Psilocybin, a serotonin receptor agonist in the brain, significantly and quickly improves depressive symptoms while inducing profound acute subjective effects.
The benefit-risk ratio of psilocybin in treatment-resistant depression seems favorable, but needs to be confirmed. Moreover, the role of 5-HT2A receptors, involved in the psychedelic experience, on the therapeutic efficacy of psilocybin is still poorly understood. For example, pre-administration of trazodone, a 5-HT2A antagonist antidepressant, could annihilate the acute subjective effects of psilocybin without altering its beneficial effects (Rosenblat et al., 2023). We intend to test this hypothesis by comparing, in a randomized, double-blind, placebo-controlled study, the effect of two possible doses of trazodone (total or partial occupancy of 5-HT2A receptors) on the benefit/risk ratio of psilocybin.
We hypothesize that the therapeutic effects of psilocybin are partially independent of 5-HT2A receptor activation and thus persist even after total or partial neutralization of its acute subjective effects.
Patient with major depressive episode without psychotic features according to DSM-5 criteria;
Treatment-resistant depressive episode, i.e. failure to respond to at least two lines of antidepressant medication at an adequate dose and for a sufficient period of time (6 weeks according to the MGH-ATRQ);
MADRS ≥ 20;
Written signed informed consent;
Bipolar disorder;
Schizophrenia and psychosis;
Personal or family history of psychotic disorder;
History of personality disorder;
Parallel
Psilocybin 25 mg per os
DrugCaps of psilocybin administered orally once (V3) under medical and psychologist supervision in group 1, 2, and 3 and in an open-label setting for group 4
Trazodone 5mg
DrugOral preparation of trazodone administered orally once (V3) with psilocybin in Group 2
Trazodone 30 mg
DrugOral preparation of trazodone administered orally once (V3) with psilocybin in Groups 3 \& 4
Placebo of psilocybin
DrugCaps of psilocybin placebo will be administered at V3 in group 4
Placebo of trazodone
DrugA placebo of trazodone will be administered orally at V3 in group 1
Change from Baseline in the mean score of Montgomery-Åsberg Depression Rating Scale (MADRS) at 1 month
Mean difference of MADRS scores between one month and Baseline, between the following groups: psilocybin + trazodone 30 mg (Group 3) and placebo + trazodone (Group 4).
Change from Baseline in the MADRS scores at Month1 in the Groups 1, 2 and 4
MADRS scores at Baseline and Month 1 in the Groups 1, 2 and 4
Change from Inclusion in the MADRS scores at Baseline, Day0 H7, Day 1, Day 7, Month 2 and Month 3 in each group
MADRS scores at Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 2 and Month 3 in each group
Change from Inclusion in the Beck Depression Inventory (BDI-II) scores at Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group
BDI-II scores at Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group
Change from Inclusion in the Columbia-Suicide Severity Rating Scale (C-SSRS) scores at Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group
C-SSRS scores at Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group
Click on the lead sponsor to view all of their trials.
