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Does Psilocybin Require Psychedelic Effects to Treat Depression? (PSI-RIS)

Primary Purpose

Treatment-resistant Depression

Status
Recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Psilocybin 25 mg
Risperidone 1 MG
Placebo
Sponsored by
Centre for Addiction and Mental Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Treatment-resistant Depression focused on measuring Psilocybin, Psychedelics, Treatment-resistant depression, Clinical trial

Eligibility Criteria

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

Inclusion Criteria: Outpatient adults 18 to 65 years old; Able to provide informed consent and read and communicate in English; Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the Structured Clinical Interview for DSM-5 (SCID-5); Diagnosis of treatment-resistant depression defined as a baseline HamD-17 score > 14 and have not responded to two or more separate trials of antidepressants at an adequate dosage and duration; Ability to take oral medication; All bloodwork within normal limits and an eGFR above 40mL/min/1.73m2; Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation; Willing to and have tapered off current antidepressant and antipsychotic medications for a minimum of 2-weeks (or more depending on the medication) prior to baseline and for the duration of the study and whose physician confirms that it is safe for them to do so; AND Willing to and have tapered off current inhibitors of 5'-diphospho-glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase inhibitors (ALDHs) and alcohol dehydrogenase inhibitors (ADHs) for a minimum of 2-weeks (or more depending on the medication) prior to baseline and for the duration of the study and whose physician confirms that it is safe for them to do so; Exclusion Criteria: Pregnant or individual's that intend to become pregnant during the study or are breastfeeding; Treatment with another investigational drug or other intervention within 30 days of screening; Have initiated psychotherapy in the preceding 12 weeks prior to screening; Have a DSM-5 diagnosis of substance use disorder (recreational use of tobacco, alcohol, cannabis and prescribed opioids are permitted) within the preceding 6-months; Have active suicidal ideation with intent and plan as determined by item 3 of the HamD-17; Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder, obsessive-compulsive disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history and the SCID-5 clinical interview; Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder; Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment; Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors; History of allergy or contraindication to risperidone including insulin-dependent diabetes, history of hypoglycemia on oral hypoglycemic agent(s) Lifetime use of serotonergic psychedelic drugs; OR Any other clinically significant physical illness including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.

Sites / Locations

  • Centre for Addiction and Mental HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Risperidone 1 mg plus Psilocybin 25 mg

Placebo plus Psilocybin 25 mg

Risperidone 1 mg plus Placebo

Arm Description

Outcomes

Primary Outcome Measures

Feasibility of administering psilocybin (25mg) with risperidone (1mg)
Percentage of participants recruited, randomized, and retained.
Tolerability and safety of administering psilocybin (25mg) with risperidone (1mg)
Frequency of dropouts attributed to adverse effects or serious adverse events

Secondary Outcome Measures

Subjective psychedelic effects as measured by the 5-Dimensional Altered States of Consciousness (5D-ASC) Rating Scale
A visual analogue scale (0-100 millimeters in length) with higher scores indicating more intense effects.

Full Information

First Posted
January 24, 2023
Last Updated
August 22, 2023
Sponsor
Centre for Addiction and Mental Health
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1. Study Identification

