A Randomized Neuroimaging Trial of Psilocybin in Depression

Study Overview
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Brief Summary
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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: changes connectivity within brain networks associated with mood and depression 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) niacin (100mg) 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.

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

Conditions
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Depressive Disorder, Major Depressive Disorder

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Niacin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This study will use a 2-group one-way crossover (AB/BB) design, with one group receiving placebo at the first visit and the investigational drug at second, and another group receiving the investigational drug at both visits.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Staged Active Treatment Arm (Psilocybin-Psilocybin)<br>This group will receive psilocybin (25mg) at the first and second treatment visit, along with supportive psychotherapy. | Drug: Psilocybin<br>* Psilocybin ([3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate), 25mg PO.<br>|
| Experimental: Placebo to Active Crossover Treatment Arm (Niacin-Psilocybin)<br>This group will receive niacin (100mg) at the first treatment visit and psilocybin (25mg) at the second treatment visit, along with supportive psychotherapy. | Drug: Psilocybin<br>* Psilocybin ([3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate), 25mg PO.<br>Drug: Niacin<br>* Niacin (Vitamin B3; nicotinic acid), 100mg PO.<br>* Other names: Vitamin B3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Treatment Visit 1 (Week 0), Treatment Visit 2 (Week 3) | 
| Change in MADRS | Changes in Montgomery-Asberg Depression Rating Scale 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 . | Baseline, Week 0, Week 3, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Network Connectivity | Changes in voxelwise 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. | Treatment Visit 1 (Week 0), Treatment Visit 2 (Week 3) | 
| Baseline GRID-HAMD-17 | Baseline grid-version of the 17-item Hamilton Depression Rating Scale (GRID-HAMD-17) 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 . | Baseline | 
| 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. | Week 0, Week 3, Week 6 | 
| 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. | Week 0, Week 3, Week 6 | 
| PHQ-9 | Patient Health Questionnaire 9-item (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). | Baseline, Week 0, Week 3, Week 6 | 
| QIDS-SR-16 | 16-item Quick Inventory of Depressive Symptomatology-Self-Report (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 . | Baseline, Week 0, Week 3, Week 6 | 
| CGI-S/I | Clinical Global Impressions Scale (CGI) will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The CGI severity module (CGI-S) assesses the severity of a person's depressive illness using a seven-point Likert scale, ranging from Normal, not at all depressed to Among the most extremely depressed patients. The CGI improvement module (CGI-I) evaluates the global improvement of a person's condition since their last visit on a seven-point Likert scale, ranging from Very much improved to Very much worse. | Baseline, Week 0, Week 3, Week 6 | 
| CSSRS | Columbia Suicide Severity Rating Scale (CSSRS) will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The CSSRS 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) . | Baseline, Week 0, Week 3, Week 6 | 
| BRPS | Brief Psychiatric Rating Scale (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. | Baseline, Week 0, Week 3, Week 6 | 
| SDS | Sheehan Disability Scale (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) . | Baseline, Week 0, Week 3, Week 6 | 
| WHO-5 | World Health Organization-5 Well-Being Index (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. | Baseline, Week 0, Week 3, Week 6 | 
| WHODAS 2.0 | World Health Organization Disability Assessment Schedule 2.0 (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, organised 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 (none, mild, moderate, severe, and extreme). | Baseline, Week 0, Week 3, Week 6 | 
| GAD-7 | Generalized Anxiety Disorder-7 (GAD-7) will be collected at baseline as well as week 3 and 6 post-psilocybin administration. Total score ranges from 0 to 21; a higher score denotes greater symptom severity. | Baseline, Week 0, Week 3, Week 6 | 
| SHAPS | Snaith-Hamilton Pleasure Scale (SHAPS) will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The SHAPS total score ranges from 14 to 56, wherein a higher score indicates greater hedonic capacity (lower anhedonic severity) . | Baseline, Week 0, Week 3, Week 6 | 
| CADSS-6 | 6-Item Clinician Administered Dissociative Symptom Scale (CADSS-6) will be collected at both treatment visits as well as week 3 and 6 post-psilocybin administration. Total scores range from 0-16, wherein a higher score indicates greater dissociation. | Treatment Visit 1 (Week 0), Treatment Visit 2 (Week 3), Week 6 | 
| SETS | Stanford Expectations of Treatment Scale (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 strongly disagree to strongly agree . | Baseline | 
| MoCA | Montreal Cognitive Assessment (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. | Baseline, Week 6 | 
| HVLT-R | Hopkins Verbal Learning Test-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. | Baseline, Week 6 | 
| 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. | Baseline, Week 6 | 
| 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. | Baseline, Week 6 | 
| CANTAB Spatial Working Memory | 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 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. | Baseline, Week 6 | 
| 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. | Baseline, Week 6 | 
| 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. | Baseline, Week 6 | 
| 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. | Baseline, Week 6 | 
| 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. | Baseline, Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psilocybin, Neuroimaging, MRI, Depression, Psychotherapy, Psychedelic