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.

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, investigators launched the "AINT Trial" (NCT05680727). Our goal was to calculate an effect size to power a confirmatory trial. Investigators matched Cole et al. on schedule, dose, intensity, and precision. Investigators 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.

Inclusion Criteria:

• 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

All study participants 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. The research assistant (RA) marking treatment sites is the only individual unblinded in this study. The unblinded RA will have no other interactions with participants after the treatment preparation visit. RAs delivering treatment with stimulate participants at a coordinate, given to them by the unblinded RA.