Psilocybin Versus Ketamine in Treatment-Resistant Depression

Study Overview
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Brief Summary
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The main goal is to compare the antidepressant effects of psilocybin and ketamine in patients with TRD versus the antidepressant inactive substance midazolam. The primary endpoint will be the antidepressant effect on the Montgomery- Asberg Depression Rating Scale (MADRS) 24 hours after treatment, the key secondary endpoints being the duration of antidepressant effect, the number of responses and remissions, and the time to standard antidepressant treatment during 3 months of observation. The exploratory part of the study aims to monitor changes in the functional brain states using simultaneous EEG / fMRI, before treatment versus 1 day and 1 week after. Based on literature data and recent data from healthy volunteers who participated in a previous study with psilocybin, the investigator will correlate antidepressant effects of drugs (using psychometric scales and reactions to emotionally salient stimuli (eye tracker)) with entropy and functional connectivity measures. Finally the investigator will explore the role of plasmatic neurobiological biomarkers in depression (BDNF, prolactin, ACTH and oxytocin).

Detailed Description
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The main aim of the study is to verify the efficacy and safety of a single dose of psilocybin 20 mg in the treatment of TRD in adults in a randomized clinical trial with active comparator ketamine 200 mg (rapid onset acting antidepressant) and negative control midazolam 5 mg (drug with no antidepressant properties). Primary objective: 1) verification of the rapid antidepressant effect of psilocybin compared to ketamine using the MADRS scale at 24 hours. Secondary objectives: 1) on days 3, 7 and 14 and 3, 4, 5, 6, 8 and 12 weeks after application of the substances, evaluate / compare: a) the duration of effects of both substances using the MADRS scale b) antidepressant effects according to the subjective evaluation of patients - QIDS scale. c) response rate (50% reduction on the MADRS scale) and remission (MADRS ? 10). 2) time to return of depressive symptoms defined according to the criteria for the use of antidepressants within 12 weeks 3) safety profile of study medication Exploratory objectives: 1) Evaluate the antidepressant effect depending on: a) the intensity of acute psychological effects assessed using the subjective scale of 5D-ASCs and the objective scale of BPRS, b) depending on the retrospective assessment of persistent effects using the Persisting effects scale, c) the degree of eye contact with negative and neutral emotion faces measured by eye-tracking before and after treatment (on days 1 and 7). 2) To evaluate the neurobiology of the antidepressant effect in relation to: a) plasma levels of the major metabolite of psilocin, markers of neuroplasticity, antidepressant effect and stress (BDNF, prolactin, oxytocin, ACTH) at 90 min, 3, and 6 h after administration of study medication compared to pre-administration levels, b) changes in resting-state brain activity (connectivity, entropy) measured by simultaneous EEG / fMRI functional imaging methods before and after 1 and 7 days after treatment.

Official Title
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Psilocybin Versus Ketamine - Fast Acting Antidepressant Strategies in Treatment-resistant Depression

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Ketamine Hydrochloride
* Drug: Midazolam Ph. Eur 9.0


