This study is a three-arm, 4-week, double blind, proof-of concept RCT for investigating psilocybin-assisted psychotherapy (PAP) administered with risperidone in treating TRD. This three-arm "double dummy" design allows for an assessment of risperidone's anti-psychedelic effects, while allowing for an assessment of psilocybin's antidepressant effects alone and combined with risperidone, compared to an "active placebo" (i.e. placebo plus risperidone 1 mg).
Overview of Study Design:
A study team member will obtain informed consent from interested participants prior to study activities being initiated. Following this, participants will undergo a screening assessment where they will complete lab tests, and clinical and psychiatric assessments to determine eligibility. Following the screening visit, eligible participants will undergo a washout period where they will be tapered off concomitant medication over a period of 4 to 6 weeks. The length of the tapering period will depend on the type of medication the participant is being tapered off (based on the half-life of the medication) and the participant's preference for the length of the tapering period. Most medications will require a minimum of a 2-week tapering period before the baseline, with the exception of fluoxetine, which will require a minimum of 4-weeks. Additional time may be added at the discretion of the study investigator. During the tapering period, the study psychiatrist will see participants weekly (V1a, V1b, etc.) for at least 4 weeks to monitor for withdrawal and worsening of depressive symptoms and suicidality. Suicidality will be closely monitored using the Columbia Suicide Severity Rating Scale (C-SSRS). Participants and their family members/carers will be educated on the signs and symptoms of worsening depression and suicidality and will be given contact details of the study team in case of major decline in mental state.
At the Baseline visit (V2), which occurs the day before the dosing session, participants will complete clinical measures, and undergo a preparatory session (up to 4 hours) with the study therapists. These sessions will build a therapeutic alliance, provide psychoeducation about, and set intentions for, the psilocybin session. To reduce participant burden, baseline can be broken up into multiple days, however all assessments must be completed within 7-days of the intervention. Ideally, baseline occurs the day before the intervention is administered.
The psilocybin session (Day 0 \[V3\]) will last 5 to 6 hours and will be conducted in the existing psychedelic treatment suite developed at the Centre for Addiction and Mental Health (CAMH) Mood Disorder Service by Dr. Husain (PI). Two trained study therapists will be supporting each participant during the dosing session. Participants will receive psilocybin 25 mg plus risperidone 1 mg, or psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 10 hours of manualized supportive psychotherapy (which includes the 5-6 hour dosing session). After 5 hours of dose administration, participants will be evaluated for safety by the study psychiatrist and discharged home in the company of a caregiver or a family member.
After the dosing session, participants will be seen for two 1-hour integration sessions (Day 1 \[V4\], Week 1 \[V5\]). Thereafter, participants will be followed-up after 2 \[V6\], 3 \[V7\] and 4 weeks \[V8\] post-dosing (see Figure 1). A study psychiatrist will be available throughout the duration of the RCT to respond to any concerns or changes in mental/physical state. Participants will not start other interventions for MDD during the study.
