Effect of psilocybin on the positive valence system in treatment-resistant depression: a pilot clinical neuroimaging study

Prior treatment

• Patients with allergy, hypersensitivity or other adverse reaction to previous use of psilocybin or other hallucinogens.
• Patients on medication or illicit substances likely to interfere with the effects of psychedelics (urinalysis and breathalyser on D0).
• Any other major clinically significant concomitant disease which, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk to the participant, should he/she participate in the study.
• Participants having sexual relations that could lead to pregnancy and who do not agree to use a highly effective contraceptive method (contraceptive ring, surgical contraception, implant, patch, contraceptive pill, male and female condoms, IUD) throughout their participation in the study and for at least three months after psilocybin administration.
• Patient already participating in an interventional drug study
• Patient with positive pregnancy test prior to psilocybin administration

Other illness

• Patients at high risk of adverse emotional or behavioral reactions according to the investigator's clinical assessment (e.g. severe personality disorder, antisocial behavior, severe current stressors, lack of significant social support or any psychotic symptoms identified during interviews).
• Patients with a lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder or psychosis not otherwise specified.
• Patients with a family history of schizophrenia, schizoaffective disorder or type 1 bipolar disorder in first- or second-degree relatives.

Lab values

• Patients with a prolonged QTc interval (>450 ms for men and >470 ms for women).
• Positive serum pregnancy test at inclusion for participants of childbearing age. NB: serum pregnancy test will be performed on the day of psilocybin administration.
• Patients with any unstable disease or physical condition as determined by clinical examination, history or laboratory tests (ECG, blood work at inclusion) Unstable physical conditions include: presence of fever or inflammatory syndrome, unstabilized hypertension or > 180/100, class IV heart failure, respiratory, hepatic or renal failure, and history of stroke, intracranial hypertension or epilepsy under treatment.

Other

• Patient at moderate or severe risk of suicide according to clinical judgment (based on the MINI suicidality module).
• Patients with contraindications to magnetic resonance imaging
• Patients who have used hallucinogenic substances (excluding cannabis) more than 5 times in their lifetime or at any time in the last two months.
• Patient with regular consumption of alcoholic beverages (>20 drinks/week)
• Participant planning to donate sperm within three months of psilocybin administration.
• Pregnant (confirmed by pregnancy test), parturient or breast-feeding patient, or patient wishing to become pregnant during the study period.
• Patient in exclusion period determined by another study.
• Patients under court protection, guardianship or curatorship, or under a non-consensual care measure.
• Patient unable to give consent.
• Patient for whom it is impossible to give informed information.
• Any patient who was hospitalized as an outpatient or inpatient between the date of inclusion and the administration of psilocybin.
• Any patient with a confirmed, interrupted or aborted suicide attempt between the date of inclusion and psilocybin administration.
• Any patient who expressed suicidal ideation associated with the planning of a suicidal act (active suicidal ideation) between the date of inclusion and the administration of psilocybin.
• Active substance dependence according to the MINI questionnaire (excluding tobacco).
• Patients whose psychotropic treatment (anxiolytics, antipsychotics, hypnotics, mood regulators) has been modified in the last month.
• Patients with intellectual disabilities (IQ less than or equal to 75).
• Subjects participating in psychotherapy during the study.

• Patient with a DSM-IV diagnosis of a current moderate or severe depressive episode without psychotic features (based on clinical assessment and confirmed by MINI interview and QIDS).
• Patient affiliated to or benefiting from a health insurance
• Patient who has failed to respond to at least 2 sequences of treatment with antidepressants of different classes at the minimum effective dose lasting at least 6 weeks.
• Patient with a score > 10 on the QIDS scale.
• Patient aged ≥ 25 years and < 60 years.
• Patient available for 6-month follow-up.
• Good physical health and absence of unstable medical pathology. These pathologies include cardiovascular comorbidities: history of stroke, myocardial infarction, heart failure, arrhythmia, uncontrolled hypertension (greater than 165/95 mmHg at screening); organic epileptic syndrome and active neurological comorbidities; endocrine pathologies (dysthyroidism and adrenal insufficiency, type I diabetes or insulin-requiring type II diabetes, history of severe hypoglycemia requiring hospital treatment); significant impairment of liver function; glaucoma; symptomatic prostate hypertrophy or bladder neck obstruction.
• Patient able to speak and understand French easily.
• Patient has given free and informed consent.
• Patient has signed consent form.