Individualized Functional Connectivity Targeting in AiTBS for Depression

Phase 2

Active, not recruiting

• Conditions: Depression; Mental Disorder; Psychiatric Disorder; Depressive Disorder, Major; Mood Disorders
• Interventions: Procedure: transcranial magnetic stimulation

• Registration Number: NCT05680727
• Lead Sponsor: Brigham and Women's Hospital

Brief Summary

The goal of this clinical trial is to estimate the importance of neuroimaging in accelerated intermittent theta burst stimulation (aiTBS) for depression. Participants will receive aiTBS treatment, but they will not know if their treatment spot was found with neuroimaging or head measurements.

Detailed Description

Techniques for modulating human brain networks are rapidly evolving. One of the most exciting new developments is accelerated intermittent theta burst stimulation (aiTBS), a transcranial magnetic stimulation (TMS) protocol that involves multiple daily treatments rather than gold standard once daily treatment. A specific accelerated iTBS protocol called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) was cleared by the FDA in September 2022 based on two pilot studies in which patients with treatment-resistant depression rapidly and robustly improved with SAINT. Many of these patients had been depressed for decades and had not improved with conventional TMS or electroconvulsive therapy. Despite these promising results, two issues may limit SAINT scalability: 1) SAINT has only been tested at a single site in a small number of patients, 2) SAINT has never been tested without individualized resting state functional connectivity (rsfc) targeting, which is not widely available or covered by insurance. In this pilot trial, patients with treatment-resistant depression (n=40) will be randomized to one of two active treatment arms: 1) Real aiTBS with real individualized rsfc targeting, or 2) Real aiTBS with sham individualized rsfc targeting (i.e. conventional TMS targeting based on scalp landmarks). All patients will receive active stimulation, which will facilitate enrollment and reduce ethical concerns about placebo treatment in a vulnerable population when there is existing evidence of treatment efficacy. Patients and clinicians will be blind to group assignment, and blind integrity will be assessed. All patients will undergo MRI scans immediately before treatment and at one month follow up, which aligns with our clinical outcome measures.

Study Timeline

• Study First Submitted: 2022-12-13
• Study First Submitted QC: 2023-01-10
• Study First Posted: 2023-01-11
• Study Start: 2023-07-15
• Status Verified: 2024-11
• Last Update Submitted: 2025-02-11
• Last Update Posted: 2025-02-12
• Primary Completion: 2026-07-15
• Study Completion: 2027-01-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
• Primary diagnosis of major depressive disorder per Diagnostic and Statistical Manual (DSM)-V criteria (MINI International Neuropsychiatric Interview)
• >20 on BDI
• >20 on the MADRS 10, 11
• Moderate to severe level of treatment resistance (Maudsley Staging Method)
• Stable antidepressant medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the study (including all follow-up assessments after the 5-day treatment protocol).
• Primary clinician responsible for psychiatric care before, during, and after the trial
• Agreement to lifestyle considerations
• Abstain from becoming pregnant from screening through end of treatment
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, soft drinks, chocolate) throughout treatment
• Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session
• Abstain from tobacco products during treatment day

Exclusion Criteria

• Active pregnancy as determined by a urine pregnancy test
• Primary psychiatric diagnosis other than major depressive disorder requiring treatment other than comorbid anxiety disorder
• Those who did not respond to electroconvulsive therapy (ECT) after 8 sessions
• Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)
• History of:
• Prior exposure to TMS
• Neurosurgical intervention for depression
• Autism spectrum disorder
• Intellectual disability
• Severe cognitive impairment
• Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion)
• Untreated or insufficiently treated endocrine disorder
• Treatment with investigational drug or intervention during the study period
• Depth-adjusted TMS treatment dose > 65% maximum stimulator output
• ≥ 30% change in MADRS score between screening and baseline
• Anyone presenting with:
• Mania or hypomania
• Psychosis
• Active suicidal ideation or a suicide attempt (defined by C-SSRS) within the past year
• Neurological lesion
• Contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).
• Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Positive urine drug screen for illicit substances
• Severe borderline personality disorder
• Any other condition deemed by the PI to interfere with the study or increase risk to the participant

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
sham individualized resting state functional connectivity targeting	transcranial magnetic stimulation	Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with head measurements (i.e., Beam F3)
real individualized resting state functional connectivity targeting	transcranial magnetic stimulation	Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with individualized resting state functional connectivity.

Primary Outcome Measures

Name	Time	Method
Montgomery-Åsberg Depression Rating Scale (MADRS)	one month after treatment	Depression severity rating scale (0-60, higher numbers indicate higher severity). The primary analysis of the primary outcome will be the effect size of imaging-guided accelerated TMS relative to scalp-targeted TMS. In other words, the "number needed to scan." This outcome has not changed since the original grant application for this study and the data remain blinded at the time of this clarification. Actual group differences will be explored in a secondary analysis of this primary outcome measure.

Secondary Outcome Measures

Name	Time	Method
Montgomery-Åsberg Depression Rating Scale (MADRS)	immediately after treatment ends	Depression severity rating scale (0-60, higher numbers indicate higher severity). The primary analysis of the primary outcome will be the effect size of imaging-guided accelerated TMS relative to scalp-targeted TMS. In other words, the "number needed to scan." This outcome has not changed since the original grant application for this study and the data remain blinded at the time of this clarification. Actual group differences will be explored in a secondary analysis of this primary outcome measure.
Beck Depression Inventory (BDI)	immediately after treatment ends and at all subsequent timepoints (1 week, 1 month, 3 months, 6 months, 9 months, 12 months)	Depression severity rating scales (0-63, higher numbers indicate higher severity)
Quick Inventory of Depressive Symptomatology (QIDS)	immediately after treatment ends and at all subsequent timepoints (1 week, 1 month, 3 months, 6 months, 9 months, 12 months)	Depression severity rating scales (0-27, higher numbers indicate higher severity)
Change in resting state functional connectivity in the depression network	one month after treatment	blood oxygen level-dependent (BOLD) signal
Percentage of screened patients from TMS clinical programs who select the accelerated iTBS trial over routine clinical TMS	through study completion, an average of 2 years	Patient preference measure
Temperament and Character Inventory, Revised 140-item	one month after treatment	Psychobiologically-based personality inventory which measures seven personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, cooperativeness, and persistence). For each dimension, this yields a scaled T-score (mean score of 50 with standard deviation of 10). This is an overall estimate of personality traits, and there are no "better" or "worse" traits.
Emotional Conflict Resolution Task	one month after treatment	Computer task measuring accuracy and reaction time
Learning, Multi-Source Interference Task (MSIT)	one month after treatment	Computer task measuring accuracy and reaction time
Penn Emotion Recognition Task (ER-40)	one month after treatment	Computer task measuring accuracy and reaction time
Death Suicide IAT (DSIAT)	one month after treatment	Computer task measuring reaction time
Beck Anxiety Inventory (BAI)	immediately after treatment ends and at all subsequent timepoints (1 week, 1 month, 3 months, 6 months, 9 months, 12 months)	Anxiety severity rating scale (0-63, higher numbers indicate higher severity)

Trial Locations

Locations (1)

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States