The Effects of Psilocybin on Self-Focus and Self-Related Processing in Major Depressive Disorder

Overview

This open-label functional Magnetic Resonance Imaging (fMRI) study will assess the effects of a single dose of psilocybin on rumination and the neural correlates of rumination in individuals with major depressive disorder.

Interventions

• Drug Psilocybin
  COMP360 (Brand name of psilocybin to be used)

Primary outcome measures

• Change in Massachusetts General Hospital Rumination Questionnaire (MGH-RQ) [Time frame: Baseline, and 3 weeks, 6 weeks, 9 weeks, and 12 weeks after psilocybin administration.]
• Change in Resting-State Functional Connectivity [Time frame: Baseline, day of psilocybin administration, and 3 weeks, and 12 weeks after psilocybin administration.]
• Change in Self-Attribution Task performance [Time frame: Baseline, day of psilocybin administration, and 3 weeks, and 12 weeks after psilocybin administration.]
• Change in Task-Based Activity during Self-Attribution Task [Time frame: Baseline, day of psilocybin administration, and 3 weeks, and 12 weeks after psilocybin administration.]

Secondary outcome measures (12)

• Change in Montgomery-Asberg Depression Rating Scale(MADRS) [Time frame: 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 Self Report - 16 item (QIDS-SR-16) [Time frame: 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) [Time frame: Baseline, the day of psilocybin administration and at 3 weeks and 12 weeks after psilocybin administration.]
• Change in Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) [Time frame: Baseline and 3 weeks and 12 weeks after psilocybin administration.]
• Change in Ruminative Response Scale (RRS) [Time frame: Baseline and 12 weeks after psilocybin administration.]
• Change in Rumination Reflection Questionnaire (RRQ) [Time frame: Baseline and 12 weeks after psilocybin administration.]
• Change in Penn State Worry Questionnaire (PSWQ) [Time frame: Baseline and 12 weeks after psilocybin administration.]
• Change in NEO-Five-Factor Inventory (NEO-FFI) [Time frame: Baseline and 12 weeks after psilocybin administration.]
• Change in Behavior Rating Inventory of Executive Function - Adult Version (BRIEF) [Time frame: Baseline and 12 weeks after psilocybin administration.]
• Change in Cognitive Flexibility Inventory (CFI [Time frame: Baseline and 12 weeks after psilocybin administration.]
• Change in Emotional Faces Flanker Task [Time frame: Baseline, day of psilocybin administration, and 3 weeks and 12 weeks after psilocybin administration.]
• Change in Depression Implicit Attitudes Task (IAT) [Time frame: Baseline, day of psilocybin administration, and 3 weeks and 12 weeks after psilocybin administration.]

Eligibility criteria

Inclusion criteria

• Must be able to sign the informed consent form (ICF). Participants will demonstrate capacity to provide informed consent by demonstrated understanding of the protocol and what their involvement in the study requires from them.
• Be 18-55 years of age at screening.
• At least moderate Major Depressive Disorder (MDD; single or recurrent episode as informed by Diagnostic and Statistical Manual Version 5 (DSM-V); if single episode, duration of ≥ 3 months and ≤ 3 years) based on clinical assessment and a structured clinical interview, the Mini International Neuropsychiatric Interview Version 7.02 (MINI).43
• Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS)44 score ≥ 18 at Screening and at Baseline.
• Failure to respond to an adequate dose and duration of 1, 2, 3, or 4 pharmacological treatments for the current episode as determined through the Massachusetts General Hospital Antidepressant Treatment History Response Questionnaire (MGH-ATRQ)45 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.
• Participants will also 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, which will be completed at least 2 weeks prior to Baseline Scan. Please see below regarding details about discontinuation of antidepressants.
• A score > 40 on the Wechsler Test of Adult Reading.46
• Be right-handed as determined by the Edinburgh Handedness Inventory.48
• 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

Patients meeting any of the following criteria are to be excluded from the study:

• 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 Magnetic Resonance 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)49 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 corrected QT interval > 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, phenylcyclohexyl piperidine(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.
• Non-native speakers of English.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Athinoula A. Martinos Center for Biomedical Imaging — Charlestown

Identifiers

NCT: NCT06247839 · 2024P000137

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