Psilocybin, the chemical component of "magic mushrooms", has been administered with psychotherapy in several randomized clinical trials (RCTs) showing large and sustained antidepressant effects. In healthy volunteers, the psychedelic effects of psilocybin have been shown to be blocked by administration of certain medications such as risperidone.
The purpose of this study is to use an established SV2A radiotracer produced at our Centre to determine the feasibility of integrating PET imaging in to psilocybin trials. The preliminary imaging data will assess whether psilocybin's antidepressant effects are related to changes in synaptic density in adults with TRD, and whether any changes in synaptic density are associated with psilocybin's actions on the 5-HT2AR.
Adults 18 to 65 years old;
Must be deemed to have capacity to provide informed consent;
Must sign and date the informed consent form;
Stated willingness to comply with all study procedures;
Pregnant as assessed by a urine pregnancy test at Screening (V1) or individual's that intend to become pregnant during the study or are breastfeeding;
Treatment with another investigational drug or other intervention within 30 days of Screening (V1);
Have initiated psychotherapy in the preceding 12 weeks prior to Screening (V1);
Have a DSM-5 diagnosis of substance use disorder (use of tobacco is permitted) within the preceding 6 months;
Sequential
Psilocybin 25 mg
DrugThe psilocybin used in this study meets quality specifications suitable for human research use. The active drug is encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin. The psilocybin will be administered once during the trial in combination with or without risperidone 1 mg. It will also be administered in conjunction with supportive therapy.
Risperidone 1 MG
DrugThe risperidone is encapsulated using a cellulose capsule and contains 1 mg of risperidone. The risperidone will be administered once during the trial in combination with psilocybin 25 mg. It will also be administered with supportive therapy.
Feasibility of obtaining PET imaging scans before and after administration of psilocybin (25 mg) with and without risperidone (1 mg) in adults with TRD.
Percentage of participants recruited, enrolled, and retained.
Obtain preliminary data on synaptic density (as measured by [18F] SynVesT-1 volume distribution, VT) in brain regions relevant to MDD (i.e., hippocampus, prefrontal cortex)
as measured by \[18F\] SynVesT-1 volume distribution, VT
Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from Baseline to 1-week post-treatment.
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item clinician-rated scale that measures depression severity. Each item can be scored from 0-6. The minimum assessment score is 0 and the maximum score is 60. Higher composite scores represent a more severe condition.
Obtain preliminary data on cortical plasticity (as measured by TMS-EEG)
obtain preliminary data on cortical plasticity, as measured by TMS-EEG in brain regions relevant to MDD at visit 2, visit 3 and visit 4
Neuroplastic changes in cortical structure and functional neuroplasticity
Diffusion MRI approaches sensitive to neurite density and changes in dynamic functional connectivity (dFC)
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