Psilocybin rTMS for Treatment Resistant Depression

NCT06132178 | Recruiting Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: STUDY00004537
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the safety and feasibility of sequencing psilocybin therapy with a short-duration, aiTBS protocol (Stanford Accelerated Intelligent Neuromodulation Therapy, or SAINT) in individuals with treatment-resistant major depressive disorder.

Conditions

Treatment Resistant Depression; MDD; Major Depressive Disorder; Recurrent Depression; Depression

Outcome Measures

Primary Outcomes (4)

• Montgomery Asberg Depression Rating Scale (MADRS)

  A ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Scoring ranging from 0 to 60, with higher scores indicating greater depressive symptomology.

  12 months

• fMRI task-evoked brain activation

  A method used in functional magnetic resonance imaging (fMRI) to observe different areas of the brain or other organs, which are found to be active at any given time.

  At both 1 week and 2 weeks

• fMRI resting state

  A method aimed at examining intrinsic networks in the brain while no task is performed (rest) in order to estimate correlations between brain regions.

  At both 1 week and 2 weeks

• EEG functional connectivity change

  A method aimed at examining intrinsic networks in the brain to estimate correlations between brain regions.

  At both 1 week and 2 weeks

Secondary Outcomes (21)

• Snaith Hamilton Pleasure Scale (SHAPS)

  12 months

• Quick Inventory of Depressive Symptom Self-Report (QIDS-SR)

  12 months

• World Health Organization Quality of Life Inventory-Brief subscale (WHO-QL-Brief)

  12 months

• Beck Depression Inventory II (BDI II)

  12 months

• Anxiety Sensitivity Index 3 (ASI-3)

  12 months

Study Arms (4)

Full dose COMP360 with active aiTBS rTMS

EXPERIMENTAL

25mg of COMP360 with the active accelerated intermittent theta burst (aiTBS) rTMS treatment known as Stanford Neuromodulation Therapy (SNT) and/or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) delivered over 10 sessions daily for 5 consecutive days.

Drug: Psilocybin; Device: Accelerated intermittent theta burst (aiTBS) rTMS treatment

Full dose COMP360 with sham aiTBS rTMS

ACTIVE COMPARATOR

25mg of COMP360 with sham iTBS delivered over 10 sessions daily for 5 consecutive days.

Drug: Psilocybin; Device: Sham Accelerated intermittent theta burst (aiTBS) rTMS treatment

Low dose comparator with active aiTBS rTMS

ACTIVE COMPARATOR

1mg of COMP360 with the active accelerated intermittent theta burst (aiTBS) rTMS treatment known as Stanford Neuromodulation Therapy (SNT) and/or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) delivered over 10 sessions daily for 5 consecutive days.

Device: Accelerated intermittent theta burst (aiTBS) rTMS treatment; Drug: Low-dose psilocybin

Low dose comparator with sham aiTBS rTMS

SHAM COMPARATOR

1mg of COMP360 with with sham iTBS delivered over 10 sessions daily for 5 consecutive days.

Drug: Low-dose psilocybin; Device: Sham Accelerated intermittent theta burst (aiTBS) rTMS treatment

Interventions

Psilocybin DRUG

A psychedelic drug found in certain mushrooms. It will be in a capsule of 25mg psilocybin (COMP360).

Also known as: COMP360

Full dose COMP360 with active aiTBS rTMS; Full dose COMP360 with sham aiTBS rTMS

Accelerated intermittent theta burst (aiTBS) rTMS treatment DEVICE

A form of non-invasive brain stimulation that delivers a series of quick magnetic pulses to the scalp and a portion of the brain. It will be targeted to a functional magnetic resonance imaging (fMRI) functional connectivity-guided personalized left dorsolateral prefrontal cortex target using neuronavigation and delivered over 10 sessions daily for 5 consecutive days at 90% of coil-to-target depth-corrected resting motor threshold.

Also known as: Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), Stanford Neuromodulation Therapy (SNT)

Full dose COMP360 with active aiTBS rTMS; Low dose comparator with active aiTBS rTMS

Low-dose psilocybin DRUG

A psychedelic drug found in certain mushrooms. It will be in a low-dose form of the experimental dose as a 1mg capsule of psilocybin (COMP360).

Also known as: low-dose COMP360

Low dose comparator with active aiTBS rTMS; Low dose comparator with sham aiTBS rTMS

Sham Accelerated intermittent theta burst (aiTBS) rTMS treatment DEVICE

The sham version is meant to look and feel like the active SAINT rTMS, but the main difference is that the brain is not being stimulated like the active condition.

Also known as: Sham Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), Sham Stanford Neuromodulation Therapy (SNT)

