Psilocybin-Assisted Therapy for Treatment-Resistant Depression in Bipolar II Disorder (PAT-BD-01)

Psilocybin-Assisted Therapy for Treatment-Resistant Depression in Bipolar II Disorder: A Randomized Controlled Trial

This study is a 12-week (in addition to up to 30 days of screening) randomized, double-blind, placebo-controlled, parallel-group trial. The primary objective of this study is to assess the effectiveness, safety, and tolerability of single-dose psilocybin (25 mg)-assisted therapy in comparison to active placebo (1 mg micro-dose) psilocybin-assisted therapy in patients with bipolar II depression who have not responded to adequate trials with at least two first or second-line treatments for bipolar II depression (i.e. quetiapine, lithium, lamotrigine, sertraline, or venlafaxine as monotherapy or adjunctive therapy, or bupropion adjunctive therapy). The active placebo is a substance that looks identical to the study medication but contains less therapeutic ingredients, and thus is less capable of producing the transformative and meaningful aspects of psychedelic experience compared to the 25 mg dose. Participants will have a total of 11 study visits over a period of up to 16 weeks, which includes 5 therapy sessions from trained study therapists.

Study Overview

• Status: Not yet recruiting
• Conditions: Bipolar II Depression
• Intervention / Treatment: Drug: psilocybin (25 mg); Drug: psilocybin 1mg micro-dose

Detailed Description

Bipolar disorders (BD) are lifelong conditions characterized by recurrent episodes of depression and (hypo)mania. Statistics Canada data indicate over a million Canadians are affected by this illness. Bipolar II disorder is characterised by recurrent episodes of hypomania and depression and individuals with BD-II are symptomatic about 50% of the time despite treatment. The majority of this time is spent being depressed thus there is an urgent need to develop new treatments that are safe and effective. Psilocybin, a naturally occurring psychedelic compound found in mushrooms, has been noted to result in an increase in psychological well-being in healthy volunteers as well as have antidepressant effects when administered in conjunction with psychological support. Two recent open-label pilot trials of Psilocybin-Assisted Therapy (PAT) in treatment-resistant depression, including BD-II participants, demonstrated high response rates and excellent tolerability, thereby providing strong justification for the current study.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Vy Ngo, B.Sc; Phone Number: 604-822-3769; Email: vy.ngo@ubc.ca
• Study Contact Backup: Name: Nazlin Walji, B.Sc, CCRC; Phone Number: 604-822-7294; Email: nazlin.walji@ubc.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 1Z3
      • Djavad Mowafaghian Centre for Brain Health
      • Contact: Vy Ngo; Phone Number: 604-822-3769; Email: vy.ngo@ubc.ca
      • Contact: Nazlin Walji; Phone Number: 604-822-7294; Email: nazlin.walji@ubc.ca
      • Principal Investigator: Dr. Lakshmi Yatham
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Department of Psychiatry, University of Ottawa, The Ottawa Hospital
      • Contact: Joseph Burns; Phone Number: 613-798-5555; Email: josburns@ohri.ca
      • Principal Investigator: Dr. Gayatri Saraf, MD
    • Toronto, Ontario, Canada, M5T 2S8
      • Department of Psychiatry, University of Toronto, University Health Network,
      • Contact: Zoe Doyle; Phone Number: 437-727-2252; Email: zoe.doyle@uhn.ca
      • Principal Investigator: Dr. Joshua Rosenblat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. You are male or female aged 19 to 65 years inclusive.
2. You have a diagnosis of bipolar disorder type II, and are currently in a major depressive episode.
3. You are willing, for the entire duration of the study, to practice highly effective methods of contraception (e.g., contraceptive pills, intrauterine device or system, vasectomy and tubal ligation, or double-barrier methods of contraception) OR agree to completely abstain from heterosexual intercourse. Females who do not have childbearing potential are required to be postmenopausal for at least 1 year before the screening visit (confirmed by an FSH test) OR surgically sterile.
4. You have sufficient English language skills to understand, consent to, and comply with study requirements, study visits, and to return to the clinic for follow-up evaluations.
5. Your current medications have been at a stable dose for two weeks prior to the dosing visit.

Exclusion Criteria:

