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

NCT ID: NCT07210112

Last Updated: 2025-10-07

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 112 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-10-08
• Study Completion Date: 2030-06-30

Brief 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)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Group 1

Psilocybin PEX010 25 mg + trazodone placebo (pharmaceutical master preparation prepared according to GPP)

Group Type: EXPERIMENTAL

Psilocybin 25 mg per os

Intervention Type: DRUG

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

Placebo of trazodone

Intervention Type: DRUG

A placebo of trazodone will be administered orally at V3 in group 1

Group 2

Psilocybin PEX010 (25 mg) + trazodone 5 mg

Group Type: EXPERIMENTAL

Psilocybin 25 mg per os

Intervention Type: DRUG

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

Trazodone 5mg

Intervention Type: DRUG

Oral preparation of trazodone administered orally once (V3) with psilocybin in Group 2

Group 3

Psilocybin PEX010 (25 mg) + trazodone 30 mg

Group Type: EXPERIMENTAL

Psilocybin 25 mg per os

Intervention Type: DRUG

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

Trazodone 30 mg

Intervention Type: DRUG

Oral preparation of trazodone administered orally once (V3) with psilocybin in Groups 3 \& 4

Group 4

PCB2 (Placebo of PEX010 (25)) + trazodone 30 mg

Group Type: PLACEBO_COMPARATOR

Trazodone 30 mg

Intervention Type: DRUG

Oral preparation of trazodone administered orally once (V3) with psilocybin in Groups 3 \& 4

Placebo of psilocybin

Intervention Type: DRUG

Caps of psilocybin placebo will be administered at V3 in group 4

Interventions

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

Intervention Type: DRUG

Trazodone 5mg

Oral preparation of trazodone administered orally once (V3) with psilocybin in Group 2

Intervention Type: DRUG

Trazodone 30 mg

Oral preparation of trazodone administered orally once (V3) with psilocybin in Groups 3 \& 4

Intervention Type: DRUG

Placebo of psilocybin

Caps of psilocybin placebo will be administered at V3 in group 4

Intervention Type: DRUG

Placebo of trazodone

A placebo of trazodone will be administered orally at V3 in group 1

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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;
• Patient covered by the social security system.

Exclusion Criteria

Psychiatric comorbidities known from medical history or identified during inclusion assessment:

• Bipolar disorder;
• Schizophrenia and psychosis;
• Personal or family history of psychotic disorder;
• History of personality disorder;
• Post-traumatic stress disorder, obsessive-compulsive disorder, eating disorders;
• Alcohol or substance use disorder in past 12 months or positive urine toxins at time of assessment;
• Significant suicide risk, as defined by: (a) suicidal ideation as indicated by items 4 or 5 on the C-SSRS within the past six months, at Screening, during the Screening Period, or at Baseline (b) demonstrating suicidal behaviors in the past six months, or; (c). clinical assessment of significant suicidal risk or risk of self-injury during participant interview;
• Patient with a psychiatric decompensation following a previous use of psychedelic substance like LSD;

Comorbidities or somatic specificities:

• Pregnancy and breastfeeding women;
• Cardiovascular history (myocardial infarction, stroke, heart rhythm disorder, uncontrolled hypertension, QT interval prolongation, tachycardia and poor cardiovascular health);
• Uncontrolled diabetes;
• Uncontrolled thyroid disorder;
• Epilepsy;
• Parkinson's disease treated by selegiline or levodopa;
• HIV treated by ritonavir and indinavir;
• Active infection treated by erythromycin;
• Fungal infection treated by ketoconazole and itraconazole;
• Contraindications to MRI;

Concomitant therapies:

• 5-HT antagonist treatment2A (including quetiapine, olanzapine, aripiprazole);
• Lithium treatment;
• Treatment with buprenorphine or opioids, clonidine, methyldopa, digoxin, Monoamine oxidase inhibitors (MAOI), aldehyde dehydrogenase (ALDH) inhibitors and alcohol dehydrogenase (ADH) inhibitors, St. John's Wort, or warfarin should be discontinued completely before study drug administration;
• Use of electroconvulsive therapy and/or transcranial magnetic stimulation, during the current depressive episode; or lifetime vagus nerve stimulation, deep brain stimulation, and/or ablative neurosurgery;
• Use of psychedelics (psilocybin, lysergic acid, ayahuasca, mescaline and derivatives) during current episode;

Legal status:

• Persons deprived of their liberty by judicial or administrative decision, persons under compulsory psychiatric care;
• Persons under legal protection or unable to give consent;

Other:

• Any clinical manifestation which, in the opinion of the investigator, may interfere with the interpretation of study results or constitute a health risk to the participant if he or she participates in the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Hospitalier St Anne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lucie BERKOVITCH, MD

Role: PRINCIPAL_INVESTIGATOR

GHU Paris Psychiatrie and Neurosciences - Neuromodulation Institute

Locations

GHU Paris Psychiatrie and Neurosciences

Paris, , France

Countries

France

Central Contacts

Lucie BERKOVITCH, MD

Role: CONTACT

l.berkovitch@ghu-paris.fr

+33 145657481

Facility Contacts

Lucie BERKOVITCH, MD

Role: primary

l.berkovitch@ghu-paris.fr

+33 145657481

Cécile BULTEZ, MSc

Role: backup

cecile.bultez@ghu-paris.fr

Other Identifiers

D24-P003

Identifier Type: -

Identifier Source: org_study_id