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.

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).

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.