Accelerated Brain Stim Curbs Resistant Bipolar Depression

An accelerated schedule of intermittent theta burst transcranial magnetic stimulation (aiTBS) completed in less than a week is effective for treatment-resistant bipolar depression, the results of a small randomized controlled trial showed.

Investigators found those who received active aiTBS had a substantial decrease in depressive symptoms compared with those who received sham stimulation.

“aiTBS offers a new potential therapy for depressed patients with bipolar disorder who may not respond well to drugs or cannot tolerate their side effects while also significantly shortening the treatment window,” lead researcher Yvette Sheline, MD, director of the Center for Neuromodulation in Depression and Stress at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said in a news release.

The study was published online on July 10 in JAMA Psychiatry.

Remission After 5 Days

As previously reported by Medscape Medical News, the US Food and Drug Administration (FDA) cleared aiTBS to treat major depressive disorder. However, the treatment is not yet approved for bipolar depression.

The investigators assessed the effectiveness of aiTBS in 12 men and 12 women (mean age, 43 years) with treatment-resistant bipolar disorder. All participants were on mood stabilizers for at least 4 weeks and had Montgomery-Åsberg Depression Rating Scale (MADRS) scores of ≥ 20.

Twenty-two of the 24 participants had a diagnosis of bipolar II disorder. Over 5 days, participants were randomized to receive, on a one-to-one basis, 10 sessions per day of imaging-guided active aiTBS or sham aiTBS over the left dorsolateral prefrontal cortex. Each session lasted for 1 hour. All 24 participants completed the assigned treatment and 1-month follow-up.

Active aiTBS was significantly more effective than sham stimulation in relieving depressive symptoms.

In the active treatment group, MADRS scores dropped from a mean of 30.4 at baseline to 10.5 after treatment. In contrast, the sham group experienced a minor change in MADRS scores, which decreased from a mean of 28.0 at baseline to 25.3 posttreatment.

After 5 days of treatment, half of the participants in the active aiTBS group were in remission compared with none in the sham group.

These results demonstrate the “clinical efficacy and a short time to achieve improvement in this difficult-to-treat condition. The effect was seen even though the participant sample had high depression severity and treatment resistance, both associated with poor response,” the investigators noted.

Sheline told Medscape Medical News there were no differences between active and sham stimulation in the “expected adverse events of headache and dizziness. There were no incidences of manic ‘flip’, and the Young Mania Rating Scale scores were stable in both active and sham groups with no difference between them.”

The researchers noted that the “large effect size” of active aiTBS could be due to several factors, including optimized stimulation targeting, accelerated time course, and high pulse number (18,000 per day, 90,000 total).

Future studies are needed to examine the relative contributions of the different protocol components to optimize and personalize treatment and evaluate the durability of the antidepressant effects of aiTBS, they added.

A Revolutionary Approach

For comment on the study, Medscape Medical News reached out to Nolan Williams, MD, associate professor of psychiatry and behavioral sciences at Stanford University and director of the Stanford Brain Stimulation Lab, Stanford, California.

His laboratory pioneered the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), which was cleared by the FDA in 2022 for treatment-resistant depression.

Williams noted that the stimulation and targeting approach used in the current study “mirrors most aspects of the SAINT protocol with very similar results.”

“It’s exciting that we see this kind of pseudo-replication essentially of our work and is supportive of the general view that this approach is revolutionary in its ability to treat people quickly and have such a dramatic clinical effect,” said Williams.

Last spring, Williams and colleagues reported the results of a pilot study of SAINT for bipolar depression, which demonstrated antidepressant efficacy akin to what was observed in the unipolar depression population.

Williams said in his experience, the accelerated treatment protocol is convenient and well-liked by patients and, in general, is where the field of psychiatric treatment is headed.

“A general theme that we see in depression and psychiatry is that patients no longer accept long time frames for treatment as being the norm. Whether it be ketamine or this or the upcoming psychedelics, rapid-acting treatments that match the level of acuity will be the norm,” Williams said.

The study was funded by the Milken Institute and the Baszucki Brain Research Fund. The authors have disclosed no conflicts of interest. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; he has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and he has equity/stock options in Magnus Medical, NeuraWell, and Nooma.