Efficacy of psilocybin and trazodone combination in treatment-resistant depression: a randomized controlled proof-of-concept study (PSILOTRAZ)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Groupe Hospitalier Universitaire Paris Psychiatrie & Neuroscience

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Decision date (initial)

2025-06-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

ANR & DGOS

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To evaluate the efficacy of a single administration of the combination of psilocybin 25 mg + trazodone 30 mg (compared to placebo), administered with psychotherapeutic support in adult patients with TRD, in improving symptoms of depression at 1 month.

Secondary objectives 14

1. To compare the efficacy of psilocybin without trazodone pretreatment, psilocybin plus trazodone 5 mg, psilocybin plus trazodone 30 mg and trazodone monotherapy, administered with psychotherapeutic support in adult patients with treatment-resistant depression, in improving symptoms of depression at 1 month
2. To compare the efficacy of a single administration of these different treatments, administered with psychotherapeutic support in adult patients with treatment-resistant depression, in improving symptoms of depression at different time points from H7 (V3) to end of study visit compared to Baseline (V2) between groups
3. To compare response rates between groups from D7 (V5) to end of study
4. To compare remission rates between groups from D7 (V5) to end of study
5. To assess tolerance of study treatments between study treatment administration and end of study
6. To assess the influence of the intensity of psychedelic experience on its therapeutic efficacy in patients with resistant depressive disorder
7. To evaluate the role of expectations in study treatment efficacy from D7 (V5) to end of study visit
8. To assess patients’ quality of life before and after study treatment administration
9. To evaluate the neuro-cognitive mechanisms involved in the subjective effects of psilocybin using EEG and cognitive tasks
10. To study the biological correlates of psilocybin ± trazodone in the short and mid-term period after study treatment administration according to the response rate, remission rate and the efficacy parameters
11. To assess demographic, clinical, neurocognitive and biological factors associated with clinical response
12. To study the brain activity and functioning before and after the effects of the study treatments
13. To measure the cross-over within-subject efficacy of psilocybin by comparing the efficacy of psilocybin administered during the open-label extension phase to placebo administered during the initial phase to the same subjects, in improving symptoms of depression at 1 month
14. To assess the influence of blindness by comparing the efficacy of psilocybin administered during the open-label extension phase to psilocybin administered during the initial phase in improving symptoms of depression at 1 month

Conditions and MedDRA coding

Treatment-resistant depression

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Age ≥ 18 years old
2. Patient with major depressive episode without psychotic features according to DSM-5 criteria
3. MADRS score ≥ 20
4. 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)
5. Free, informed and prior written consent of the patient
6. Persons covered by the social security system

Exclusion criteria 28

1. Bipolar disorder
2. Any clinical event that, 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
3. Personal or family history of psychotic disorder
4. History of personality disorder
5. Post-traumatic stress disorder, obsessive-compulsive disorder, eating disorders
6. Alcohol or substance use disorder in past 12 months or positive urine toxins at time of assessment
7. Pregnancy and breastfeeding women
8. Cardiovascular history (myocardial infarction, stroke, heart rhythm disorder, uncontrolled hypertension, QT interval prolongation, tachycardia and poor cardiovascular health)
9. Uncontrolled diabetes
10. Uncontrolled thyroid disorder
11. 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
12. Epilepsy
13. Contraindications to MRI: Implants (mechanical or electronic: cochlear implants, pacemakers, infusion pumps, magnetic clips, etc.) incompatible with the magnetic field; Metallic foreign bodies in the eye or nervous system; Claustrophobia; Non-removable dental removable braces
14. 5-HT2A antagonist treatment (including quetiapine, olanzapine, aripiprazole)
15. Lithium treatment
16. Treatment with buprenorphine or opioids
17. Use of psychedelics (psilocybin, lysergic acid, ayahuasca, mescaline and derivatives) during current episode
18. Persons deprived of their liberty by judicial or administrative decision, persons under compulsory psychiatric care
19. Persons under legal protection or unable to give consent
20. Schizophrenia and psychosis
21. Patient with a psychiatric decompensation following a previous use of psychedelic substance like LSD
22. Parkinson’s disease treated by selegiline or levodopa
23. HIV treated by ritonavir and indinavir
24. Active infection treated by erythromycin
25. Fungal infection treated by ketoconazole and itraconazole
26. Concomitant therapies
27. Legal status
28. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The efficacy of the single administration of the psilocybin + trazodone 30 mg combination at 1 month will be assessed by the mean difference of Montgomery-Åsberg Depression Rating Scale (MADRS) scores between M1 (V6) and Baseline (V2), between the following groups: psilocybin + trazodone 30 mg (Group 3) and placebo + trazodone (Group 4).

