The Effects of Psilocybin on Self-Focus and Self-Related Processing in Treatment Resistant MDD

Study Overview
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Brief Summary
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This open-label fMRI study will assess the effects of a single dose of psilocybin on rumination and the neural correlates of rumination in individuals with treatment-resistant major depressive disorder.

Official Title
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The Effects of Psilocybin on Self-Focus and Self-Related Processing in Treatment Resistant MDD

Conditions
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Treatment-Resistant Major Depressive Disorder

Intervention / Treatment
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* Drug: Psilocybin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be able to sign the informed consent form (ICF). Be 18-55 years of age at screening. At least moderate MDD based on clinical assessment and a structured clinical interview, the Mini International Neuropsychiatric Interview Version 7.02 (MINI). Hamilton Depression Rating Scale - 17 item (HAM-D-17) score ≥ 18 at Screening and at Baseline. Failure to respond to an adequate dose and duration of 2, 3, or 4 pharmacological treatments for the current episode as determined through the Massachusetts General Hospital Antidepressant Treatment History Response Questionnaire (MGH-ATRQ) and using the supplementary advice on additional antidepressants not included in MGH-ATRQ. Augmentation with an add-on treatment counts as a second treatment, provided it is approved for the adjunctive treatment of MDD. McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) < 7 at Screening. Have successfully discontinued all antidepressant medications at least 2 weeks prior to Baseline Scan. (Please note: once enrolled in the study, participants will have to successfully undergo a taper off of all psychotropic medications under the supervision of a study psychiatrist and in coordination with their treatment team). A score > 40 on the Wechsler Test of Adult Reading. Be right-handed as determined by the Edinburg Handedness Inventory. Ability to complete all protocol required assessment tools without any assistance or alteration to the copyrighted assessments, and to comply with all study visits. Have ongoing established mental health care. Exclusion Criteria: Current, past history, or family history, of schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), bipolar disorder, delusional disorder, paranoid personality disorder, schizoaffective disorder, borderline personality disorder, or any serious psychiatric comorbidity as assessed by medical history and a structured clinical interview (version 7.0.2 MINI). Positive MR screen (e.g., metal implant, claustrophobia, etc). Prior electroconvulsive therapy and/or ketamine for current episode. Current cognitive behavioral therapy (CBT) that will not remain stable for the duration of the study. CBT cannot be initiated within 21 days of Baseline. Current (within the last year) alcohol or substance abuse as informed by DSM-5 at Screening. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) within the past year, at Screening or at Baseline, or; (2) suicidal behaviors within the past year, or; (3) clinical assessment of significant suicidal risk during clinical interview. Significant homicide risk as defined by clinical interview. Depression secondary to other severe medical conditions. Currently taking benzodiazepines daily. Other personal circumstances and behavior judged to be incompatible with establishment of rapport or safe exposure to psilocybin, as well as exposure to psilocybin or other psychedelics within one year of screening. Women who are pregnant, nursing, or planning a pregnancy. Participants who are sexually active must agree to use a highly effective contraceptive method throughout their participation in the study. Women of childbearing potential must have a negative urine pregnancy test at Screening and Day Before Psilocybin. Cardiovascular conditions: recent stroke (< 1 year from signing of consent), recent myocardial infarction (< 1 year from signing of ICF), hypertension (blood pressure > 140/90 mmHg) or QTc > 450 msec) or clinically significant arrhythmia within 1 year of signing the ICF, current anticoagulant therapy, aneurysmal disease. Uncontrolled insulin dependent diabetes. Seizure disorder. Positive urine drug screen for illicit drugs or drugs of abuse (to include but not limited to opiates, PCP, cocaine, amphetamines, methamphetamines, benzodiazepines, barbiturates, and cannabis) at Screening and Day Before Psilocybin. 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. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention which, according to the screening clinician, is deemed associated with significant injury to or malfunction of the CNS, or history of significant head trauma within the past 2 years. Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation. Current enrollment in any investigational drug or device study or participation in such within 6 months of Screening. Current enrollment in an interventional study for depression or participation in such within 6 months of Screening Visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin<br>25mg of Psilocybin | Drug: Psilocybin<br>* Open-Label<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Massachusetts General Hospital Rumination Questionnaire (MGH-RQ) | A transdiagnostic state measure of rumination over the previous two weeks consisting of 9 items on a 5 point Likert scale from 0 (Never/Rarely) to 4 (All The Time). | Baseline, and 3 weeks, 6 weeks, 9 weeks, and 12 weeks after psilocybin administration. | 
| Change in Resting-State Functional Connectivity | Changes in resting-state activity during functional magnetic resonance imaging(fMRI) scans. | Baseline, day of psilocybin administration, and 3 weeks, and 12 weeks after psilocybin administration. | 
