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

NCT06650800 | Completed

• 1 other identifier: NIMAO/2021-2/JLC-01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The study hypothesis is that the antidepressant effect of psilocybin is mediated by a normalization of the functioning of the positive valence system. Depressive states, especially moderate to severe depressions that associate a certain level of anhedonia, produce an overvaluation of the cost of efforts and an infra-evaluation of the possible rewards derived from an action. Psilocybin would reduce anhedonia and the cost of efforts, facilitating the anticipation of reward. Thus, the antidepressant effect of psilocybin would be mediated by a greater anticipation of rewards (reduction of anhedonia) and a more optimistic estimation of the results of efforts (increase in motivation). Psilocybin-induced changes in the positive valence system will be observable on brain MRI images, particularly in the effort evaluation circuits: basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum (VS), ventral tegmental area (VTA). The mesolimbic circuit (VS, VTA) is the anatomical substrate of anticipation of rewarding stimuli (food, sex, drugs). The amygdala also fulfills an associative function between environmental cues and rewarding stimuli. Structural and functional alterations in this circuit are associated with depressive symptoms such as anhedonia or distortions in the perception and memories of rewards. This hypothesis will be tested on a population of patients with moderate or severe depressive symptoms who meet the criteria for TRD.

Conditions

Depressive Disorder; Depressive Disorder, Treatment-Resistant; Hallucinogens; Reinforcement, Psychology

Outcome Measures

Primary Outcomes (2)

• Activity of the neural circuits responsible for the evaluation of effort before taking psilocybin

  Brain activity measured by fMRI at resting state and during Effort Expenditure for Rewards Task in the basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum and ventral tegmental area

  Two days before administration of psilocybin

• Activity of the neural circuits responsible for the evaluation of effort after taking psilocybin

  Brain activity measured by fMRI at resting state and during Effort Expenditure for Rewards Task in the basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum and ventral tegmental area

  Five days after administration of psilocybin

Secondary Outcomes (19)

• Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression

  Day 0

• Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression

  Day 4

• Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression

  Month 1

• Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression

  Month 3

• Effect of a single-dose administration of psilocybin on clinician-rated treatment-resistant depression

  Day 0

Study Arms (1)

Patient with major depressive episode

EXPERIMENTAL

Drug: Psilocybin; Other: MRI

Interventions

Psilocybin DRUG

Single-dose psilocybin administration: oral ingestion of one 25 mg capsule

Patient with major depressive episode

MRI OTHER

1.5 hour brain MRI before and after psilocybin administration

Patient with major depressive episode

Eligibility Criteria

• Age: 25 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• The patient must have given their free and informed consent and signed the consent form
• 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 depressive episode (MDE) without psychotic features (based on clinical assessment and confirmed by the MINI interview and the QIDS).
• Patient who has not responded to at least two antidepressant treatments of different classes, administered appropriately in terms of dose and duration, for a moderate to severe major depressive episode.
• Patients receiving antidepressant treatment of the SSRI (Selective Serotonin Reuptake Inhibitors) or SNRI (Serotonin Norepinephrine Reuptake Inhibitors) classes may 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.

You may not qualify if:

• 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 of psilocybin or other hallucinogens.
• Patient who has used hallucinogenic substances (excluding cannabis) more than 5 times 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 of psychedelics (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 of the investigator, may interfere with the interpretation of the study results or constitute a risk to the health of the participant, if he or she participates in the study
• 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 psilocybin administration
• Female participant having sexual intercourse that could result in pregnancy and not agreeing to use a highly effective contraceptive method (combined hormonal contraception (containing estrogen and progestin), contraception associated with inhibition of ovulation, hormonal progestin-only contraception associated with inhibition of ovulation, intrauterine device intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence) throughout their participation in the study and for at least three months after psilocybin administration.
• Pregnant patient (confirmed by pregnancy test), parturient or breastfeeding, or wishing 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, mood stabilizers) has been modified in the last month.
• Patient on antidepressant treatment other than SSRIs or SNRIs. (Antidepressant treatments other than SSRIs or SNRIs are prohibited in the trial. Patients receiving antidepressant treatment of a different class (MAOIs, tricyclics, tetracyclics), alone or in combination, will not be included in the study).

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Nīmes: lead

Study Sites (1)

CHU de Nîmes, Hôpital Universitaire Carémeau

Nîmes, 30029, France

Location

MeSH Terms

Conditions

Depressive Disorder; Depressive Disorder, Treatment-Resistant

Interventions

Psilocybin

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Study Officials

• Ismaël Conejero

  CHU Nimes

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2024
• First Posted: October 21, 2024
• Study Start: November 19, 2024
• Primary Completion: March 26, 2025
• Study Completion: June 26, 2025
• Last Updated: August 20, 2025

Record last verified: 2025-08

Locations

FR (1)