Unique Protocol Identification Number
NCT05710237
Brief Title
Does Psilocybin Require Psychedelic Effects to Treat Depression?
Acronym
PSI-RIS
Official Title
Does Psilocybin Require Psychedelic Effects to Treat Depression? A 4-Week, Double-Blind, Proof-of-Concept Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2023 (Actual)
Primary Completion Date
February 2026 (Anticipated)
Study Completion Date
February 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre for Addiction and Mental Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Psilocybin, the chemical component of "magic mushrooms", has been administered with psychotherapy in several randomized clinical trials (RCTs) showing large and sustained antidepressant effects. In healthy volunteers, the psychedelic effects of psilocybin have been shown to be blocked by administration of serotonin (5HT)2A receptor antagonists such as risperidone. The purpose of this "double dummy" proof-of-concept trial is to evaluate whether psilocybin's antidepressant effects are dependent on its psychedelic effects. Sixty participants with treatment-resistant depression will be randomly assigned to one of three groups: 1) Psilocybin 25 mg plus risperidone 1 mg; 2) Psilocybin 25 mg plus placebo; and 3) Placebo plus risperidone 1 mg. The investigator's hypothesize that the combination of psilocybin and risperidone will be well tolerated, safe, and will block the psychedelic effects of psilocybin in patients diagnosed with treatment-resistant depression.
Detailed Description
This study is a three-arm, 4-week, double blind, proof-of concept RCT for investigating psilocybin-assisted psychotherapy (PAP) administered with risperidone in treating TRD. This three-arm "double dummy" design allows for an assessment of risperidone's anti-psychedelic effects, while allowing for an assessment of psilocybin's antidepressant effects alone and combined with risperidone, compared to an "active placebo" (i.e. placebo plus risperidone 1 mg). Overview of Study Design: A study team member will obtain informed consent from interested participants prior to study activities being initiated. Following this, participants will undergo a screening assessment where they will complete lab tests, and clinical and psychiatric assessments to determine eligibility. Following the screening visit, eligible participants will undergo a washout period where they will be tapered off concomitant medication over a period of 4 to 6 weeks. The length of the tapering period will depend on the type of medication the participant is being tapered off (based on the half-life of the medication) and the participant's preference for the length of the tapering period. Most medications will require a minimum of a 2-week tapering period before the baseline, with the exception of fluoxetine, which will require a minimum of 4-weeks. Additional time may be added at the discretion of the study investigator. During the tapering period, the study psychiatrist will see participants weekly (V1a, V1b, etc.) for at least 4 weeks to monitor for withdrawal and worsening of depressive symptoms and suicidality. Suicidality will be closely monitored using the Columbia Suicide Severity Rating Scale (C-SSRS). Participants and their family members/carers will be educated on the signs and symptoms of worsening depression and suicidality and will be given contact details of the study team in case of major decline in mental state. At the Baseline visit (V2), which occurs the day before the dosing session, participants will complete clinical measures, and undergo a 2-hour preparatory session with the study therapists. These sessions will build a therapeutic alliance, provide psychoeducation about, and set intentions for, the psilocybin session. To reduce participant burden, baseline can be broken up into multiple days, however all assessments must be completed within 7-days of the intervention. Ideally, baseline occurs the day before the intervention is administered. The psilocybin session (Day 0 [V3]) will last 5 to 6 hours and will be conducted in the existing psychedelic treatment suite developed at the Centre for Addiction and Mental Health (CAMH) Mood Disorder Service by Dr. Husain (PI). Two trained study therapists will be supporting each participant during the dosing session. Participants will receive psilocybin 25 mg plus risperidone 1 mg, or psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 10 hours of manualized supportive psychotherapy (which includes the 5-6 hour dosing session). After 5 hours of dose administration, participants will be evaluated for safety by the study psychiatrist and discharged home in the company of a caregiver or a family member. After the dosing session, participants will be seen for two 1-hour integration sessions (Day 1 [V4], Week 1 [V5]). Thereafter, participants will be followed-up after 2 [V6], 3 [V7] and 4 weeks [V8] post-dosing (see Figure 1). A study psychiatrist will be available throughout the duration of the RCT to respond to any concerns or changes in mental/physical state. Participants will not start other interventions for MDD during the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Treatment-resistant Depression
Keywords
Psilocybin, Psychedelics, Treatment-resistant depression, Clinical trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Patients, their families, the study investigator, study therapists, and research assistants carrying out assessments will be concealed from allocation.
