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Psilocybin Versus Ketamine in Treatment-Resistant Depression (PSIKET_001)

Primary Purpose

Treatment Resistant Depression

Status

Recruiting

Phase

Phase 2

Locations

Czechia

Study Type

Interventional

Intervention

Psilocybin

Ketamine Hydrochloride

Midazolam Ph. Eur 9.0

About this trial

This is an interventional health services research trial for Treatment Resistant Depression

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:
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.
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

Sites / Locations

National Institute of Mental HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Psilocybin

Ketamine

Midazolam

Arm Description

25 mg, orally (capsule), single administration

250 mg, orally (capsule), single administration

5 mg, orally (capsule), single administration

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).

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).

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.

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

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.

Full Information

NCT ID

NCT05383313

First Posted

September 7, 2021

Last Updated

May 16, 2022

Sponsor

National Institute of Mental Health, Czech Republic

Collaborators

Czech Health Research Council, Czech Clinical Research Infrastructure Network

1. Study Identification

Unique Protocol Identification Number

NCT05383313

Brief Title

Psilocybin Versus Ketamine in Treatment-Resistant Depression

Acronym

PSIKET_001

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2021

Overall Recruitment Status

Recruiting

Study Start Date

May 1, 2021 (Actual)

Primary Completion Date

April 30, 2025 (Anticipated)

Study Completion Date

April 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Mental Health, Czech Republic

Collaborators

Czech Health Research Council, Czech Clinical Research Infrastructure Network

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Treatment Resistant Depression

7. Study Design

Primary Purpose

Health Services Research

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Psilocybin

Arm Type

Experimental

Arm Description

25 mg, orally (capsule), single administration

Arm Title

Ketamine

Arm Type

Active Comparator

Arm Description

250 mg, orally (capsule), single administration

Arm Title

Midazolam

Arm Type

Placebo Comparator

Arm Description

5 mg, orally (capsule), single administration

Intervention Type

Drug

Intervention Name(s)

Psilocybin

Intervention Description

Effect of psilocybin on treatment-resistant depression

Intervention Type

Drug

Intervention Name(s)

Ketamine Hydrochloride

Intervention Description

Effect of ketamine on treatment-resistant depression

Intervention Type

Drug

Intervention Name(s)

Midazolam Ph. Eur 9.0

Intervention Description

Effect of midazolam on treatment-resistant depression

Primary Outcome Measure Information:

Title

Verification of the rapid antidepressant effect of Psilocybin compared to Ketamine using the Montgomery-Asberg Depression Rating Scale at 24 hours post administration

Description

The overall score of the Montgomery-Asberg Depression Rating Scale ranges from 0 to 60, a higher score indicates more severe depression.

Time Frame

24 hours post drug administration

Secondary Outcome Measure Information:

Title

Comparing the response rate and duration of antidepressant effects of Psilocybin or Ketamine versus Midazolam (placebo)

Description

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).

Time Frame

At days 3, 7, 14, 21, 28, 35, 42, 56 and 84 post drug administration.

Title

Comparing the remission rate of depression after administration of Psilocybin or Ketamine versus placebo (Midazolam)

Description

Remission (defined as a score of ≤10 on the Montgomery-Asberg Depression Rating Scale).

Time Frame

At days 3, 7, 14, 21, 28, 35, 42, 56 and 84 post drug administration.

Title

Comparing the time to return of depressive symptoms after administration of Psilocybin or Ketamine versus Midazolam (placebo)

Description

Time Frame

At 12 weeks post drug administration.

Title

Incidence of Treatment-Emergent Adverse Events

Description

The safety of the study medications will be assessed by the analysis of the incidence of treatment-emergent adverse events

Time Frame

Through study completion, an average of 1 year.

Title

Comparing the response rate and duration of antidepressant effects of Psilocybin or Ketamine versus Midazolam (placebo) as rated by participants.

Description

Time Frame

At days 1, 3, 7, 14, 21, 28, 35, 42, 56 and 84 post drug administration.

Other Pre-specified Outcome Measures:

Title

Assessment of the antidepressant effect in relation to the acute subjective psychological drug effects

Description

Intesity of subjectively perceived acute psychological drug effects measured by the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC)

Time Frame

At the end of dosing day, cca. 6 hours after drug administration

Title

Assessment of the antidepressant effect in relation to the acute objective psychological drug effects

Description

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".

Time Frame

At the end of dosing day, cca. 6 hours after drug administration

Title

Assessment of the antidepressant effect in relation to the retrospective assessment of persistent effects

Description

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.

Time Frame

At 1, 3, 6 and 12 months post drug administration.

Title

Assessment of the antidepressant effect in relation to the degree of eye contact with negative and neutral emotional faces

Description

Measured by eye-tracking.

Time Frame

Cca. 0.5 hours before and cca. 6 hours after treatment.

Title

Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Psilocin

Description

Plasmatic levels of Psilocin, the major active metabolite of psilocybin will be measured in blood samples drawn from the participants.

Time Frame

1.5 hours after drug administration

Title

Evaluate the neurobiology of the antidepressant effect in relation to plasmatic levels of Brain-Derived Neurotrophic Factor

Description

Changes of plasmatic concentrations of Brain-Derived Neurotrphic Factor (BDNF), a marker of neuroplasticity, will be measured in blood samples drawn from the participants.

Time Frame