A Randomized Neuroimaging Trial of Psilocybin in Depression

Major Depressive Disorder Clinical Trial

— EMBRACE  

Official title:

Engaging Mood Brain Circuits With Psilocybin: a Randomized Neuroimaging Trial in Depression

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06072898
• Other study ID #: 5423
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: August 2024
• Est. completion date: November 2027

Study information

• Verified date: April 2024
• Source: Sunnybrook Health Sciences Centre
• Contact: Sean Nestor, PhD MD FRCPC
• Phone: 416-480-4085
• Email: sean.nestor[@]sunnybrook.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this neuroimaging clinical trial is to test whether psilocybin produces significant immediate changes in functional brain activity in networks associated with mood regulation and depression compared to placebo in patients with depression. The trial aims to determine if psilocybin:

1. Changes connectivity within brain networks associated with mood and depression

2. Changes blood flow in brain regions associated with mood and depression

Participants will be attend two treatment sessions where they receive an oral medication and supportive psychotherapy. At each session, participants will undergo an MRI scan after drug administration but prior to psychotherapy. Participants will be randomly to assigned to one of two groups that will receive, 1) microcrystalline cellulose (25mg) at the first visit and psilocybin (25mg) at the second visit, or 2) psilocybin (25mg) at both visits, respectively. Differences between groups will be compared to understand what effects on brain activity are specific to psilocybin.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: November 2027
• Est. primary completion date: August 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

Inclusion Criteria:

• Able and voluntarily willing to provide written informed consent at the screening visit.

• Over 18 and under 65 years old

• Able to attend all study visits and complete all required assessment tools without assistance or alteration

• Have a responsible individual/caregiver who is able to monitor the participant at home for 24 hours after each treatment visit

• Must have a psychiatrist and/or general practitioner who is able to provide psychiatric follow-up care

• Mini International Neuropsychiatric Interview (MINI)-confirmed diagnosis of depressive disorder, recurrent or single episode, without psychotic features where the duration of the current episode is at least 3 months

• Depression of at least moderate severity as defined by a Hamilton Depression Rating Scale (HAMD-17) score >17

Exclusion Criteria:

• Uncontrolled or insulin-dependent diabetes

• Women who are pregnant (self-report or via urine test), nursing, or planning a pregnancy during the timespan of the study

• History of seizure disorder except for seizures from electroconvulsive therapy and/or febrile seizures in childhood

• History of stroke, recent myocardial infarction (< 1 year from signing of ICF), uncontrolled hypertension (blood pressure > 140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF

• Abnormal and clinically significant results on a physical examination performed within one month of study participation by a general practitioner, vital signs, ECG, or laboratory test at screening

• QTc prolongation on ECG defined by > 450 ms in males and > 460 ms in females in V5 on a 12-lead ECG

• Positive urine drug screen for illicit drugs or drugs of abuse at screening, a week prior to treatment, and during the trial (any positive urine drug test will be reviewed with participants to determine the pattern of use and eligibility will be determined at the investigator's discretion)

• Serial blood counts to achieve a value to meet eligibility

• Eligible to receive blood product transfusions

• Any symptoms consistent with psychosis

• Any symptoms consistent with hypomania and/or mania as assessed by a psychiatrist

• Other personal circumstances or behavior judged to be incompatible with establishment of rapport or safe exposure to psilocybin

• Current or past history of bipolar I/II disorder, schizophrenia, schizoaffective disorder, psychotic disorder, or delusional disorder as assessed by a structured clinical interview (MINI)

• = 1 suicide attempt in the past year requiring hospitalization, defined using the Columbia Suicide Severity Rating Scale (CSSRS) (Q6 (past year) = "y") and clinical interview with a psychiatrist

• History of substance use and/or alcohol use disorder, of moderate severity or greater, in the past 12 months

• Lifetime history of substance use disorder with a hallucinogen

• Lifetime history of substance-induced psychosis

• Depression secondary to other medical conditions or bipolar I and II disorder

• Family history of a first degree relative with a diagnosis of schizophrenia or a primary psychotic disorder and/or bipolar disorder

• Exposure to psilocybin or any other psychedelic in the past 12 months prior to screening and/or during the current MDE and use of psychedelics, such as ayahuasca/LSD, during the current depressive episode

• A clinical diagnosis of antisocial personality disorder and/or paranoid personality disorder (defined as meeting DSM-5.0 criteria) based on clinical interview and the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at a clinical interview by a psychiatrist

• An active clinical diagnosis of borderline personality disorder as confirmed by the MINI 7.0

• Diagnosis of any mild or major neurocognitive disorder meeting DSM-5 criteria and based on clinical interview/cognitive screening by a psychiatrist

• Current enrolment in an interventional study for depression or participation in such within 30 days of screening

• Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal 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 he/she takes part in the study

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• Psilocybin
Psilocybin ([3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate), 25mg PO.

Other:
• Microcrystalline cellulose
MCC (excipient), 25mg PO.

Behavioral:
• Supportive psychotherapy
Supportive psychotherapy in the form of reassurance, integration, and de-escalatory techniques (if needed). Facilitating rapport and a positive environment.

