NCT07210112

Efficacy of Psilocybin and Trazodone Combination in Treatment-resistant Depression: a Randomized Controlled Proof-of-concept Study (PSILOTRAZ)

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 112 (estimated)
• Sponsor: Centre Hospitalier St Anne · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

Treatment-resistant depression (TRD) is a frequent and potentially severe psychiatric disorder characterized by specific neurocognitive impairments. It has previously been demonstrated that psilocybin, a serotonin receptor agonist in the brain, significantly and quickly improved depressive symptoms while inducing profound acute subjective effects. The benefit-risk ratio of psilocybin in TRD 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 in a randomized, double-blind, placebo-controlled phase II, monocentric, 4 parallel-group proof-of-concept study involving 112 adult subjects with a depressive episode who had failed to respond to at least two lines of antidepressant treatment. Patients will be randomized in a 1:1:1:1 ratio to one of the following treatment groups: * Group 1: Psilocybin PEX010 (25 mg) + trazodone placebo (pharmaceutical master preparation prepared according to GPP) * Group 2: Psilocybin PEX010 (25 mg) + trazodone 5 mg * Group 3: Psilocybin PEX010 (25 mg) + trazodone 30 mg * Group 4: PCB2 (Placebo of PEX010 (25)) + trazodone 30 mg Stratification factors: gender (M/F).

Conditions

• Depression - Major Depressive Disorder
• Treatment-resistant Depression (TRD)

Interventions

Type	Name	Description
DRUG	Psilocybin 25 mg per os	Caps 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
DRUG	Trazodone 5mg	Oral preparation of trazodone administered orally once (V3) with psilocybin in Group 2
DRUG	Trazodone 30 mg	Oral preparation of trazodone administered orally once (V3) with psilocybin in Groups 3 \& 4
DRUG	Placebo of psilocybin	Caps of psilocybin placebo will be administered at V3 in group 4
DRUG	Placebo of trazodone	A placebo of trazodone will be administered orally at V3 in group 1

Timeline

• Start date: 2025-10-08
• Primary completion: 2029-12-31
• Completion: 2030-06-30
• First posted: 2025-10-07
• Last updated: 2025-10-07

Locations

1 site across 1 country: France