Neurobiological Effects of Psilocybin in Treatment Resistant Bipolar Depression

NCT06506019 | Recruiting Phase 1 DMC

• 1 other identifier: 22-5067
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This study is an open-label, single-arm, proof-of-concept study, wherein treatment resistant bipolar depression (TRBD) participants will receive one 25 mg dose of oral psilocybin accompanied by preparatory, monitoring, and integration psychotherapy sessions (psilocybin-assisted psychotherapy, or PAP). Using fMRI (functional magnetic resonance imaging), the findings of this study will provide data on the neurobiological mechanism of psilocybin in TRBD. The primary objective is to understand the dynamic role of amygdala activity by evaluating the neurobiological effects of a single psychedelic dose (25 mg) of oral psilocybin in individuals with a moderate to severe major depressive episode and a primary diagnosis of Bipolar II Disorder, with 2 or more failed treatment trials (i.e., treatment resistant bipolar depression \[TRBD\]). Neurobiological effects will be determined by evaluating the association between post-treatment right amygdala activity during the facial affect task (determined by fMRI one day after the psilocybin dose) and antidepressant effects (determined by changes in the Montgomery-Åsberg Depression Rating Scale \[MADRS\] scores over time, during the one-week period post-psilocybin dose). This is a single-arm, open-label clinical trial wherein all participants will receive the same study intervention. Hypothesis: Increased right amygdala activity on fMRI with emotional stimuli one day after psilocybin treatment will be associated with greater antidepressant effects in the one-week period post-treatment in individuals with TRBD.

Conditions

Bipolar Depression

Keywords

Depression; Bipolar Disorder; Bipolar Depression; Treatment-Resistant Depression; Psilocybin; Psychedelics; Psychotherapy; fMRI; Bipolar Disorder II; Bipolar Disorder 2; Psilocybin-Assisted Psychotherapy

Outcome Measures

Primary Outcomes (4)

• Correlation of Amygdala Activity on fMRI with MADRS Score

  Correlation between changes in the right amygdala signal activity on fMRI during negative emotional stimuli in the facial affect task before and after psilocybin dosing will be evaluated in relation to change in MADRS score.

  Baseline to 1 and 4 weeks post psilocybin dosing

• Change in Depression Symptoms

  Depression symptoms will be evaluated using change in Montgomery-Åsberg Depression Rating Scale (MADRS) score, a clinician-administered depression severity rating scale where higher scores indicate greater severity of depression symptoms on a scale of 0-60.

  Baseline to 4 weeks post psilocybin dosing

• Clinical Global Impressions Scale (CGI)

  Clinician judgement of illness severity and improvement on a seven-point Likert scale, ranging from "Normal, not at all depressed" to "Among the most extremely depressed patients" and "Very much improved" to "Very much worse". The CGI is evaluated on a scale from 0-30.

  Baseline to 1 week post psilocybin dosing

• Study Recruitment and Retention Rates

  Evaluating study feasibility based on recruitment and retention rates

  Washout period to 4 week post psilocybin dosing

Secondary Outcomes (7)

• Self-Reported Depression Symptoms

  Baseline to 4 weeks post psilocybin dosing

• Self-Reported Anxiety Symptoms

  Baseline to 4 weeks post psilocybin dosing

• Subjective Functioning

  Baseline to 4 weeks post psilocybin dosing

• Self-Reported Quality of Life

  Baseline to 4 weeks post psilocybin dosing

• Self-Reported Rapid Changes in Depression Symptoms

  Baseline to 4 weeks post psilocybin dosing

Other Outcomes (8)

• Self-Reported Mystical Experience

  Immediately post psilocybin dosing

• Self-Reported Anhedonia Symptoms and Reward Thinking

  Baseline to 4 weeks post psilocybin dosing

• Psychomotor Speed, Visual search, and Attention

  Baseline to 4 weeks post psilocybin dosing

Study Arms (1)

Single Dose Psilocybin

EXPERIMENTAL

Single dose of orally administered 25 mg of psilocybin taken in conjunction with supportive therapy

Drug: Psilocybin; Device: Functional MRI

Interventions

Psilocybin DRUG

25 mg psilocybin

Single Dose Psilocybin

Functional MRI DEVICE

The fMRI involving resting state measures and a facial affect task will be conducted one-day and one-month after the dosing session.

