SAINT iTBS Protocol Shows Promise for Bipolar I Depression

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The Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT),¹ a refined, rapidly acting protocol of repetitive transcranial magnetic stimulation (rTMS) approved for treatment-resistant major depressive disorder,² has now demonstrated promise for reducing depressive symptoms of bipolar I disorder in an open-label, feasibility and safety trial.³

“We found that SAINT rapidly reduced depressive symptoms with 60% of participants meeting remission criteria during the 1-month period following treatment,” reported lead author Kevin Li, MD, Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine Baltimore, MD, and colleagues.

“Moreover, the treatment was not associated with adverse cognitive or other side effects, including the emergence of manic symptoms,” Li and colleagues added.

Brandon Bentzley, MD, PhD, cofounder and chief scientific officer, Burlingame, CA, the licensee of the SAINT protocol, remarked on the importance of investigating possible application for patients with bipolar disorder in discussing the trial with Psychiatric Times.

“People with bipolar 1 disorder spend much more time in depressive episodes than manic episodes. Depression causes severe disability to those who suffer from bipolar I disorder, and many do not benefit or cannot tolerate current treatments for their bipolar I depression,” Bentzley said.

The investigators identified 14 patients with bipolar I disorder experiencing moderate to severe depression unrelieved by antidepressant treatment at the 2 study sites at Johns Hopkins University and the University of Texas at Austin. Four of the candidates were excluded due to a current mixed episode, severe ongoing cannabis abuse, an insufficient prior antidepressant trial, or a manic episode with the prior 6 months.

The 10 trial participants, 6 of them female, were White and ranged between 21 to 63 years of age. At screening, each of the participants was experiencing a major depressive episode (MADRS score greater than 20) while on an antidepressant and had been on an antimanic agent at adequate dose and without dose change for at least 6 weeks. Additional requirements of participation were a minimum of 6 months since the last manic or hypomanic episode and 3 months since electroconvulsive therapy.

In the SAINT protocol, participants undergo structural and resting-state functional magnetic resonance imaging (fMRI) to identify the target above the scalp to focus intermittent theta burst stimulation (iTBS) above the dorsolateral prefrontal cortex (DLPFC). Participants underwent 10 sessions of the targeted iTBS daily, with 50-minute intervals, for up to 5 days.

A battery of measures was applied at baseline, immediately after completion of the iTBS series and at 1 month follow-up. The study primary outcome was change in MADRS score from baseline. Secondary outcomes included rates of clinical response (MADRS score reduction of greater than or equal to 50%) and remission (MADRS score of 10 or less). The possible emergence of mania/hypomania was evaluated with the Young Mania Rating Scale at the beginning and end of each treatment day.

Li and colleagues reported a mean reduction of 16.9 in MADRS scores, with a 50% response rate and 40% remission rate immediately after treatment. Remission criteria were met by 60% of participants within the 1-month follow-up period. No serious adverse events, manic episodes, or cognitive adverse effects were reported.

"We are very pleased by the outcomes of this pilot trial, especially given that the participants all had already tried first-line medication treatments for their depression, without improvement in their conditions, even after months-to-years of treatment," Bentzley commented.

SAINT iTBS Refines rTMS for Depression

In 2022, 14 years after the 2008 US Food and Drug Administration (FDA) approval of an rTMS system for treatment-resistant major depressive disorder,⁴ the FDA approved the SAINT Neuromodulation System (Magnus Medical).² The product name is derived from the SAINT acronym for the protocol developed by Nolan Williams, MD, and colleagues at Stanford University.

Williams, a coauthor of the present study, and colleagues had found that while rTMS magnetic pulses could not directly reach the subgenual anterior cingulate cortex associated with affect, activity in that region could be modulated through stimulation pulses to the DLPFC. Identifying a target point above the scalp with fMRI to maximize effect on the DLPFC was necessary as it varies between individuals.

The SAINT protocol of iTBS administers the same amount of brain stimulation as the weeks-long FDA-approved rTMS regimen but does so within 5 days. Sessions last for 3 minutes compared with 37 minutes in conventional TMS. Ten sessions of iTBS are administered per day for up to 5 days, with 50 minutes separating the sessions.

The administration schedule, Williams recounted in an earlier interview,⁵ was designed to "build upon one another to amplify the antidepressant effect."

In that interview, Williams acknowledged that the use of the fMRI scan to pinpoint the target for stimulation adds to the cost of the procedure. He indicated, however, that it also increases its accuracy and effectiveness, which could be lifesaving in patients with refractory major depression.

The current study is the first to use SAINT in patients with bipolar I depression since its development at Stanford. Li and colleagues consider the findings promising and indicate that further investigation is warranted; suggesting that it be double-blinded, sham-controlled, and conducted with a larger sample size and longer follow-up.

Bentzley confirmed intention to further investigate the SAINT protocol for bipolar depression. “The next step will be a larger clinical trial, and we are currently investigating the best path to undertake this next step,” he said.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Cole EJ, Stimpson RH, Bentzley BS, et al. Stanford accelerated intelligent neuromodulatoin therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-726.

2. Magnus Medical receives FDA clearance for the SAINT neuromodulation system for non-invasive, individualized and precise treatment of severe depression. Magnus Medical. News release. September 6, 2022. Accessed November 1, 2024. https://www.magnusmed.com/press-releases/magnus-medical-receives-fda-clearance-for-the-saint-neuromodulation-system/

3. Li K, Bichlmeier A, DuPont C, et al. Fast depressive symptoms improvement in bipolar 1 disorder after Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT): a two-site feasibility and safety open-label trial. J Affect Disord. 2024;365:359-363.

4. Horvath JC, Mathews J, Demitrack MA, Pascual-Leone A. The NeuroStar TMS device: conducting the FDA approved protocol for treatment of depression. J Vis Exp. 2010;45:2345.

5. Tarr P. FDA clears SAINT rapid-acting brain stimulation approach for those suffering from resistant major depression. Brain & Behavior Research Foundation. September 15, 2022. Accessed November 1, 2024. https://bbrfoundation.org/content/fda-clears-saint-rapid-acting-brain-stimulation-approach-those-suffering-resistant-major