1. You have a history of psychotic symptoms.
2. You have a history of seizures.
3. You have a current unstable or inadequately treated medical illness, especially cardiovascular illness, except for the current depression.
4. You recently (i.e., within the past 6 weeks) started taking treatment for your acute bipolar depressive episode.
5. You recently (i.e., within the past 8 weeks) began structured psychotherapy (e.g., cognitive-behavioral therapy, interpersonal psychotherapy, family-focused therapy, or interpersonal and social rhythm therapy).
6. You have a history of nonresponse or intolerance to psilocybin.
7. You have, in the past 6 months, used any psychedelic drugs, including ketamine, LSD, or psilocybin-containing mushrooms.
8. You have a history of non-response to electroconvulsive therapy.
9. You are pregnant or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active; 25 mg psilocybin.	Drug: psilocybin (25 mg); Single-dose psilocybin (25 mg)-assisted therapy (PAT)
Placebo Comparator: Placebo; 1 mg psilocybin (micro-dose)	Drug: psilocybin 1mg micro-dose; Single dose active placebo psilocybin-assisted therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in depressive symptoms	The Montgomery Asberg Depression Rating Scale (MADRS) will be used to measure change in depressive symptoms. Scores range from 0 to 60, and lower scores reflect better clinical outcomes.	Baseline to Week 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rates	Patients showing ≥50% reduction in the Montgomery Asberg Depression Rating Scale (MADRS) scores from Baseline. Scores range from 0 to 60, and lower scores reflect better clinical outcomes.	Week 3, Week 6, Week 12
Remission Rates	Defined as Montgomery Asberg Depression Rating Scale (MADRS) scores ≤ 10 and Young Mania Rating Scale (YMRS) scores ≤ 8. Scores for the MADRS range from 0 to 60, with lower scores reflecting better clinical outcomes. Scores for the YMRS range from 0 to 60, with lower scores reflecting better clinical outcomes.	Endpoint
Treatment-emergent manic/hypomanic events	The Young Mania Rating Scale (YMRS) will be used to determine the presence of any treatment-emergent manic or hypomanic events from baseline to endpoint. Scores range from 0 to 60, and lower scores reflect better clinical outcome	12 weeks
Mean change in depressive symptoms	The Montgomery Asberg Depression Rating Scale (MADRS) will be used to measure mean change in depressive symptoms. Scores range from 0 to 60, and lower scores reflect better clinical outcomes.	Week 6 and 12
Subjective depressive symptoms	The Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) will be used to measure change in subjective depressive symptoms from baseline to endpoint. Scores on the QIDS-SR range from 0 to 27; lower scores on the QIDS-SR reflect better clinical outcomes.	12 weeks
Symptoms of anhedonia	The Snaith-Hamilton Pleasure Scale (SHAPS) will be used to measure change in subjective symptoms of anhedonia from baseline to endpoint. Scores on the SHAPS range from 0 to 42; higher SHAPS scores indicate a reduced ability to experience pleasure and reduced capacity to feel pleasure.	12 weeks
Objective anxiety symptoms	The Hamilton Anxiety Rating Scale (HAM-A) will be used to measure change in objective anxiety symptoms from baseline to endpoint. Scores range from 0 to 56 and lower scores reflect better clinical outcomes.	12 weeks
Overall psychiatric status	The Clinical Global Impression - severity & change scales will be used to measure change in global severity and global improvement in symptoms from baseline to endpoint. Scores range from 3 to 42, and higher scores reflect worsening in overall psychiatric status.	12 weeks
Psychotic symptoms	The Positive and Negative Syndrome Scale (PANSS) will be used to measure change in psychotic symptoms from baseline to endpoint. Scores range from 7 to 49, and lower scores reflect better clinical outcomes.	12 weeks
Subjective cognitive functioning	The Cognitive Complaints in Bipolar Disorder Risk Assessment (COBRA) scale will be used to measure change in subjective cognitive functioning from baseline to endpoint. COBRA scores range from 0 to 48, and lower scores reflect better outcomes.	12 weeks
Objective cognitive functioning	The Screen for Cognitive Impairment in Psychiatry (SCIP) will be used to measure change in objective cognitive functioning from baseline to endpoint. Higher scores reflect better outcomes.	12 weeks
Sleep quality	The Pittsburgh Sleep Quality Index (PSQI) will be used to measure changes in sleep quality and disturbance from baseline to endpoint. Lower scores reflect better sleep quality.	12 weeks
Quality of Life assessed by QoL.BD	The Brief Quality of Life in Bipolar Disorder (QoL.BD) will be used to measure change in quality of life from baseline to endpoint. Higher scores reflect higher quality of life.	12 weeks
Daily functioning	The Functioning Assessment Short Test (FAST) will be used to measure change in daily functioning from baseline to endpoint. Scores range from 0 to 72 with lower scores reflecting better daily functioning.	12 weeks
Suicidal thoughts and behaviours	The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to measure change in suicidal thoughts and behaviours from baseline to endpoint. Scores range from 0 to 37, and lower scores reflect better clinical outcomes.	12 weeks
MEQ30	Psychedelic experience will be measured by the MEQ30. Scores range from 30 to 150; higher scores reflect stronger (more profound) experiences.	Dosing Visit (Day 0)
Clinician's perspective on the therapeutic relationship	The Therapeutic Relationship will be measured with the Scale to Assess the Therapeutic Relationship - Clinician version (STAR-C). Scores range from 0 to 48 respectively; higher scores reflect better therapeutic relationships.	Baseline and Week 1
Patient's perspective on the therapeutic relationship	The Therapeutic Relationship will be measured with the Scale to Assess the Therapeutic Relationship - Patient version (STAR-P). Scores range from 0 to 48 respectively; higher scores reflect better therapeutic relationships.	Baseline and Week 1

Collaborators and Investigators

• Sponsor: Lakshmi N Yatham
• Investigators: Principal Investigator: Dr. Lakshmi N Yatham, UBC Department of Psychiatry

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: April 1, 2025
• First Submitted That Met QC Criteria: April 17, 2025
• First Posted (Actual): April 24, 2025

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Mood Disorder; Bipolar Disorder; Treatment resistant; Psilocybin; Psychedelics; Psychedelic-assisted therapy
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Mental Disorders; Behavioral Symptoms; Behavior; Depression; Bipolar Disorder; Mood Disorders; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin
• Other Study ID Numbers: H25-00074

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