Depression, Depressive Disorder, Major, Mental Disorder, Mood Disorders, Psychiatric Disorder
Conditions
Keywords
transcranial magnetic stimulation, accelerated intermittent theta burst stimulation, theta burst stimulation, brain stimulation, neuromodulation, depression, transcranial, TMS, neuronavigation, functional connectivity, neuroimaging
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.
Interventions
PROCEDUREtranscranial 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.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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.
Intervention model description
Parallel-group double-blind randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
22 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Åsberg Depression Rating Scale (MADRS) | Baseline, one month after treatment | Depression severity rating scale (0-60, higher numbers indicate higher severity). The primary outcome measure was the baseline-adjusted MADRS score one month after treatment. The primary analysis of this primary outcome measure was the effect size of connectivity-based targeting. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Beck Depression Inventory (BDI) | Screening, Day 5 of Treatment, 1 Week Post Treatment, & 1 Month Post Treatment | Depression severity rating scales (0-63, higher numbers indicate higher severity) |
| Beck Anxiety Inventory (BAI) | Screening, Day 5 of Treatment, 1 Week Post Treatment, & 1 Month Post Treatment | Anxiety severity rating scale (0-63, higher numbers indicate higher severity) |
| Montgomery-Åsberg Depression Rating Scale (MADRS) | Baseline & 1 Month Post 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. |
| Change in Resting State Functional Connectivity in the Depression Network | Baseline, one month after treatment | Blood oxygen level-dependent (BOLD) signal. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoseph J Taylor, MD, PhD
Brigham and Women's Hospital
Participant flow
Recruitment details
Recruitment ran July 2023-March 2025. Recruitment sources included Rally, Mass General Brigham outpatient clinics/healthcare providers, and clinicaltrials.gov. Additionally, flyers were posted around the greater Mass General Brigham area.
Pre-assignment details
A total of 40 participants were assigned to either a connectivity-based target or scalp-based target. Participants were ineligible after screening due to the following reasons: not meeting depression threshold cutoffs (\<20 BDI/MADRS & mild Maudsley Staging Method) defined by inclusion criteria, history of tinnitus (ringing in the ears), symptoms of post-traumatic stress disorder, risk of seizure, active symptoms of substance use disorder, and history of brain tumor.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized Age (Mean, SD) | 45.70 Years STANDARD_DEVIATION 15.18 |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Multiracial | 4 Participants |
| Race/Ethnicity, Customized Unknown/not reported | 1 Participants |
| Race/Ethnicity, Customized White | 29 Participants |
| Sex/Gender, Customized Female | 12 Participants |
| Sex/Gender, Customized Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 16 / 20 | 14 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
None listed