Locations

Country	Name	City	State
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood biomarkers	Correlation of blood for circulating biomarkers will occur at baseline. Plasma-derived proteins (brain-derived neurotrophic factor, S100Beta, C-reactive protein) will be measured in blood samples collected at the baseline visit and second treatment visit using fluorometric immunoassays and evaluated as predictors of subsequent treatment response as defined above based on MADRS scores.	up to 5 weeks
Primary	Regional Blood Flow	Changes in cerebral blood flow within three a priori-defined brain regions relevant to mood regulation and depression as assessed by arterial spin labeling acutely at expected peak drug concentration during treatment visits.	Up to 3 weeks
Primary	Change in Montgomery-Asberg Depression Rating Scale (MADRS)	Changes in the MADRS relative to baseline at study follow-up visits. Higher scores with respect to the MADRS minimum (0) and maximum (60) values represent a worse treatment outcome .	Up to 6 weeks
Secondary	Functional Network Connectivity	Changes in voxel-wise functional connectivity within four a priori-defined and established functional networks relevant to mood regulation and depression as assessed by resting state functional magnetic resonance imaging acutely at the time of expected peak drug concentration during treatment visits.	Up to 3 weeks
Secondary	17-item Hamilton Depression Rating Scale (GRID-HAMD-17)	Baseline grid-version of the 17-item Hamilton Depression Rating Scale score. The GRID-HAMD is a 17-item clinician-administered rating scale designed to assess severity of depressive symptoms. The score range is 0 to 52, with higher score indicating more severe depression .	24 hours
Secondary	Incidence of response	Incidence of response, calculated as the proportion of participants with a response (defined as a = 50% improvement in MADRS total score from Baseline) at at follow-up after psilocybin administration.	up to 6 weeks
Secondary	Incidence of remission	Incidence of remission, calculated as the proportion of participants with remission (defined as MADRS total score <11) at week 3 and 6 following the initial psilocybin/niacin administration.	up to 6 weeks
Secondary	Patient Health Questionnaire 9-item (PHQ-9)	The PHQ-9 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The PHQ-9 is a self-rated measure of depressive symptom severity in the past two weeks. Each of the nine items is rated on a Likert scale, ranging from 0 (not at all) to 3 (nearly every day), and summed for a total score between 0 (no symptoms) to 27 (most severe).	up to 6 weeks
Secondary	16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16)	The QIDS-SR-16 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The QIDS-SR-16 is a self-report scale with scores that range from 0 to 27. Higher scores indicate greater depression .	up to 6 weeks
Secondary	Clinical Global Impression (CGI)	The CGI scale will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The CGI-Severity (CGI-S) assesses the severity of a person's depressive illness using a seven-point Likert scale, ranging from 1 ("Normal, not at all depressed") to 7 ("Among the most extremely depressed patients"). The CGI global improvement or change (CGIC) evaluates the global improvement of a person's condition since their last visit on a seven-point Likert scale, ranging from 1 ("Very much improved") to 7 ("Very much worse").	up to 6 weeks
Secondary	Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The C-SSRS evaluates suicidal ideation and behaviour. The suicidal ideation score ranges from 0 (no ideation) to 5 (active suicidal ideation with specific plan and intent). Suicidal ideation intensity score ranges from 0 (no ideation) to 25 (most severe). The presence of suicidal behaviour is rated as a binary response; the lethality of previous actual attempts is rated on a scale of 0 (no or very minor physical damage) to 5 (death) and the potential lethality of actual attempts are rated on a scale of 0 (behaviour not likely to result in injury) to 2 (behaviour likely to result in death despite available medical care) .	up to 6 weeks
Secondary	Brief Psychiatric Rating Scale (BPRS)	The BPRS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The BPRS rating scale has 18 items, each item rated on a severity scale of 1 (not present) to 7 (extremely severe). 0 is entered if the item is not assessed.	up to 6 weeks
Secondary	Sheehan Disability Scale (SDS)	The SDS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The SDS total score ranges from 0 to 30, with 0 representing no impairment and 30 representing severe impairment. The last two items of the scale (Days Lost and Days Unproductive) range from 0 to 7 (higher number denotes greater impairment) .	up to 6 weeks
Secondary	World Health Organization-5 Well-Being Index (WHO-5)	The WHO-5 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The WHO-5 is a measure of overall well-being, rated on a scale of 0 to 25, with higher scores denoting higher quality of life.	up to 6 weeks
Secondary	World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)	The WHODAS 2.0 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The WHODAS 2.0 is a self-reported disability questionnaire based on the International Classification of Functioning, Disability, and Health (ICF). It includes 36 questions, organized under six domains (cognition, mobility, self-care, getting along, life activities and participation). Each question must be answered based on the perceived difficulty for performing activities using a 5-point scale from 0 ("none") to 4 ("extreme").	up to 6 weeks
Secondary	Generalized Anxiety Disorder-7 (GAD-7)	The GAD-7 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. Scores from 0 ("Not at all") to 3 ("Nearly every day"), and total score ranges from 0 to 21; a higher score denotes greater symptom severity.	up to 6 weeks
