Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression

NCT04670081 | Completed Phase 2 DMC

• 1 other identifier: EPIsoDE_01
• Study Type: interventional
• Target: 144
• Locations: 1 country
• Sites: 2

Brief Summary

The study aims to investigate the safety and efficacy of oral psilocybin administered under supportive conditions in treatment-resistant major depression (TRD). The study is a bi-centric, prospective, randomized, active placebo-controlled study investigating the effects of 25 mg and 5 mg (p.o.) psilocybin versus placebo (100 mg nicotinamide) in a psychotherapeutic context in 144 patients with TRD from moderate to severe degree (ICD-10 F32/F33). After giving written informed consent and down-titration of their monoaminergic medication under supervision of the treating psychiatrist and the study team, patients will be randomly assigned to one of four trial arms using an online randomization tool: 1) receiving placebo (100 mg nicotinamide) at the first session and the full dose (25 mg) at the second; 2) receiving the presumably sub-effective dose (5 mg) at the first session and the full dose (25 mg) at the second; 3a) receiving the full dose (25 mg) at the first session and 5 mg at the second; 3b) receiving the full dose at both sessions. The two dosing sessions are accompanied by three preparatory and four integration sessions. Drug administration must occur under psychotherapeutic conditions. Two trained therapists (one male, one female) will be assigned to each patient and be present during each dosing, preparatory and integration sessions. We will follow the safety guidelines provided by Johnson et al. (2), including a thorough preparation, establishment of trust/rapport, a safe and pleasing physical environment and sufficient interpersonal support. For safety reasons and close monitoring, patients will stay hospitalized for one night after each dosing session (i.e. in-patient setting).

Conditions

Treatment-resistant Depression

Keywords

Psilocybin; Major depressive disorder; MDD; Psychedelics; 5-HT2A; double-blind

Outcome Measures

Primary Outcomes (1)

• Treatment Response (defined as a ≥ 50% drop in depressive symptom severity as measured by the Hamilton Rating Scale for Depression; HAM-D)

  The HAM-D is a 21-item rating scale to assess the severity of depressive symptoms after a semi-structured clinical interview. Items are rated on a scale from 0 (absent) to 4. The total score is calculated by summing the first 17 items (HAM-D17) and ranges between 0 and 51.

  Baseline - 6 weeks after the first dose

Secondary Outcomes (4)

• % change in HAM-D total score

  Baseline - 1 day/1 week/6 weeks after the first dose

• Treatment Response (defined as a ≥ 50% drop in depressive symptom severity as measured by the Hamilton Rating Scale for Depression; HAM-D)

  Baseline - 1 day/1 week after the first dose

• Treatment response (≥ 50% drop) and % change in HAM-D total score

  Baseline - 12 weeks after the first dose

• Treatment response (≥ 50% drop) and % change in the Beck Depression Inventory (BDI) - II

  Baseline - 1 day/1 week/6 weeks after both doses

Study Arms (3)

Nicotinamide

PLACEBO COMPARATOR

1st dose: 100 mg Nicotinamide (Vitamin B3) - 2nd dose (after 6 weeks/after assessment of the primary endpoint): 25 mg Psilocybin

Drug: Psilocybin; Drug: Nicotinamide

Psilocybin (low-dose)

EXPERIMENTAL

1st dose: 5 mg Psilocybin - 2nd dose (after 6 weeks/after assessment of the primary endpoint): 25 mg Psilocybin

Drug: Psilocybin

Psilocybin (high-dose)

EXPERIMENTAL

1. 1st dose: 25 mg Psilocybin - 2nd dose (after 6 weeks/after assessment of the primary endpoint): 5 mg Psilocybin 2. 1st dose: 25 mg Psilocybin - 2nd dose (after 6 weeks/after assessment of the primary endpoint): 25 mg Psilocybin

Drug: Psilocybin

Interventions

Psilocybin DRUG

25 mg, p.o.

Nicotinamide; Psilocybin (high-dose); Psilocybin (low-dose)

Nicotinamide DRUG

100 mg, p.o.

