Abstract
BACKGROUND: Depressive disorders are a major global health challenge, with many individuals unresponsive to existing treatments. Novel psychedelic therapies show promise but require further research. OBJECTIVES: This study aimed to evaluate the feasibility, safety and effectiveness of psilocybin with psychotherapeutic support for treatment-resistant depression (TRD), investigate predictors of treatment outcomes and deepen understanding of individual variability in response. DESIGN: Open-label, single-arm pilot trial with mixed-methods assessment. METHODS: Treatment consisted of two 25 mg psilocybin sessions, alongside three preparatory and six integration sessions. Depression severity was assessed using the self-rated Quick Inventory of Depressive Symptomatology at 3 weeks (primary endpoint) and at 20 weeks post-dose 2 (long-term follow-up). Potential predictors of clinical outcomes were evaluated using questionnaires, and qualitative interviews were used to capture individual experiences. RESULTS: At the aggregate level, a clinically meaningful reduction in depressive symptoms was observed at the primary endpoint (mean change = -7.14; p = 0.02; Hedges' g = -1.27; 95% CI [-2.40, -0.37]) and maintained long-term. Individual participant data revealed diverse response patterns. Two participants displayed a sustained treatment response, three relapsed, and two exhibited no substantial improvement. Exploratory analyses identified mindset prior to dosing, spiritual experiences and perceptual shifts during dosing as predictors of treatment trajectory, while treatment expectations were not a reliable predictor. Adverse events were largely consistent with previous studies, with no serious adverse events. CONCLUSION: Findings add to the growing evidence base for psilocybin therapy and provide direction for further research on individual variability in response to better tailor treatments and enhance efficacy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12621001097831).