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Risperidone 1 mg plus Psilocybin 25 mg
Arm Type
Experimental
Arm Title
Placebo plus Psilocybin 25 mg
Arm Type
Experimental
Arm Title
Risperidone 1 mg plus Placebo
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Psilocybin 25 mg
Intervention Description
The psilocybin used in this study meets quality specifications suitable for human research use. The active drug is encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin. The psilocybin will be administered once during the trial in combination with either risperidone 1 mg or place. It will also be administered in conjunction with supportive therapy.
Intervention Type
Drug
Intervention Name(s)
Risperidone 1 MG
Intervention Description
The risperidone is encapsulated using a cellulose capsule and contains 1 mg of risperidone. The risperidone will be administered once during the trial in combination with either psilocybin 25 mg or placebo. It will also be administered with supportive therapy.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg.
Primary Outcome Measure Information:
Title
Feasibility of administering psilocybin (25mg) with risperidone (1mg)
Description
Percentage of participants recruited, randomized, and retained.
Time Frame
4 weeks
Title
Tolerability and safety of administering psilocybin (25mg) with risperidone (1mg)
Description
Frequency of dropouts attributed to adverse effects or serious adverse events
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Subjective psychedelic effects as measured by the 5-Dimensional Altered States of Consciousness (5D-ASC) Rating Scale
Description
A visual analogue scale (0-100 millimeters in length) with higher scores indicating more intense effects.
Time Frame
Visit 3 (Day 0)
Other Pre-specified Outcome Measures:
Title
Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from Baseline to 1-week post-treatment.
Description
The Montgomery-Åsberg Depression Rating Scale is a clinician-rated scale that measures depression severity. It is 10-items which are scored from 0 (not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.
Time Frame
Baseline (Day -1) to visit 5 (Day 7)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Outpatient adults 18 to 65 years old; Able to provide informed consent and read and communicate in English; Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the Structured Clinical Interview for DSM-5 (SCID-5); Diagnosis of treatment-resistant depression defined as a baseline HamD-17 score > 14 and have not responded to two or more separate trials of antidepressants at an adequate dosage and duration; Ability to take oral medication; All bloodwork within normal limits and an eGFR above 40mL/min/1.73m2; Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation; Willing to and have tapered off current antidepressant and antipsychotic medications for a minimum of 2-weeks (or more depending on the medication) prior to baseline and for the duration of the study and whose physician confirms that it is safe for them to do so; AND Willing to and have tapered off current inhibitors of 5'-diphospho-glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase inhibitors (ALDHs) and alcohol dehydrogenase inhibitors (ADHs) for a minimum of 2-weeks (or more depending on the medication) prior to baseline and for the duration of the study and whose physician confirms that it is safe for them to do so; Exclusion Criteria: Pregnant or individual's that intend to become pregnant during the study or are breastfeeding; Treatment with another investigational drug or other intervention within 30 days of screening; Have initiated psychotherapy in the preceding 12 weeks prior to screening; Have a DSM-5 diagnosis of substance use disorder (recreational use of tobacco, alcohol, cannabis and prescribed opioids are permitted) within the preceding 6-months; Have active suicidal ideation with intent and plan as determined by item 3 of the HamD-17; Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder, obsessive-compulsive disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history and the SCID-5 clinical interview; Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder; Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment; Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors; History of allergy or contraindication to risperidone including insulin-dependent diabetes, history of hypoglycemia on oral hypoglycemic agent(s) Lifetime use of serotonergic psychedelic drugs; OR Any other clinically significant physical illness including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
M. Ishrat Husain, MBBS, MD (Res.)
Phone
4165358501
Ext
37838
Email
Ishrat.Husain@camh.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Alexandria Coles, MSc
Phone
4165358501
Ext
33180
Email
psychedelics.research@camh.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
M. Ishrat Husain, MBBS, MD
Organizational Affiliation
Centre for Addiction and Mental Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre for Addiction and Mental Health
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M6J1H4
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alex Coles, MSc
Phone
4165503940
Ext
33180
Email
psychedelics.research@camh.ca
First Name & Middle Initial & Last Name & Degree
M. Ishrat Husain, MBBS, MD (Res.)

12. IPD Sharing Statement

Plan to Share IPD
No

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Does Psilocybin Require Psychedelic Effects to Treat Depression?

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