Psilocybin rTMS for Treatment Resistant Depression

The purpose of this study is to determine the safety and feasibility of sequencing psilocybin therapy with a short-duration, aiTBS protocol (Stanford Accelerated Intelligent Neuromodulation Therapy, or SAINT) in individuals with treatment-resistant major depressive disorder.

This will be a phase II 2x2 design (device and dose) clinical trial. 100 participants, ages 22-76, with treatment-resistant MDD will be randomized to treatment with either: a) 25mg of COMP360 (N=50); or b) 1mg of COMP360 (low-dose comparator; N=50) with appropriate psychological preparation, support, and integration sessions with trained therapists. This will then be directly followed by one of two subsequent treatment conditions: i) the active accelerated intermittent theta burst (aiTBS) rTMS treatment known as Stanford Neuromodulation Therapy (SNT) and/or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) targeted to a functional magnetic resonance imaging (fMRI) functional connectivity-guided personalized left dorsolateral prefrontal cortex target using neuronavigation and delivered over 10 sessions daily for 5 consecutive days at 90% of coil-to-target depth-corrected resting motor threshold50,51; or ii) sham iTBS delivered in the same fashion. Individuals will undergo screening, a baseline clinical assessment and neurobiological assessment of functional magnetic resonance imaging (fMRI) and electroencephalographic (EEG) recordings. Individuals will then return on a subsequent day to begin the course of psilocybin therapy. Preparation sessions will occur on the first two out of five days (\~1.5-2 hrs each day), psilocybin dosing will occur on the third day (\~6-8 hours), integration session (\~1 hour) and post-dosing assessments will occur on the fourth day, and a final integration session (\~1 hour) and post-psilocybin clinical and neurobiological assessments will occur on the last of the five days. The following week, the individual will return to the lab to begin the course of active or sham SNT, for 10 hrs. a day (10 min once per 60 min, 50-minute inter-session interval, repeated 10 times daily) for 5 days. This is the protocol now FDA-cleared for treatment of treatment-resistant MDD, known as Stanford Neuromodulation Therapy and commercialized by Magnus Medical (see support letter from Magus Medical). In the third week, the individual will return to complete post-SNT clinical assessments and to complete a post-SNT neurobiological (fMRI and EEG) assessment. Individuals will complete long-term follow-up clinical assessments at 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, and 12 months post-initiation of first treatment (psilocybin administration) to assess durability of clinical response and identify potential points of depression relapse over a sustained period of time. Aims: To determine the safety and feasibility of sequencing psilocybin therapy with a short-duration, aiTBS protocol (Stanford Accelerated Intelligent Neuromodulation Therapy, or SAINT) in individuals with treatment-resistant major depressive disorder. To determine if the combination of psilocybin therapy followed by SAINT demonstrates superior efficacy relative to either treatment alone acutely (primary acute endpoint will be \~14 days after the initiation of the treatment sequence) and over time (additional endpoints at 2 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, and 12 months following cessation of the treatment protocol). To determine the neurobiological changes following the combination treatment (assessment points at baseline, 2 days post-psilocybin, and \~14 days post-psilocybin/2-4 days post cessation of accelerated theta burst), and if the magnitude or nature of such changes are different from those demonstrated in either treatment alone. Investigate how psychedelic treatment may impact blood biomarkers of inflammation (e.g., inflammatory cytokines) and how select functional genetic polymorphisms may moderate the effect of the psychedelic treatment on subsequent functional brain changes.