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

Prior treatment

• Patient with a psychiatric decompensation following a previous use of psychedelic substance like LSD;
  • Comorbidities or somatic specificities:
• Contraindications to MRI;
  • Concomitant therapies:
• 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;

Other illness

• Psychiatric comorbidities known from medical history or identified during inclusion assessment:
• Bipolar disorder;
• 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;
• 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;
• Persons deprived of their liberty by judicial or administrative decision, persons under compulsory psychiatric care;

Lab values

• Cardiovascular history (myocardial infarction, stroke, heart rhythm disorder, uncontrolled hypertension, QT interval prolongation, tachycardia and poor cardiovascular health);

Other

• Schizophrenia and psychosis;
• 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;
• Pregnancy and breastfeeding women;
• 5-HT antagonist treatment2A (including quetiapine, olanzapine, aripiprazole);
• Lithium treatment;
• Use of psychedelics (psilocybin, lysergic acid, ayahuasca, mescaline and derivatives) during current episode;
  • Legal status:
• 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.

• 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.