| Change in Self-Attribution Task performance | Participants are shown words one at a time and asked to answer if each of the words apply to 'Self' or 'Other' | Baseline, day of psilocybin administration, and 3 weeks, and 12 weeks after psilocybin administration. | 
| Change in Task-Based Activity during Self-Attribution Task | Changes in task-based activity during functional magnetic resonance imaging(fMRI) scans. | Baseline, day of psilocybin administration, and 3 weeks, and 12 weeks after psilocybin administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery-Asberg Depression Rating Scale(MADRS) | The MADRS is a clinician-rated scale measuring depression severity, consisting of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60; higher scores denote greater severity. | Baseline, the day before psilocybin administration and at 1 day, 1 week, 2 weeks, 3 weeks, 6 weeks, 9 weeks and 12 weeks after psilocybin administration. | 
| Change in Quick Inventory of Depressive Symptomatology - 16 item (QIDSR-SR-16) | The 16-item QIDS-SR-16 a self-rated scale designed to assess the severity of depressive symptoms in the nine diagnostic symptom domains of a major depressive episodes, exclusive of atypical or melancholic symptoms. The QIDS-SR-16 is sensitive to change with various treatments, demonstrating its utility in research settings. The total score ranges from 0 to 27 with 0 representing no depression and 27 representing severe depression. | Baseline, the day before psilocybin administration and at 1 day, 1 week, 2 weeks, 3 weeks, 6 weeks, 9 weeks and 12 weeks after psilocybin administration. | 
| Change in Positive and Negative Affect Schedule (PANAS) | The PANAS measures the acute emotional drug effects and comprises 2 mood scales that measure positive and negative affect. Participants respond to 20 items using a 5-point scale that ranges from slightly or not at all (1) to extremely (5). A total higher score on the positive affect questions indicates more of a positive affect while a lower score on the negative affect questions indicates less of a negative affect. | Baseline, the day of psilocybin administration and at 3 weeks and 12 weeks after psilocybin administration. | 
| Change in Hamilton Depression Rating Scale - 17 item (HAM-D-17) | The HAM-D-17 is a 17 item scale used to assess the degree of symptom severity in depressed patients. | Baseline and 3 weeks and 12 weeks after psilocybin administration. | 
| Change in Ruminative Response Scale (RRS) | A self-report measure of describing one's responses to depressed mood, consists of 22 items and three factors (Depression, Brooding, and Reflection). Each item is rated on a 4-point Likert scale ranging from 1 (never) to 4 (always). The total score ranges from 22 to 88, with higher scores indicating higher tendency to ruminate, i.e. higher trait rumination. | Baseline and 12 weeks after psilocybin administration. | 
| Change in Rumination Reflection Questionnaire (RRQ) | The RRQ measures the extent to which a person tends to ruminate or engage in self-reflection. It consists of 24 items measured on a 5 point Likert scale from 1 (Strongly Disagree) to 5 (Strongly Agree),12 items which assess the tendency to ruminate, and 12 items which assess the tendency to engage in self reflection. | Baseline and 12 weeks after psilocybin administration. | 
| Change in Penn State Worry Questionnaire (PSWQ) | The PSWQ is a 16-item questionnaire that aims to measure the trait of worry, using Likert rating from 1 (not at all typical of me) to 5 (very typical of me). The PSWQ attempts to measure the excessiveness, generality, and uncontrollable dimensions of worry. | Baseline and 12 weeks after psilocybin administration. | 
| Change in NEO-Five-Factor Inventory (NEO-FFI) | The NEO-FFI is a 60-item psychological personality inventory that assesses based on the five- factor model: Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism. Participants are asked to select the response that best represents their opinion on a 5-point scale: 0-Strongly Agree, 1-Agree, 2-Neutral, 3-Disagree, 4-Strongly Disagree. | Baseline and 12 weeks after psilocybin administration. | 
| Change in Behavior Rating Inventory of Executive Function - Adult Version (BRIEF) | The BRIEF is a 75-item scale designed to assess executive function and self-regulation. Participants choose how often certain behaviors were problematic over the past month N-never, S-sometimes, O-often. | Baseline and 12 weeks after psilocybin administration. | 
| Change in Cognitive Flexibility Inventory (CFI) | The CFI is a brief self-report measure of the type of cognitive flexibility necessary for individuals to successfully challenge and replace maladaptive thoughts with more balanced and adaptive thinking. The measure consists of 20 items and participants indicate the extent to which they agree or disagree with the statements in the items, on a scale from 1-Strongly Disagree to 7-Strongly Agree. | Baseline and 12 weeks after psilocybin administration. | 
| Change in Emotional Faces Flanker Task | This task examines executive functioning as it assesses the ability to ignore/inhibit irrelevant flanking information in order to respond to the central task. | Baseline, day of psilocybin administration, and 3 weeks and 12 weeks after psilocybin administration. | 
| Change in Depression Implicit Attitudes Task (IAT) | The IAT provides a measure of the strength of association between four categories by pairing two concept categories (e.g., Me/Not-Me) with two attribution categories (e.g., Happy/Sad). | Baseline, day of psilocybin administration, and 3 weeks and 12 weeks after psilocybin administration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psilocybin, Neuroimaging, Rumination, Treatment-Resistant Depression