Nicotinamide

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 65 years of age
• Diagnosis of major depressive disorder (single and recurrent episodes) of moderate to severe degree (HAM-D score ≥ 17) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) without psychotic features. Included ICD-10 diagnoses are ICD-10: F32.1, F32.2, F33.1, F33.2.
• a. If single episode, duration must be ≥ 3 months.
• Patients must meet criteria for treatment-resistance, defined as
• a. no adequate improvement despite two adequate courses of antidepressant treatment (6 weeks each, minimum) with drugs of different pharmacological classes in the current depressive episode. Augmentation with an add-on treatment counts as a second treatment.
• Patients have discontinued any monoaminergic psychiatric medication (i.e. SRIs, antipsychotic medication) for at least 2 weeks before the first dosing session.
• Patients who are still on any monoaminergic psychiatric medication at screening must agree to down-titrate over an individualized down-titration schedule (minimum 2 weeks; if they have been taken Fluoxetine the down-titration phase should be minimum 5 weeks) in close supervision by their out-patient psychiatrist and the study team. The treating psychiatrist must agree to supervise and monitor the down-titration and to collaborate with the study team by signing a "treatment agreement form".
• If the treating psychiatrist refuses to monitor the down-titration, the patient has to agree to down-titrate under supervision of clinicians in the outpatient clinics of the two study sites or trial physicians and to come in for weekly monitoring visits.
• The subjects are abstinent from alcohol (breathalyzer blood alcohol concentration (BAC) level 0.00) and a negative urine drug screen at days of dosing
• The subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• The subject must sign an informed consent form indicating that he/she understands the purpose of and procedures required for the study including peripheral biomarker monitoring (i.e. blood) and is willing to participate in the study.

You may not qualify if:

• Currently comorbid or previously diagnosed DSM-5 diagnosis of a
• major depressive episode with psychotic features/major depressive disorder with psychotic features (ICD-10: F32.3)
• schizophrenia spectrum and other psychotic disorders, including schizotypal (personality) disorders, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance/medication-induced psychotic disorder and psychotic disorder due to another medical condition (ICD-10: F20 - F29)
• bipolar and related disorders (ICD-10: F30/F31)
• cluster A personality disorders (paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder) and/or borderline personality disorder (Patients will be carefully screened for presence of those personality disorders by using the SCID-5-PD)
• Post-traumatic stress disorder (PTSD; ICD-10: F43.1)
• A family history (first-degree relative) of psychosis and/or bipolar disorder
• The subject has a current or recent history of clinically significant suicidal ideation within the past 6 months, corresponding to a score of 4 (active suicidal ideation with some intent to act, without specific plan) or 5 (active suicidal ideation with specific plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior within the past 1 year, as validated by the C-SSRS at screening. Subjects with a prior suicide attempt of any sort, or prior serious suicidal ideation/plan \> 6 months ago, should be carefully screened for current suicidal ideation and only included at the discretion of the investigator.
• Use of classical psychedelics (i.e. LSD, psilocybin, mescaline, dimethyltryptamine) in the past year and or more than five life-time uses of classical psychedelics.
• Failure to establish sufficient rapport with the two therapists as judged by them after the first two preparation sessions
• Lithium intake
• The patient has any disorder for which the treatment takes priority over treatment of depression or is likely to interfere with the study treatment or impair treatment compliance. This includes current signs/symptoms of liver or renal insufficiency, hypothyroidism or hyperthyroidism (subjects who are on stable treatment with thyroid supplementation and show an euthyroid metabolism with normal thyroid-stimulating hormone \[TSH\] may participate), significant cardiac disease (including current or past history of atrial fibrillation/flutter), vascular, pulmonary, endocrine, neurologic (including epilepsy), hematologic, inflammatory (e.g., rheumatoid arthritis, inflammatory bowel disease, Crohn's disease) or metabolic diseases as long as these diseases are not medically controlled or might significantly interfere with participation in the study. Diabetes mellitus (DM) may be allowed when blood glucose is stably controlled (HbA1c less than 7.5% or 58 mmol/mol).
• a. To rule out the presence of any serious neurological condition that might be underlying the depression (e.g. Parkinson's Disease, dementia), patients must provide a recent (i.e. not older than 5 years) brain neuroimaging (MRI or CT). If the clinical manifestation has changed qualitatively or in severity, a more recent neuroimaging is required.
• Women who are pregnant, nursing or refuse to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) throughout their study participation. Women of childbearing potential must have a negative urine pregnancy test at screening and the two dosing days.
• Positive urine drug screen for any illicit drugs of abuse or alcohol at any of the two dosing days. The regular drug screen includes cocaine, amphetamine, opiates, ecstasy, EDDP, cannabinoids, benzodiazepines and barbiturates.

Sponsors & Collaborators

• Central Institute of Mental Health, Mannheim: lead
• Charite University, Berlin, Germany: collaborator
• MIND Foundation gGmbH: collaborator
• German Federal Ministry of Education and Research: collaborator
• Usona Institute: collaborator

Study Sites (2)

Charité Berlin, Campus Mitte, Department of Psychiatry and Psychotherapy

Berlin, 10117, Germany

Location

Central Institute of Mental Health (CIMH)

Mannheim, 68159, Germany

Location

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major

Interventions

Psilocybin; Niacinamide

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Gerhard Gründer, Prof. Dr.

  Central Institute of Mental Health, Mannheim

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2020
• First Posted: December 17, 2020
• Study Start: June 10, 2021
• Primary Completion: February 27, 2024
• Study Completion: December 11, 2024
• Last Updated: January 20, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share

Locations

DE (2)