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18-65 Diagnosis of moderate to severe depressive disorder without psychotic symptoms - ICD-10 criteria F32.1-2 or F33.1-2 and at the same time MADRS score > 20 The duration of the current depressive episode is at least 3 months and maximum 2 years Treatment-resistant depression defined as: Failure of at least 2 and at most 4 adequate treatments (6 weeks of full therapeutic dose of antidepressant or adequate non-pharmacological treatment - e.g. psychotherapy, neurostimulation treatment, phototherapy, etc.) within the current depressive episode, using at least 2 types of antidepressants with different pharmacological mechanisms of action (augmentation is taken as a second treatment) or Intolerance of 2 different treatments and 1 adequate treatment or Intolerance of 3 different antidepressant treatments. Ability to understand the study protocol and to be able to complete all study visits and examinations as defined per protocol. Participants in a clinical trial of childbearing potential must agree to the use of prescribed contraceptive methods for the duration of the study Exclusion Criteria: Severe psychiatric comorbidity (axis I MINI, ICD-10 F0.X - F99.X, the intensity of the disorder will be clinically assessed by the study clinician) The current depressive phase is severe with psychotic symptoms (ICD-10: F32.3, F33.3) MADRS suicidality score (item 10)> 4 Duration of the current depressive episode longer than 2 years Current drug or alcohol dependence (ICD-10: F17.x) with the exception of tobacco and with the exception of abstinence lasting more than 2 years Claustrophobia, inability to undergo MR examination Pregnancy or breast-feeding or plan to become pregnant within the next 12 months Intracranial hypertension, pulmonary hypertension, uncorrected arterial hypertension (BP> 150/100 mmHg) Condition after stroke, myocardial infarction in the last 6 months Heart failure Untreated or decompensated hyperthyroidism Glaucoma Severe respiratory failure or acute respiratory depression History of seizures Other serious somatic disease or any other circumstance in which a significant increase in blood pressure would pose a serious threat to health (to be assessed by the study clinician) Pacemaker Metal implants made of MR incompatible materials Regular use of medication that could interact with psilocybin (to be assessed by the investigator) Regular use of antipsychotics with 5-HT2A receptor antagonist activity or discontinuation of their use for less than 14 days (eg risperidone, olanzapine, clozapine, quetiapine, ziprasidone) Current use of monoamine oxidase inhibitors (MAOIs) Previous experience with psilocybin, hallucinogenic mushrooms or ketamine is possible in a maximum of 10% of patients. This experience must not be during the last 12 months or during the current depressive episode. Recent use of antidepressants with a direct antagonistic effect on 5-HT2A receptors such as SARI and tetracyclic antidepressants (eg trazodone, mirtazapine, mianserin) or discontinuation of their use for less than 14 days Electroconvulsive therapy in the previous 3 months Daily use of benzodiazepine anxiolytics higher than the equivalent of 10 mg diazepam Allergy to any of the components of study drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin<br>25 mg, orally (capsule), single administration | Drug: Psilocybin<br>* Effect of psilocybin on treatment-resistant depression<br>|
| Active Comparator: Ketamine<br>250 mg, orally (capsule), single administration | Drug: Ketamine Hydrochloride<br>* Effect of ketamine on treatment-resistant depression<br>|
| Placebo Comparator: Midazolam<br>5 mg, orally (capsule), single administration | Drug: Midazolam Ph. Eur 9.0<br>* Effect of midazolam on treatment-resistant depression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verification of the rapid antidepressant effect of Psilocybin compared to Ketamine using the Montgomery-Asberg Depression Rating Scale at 24 hours post administration | The overall score of the Montgomery-Asberg Depression Rating Scale ranges from 0 to 60, a higher score indicates more severe depression. | 24 hours post drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparing the response rate and duration of antidepressant effects of Psilocybin or Ketamine versus Midazolam (placebo) | Response rate defined as a 50% reduction on the Motgomery-Asberg Depression Rating Scale (range 0 to 60, a higher score indicates more severe depression). | At days 3, 7, 14, 21, 28, 35, 42, 56 and 84 post drug administration. | 
| Comparing the remission rate of depression after administration of Psilocybin or Ketamine versus placebo (Midazolam) | Remission (defined as a score of ≤10 on the Montgomery-Asberg Depression Rating Scale). | At days 3, 7, 14, 21, 28, 35, 42, 56 and 84 post drug administration. | 
| Comparing the time to return of depressive symptoms after administration of Psilocybin or Ketamine versus Midazolam (placebo) | Return of depressive symptoms as defined by the clinical need to prescribe antidepressant medication by the study clinician. Criteria for the prescription of antidepressant medication are defined in the study protocol. | At 12 weeks post drug administration. | 
| Incidence of Treatment-Emergent Adverse Events | The safety of the study medications will be assessed by the analysis of the incidence of treatment-emergent adverse events | Through study completion, an average of 1 year. | 
| Comparing the response rate and duration of antidepressant effects of Psilocybin or Ketamine versus Midazolam (placebo) as rated by participants. | Assessment via the Quick Inventory of Depressive Symptomatology (QIDS) which rates depression symptoms via self-assessment. Total QIDS scores range from 0 to 27 with higher scores indicating more severe depression. | At days 1, 3, 7, 14, 21, 28, 35, 42, 56 and 84 post drug administration. |