Single Dose Psilocybin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults 18 to 65 years old.
• Must be deemed to have capacity to provide informed consent;
• Must sign and date the informed consent form;
• Stated willingness to comply with all study procedures;
• Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent;
• Primary DSM-5 diagnosis of Bipolar II Disorder (BD-II) currently experiencing a Major Depressive Episode (MDE) without psychotic features as diagnosed by a mood disorder specialist and confirmed using the Mini-International Neuropsychiatric Interview (MINI);
• Current MDE must be moderate to severe, as determined by the Hamilton Depression Rating Scale (HDRS-17) score greater than 20 with inadequate response to two or more adequate evidence-based treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. Treatment trials are specific to current MDE rather than lifelong trials;
• Ability to take oral medication;
• Must be currently taking lamotrigine or planning on starting lamotrigine outside of the trial for the duration of the study, including the 1-month follow-up period, without changes in the medication;
• Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 3 months prior to screening and agreement to use such a method during study participation;
• Individuals who are capable of fathering a child: use of condoms or other methods for the duration of study participation to ensure effective contraception with partner;
• Individuals who are willing to taper off current medications for a minimum of 1-month prior to Baseline (V3, Day -1) and whose physician confirms that it is safe for them to do so;
• Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration.

You may not qualify if:

• Pregnant as assessed by a urine pregnancy test at Screening (Visit 1) 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 (Visit 1);
• Current symptoms of mania, hypomania or mixed features, as determined by the Young Mania Rating Scale (YMRS) score greater than 12;
• History of mania or hypomania in the past 6 months as determined by psychiatric history;
• Have a DSM-5 diagnosis of substance use disorder (excluding use of tobacco) within the preceding 12 months;
• Have active suicidal ideation as determined by the C-SSRS and/or clinical interview Significant suicide risk is defined by suicidal ideation as endorsed by items 4 or 5 of the C-SSRS, OR active suicidality requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months;
• Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; psychotic disorder (including but not limited to during previous mood episodes or substance-induced psychosis), bipolar I disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history, the MINI clinical interview, and the International Personality Disorder Examination (IPDE) administered at V1;
• Have contraindications to fMRI as determined by the MRI questionnaire;
• Have a history of seizures;
• Are taking anticonvulsants (with the exception of lamotrigine) or benzodiazepines (lorazepam up to 2mg/day is acceptable);
• History of Steven-Johnson Syndrome (SJS) or suspected SJS as determined by medical history;
• 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 disorder as determined by the family medical history form and discussions with the participant;
• 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 to lamotrigine or psilocybin, or inability to tolerate lamotrigine during trial.

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Centre for Addiction and Mental Health: collaborator

Study Sites (1)

Toronto Western Hospital - University Health Network

Toronto, Ontario, M5T 2S8, Canada

RECRUITING

MeSH Terms

Conditions

Bipolar Disorder; Depression; Depressive Disorder, Treatment-Resistant

Interventions

Psilocybin; Magnetic Resonance Imaging

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior; Depressive Disorder

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis

Study Officials

• Joshua Rosenblat, MD, MSc

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Erica Kaczmarek, HBSc

CONTACT

416-603-5106; erica.kaczmarek@uhn.ca

Zoe Doyle, BScN

CONTACT

zoe.doyle@uhn.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Psychiatrist, Assistant Professor, Clinician-Investigator

Model Details: All participants will receive a single dose of orally administered 25mg of psilocybin taken in conjunction with supportive therapy.

Study Record Dates

• First Submitted: June 26, 2024
• First Posted: July 17, 2024
• Study Start: October 9, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): January 1, 2027
• Last Updated: October 18, 2024

Record last verified: 2024-10

Locations

CA (1)