Imaging- vs. Scalp-Targeted Accelerated TMS for Depression: The Number Needed to Scan Trial
- Conditions
- Major Depressive Disorder (MDD)
- Registration Number
- NCT07043738
- Lead Sponsor
- Brigham and Women's Hospital
- Brief Summary
Transcranial magnetic stimulation(TMS) is a non-invasive form of brain stimulation that is cleared by the United States Food and Drug Administration (FDA) for depression. Conventional TMS involves daily weekday treatments for 6-8 weeks. These treatments are targeted using each person's scalp measurements. With conventional TMS, approximately 50-55% of people show a 50% or more improvement in depressive symptoms (in other words, they "respond" to treatment).
Studies are trying to make TMS work better and faster. A new form of TMS called accelerated TMS (aTMS) involves mutliple treatments a day. One specific aTMS protocol involves 10 treatments per day for 5 days. These treatments are targeted using each person's brain scan (magentic resonance imaging, MRI). With this specific aTMS protocol, approximately 70-90% of people show a 50% or more imporvement in depressive symptoms. While these results are exciting, scientists are not sure why this specific aTMS protocol works better than conventional TMS. It could be the dose and schedule of treatment, or it could be the MRI-based targeting. Answering this question is important because MRI-based targeting is expensive and difficult to do in many settings.
This study aims to determine if MRI-based targeting is better than scalp-based targeting for aTMS for depression. In this study, everyone who enrolls and meets criteria will be randomly assigned to MRI- versus scalp-based aTMS targeting.
- Detailed Description
Major depressive disorder (MDD) remains a leading cause of global disease burden and disability. In addition to increasing the risk of death by suicide, MDD also shows a graded positive association with all-cause mortality. Antidepressants are the most frequently prescribed medication class in psychiatry and, once started, are often continued for many year. However, antidepressants have a small-to-moderate effect size that might be inflated by publication bias. Most people with MDD do not achieve remission with their first antidepressant, and the probability of getting well and staying well diminishes with each sequential trial. By the fourth trial, remission rates approach single digits. Depression that does not improve with one or more antidepressant classes is often considered "difficult-to-treat" or "treatment-resistant" depression (TRD). Taken together, these data highlight the need for better and faster treatments for TRD.
TMS for TRD is safe, well-tolerated, and often covered by insurance. Unlike esketamine and ECT, TMS does not require supervised transportation after treatment. However, TMS is: 1) time intensive, requiring daily weekday treatments for 6-8 weeks; 2) imprecisely targeted based on scalp measurements, which means that each person is stimulated at a slightly different site; and 3) ineffective approximately half the time, with response and remission rates around 50% and 33%, respectively. A new form of accelerated TMS (aTMS) by Cole et. al was designed to address these limitations. In the open-label trial (n=21), the Cole et a. protocol significantly reduced Montgomery-Åsberg Depression Rating Scale (MADRS) in a single day and resulted in a 79.5% reduction one month after treatment. Remission rates were 86% and 57% one week and one month after open-label aTMS, respectively. From this perspective, this specific aTMS protocol works better and faster than conventional TMS and even rivals ECT. The only double-blind randomized controlled trial of this Cole et al. protocol was discontinued after an interim analysis (n=29) revealed a large effect size (Cohen's d\>0.8) for active vs. sham (52.5% vs. 11.1% MADRS reduction, respectively). In this trial, remission rates were 57% and 46% one week and month after active aTMS, respectively. There are also emerging data on retreatment and durability. In a recent open-label extension study (n=27), 91% of people who achieved remission with an index course of this specific aTMS protocol (n=22) also achieved remission with aTMS retreatment 6 months later.
In July 2023, we launched the "AINT Trial" (NCT05680727). Our goal was to calculate an effect size to power a confirmatory trial. We matched Cole et al. on schedule, dose, intensity, and precision. We also matched Cole et al. inclusion/exclusion criteria (based on published trials and feedback from Stanford colleagues) and its primary outcome measure (i.e., MADRS reduction (% change) one month after aTMS). The goal was to isolate the variable of targeting. Based on our results (in preparation), a sample size of 40 per group will provide \~95% power to detect a between-group difference. Therefore, this study will be a fully powered, double-blind, confirmatory efficacy trial (n=80) for imaging- vs. scalp-targeted aTMS for TRD.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 160
-
Age 22-80
-
English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
-
Primary diagnosis of major depressive disorder per DSM-V criteria (Quick Structured Clinical Interview for DSM-5)
- >20 on Beck Depression Inventory (BDI)
- >20 on the Montgomery-Åsberg Depression Rating Scale (MADRS)
- 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 until the 1-month post-treatment visit.
-
Primary clinician (e.g. psychiatrist, therapist, psychologist, APRN, PA, etc.) responsible for psychiatric care before, during, and after the trial
-
Agreement to lifestyle considerations
- Abstain from becoming pregnant from screening to one-month after treatment (the MRI visit)
- Continue usual intake patterns of caffeine- or xanthine-containing products (e.g. coffee, tea, soft drinks, chocolate) throughout treatment
- Abstain from alcohol, tobacco, and recreational drugs for at least 24 hours before the start of each MRI and TMS session
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Montgomery-Åsberg Depression Rating Scale (MADRS) Baseline to one month post treatment Depression severity rating scale (0-60, higher numbers indicate higher depressive symptom severity). The MADRS is a clinician rated scale consisting of 10 items, with each item scored on a 7 point scale.
For the primary outcome, we will assess MADRS as a continuous variable (i.e., MADRS change from baseline to one month after treatment) using a mixed-effects model for repeated measures (MMRM). The model will include group assignment, baseline MADRS score, assessment time point, and time point by treatment interaction as explanatory variables.
- Secondary Outcome Measures
Name Time Method Montgomery-Åsberg Depression Rating Scale (MADRS) Baseline to one month post treatment Depression severity rating scale (0-60, higher numbers indicate higher depressive symptom severity). The MADRS is a clinician rated scale consisting of 10 items, with each item scored on a 7 point scale. For the secondary outcomes, we will assess MADRS as a categorical variable (i.e., MADRS response defined as ≥ 50% improvement one month after treatment) using a generalized estimating equations approach (GEE).
Relationship between treatment target location and response in scalp-targeted aTMS for MDD Before treatment to 1 month post treatment The correlation between clinical improvement (i.e., BDI-II) and the distance between the actual (stimulated) scalp-based target and the (predicted but not stimulated) imaging-based target. The BDI-II is a depression severity rating scales (0-63, higher numbers indicate higher severity).
Mediation analyses that includes the mediator variable (i.e., distance) in the multivariable model for the outcome (i.e., MADRS improvement). We will implement a form (i.e., counterfactual-based) causal mediation analysis that estimates the controlled direct and indirect effects and the bias-corrected bootstrap confidence intervals while controlling for confounders such as age, sex, and other related variables (e.g., baseline antidepressant use, etc.).