for the difference between psilocybin and escitalopram for four different depression scales. Results: Using Bayes factors and “skeptical priors” that bias estimates toward zero, for the hypothesis that psilocybin is superior by any margin, we found indeterminate evidence for QIDS SR-16, strong evidence for BDI-1A and MADRS, and extremely strong evidence for HAMD-17. For the stronger hypothesis that psilocybin is superior by a “clinically meaningful amount” (using literature-defined values of the minimally clinically important difference), we found moderate evidence against it for the QIDS-SR-16, but indeterminate evidence to support it for the BDI-1A. Further, we found moderate evidence supporting psilocybin's clinically meaningful superiority on the MADRS and HAMD-17. For all scales, we found extremely strong evidence for psilocybin's noninferiority versus escitalopram. Findings were robust to prior sensitivity analysis. Conclusions: The overall pattern of evidence provided by this Bayesian reanalysis supports the following inferences: (1) psilocybin did indeed outperform escitalopram in this trial, but not to an extent that was uniformly clinically meaningful and (2) psilocybin is almost certainly noninferior to escitalopram. These results provide a more precise and nuanced interpretation to previously reported results from this trial and support the need for further research into the relative efficacy of psilocybin therapy for depression with respect to current leading treatments.