Secondary endpoints 19

1. MADRS scores at Baseline (V2) and M1 (V6) in the groups not tested in the primary endpoint (Group 1, 2 and 4)
2. MADRS scores at Inclusion (V1), Baseline (V2), H7 (V3), D1 (V4), D7 (V5), M2 (V7) and M3 (V8) in each group (Group 1, 2, 3 and 4)
3. Beck Depression Inventory (BDI) questionnaire scores at Inclusion (V1), Baseline (V2), H7 (V3), D1 (V4), D7 (V5), M1 (V6), M2 (V7) and M3 (V8) in each group
4. C-SSRS scores at Inclusion (V1), Baseline (V2), H7 (V3), D1 (V4), D7 (V5), M1 (V6), M2 (V7) and M3 (V8) in each group
5. The response rate, defined as the proportion of patients with 50% reduction in MADRS score in each group at D7 (V5), M1 (V6), M2 (V7) and M3 (V8)
6. The remission rate defined as the proportion of patients with remission (i.e. MADRS score <10) in each group at D7 (V5), M1 (V6), M2 (V7) and M3 (V8)
7. Side effects in all groups between study drug administration at D0 (V3), D1 (V4), D7 (V5), M1 (V6), M2 (V7) and M3 (V8) including vital signs worsening and biological adverse events (AE) (laboratory exams worsening)
8. YMRS scores at Inclusion (V1), Baseline (V2), H7 (V3), D1 (V4), D7 (V5), M1 (V6), M2 (V7) and M3 (V8) in each group
9. Proportion of patients with an introduction of a new antidepressant after study treatment administration (D0) in each group
10. Correlation degree between maximal 5D-ASC and Mystical Experience Questionnaire (MEQ30) scores recorded during study drug administration (D0) and therapeutic efficacy assessed by MADRS score at M1 (V6)
11. Stanford Expectations of Treatment Scale (SETS) score and the Credibility/Expectancy Questionnaire (CEQ) score at Baseline (V2) according to MADRS score at D7 (V5), M1 (V6), M2 (V7) and M3 (V8)
12. Quality of Life in Depression Scale (QLDS) score at Inclusion (V1), Baseline (V2), D7 (V5), M1 (V6), M2 (V7) and M3 (V8)
13. Cognitive task performance measured before (Baseline (V2)), during (D0 (V3)) and after study treatment administration (D7 (V5), M1 (V6) and M3 (V8)) by accuracy, reaction time and EEG signals
14. Brain activity measured by resting EEG before (Baseline (V2)), during (D0 (V3)) and after study treatment administration (D7 (V5), M1 (V6) and M3 (V8))
15. Immune and neuroplasticity biomarkers dosage before (Baseline (V2)) and after study treatment administration (D1 (V4), D7 (V5), M1 (V6) and M3 (V8))
16. Independent factors and clinical response obtained during the study, defined as a 50% reduction in MADRS score
17. Brain structure and activity measured by Magnetic Resonance Imaging (MRI) and EEG in the Group 4 during the open-label extension phase (if applicable). MRI + EEG will be recorded at rest and during the performance of cognitive tasks, before psilocybin administration (V2) and after administration (D7 ± 1 day (V5) and M1 ± 3 days (V6))
18. MADRS scores at Baseline (V2) and M1 (V6) in the Group 4 and 4C (receiving psilocybin 25 mg in the open-label extension phase) as within-subject measures of psilocybin efficacy
19. MADRS scores at Baseline (V2) and M1 (V6) in the Group 1 and 4C (receiving psilocybin 25 mg in the open-label extension phase) as within-subject measures of efficacy and in the Group 1 and 4C to assess the influence of blindness

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Groupe Hospitalier Universitaire Paris Psychiatrie & Neuroscience

Sponsor organisation

Groupe Hospitalier Universitaire Paris Psychiatrie & Neuroscience

Address

1 Rue Cabanis

City

Paris

Postcode

75014

Country

France

Scientific contact point

Organisation

Groupe Hospitalier Universitaire Paris Psychiatrie & Neuroscience

Contact name

Sylla

Public contact point

Organisation

Groupe Hospitalier Universitaire Paris Psychiatrie & Neuroscience

Contact name

Sylla

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications