Psilocybin-Assisted Therapy for Major Depressive Disorder versus Treatment-Resistant Depression: A Systematic Review Comparing Clinical Outcomes and Trial Methodology

Abstract

Psilocybin-assisted therapy has produced promising results in clinical trials for depression, but most existing reviews treat major depressive disorder (MDD) and treatment-resistant depression (TRD) as a single category. This conflation is a problem. MDD and TRD differ in diagnostic criteria, illness severity, prior treatment failure, and likely neurobiological profile. Pooling their results risks masking differences that matter for clinical decision-making. This systematic review pulls the two populations apart. I will collect all published clinical trials (randomized controlled trials and open-label studies) that administered psilocybin to adults diagnosed with either MDD or TRD, then compare the reported effect sizes, response rates, and remission rates between the two groups. Because the MDD and TRD trials used different comparator conditions, different psilocybin doses, and different amounts of psychological support alongside the drug, the review will also map these methodological variations and consider how they might confound the comparison. I will pay particular attention to whether the psilocybin dose (25 mg versus 10 mg versus 1 mg active placebo) is associated with different response patterns across the two populations. I will search PubMed, PsycINFO (via Ovid), and the Cochrane Central Register of Controlled Trials, following PRISMA 2020 reporting guidelines. Quality assessment will use the Cochrane Risk of Bias tool (RoB 1.0) for RCTs and the JBI Critical Appraisal Checklist for Quasi-Experimental Studies for open-label trials. Given the heterogeneity in trial design and the clinical distinctness of the two populations, I will use narrative synthesis rather than meta-analysis, following the approach described by Popay et al. (2006). The review has direct practical relevance. COMPASS Pathways is currently seeking FDA approval for psilocybin specifically for TRD, while the Usona Institute ran its trials in broader MDD. If the two populations respond differently, or if the apparent differences are better explained by trial design choices, that matters for who should eventually receive this treatment and under what conditions.

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