Effect of Psilocybin on the Positive Valence System in Treatment-resistant Depression

Inclusion Criteria:

• The patient must have given their free and informed consent and signed the consentform

• The patient must be a member or beneficiary of a health insurance plan

• Patient with a current DSM-IV diagnosis of moderate or severe major depressiveepisode (MDE) without psychotic features (based on clinical assessment and confirmedby the MINI interview and the QIDS).

• Patient who has not responded to at least two antidepressant treatments of differentclasses, administered appropriately in terms of dose and duration, for a moderate tosevere major depressive episode.

• Patients receiving antidepressant treatment of the SSRI (Selective SerotoninReuptake Inhibitors) or SNRI (Serotonin Norepinephrine Reuptake Inhibitors) classesmay maintain this treatment for the duration of the trial, without modification •Patient with a score > 10 on the QIDS scale.

• Patient available for a 4-month follow-up.

• Patient able to speak and understand French easily.

Exclusion Criteria:

• The patient is participating in a medical product-based interventional study, or isin a period of exclusion determined by a previous study

• Patient unable to express consent

• It is impossible to give the subject informed information

• The patient is under safeguard of justice or state guardianship

• Patient with allergy, hypersensitivity or other adverse reaction to previous use ofpsilocybin or other hallucinogens.

• Patient who has used hallucinogenic substances (excluding cannabis) more than 5times in his/her lifetime or at any time in the last twelve months.

• Patient on medication or illicit substances likely to interfere with the effects ofpsychedelics (urine analysis and breathalyzer on D0).

• Patient with regular consumption of alcoholic beverages (>20 drinks/week)

• Any other major clinically significant concomitant disease that, in the opinion ofthe investigator, may interfere with the interpretation of the study results orconstitute a risk to the health of the participant, if he or she participates in thestudy

• Patient with a prolonged QTc interval (interval corrected by the Fridericia formula >450 ms for men and >470 ms for women

• Participant planning to donate sperm within three months of psilocybinadministration

• Female participant having sexual intercourse that could result in pregnancy and notagreeing to use a highly effective contraceptive method (combined hormonalcontraception (containing estrogen and progestin), contraception associated withinhibition of ovulation, hormonal progestin-only contraception associated withinhibition of ovulation, intrauterine device intrauterine device (IUD), intrauterinehormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, andsexual abstinence) throughout their participation in the study and for at leastthree months after psilocybin administration.

• Positive serum pregnancy test at inclusion for participants of childbearingpotential. NB: a urine pregnancy test will also be performed on the day ofpsilocybin administration.

• Pregnant patient (confirmed by pregnancy test), parturient or breastfeeding, orwishing to become pregnant during their participation in the study

• Active substance dependence according to the MINI questionnaire (excluding tobacco).

• Patient whose psychotropic treatment (anxiolytics, antipsychotics, hypnotics, moodstabilizers) has been modified in the last month.

• Patient on antidepressant treatment other than SSRIs or SNRIs. (Antidepressanttreatments other than SSRIs or SNRIs are prohibited in the trial. Patients receivingantidepressant treatment of a different class (MAOIs, tricyclics, tetracyclics),alone or in combination, will not be included in the study).

• Patient suffering from intellectual disability (IQ less than or equal to 75).

• Patient with a history of bipolar disorder, schizophrenia, schizoaffective disorderor psychosis not otherwise specified during life.

• Patient with a family history of schizophrenia, schizoaffective disorder or bipolardisorder type 1 in first or second degree relatives.

• Patient who has started psychotherapy in the 30 days preceding the screening visit,or whose psychotherapy is likely to undergo changes during the clinical trial.

• Patient who has received in the last 6 months treatments such as: ECT, vagus nervestimulation, deep brain stimulation, transcranial magnetic stimulation.

• Patient with any disease or unstable physical condition determined by clinicalexamination, history or laboratory tests (ECG, blood test at inclusion) Thesepathologies include cardiovascular comorbidities: history of stroke, myocardialinfarction, heart failure, intracranial hypertension, arrhythmia, uncontrolledhypertension (greater than 140/90 mmHg at screening), tachycardia (resting heartrate > 100 beats per minute); organic epileptic syndrome and active neurologicalcomorbidities; endocrine pathologies (dysthyroidism and adrenals, type I diabetes orinsulin-requiring type II diabetes, history of severe hypoglycemia requiringhospitalization); significant impairment of liver function; glaucoma; symptomaticprostatic hypertrophy or bladder neck obstruction; renal failure; respiratoryfailure; presence of fever or inflammatory syndrome.

• Patient with contraindications to magnetic resonance imaging: patients with ametallic foreign body, pacemaker, neurostimulator or any electronic medicalequipment implanted in a non-removable manner, implantable cardiac defibrillators,prostheses, transdermal patches (placed under the skin), catheters (tubes introducedinto a vessel or organ), implantable pumps, artificial heart valves, implants totreat deafness.

• Patient at moderate or severe risk of suicide based on clinical judgment (accordingto the MINI Suicidality Module).

• Patient at high risk of adverse emotional or behavioral reaction based on theinvestigator's clinical assessment (e.g., severe personality disorder, antisocialbehavior, severe current stressors, lack of significant social support, or anypsychotic symptoms identified during interviews).