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

Phase 2Not Yet RecruitingNCT07210112

Centre Hospitalier St Anne112 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Interventions

Psilocybin 25 mg per osDRUG

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 5mgDRUG

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

Trazodone 30 mgDRUG

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

Placebo of psilocybinDRUG

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

Placebo of trazodoneDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

Time frame: Baseline, Month 1

Secondary Outcomes

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

Time frame: Baseline and Month 1

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

Time frame: Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 2 and Month 3

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

Time frame: Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3

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

Time frame: Inclusion, Baseline, Day0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3

Response rate

Proportion of patients with 50% reduction in MADRS scores in each group at Day 7, Month 1, Month 2 and Month 3 compared to Baseline

Time frame: Baseline, Day 7, Month 1, Month 2 and Month 3

Remission rate

Remission rates defined as the proportion of patients with a MADRS score \<10 in each group at Day 7, Month 1, Month 2 and Month 3 compared to Baseline score

Time frame: Baseline, Day 7, Month 1, Month 2 and Month 3

Number of adverse events observed including vital signs and clinical laboratory abnormalities

Side effects in all groups between study drug administration at Day 0, Day 1, Day 7, Month 1, Month 2 and Month 3 including vital signs worsening and biological adverse events (laboratory exams worsening)

Time frame: Day 0, Day 1, Day 7, Month 1, Month 2, Month 3

Change from Inclusion in the mean YMRS at Baseline, Day 0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3

Mean YMRS scores at Inclusion, Baseline, Day 0 H7, Day 1, Day 7, Month 1, Month 2 and Month 3 in each group

Time frame: Inclusion, Baseline, Day 0 H7, Day 1, Day 7, Month 1, Month 2, Month 3

Proportion of patients with a new antidepressant after study treatment administration (Day 0)

Proportion of patients with an introduction of a new antidepressant after Day 0 in each group

Time frame: From Day 0 to end of study

Mean score of visual analog scale (VAS) of patients' drug acute subjective effects at Day 0

Time frame: Day 0

Mean scores of Mystical Experience Questionnaire (MEQ30) at Day 0

Time frame: Day 0

Mean score of 5-Dimensional Altered States of Consciousness (5D-ASC) at Day 0

Time frame: Day 0

Mean score of Stanford Expectations of Treatment Scale (SETS) at Baseline

Time frame: Baseline

Mean score of the Credibility/Expectancy Questionnaire (CEQ) at Baseline

Time frame: Baseline

Change from Inclusion in the mean score of Quality of Life in Depression Scale (QLDS) at Baseline, Day 7, Month 1, Month 2 and Month 3

Time frame: Inclusion, Baseline, Day 7, Month 1, Month 2 and Month 3

Change in mean reaction time from Baseline at Day 0, Day 7, Month 1and Month 3

Time frame: Baseline, Day 0, Day 7, Month 1, Month 3

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts