Psilocybin Versus Ketamine in Treatment-Resistant Depression (PSIKET_001)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Treatment Resistant Depression
• Intervention / Treatment: Drug: Psilocybin; Drug: Ketamine Hydrochloride; Drug: Midazolam Ph. Eur 9.0

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Vivian Winkler, MD; Phone Number: +420773137373; Email: vivian.winkler@nudz.cz
• Study Contact Backup: Name: Nikola Leca, PhD; Phone Number: +420608049831; Email: nikola.leca@nudz.cz

Study Locations

• Czechia
  • Klecany, Czechia, 250 67
    • Recruiting
    • National Institute of Mental Health
    • Contact: Vivian Winkler, MD; Phone Number: 773137373; Email: vivian.winkler@nudz.cz
    • Contact: Nikola Leca, PhD; Phone Number: 608049831; Email: nikola.leca@nudz.cz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women aged 18-65
2. 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
3. The duration of the current depressive episode is at least 3 months and maximum 2 years

4. Treatment-resistant depression defined as:

   1. 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
   2. Intolerance of 2 different treatments and 1 adequate treatment or
   3. Intolerance of 3 different antidepressant treatments.
5. Ability to understand the study protocol and to be able to complete all study visits and examinations as defined per protocol.
6. 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:

1. 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)
2. The current depressive phase is severe with psychotic symptoms (ICD-10: F32.3, F33.3)
3. MADRS suicidality score (item 10)> 4
4. Duration of the current depressive episode longer than 2 years
5. 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
6. Claustrophobia, inability to undergo MR examination
7. Pregnancy or breast-feeding or plan to become pregnant within the next 12 months
8. Intracranial hypertension, pulmonary hypertension, uncorrected arterial hypertension (BP> 150/100 mmHg)
9. Condition after stroke, myocardial infarction in the last 6 months
10. Heart failure
11. Untreated or decompensated hyperthyroidism
12. Glaucoma
13. Severe respiratory failure or acute respiratory depression
14. History of seizures
15. 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)
16. Pacemaker
17. Metal implants made of MR incompatible materials
18. Regular use of medication that could interact with psilocybin (to be assessed by the investigator)
19. 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)
20. Current use of monoamine oxidase inhibitors (MAOIs)
21. 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.
22. 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
23. Electroconvulsive therapy in the previous 3 months
24. Daily use of benzodiazepine anxiolytics higher than the equivalent of 10 mg diazepam
25. Allergy to any of the components of study drugs

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the antidepressant effect in relation to the acute subjective psychological drug effects	Intesity of subjectively perceived acute psychological drug effects measured by the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC)	At the end of dosing day, cca. 6 hours after drug administration
Assessment of the antidepressant effect in relation to the acute objective psychological drug effects	Intesity of objectively perceived acute psychological drug effects measured by the Brief Psychiatric Rating Scale (BPRS). The BPRS consists of 18 items measuring the following factors: (1) anxiety, (2) emotional withdrawal, (3) conceptual disorganization, (4) guilt feelings, (5) tension, (6) mannerisms and posturing, (7) grandiosity, (8) depressive moods, (9) hostility, (10) suspiciousness, (11) hallucinatory behavior, (12) motor hyperactivity, (13) uncooperativeness, (14) unusual thought content, (15) blunted affect, (16) somatic concern, (17) excitement, and (18) disorientation. It uses a seven-item Likert scale with the following values: 1 = "not present", 2 = "very mild", 3 = "mild", 4 = "moderate", 5 = "moderately severe", 6 = "severe", 7 = "extremely severe".	At the end of dosing day, cca. 6 hours after drug administration
Assessment of the antidepressant effect in relation to the retrospective assessment of persistent effects	Persistent effects are measured by the Persistent Effects Questionnaire (A 143-item questionnaire detects information about changes in attitudes, moods, behavior, and spiritual experience that, on the basis of prior research (Pahnke 1969; Doblin 1991, Griffiths et al. 2006), is sensitive to the effects of psilocybin a month after the session.	At 1, 3, 6 and 12 months post drug administration.
Assessment of the antidepressant effect in relation to the degree of eye contact with negative and neutral emotional faces	Measured by eye-tracking.	Cca. 0.5 hours before and cca. 6 hours after treatment.
Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Psilocin	Plasmatic levels of Psilocin, the major active metabolite of psilocybin will be measured in blood samples drawn from the participants.	1.5 hours after drug administration
Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Brain-Derived Neurotrophic Factor	Changes of plasmatic concentrations of Brain-Derived Neurotrphic Factor (BDNF), a marker of neuroplasticity, will be measured in blood samples drawn from the participants.	Before drug administration (cca. 0.5 hours), then 1.5, 3 and 6 hours after drug administration.
Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Prolactine	Changes of plasmatic concentrations of Prolactine, a marker of neuroplasticity, will be measured in blood samples drawn from the participants.	Before drug administration (cca. 0.5 hours), then 1.5, 3 and 6 hours after drug administration.
Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Oxytocine	Changes of plasmatic concentration of Oxytocine, a marker of antidepressive effects, will be measured in blood samples drawn from the participants.	Before drug administration (cca. 0.5 hours), then 1.5, 3 and 6 hours after drug administration.
Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Adenocorticotropic Hormone.	Changes of plasmatic concentration of Adenocorticotropic Hormone (ACTH), a marker of stress, will be measured in blood samples drawn from the participants.	Before drug administration (cca. 0.5 hours), then 1.5, 3 and 6 hours after drug administration.
Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Cortisol	Changes of plasmatic concentration of Cortisol, a hormonal marker of stress, will be measured in blood samples drawn from the participants.	Before drug administration (cca. 0.5 hours), then 1.5, 3 and 6 hours after drug administration.
Evaluate the neurobiology of the antidepressant effect in relation to changes in resting state activity (connectivity, entropy) of the brain before and after drug administration.	Resting state activity will be evaluated by simultaneous fMRI + EEG.	Before (approx. 7 days) and after drug administration (1 and 7 days)

Collaborators and Investigators

• Sponsor: National Institute of Mental Health, Czech Republic
• Collaborators: Czech Health Research Council; Czech Clinical Research Infrastructure Network

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2021
• Primary Completion (Anticipated): April 30, 2025
• Study Completion (Anticipated): April 30, 2025

Study Registration Dates

• First Submitted: September 7, 2021
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 20, 2022

Study Record Updates

• Last Update Posted (Actual): May 20, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Hallucinogens; Ketamine; Midazolam; Psilocybin
• Other Study ID Numbers: PSIKET_001CZE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No