Clinical TrialTreatment-Resistant Depression (TRD)PsilocybinKetaminePlaceboRecruiting

Psilocybin versus ketamine – fast acting antidepressant strategies in treatment-resistant depression

Randomised, double‑blind, parallel group Phase II trial (n=60) comparing a single oral dose of psilocybin 25 mg versus ketamine 250 mg and midazolam 5 mg in patients with treatment‑resistant depression, primary endpoint MADRS at 24 hours.

Target Enrollment
60 participants
Study Type
Phase II interventional
Design
Randomized, double Blind

Detailed Description

A single‑site, randomised, double‑blind, parallel group trial enrolling 60 patients with treatment‑resistant moderate to severe depression to compare rapid antidepressant effects of psilocybin (25 mg), ketamine hydrochloride (250 mg) and an antidepressant‑inactive midazolam control (5 mg), assessed primarily by MADRS at 24 hours.

Secondary outcomes include duration of antidepressant effect at multiple timepoints up to 12 weeks (MADRS, QIDS), response and remission rates, time to relapse, and safety measures including vital signs, BPRS, psilocin levels and persistent effects scales.

Study Protocol

Preparation

sessions

Dosing

1 sessions

Integration

sessions

Study Arms & Interventions

Psilocybin 25 mg

experimental

Single oral dose psilocybin 25 mg given to patients with treatment‑resistant depression.

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total

Ketamine 250 mg

active comparator

Single oral dose ketamine hydrochloride 250 mg as active comparator.

Interventions

  • Ketamine250 mg
    via Oral• single dose• 1 doses total

Midazolam 5 mg

inactive

Single oral midazolam 5 mg used as antidepressant‑inactive control.

Interventions

  • Placebo5 mg
    via Oral• single dose• 1 doses total

    Midazolam 5 mg (antidepressant‑inactive comparator)

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • 1) Men and women aged 18–65.
  • 2) Diagnosis of moderate to severe depressive episode without psychotic symptoms (ICD‑10 F32.1–2 or F33.1–2) and MADRS score > 20.
  • 3) Duration of current depressive episode ≥3 months and ≤2 years.
  • 4) Treatment‑resistant depression defined as failure of ≥2 and ≤4 adequate treatments (or specified combinations/intolerances) during the current episode.
  • 5) Ability to understand protocol and attend all visits.
  • 6) Have a designated caregiver able to be in contact 5× weekly.
  • 7) Participants of childbearing potential must agree to reliable contraception during the study.

Exclusion Criteria

  • 1) Serious psychiatric comorbidity (Axis I MINI, ICD‑10 F0x–F99x, as assessed clinically).
  • 2) Current depressive episode with psychotic symptoms (ICD‑10 F32.3, F33.3).
  • 3) MADRS suicidality item (item 10) > 4.
  • 4) Suicide attempt within the last 6 months.
  • 5) Current episode duration > 2 years.
  • 6) Current drug or alcohol dependence (except tobacco) unless abstinent >2 years.
  • 7) Claustrophobia or inability to undergo MRI.
  • 8) Pregnancy, breastfeeding or plan to become pregnant within 3 months.
  • 9) Intracranial hypertension, pulmonary hypertension, uncontrolled arterial hypertension (BP >150/100 mmHg).
  • 10) Recent stroke or myocardial infarction (last 6 months); heart failure.
  • 11) Untreated or decompensated hyperthyroidism.
  • 12) Glaucoma.
  • 13) Severe respiratory failure or acute respiratory depression.
  • 14) History of seizures.
  • 15) Any other serious somatic disease posing risk with BP rise (assessed clinically).
  • 16) Pacemaker or MR‑incompatible metal implants.
  • 17) Regular use of medications that could interact with psilocybin (assessed by investigator).
  • 18) Current MAOI use (must be discontinued with taper ≥14 days prior to dosing).
  • 19) Prior experience with psilocybin, hallucinogenic mushrooms or ketamine permitted in ≤10% of patients, not within past 12 months or current episode.
  • 20) Recent antidepressant/antipsychotic or 5‑HT2A‑antagonist drugs unless tapered ≥7 days prior to dosing.
  • 21) ECT in previous 3 months; rTMS in previous 4 weeks.
  • 22) Daily benzodiazepine use > diazepam 10 mg equivalent.
  • 23) Allergy to study drug components.

Study Details

Locations

Czechia

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