Full dose COMP360 with sham aiTBS rTMS; Low dose comparator with sham aiTBS rTMS

Eligibility Criteria

• Age: 22 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults, ages 22-65.
• English language comprehension suitable to understand experimenter instructions and to communicate to study personnel/staff reasonably easily.
• Current major depressive episode (without psychotic features), either as part of recurrent major depressive disorder (MDD) or single episode MDD with current episode present for at least the past 3 months (as determined by the Structured Clinical Interview for DSM-5; SCID-5).
• Montgomery Asberg Depression Rating Scale (MADRS) score of 20 or greater at baseline assessment (at least moderate severity).
• \. Treatment-resistant MDD, defined as either: a) failure to respond to an adequate dose and duration of two or more pharmacological treatments, with at least one failed medication trial occurring in the current major depressive episode; or b) failure to respond to an adequate dose and duration of 2 or more pharmacological treatments of different pharmacological classes in one or more past major depressive episodes. Adequate treatment dose and duration will be determined through the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ). Augmentation, where an add-on medication is used, will be counted as a second treatment, provided it is approved as an adjunctive treatment of MDD in the country where prescribed.
• Willingness and ability to attend daily, full-day visits to the research site for a period of \~2 weeks and to participate in all study procedures (clinical assessments, treatments, and neurobiological assessments).
• If currently taking an antidepressant medication (an SSRI, SNRI, or atypical antidepressant), antipsychotic, and/or other augmenting medication (e.g., lithium), willingness to discontinue medication(s) over a 2-8 week period with the assistance of study staff and maintain at least a 2-5 week period (5-week period for fluoxetine) off of medications prior to the baseline visit AND willingness to remain off medications for a period of 1 month following the end of the treatment course (approximately 6-8 weeks after the baseline visit).

You may not qualify if:

• Prior history or current diagnosis of a psychotic disorder (including MDD with psychotic features), bipolar disorder, or personality disorder (based on medical history, clinician judgement, SCID-5 and/or SCID for Personality Disorders).
• Current diagnosis of posttraumatic stress disorder, acute stress disorder, obsessive-compulsive disorder, anorexia nervosa, bulimia nervosa, or alcohol or substance-use disorder.
• Having met criteria for an alcohol or substance-use disorder within the past year.
• Use of electroconvulsive therapy, deep brain stimulation, or vagus nerve stimulation during the current major depressive episode.
• Any prior rTMS treatment (10Hz, 5Hz, 1Hz, or conventional intermittent theta burst).
• Current participation in an evidence-based psychotherapy for major depression (e.g., cognitive behavioral therapy, behavioral activation). Ongoing supportive psychotherapy is allowable if maintained at the same frequency throughout the duration of the short-term follow-up clinical endpoint (1 month after treatment cessation) of the study and if no recent change in therapy type or frequency for 1 month prior to enrollment.
• Exhibiting significant suicide risk within the past 12 months, at screening, or at baseline, as evidenced by: a) suicidal ideation with some intent to act but no specific plan (item #4 from the Columbia Suicide Severity Rating Scale57; C-SSRS); b) suicidal ideation with intent to act and a specific plan (item #5 from the C-SSRS); c) suicide attempt or non-suicidal self-injury requiring medical attention in the past 12 months; or d) self-report of significant suicidal ideation with intent or significant non-suicidal self-injury during screening or baseline clinical interview.
• Major depressive episode that is secondary to a medication or a general medical condition, as judged by investigators.
• Any other factors, such as major medical conditions, unstable housing or threatening life circumstances, erratic behavior, etc. that are judged by the investigators to be a significant barrier to participation in the study protocol and/or to establishing therapeutic rapport necessary for safe administration of psilocybin.
• Prior past-year ingestion of a serotonergic psychedelic, e.g., psilocybin, LSD, mescaline, dimethyltryptamine, etc. or more than 5 lifetime ingestions of a serotonergic psychedelic on separate occasions.
• Participant unwillingness to not ingest or use additional serotonergic psychedelics outside the context of study procedures for the duration of the study follow-up period (12 months).
• Ferrous metal, metallic implants, or implanted medical devices that would preclude administration of rTMS and/or participation in MRI procedures, including but not limited to: cochlear implants, implanted brain stimulators, aneurysm clips.
• Past history of seizures or epilepsy (rTMS risk).
• Neurological disorder, including epilepsy, stroke, or history of brain surgery.
• Past penetrating brain injury or any head injury resulting in a loss of consciousness for 30 minutes or more or post-concussive symptoms for more than seven days following a head injury.

Sponsors & Collaborators

• University of Texas at Austin: lead

Study Sites (1)

Health Discovery Building (HDB), 1601 Trinity St., Bldg B., Z0600

Austin, Texas, 78712, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major; Depression

Interventions

Psilocybin

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Study Officials

• Gregory A Fonzo, Ph.D.

  The University of Texas at Austin

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lauren K Enten, B.S.A.

CONTACT

512-495-5856; psychedelics@utexas.edu

Gregory A Fonzo, Ph.D.

CONTACT

fonzolab@austin.utexas.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: This will be a phase II 2x2 design (device and dose) clinical trial. 100 participants, ages 22-76, with treatment-resistant MDD will be randomized to treatment with either: a) 25mg of COMP360 (N=50); or b) 1mg of COMP360 (low-dose comparator; N=50) with appropriate psychological preparation, support, and integration sessions with trained therapists. This will then be directly followed by one of two subsequent treatment conditions: i) the active accelerated intermittent theta burst (aiTBS) rTMS treatment known as Stanford Neuromodulation Therapy (SNT) and/or Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) targeted to a functional magnetic resonance imaging (fMRI) functional connectivity-guided personalized left dorsolateral prefrontal cortex target using neuronavigation and delivered over 10 sessions daily for 5 consecutive days at 90% of coil-to-target depth-corrected resting motor threshold50,51; or ii) sham iTBS delivered in the same fashion.

Study Record Dates

• First Submitted: November 9, 2023
• First Posted: November 15, 2023
• Study Start: January 10, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2030
• Last Updated: November 26, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)