Psilocybin Versus Escitalopram for Treatment-Resistant Depression: A Phase 2b Randomized Clinical Trial

Background

Treatment-resistant depression affects approximately 30% of patients with major depressive disorder and is associated with substantial morbidity. Psilocybin, a serotonin 2A receptor agonist, has shown promising antidepressant effects in preliminary studies. This phase 2b randomized trial compared psilocybin-assisted therapy with the selective serotonin reuptake inhibitor (SSRI) escitalopram in patients with treatment-resistant depression.

Methods

In this double-blind, randomized, active-controlled trial, 233 adults aged 25 to 65 years with treatment-resistant major depressive disorder (failure of at least two adequate antidepressant trials) were randomized 1:1:1 to receive psilocybin 25 mg in two sessions plus daily placebo capsules, psilocybin 10 mg in two sessions plus daily placebo capsules, or psilocybin placebo in two sessions plus daily escitalopram 20 mg. All psilocybin sessions were accompanied by psychological support. The primary endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to week 12.

Results

At 12 weeks, the psilocybin 25 mg group showed a mean reduction in MADRS score of 20.3 points (SD 12.1) from a baseline of 32.5, compared with 14.1 points (SD 11.8) in the escitalopram group (adjusted difference, -6.2 points; 95% CI, -9.4 to -3.0; P<0.001). Response rates (defined as 50% or greater reduction in MADRS) were 54% in the psilocybin 25 mg group versus 33% in the escitalopram group (P=0.003). Remission rates (MADRS score of 10 or less) were 37% versus 19% (P=0.006). The onset of antidepressant effect was significantly faster with psilocybin, with separation from escitalopram evident by week 2. Adverse events included transient headache (61%), nausea (29%), and anxiety during sessions (22%) in the psilocybin group. No serious psychiatric adverse events were reported.

Conclusions

Psilocybin-assisted therapy at the 25 mg dose produced clinically meaningful and statistically significant improvements in treatment-resistant depression compared with escitalopram, with rapid onset of action and durable effects through 12 weeks.