Treatment-resistant depression (TRD), defined as failure to respond to two or more adequate antidepressant trials, affects a significant portion of individuals with major depressive disorder (MDD). TRD is associated with substantial disability, high suicide rates, and increased mortality. Current treatments, including augmentation strategies and electroconvulsive therapy (ECT), have limitations in efficacy and tolerability. Recent research has shown promise for psilocybin, a psychedelic compound, in treating depression, particularly when combined with psychological support (psychedelic-assisted psychotherapy or PAP). However, PAP's scalability is limited due to its intensive nature. The current understanding suggests that psilocybin's therapeutic effects are linked to serotonin 2A (5-HT2A) receptor activation, which also mediates its psychedelic effects. This study aims to determine if psilocybin's antidepressant effects can be achieved without the psychedelic experience by using a 5-HT2A receptor antagonist, risperidone, to block the psychedelic effects. This approach could greatly improve the acceptability and accessibility of psilocybin as a treatment for TRD.

Several studies have demonstrated the efficacy of psilocybin-assisted psychotherapy (PAP) for treatment-resistant depression (TRD) and major depressive disorder (MDD). These studies, while showing promising results, often suffer from small sample sizes, lack of blinding, or highly selective participant populations. The general assumption is that psilocybin's therapeutic effects require the psychedelic experience, which is dependent on 5-HT2A receptor activation. However, recent findings suggest that a correlation between the psychedelic effects and sustained improvement in depressive symptoms might not exist. Preclinical studies using a mouse model of depression suggest that psilocybin's antidepressant effects may be independent of 5-HT2A receptor activation. This research gap necessitates a study to investigate whether blocking the psychedelic effects of psilocybin with a 5-HT2A receptor antagonist, such as risperidone, would maintain its antidepressant efficacy.

This study is a single-site, phase 2, 4-week, double-blind, placebo-controlled, three-arm RCT conducted at the Centre for Addiction and Mental Health (CAMH). Sixty adults with TRD (meeting DSM-5 criteria and unresponsive to at least two antidepressant trials) will be recruited. Participants will be randomized in a 1:1:1 ratio to one of three groups: 1. Risperidone 1mg + Psilocybin 25mg 2. Placebo Risperidone + Psilocybin 25mg 3. Risperidone 1mg + Placebo Psilocybin Participants will undergo a 12-hour manualized psychotherapy intervention consisting of a preparatory session, the dosing session (with a 60-minute interval between risperidone/placebo and psilocybin/placebo administration), and two integration sessions. Primary outcome measures will assess recruitment and retention rates, as well as the rates of adverse events and serious adverse events. The secondary outcome measure will be the total score on the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) to evaluate psychedelic effects. The exploratory outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS) to assess antidepressant effects. Other outcome measures will include Clinical Global Impressions scale, GAD-7, Snaith-Hamilton Anhedonia Scale, WHOQOL-BREF, WEMWBS, and the Stanford Expectations of Treatment Scale (SETS). Statistical analysis will utilize intention-to-treat principles, generalized linear models, mixed-effects models, and appropriate tests for categorical data. Subgroup analyses will examine differences by sex and gender.

This study is a protocol and therefore does not yet present key findings. The expected outcomes of this study will include data on the feasibility and tolerability of combining psilocybin with risperidone in patients with TRD. The researchers will also collect data on the psychedelic effects of the psilocybin treatment in each of the three study groups. Finally, this research will gather preliminary data on the antidepressant effects of the combined treatment compared to psilocybin alone. Specific statistical analyses will focus on the recruitment and retention rates, the incidence of adverse events, and changes in scores on the 5D-ASC and the MADRS.

This study addresses the critical question of whether psilocybin's psychedelic effects are necessary for its antidepressant efficacy. If successful, it could significantly advance the field by demonstrating a novel treatment approach for TRD that eliminates the need for the psychedelic experience and reduces the barriers to access and acceptability associated with PAP. The results will contribute to a better understanding of psilocybin's mechanism of action, potentially identifying alternative pathways to its antidepressant effects beyond 5-HT2A receptor agonism. This line of research offers a significant potential for improving treatments for TRD by increasing accessibility and reducing patient apprehension around the psychedelic experience.

This proof-of-concept RCT will provide valuable data on the feasibility, tolerability, and potential efficacy of combining psilocybin with risperidone in treating TRD. Positive results could significantly improve access to psilocybin treatment and offer a more scalable and acceptable therapeutic approach. Future research, contingent on these results, should focus on larger, adequately powered RCTs to confirm efficacy and explore the role of psychotherapy in enhancing the treatment's effectiveness.

The main limitations of this study are its relatively small sample size and the single-site nature, which might limit the generalizability of the findings. The reliance on self-reported measures for some outcomes may also introduce biases. The use of a manualized psychotherapy approach, while controlled, may not fully capture the nuances of individual therapeutic interactions. While the study addresses the issue of scalability, the need for medical supervision during dosing could still limit the overall accessibility of this treatment model.