Secondary	Snaith-Hamilton Pleasure Scale (SHAPS)	The SHAPS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The SHAPS is rated on a 4-point Likert scale from 0 ("strongly disagree") to 3 ("strongly agree"). Total score ranges from 14 to 56, wherein a higher score indicates greater hedonic capacity (lower anhedonic severity) .	up to 6 weeks
Secondary	6-Item Clinician Administered Dissociative Symptom Scale (CADSS-6)	The CADSS-6 is a simplified 6-item scale that will be collected at both treatment visits as well as week 3 and 6 post-psilocybin administration. Responses range from 0 ("not at all") to 4 ("extremely"). Total scores range from 0-24, wherein a higher score indicates greater dissociation.	up to 6 weeks
Secondary	Stanford Expectations of Treatment Scale (SETS)	The SETS will be collected at baseline. This scale contains six items measuring positive (3 items) and negative (3 items) treatment expectancies. Each of the six items is coded with a similar 7-point scale starting from 0 ("not agree at all")" to 6 ("fully agree").	24 hours
Secondary	Montreal Cognitive Assessment (MoCA)	The MoCA total score will be collected at baseline as well as week 6 (3 weeks after second treatment visit). This is scale is a cognitive screening assessment tool that tests six domains of cognition, with scores ranging from 0-30, wherein a higher score indicates better cognitive performance: 18-25 points ("Mild cognitive impairment"), 10-17 points ("Moderate cognitive impairment"), less than 10 points ("Severe cognitive impairment").	up to 6 weeks
Secondary	Hopkins Verbal Learning Test-Revised (HVLT-R)	The revised HVLT-R total Score will be collected at baseline as well as week 6 (3 weeks after second treatment visit). A list learning test that contains 12 nouns that are read to a participant for three consecutive trials. After each trial, a participant is asked to recall the words that were read to them. The number of words recalled on each trial is summed together to produce a total score. The higher total score equates to a better outcome.	up to 6 weeks
Secondary	CANTAB Rapid Visual Information Processing	We will use the CANTAB software program for evaluating cognitive domains baseline as well as week 6 (3 weeks after second treatment visit). Sustained attention will be measured by the Rapid Visual Information Processing task. Responses will be scored as the number of responses recorded as having occurred within 1800 milliseconds of the final digit presentation for each of the target sequences, with more responses reflecting better sustained attention.	up to 6 weeks
Secondary	CANTAB Reaction Time	We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Psychomotor speed will be measured by the Reaction Time (RTI) task. Simple reaction time will be the outcome of interest, with faster reaction time (lower latency) reflecting better psychomotor speed.	up to 6 weeks
Secondary	CANTAB Spatial Working Memory	The CANTAB software program for evaluating cognitive domains is used at baseline as well as week 6 (3 weeks after second treatment visit). Executive function will be measured by the Spatial Working Memory (RTI) task. This is a search task that stresses executive function and spatial working memory, requiring subjects to use heuristic search strategies. A higher score indicates better performance in spatial working memory.	up to 6 weeks
Secondary	CANTAB One Touch Stockings of Cambridge	We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Executive function will be measured by the One Touch Stockings of Cambridge (OTS) task. This is a spatial planning task that stresses executive function, requiring subjects to use reordered stacked objects to match a presented pattern. Fewer 'moves' indicates better executive function.	up to 6 weeks
Secondary	CANTAB Delayed Matching to Sample	We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Memory will be measured by the Delayed Matching to Sample (DMS) task. This is a memory task that stresses encoding, requiring subjects to remember and differentiate complex patterns when presented after a delay. More correct responses, or greater accuracy, reflects better memory.	up to 6 weeks
Secondary	CANTAB Paired-Associates Learning	We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Memory will be measured by the Paired-Associates Learning (PAL) task. This is a memory task =sensitive to changes in functioning of the medial temporal lobe, requiring subjects to remember and identify previous locations of complex patterns when presented after a delay. More correct responses, or greater accuracy, reflects better memory.	up to 6 weeks
Secondary	CANTAB Emotion Recognition Task	We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Social/emotional cognition will be assessed by the Emotion Recognition Task (ERT). Subjects are briefly shown faces morphed to display various emotions of varying intensities, and then required to identify the emotion. Better accuracy defined as number of correct responses reflects better emotional cognition.	up to 6 weeks
Secondary	Revised Mystical Experience Questionnaire (MEQ30)	The MEQ30 is a validated self-report revised 30-item questionnaire recording elements that comprise the mystical experience. 0 ("none (not at all)") to 5 ("extreme (more than any other time in my life and stronger than 4)"), with a total scoring range from 0 to 150. Higher scores indicate a more profound mystical experience.	up to 8 weeks
Secondary	Persistent Effects Questionnaire (PEQ)	The PEQ is a non-validated self-report 145-item questionnaire that describe any changes in the participants' lives that may be attributed to the psilocybin treatment. Comprises of 6 categories with items rated on a 6-point scale from 0 ("none") to 5 ("extreme"). Higher scores indicate a greater magnitude of the persistent effects following their psilocybin experience.	24 hours