The Safety and Efficacy of Psilocybin in Participants With Treatment Resistant Depression

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Sponsors & Collaborators

COMPASS Pathways
COMPASS Pathways is a publicly listed company (NASDAQ) that is developing psilocybin for treatment-resistant depression (TRD) for which it has completed a successful Phase IIb trial. COMPASS is one of the largest psychedelic companies and has received substantial investment from atai.

Papers

Psilocybin Therapy for Treatment Resistant Depression: Prediction of Clinical Outcome by Natural Language Processing
This article of a language model (NLP, BART) finds that the audio from psychological support sessions (in the COMP360 trial for treatment-resistant depression, n=90 at 12 weeks) can predict clinical outcomes with high (85%) accuracy. The implications of this research signal that audio recordings can be used to predict who will respond to treatment and possibly aid in helping identify who would need more support.

Patient perspectives and experiences with psilocybin treatment for treatment-resistant depression: a qualitative study
This qualitative study (n=11) explores the experiences of treatment-resistant depression (TRD) patients undergoing a double-blind, randomized clinical trial with a single session of oral psilocybin treatment (1, 10, or 25 mg). Three major themes emerged: trust-building and expectation management challenges, navigating the experience, and the need for a more comprehensive treatment. Subthemes included distrust in mental healthcare, managing expectations, profound experiences during the session, and a desire for multiple psilocybin sessions. Insights from patients' perspectives suggest strategies for optimizing psilocybin treatment for TRD, such as individualized preparation, trust-building, additional sessions, and personalized therapy approaches.

Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder
This one-year observational follow-up study (n=66) examined the long-term outcomes of psilocybin (25 mg, 10 mg, 1 mg; COMP360) in treatment-resistant depression (TRD). Median time to depressive relapse was longest in the 25 mg group (92 days) compared to 10 mg (83 days) and 1 mg (62 days), with most participants relapsing by week 12. A post hoc analysis of those entering the follow-up study (n=58) found a more pronounced difference, with the 25 mg group maintaining benefits for 189 days. Adverse events were minimal, with one case of mild suicidal ideation in the 1 mg group.

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression
This double-blind active-placebo controlled trial (n=233) tested the effect of a single dose of psilocybin (25/10/1mg) with supportive therapy for treatment-resistant depression. The primary endpoint at three weeks finds a significant reduction in depressive symptoms (MADRS, 12-point drop from baseline of 32) that was significantly greater in the 25mg group vs the 1mg (placebo) group (6.6 points larger drop). The response (>50% drop in MADRS score) in the 25mg group dropped from 37% at 3 weeks to 20% at 12 weeks.

The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression
This re-analysis of the COMPASS Phase IIb trial (n=233) investigates the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcomes in treatment-resistant depression. Participants received a single dose of 25, 10, or 1 mg of psilocybin (COMP360) with psychological support. Higher doses produced stronger psychedelic effects, and reductions in depression (MADRS scores) at Week 3 correlated most strongly with dimensions of Oceanic Boundlessness (r = −0.508), Visual Restructuralization (r = −0.516), and Emotional Breakthrough Inventory (r = −0.637). Findings suggest the quality and intensity of psychedelic experiences mediate therapeutic outcomes and support dose-response mechanisms.

The Impact of Antidepressant Discontinuation Prior to Treatment with Psilocybin for Treatment-Resistant Depression
This post hoc analysis (n=233) of a Phase II RCT investigates the impact of recent antidepressant discontinuation (n=156) on the efficacy of psilocybin in treating treatment-resistant depression (TRD). The study compares outcomes between participants who discontinued antidepressants during screening and those who entered the trial free of these medications, finding no significant relationship between antidepressant discontinuation and worsening depression severity or compromised psilocybin treatment efficacy.

Measures Used

Montgomery-Asberg Depression Rating Scale
A ten-item diagnostic questionnaire used to measure the severity of depressive symptoms in patients with mood disorders.