Neurobiological Effects of Psilocybin in Treatment Resistant Bipolar Depression
NCT Number: NCT06506019
Acronym: Psilo-BD
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1
Conditions: Bipolar Depression
Interventions: DRUG: Psilocybin|DEVICE: Functional MRI
Sponsor: University Health Network, Toronto
Collaborators: Centre for Addiction and Mental Health
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 30
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-08-01
Completion Date: 2027-01-01

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.

Primary Outcome Measures: 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 Outcome Measures: Self-Reported Depression Symptoms, Self-assessment of depression symptoms using the Quick Inventory for Depressive Symptomatology, Self-Report (QIDS-SR) where higher scores indicate greater severity on a scale of 0-42., Baseline to 4 weeks post psilocybin dosing|Self-Reported Anxiety Symptoms, Self-assessment of anxiety symptoms using the Generalized Anxiety Disorder 7-Item (GAD-7) where higher scores indicate greater severity on a scale from 0-21., Baseline to 4 weeks post psilocybin dosing|Subjective Functioning, Self-assessment of subjective function as measured by the Sheehan Disability Scale (SDS) where higher scores indicate greater severity of disability symptoms on a scale from 0-30., Baseline to 4 weeks post psilocybin dosing|Self-Reported Quality of Life, Self-assessment of quality of life measured by the World Health Organization-5, Well-Being Index (WHO-5) where higher scores indicate a better quality of life score on a scale from 0-25., Baseline to 4 weeks post psilocybin dosing|Self-Reported Rapid Changes in Depression Symptoms, Self-assessment of changes in depression symptoms in the past 72 hours (3 days) as measured by the McIntyre And Rosenblat Rapid Response Scale 14-Item (MARRRS-14). Higher scores indicate greater severity of depression symptoms in the last 72 hours on a scale from 0-63., Baseline to 4 weeks post psilocybin dosing|Self-Reported Cognitive Impairment, Self-assessment of cognitive impairment in the past 7 days as measured by the Perceived Deficits Questionnaire for Depression (PDQ-5-D) on a scale from 0-20., Baseline to 4 weeks post psilocybin dosing|Self-Reported Anhedonia Symptoms, Self-assessment of anhedonic symptoms (inability to experience pleasure or enjoy previously enjoyed activities) as measured by the Snaith Hamilton Pleasure Scale (SHAPS). Lower scores indicate greater severity of anhedonic symptoms on a scale from 1-56., Baseline to 4 weeks post psilocybin dosing
Other Outcome Measures: Self-Reported Mystical Experience, Self-assessment of the degree of mystical experiences following psilocybin administration using the Mystical Experience Questionnaire (MEQ). The MEQ assesses 4 empirically derived factors: mystical experiences, positive mood, transcendence of time and space and ineffability (e.g. inability to adequately describe experience in words). Responses are rated on a 6-point Likert scale ranging from 0 (none, not at all), through to 5 (extreme, more than ever before in my life)., Immediately post psilocybin dosing|Self-Reported Anhedonia Symptoms and Reward Thinking, Self-assessment of anhedonia symptoms across four domains: hobbies/past-times, food/drinks, social activities, and sensory experiences as measured by the Dimensional Anhedonia Rating Scale (DARS). Participants are asked to provide at least two of their own examples of what they find rewarding under each domain. The DARS is evaluated on a scale from 0-51 where lower scores indicate greater anhedonic symptoms., Baseline to 4 weeks post psilocybin dosing|Psychomotor Speed, Visual search, and Attention, The Trail Making Test B (TMT-B) requires participants to connect numbered circles with a pencil as quickly as possible in an alternating alphanumeric sequence respectively. Shorter time to complete these tests and fewer errors denotes higher performance., Baseline to 4 weeks post psilocybin dosing|Psychomotor Performance, The Digit Symbol Substitution Test (DSST) is a pencil and paper test of psychomotor performance. Participants will be key grid of numbers and matching symbols and are asked to fill as many empty boxes as possible with the symbol matching each number. The score is the number of correct number-symbol matches achieved in 90 seconds., Baseline to 4 weeks post psilocybin dosing|Phonemic Word Fluency, The FAS Verbal Fluency Test is a measure of phonemic word fluency. The number of words recited that begin with the letters 'F', 'A', and 'S' within a one-minute time frame serves as a measure of word fluency., Baseline to 4 weeks post psilocybin dosing|MATRICS Consensus Cognitive Battery Score, The MATRICS Consensus Cognitive Battery (MCCB) consists of 10 tests that measure outcomes across seven cognitive domains: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, social cognition. T scores will be generated by the MCCB based on the corresponding raw data for each test., Baseline to 4 weeks post psilocybin dosing|Changes in Default Mode Network Connectivity, Resting state fMRI will be used to evaluate changes in connectivity within the default mode network by comparing pre- and post-psilocybin dose., Baseline to 4 weeks post psilocybin dosing|Association of Default Mode Network Connectivity with MADRS Score, Correlation of changes in MADRS score with changes DMN connectivity (measured using resting state fMRI) will be evaluated from baseline to 4 weeks post psilocybin dosing. The correlation is being assessed to determine if changes in DMN connectivity are associated with and can predict improvements in depression symptoms., Baseline to 4 weeks post psilocybin dosing