Effect of psilocybin on the positive valence system in treatment-resistant depression: a pilot clinical neuroimaging study
- Trial ID
- 2022-501092-11-00
- Protocol
- NIMAO/2021-2/JLC-01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the activity of neural circuits responsible for effort assessment before and after **psilocybin** administration. This is clinically relevant as it aims to elucidate the neurobiological mechanisms underlying the therapeutic effects of psilocybin in individuals with treatment-resistant depression, potentially informing future therapeutic strategies.
Secondary objectives include:
- Evaluating the effect of single-dose psilocybin administration, accompanied by a caregiver, on treatment-resistant depression at the inclusion visit, 4 days, 1 month, and 3 months.
- Assessing changes in anhedonia and behavioral activation scores following treatment at the inclusion visit, 4 days, 1 month, and 3 months.
- Studying the acceptability and feasibility of a clinical protocol for augmented therapy with psilocybin.
- Examining the effect of psilocybin treatment on states of consciousness.
Participants
The clinical trial involves participants diagnosed with **depression**, specifically those experiencing a current moderate or severe depressive episode without psychotic features. The study population includes both male and female subjects aged between 25 and 59 years, who are in good physical health and free from unstable medical pathologies. Participants must have a history of treatment-resistant depression, having failed to respond to at least two different classes of antidepressants. They are required to have a score greater than 10 on the QIDS scale and must be available for a 6-month follow-up period. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to be affiliated with or benefit from health insurance and must be able to speak and understand French easily. They have given free and informed consent to participate in the study.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **psilocybine** on the positive valence system in individuals with treatment-resistant **depression**. This study is a randomized, double-blind, controlled trial, conducted in a single center, and is classified as a Phase 4 trial. The primary objective is to compare the activity of neural circuits responsible for effort assessment before and after the administration of psilocybine. The trial is expected to commence recruitment on November 4, 2024, and conclude by March 31, 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a DSM-IV diagnosis of a current moderate or severe depressive episode without psychotic features, and a history of inadequate response to at least two antidepressant treatments. The inclusion visit will also involve assessments using the MINI interview and QIDS scale. Following the screening, eligible participants will be randomized to receive either psilocybine or a control treatment, administered in capsule form for oral use, with a maximum daily dose of 25 mg.
Subsequent follow-up visits are scheduled at 4 days, 1 month, and 3 months post-treatment to evaluate changes in brain activity using fMRI, as well as secondary endpoints such as changes in depression scores, Behavioral Activation for Depression Scale (BADS), and Snaith-Hamilton Pleasure Scale (SHAPS) scores. Participants will also complete the 5-Dimensional Altered States of Consciousness Questionnaire to assess subjective experiences. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last approximately 6 months.
Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial aims to provide insights into the neural mechanisms underlying treatment-resistant depression and the potential therapeutic effects of psilocybine.
Treatment
The clinical trial involves the administration of **psilocybine**, an experimental medication, to evaluate its effects on treatment-resistant depression. Psilocybine is provided in the form of a **capsule for oral use**. Each capsule contains a maximum daily dose of 25 mg, with the total dose not exceeding 25 mg per day. The administration route is oral, and the treatment period is limited to a single day. The active substance, psilocybine, is of chemical origin and is not formulated for pediatric use. The trial aims to assess the activity of neural circuits responsible for effort assessment before and after psilocybine administration.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the effects of psilocybine. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial is conducted under the auspices of CHU DE NÎMES, and the product is authorized for use in this specific clinical investigation.
Efficacy
Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint involves measuring brain activity using functional magnetic resonance imaging (fMRI) in specific regions associated with effort assessment, including the basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum, and ventral tegmental area. These measurements will be taken before and after the administration of **psilocybine**.
Secondary endpoints include the evaluation of changes in depression scores using the Quick Inventory of Depressive Symptomatology (QIDS), both clinician-rated and self-reported, at various timepoints: the inclusion visit, 4 days, 1 month, and 3 months post-treatment. Additionally, changes in scores from the Behavioral Activation for Depression Scale (BADS) and the Snaith-Hamilton Pleasure Scale (SHAPS) will be assessed. Patient evaluations of therapy sessions, including satisfaction, the number and severity of adverse events, and tolerance issues, will also be considered. Furthermore, the 5-Dimensional Altered States of Consciousness Questionnaire will be utilized to assess altered states of consciousness.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 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.
- Patient affiliated to or benefiting from a health insurance
Exclusion Criteria
- Patient at moderate or severe risk of suicide according to clinical judgment (based on the MINI suicidality module).
- 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).
- 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).
- 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.
- Subjects participating in psychotherapy during the study.
- 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.
- Patients with contraindications to magnetic resonance imaging
- Patients with allergy, hypersensitivity or other adverse reaction to previous use of psilocybin or other hallucinogens.
- Patients who have used hallucinogenic substances (excluding cannabis) more than 5 times in their lifetime or at any time in the last two months.
- Patients on medication or illicit substances likely to interfere with the effects of psychedelics (urinalysis and breathalyser on D0).
- Patient with regular consumption of alcoholic beverages (>20 drinks/week)
- 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.
- Patients with a prolonged QTc interval (>450 ms for men and >470 ms for women).
- Participant planning to donate sperm within three months of psilocybin administration.
- 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.
- Positive serum pregnancy test at inclusion for participants of childbearing age. NB: serum pregnancy test will be performed on the day of psilocybin administration.
- Pregnant (confirmed by pregnancy test), parturient or breast-feeding patient, or patient wishing to become pregnant during the study period.
- Patient already participating in an interventional drug study
- 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.
- Patient with positive pregnancy test prior to psilocybin administration
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 04 Nov 2024 | 20 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PSILOCYBINE | Test | CAPSULE FOR ORAL USE | ORAL USE | 25 | 1 | PRD10762928 |