ANT: Individualized Functional Connectivity Targeting in aiTBS for Depression

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05680727

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major Depression Mood Disorders Mental Disorder Psychiatric Disorder	Procedure: transcranial magnetic stimulation	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Parallel-group double-blind randomized controlled trialParallel-group double-blind randomized controlled trial

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Participants will put on a swim cap and undergo treatment site-marking according to standard protocols. All individuals will get two treatment sites marked: 1) Their individualized target based on resting state functional connectivity data, and 2) Beam F3 target based on head measurements. One group will be treated at target #1, and the other group will be treated at target #2. Neither group will be able to see the computer screen that shows the neuronavigation in real-time, although they will be able to see their MRI scan on a monitor.

Primary Purpose:

Treatment

Official Title:

Individualized Functional Connectivity Targeting in aITBS for Depression

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jan 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Other: real individualized resting state functional connectivity targeting Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with individualized resting state functional connectivity.	Procedure: transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation will be administered under the supervision of a physician with TMS expertise. This protocol will be modeled after the FDA cleared Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, but the patented SAINT rsfc targeting algorithm will not be used for either arm. Other Names: TMS theta burst stimulation accelerated intermittent theta burst stimulation aiTBS
Other: sham individualized resting state functional connectivity targeting Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with head measurements (i.e., Beam F3)	Procedure: transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation will be administered under the supervision of a physician with TMS expertise. This protocol will be modeled after the FDA cleared Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, but the patented SAINT rsfc targeting algorithm will not be used for either arm. Other Names: TMS theta burst stimulation accelerated intermittent theta burst stimulation aiTBS

Arm

Intervention/Treatment

Other: real individualized resting state functional connectivity targeting

Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with individualized resting state functional connectivity.

Procedure: transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation will be administered under the supervision of a physician with TMS expertise. This protocol will be modeled after the FDA cleared Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, but the patented SAINT rsfc targeting algorithm will not be used for either arm.

Other Names:

TMS

theta burst stimulation

accelerated intermittent theta burst stimulation

aiTBS

Other: sham individualized resting state functional connectivity targeting

Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with head measurements (i.e., Beam F3)

Procedure: transcranial magnetic stimulation

Other Names:

TMS

theta burst stimulation

accelerated intermittent theta burst stimulation

aiTBS

Outcome Measures

Primary Outcome Measures

Montgomery-Åsberg Depression Rating Scale (MADRS) [one month after treatment]
Depression severity rating scale (0-60, higher numbers indicate higher severity)

Secondary Outcome Measures

Montgomery-Åsberg Depression Rating Scale (MADRS) [immediately after treatment ends]
Depression severity rating scale (0-60, higher numbers indicate higher severity)
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

22 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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