Published research is providing additional evidence of the effectiveness and safety of rapid-acting non-invasive brain stimulation therapy to treat people suffering from bipolar depression.

Bipolar disorder (BD) involves fluctuations in in mood and energy that can result in severe cognitive and functional impairment. High-energy moods (mania or less intense hypomania) can be treated with lithium or anticonvulsants. Depressive moods are treated with a variety of medications. Although patterns can vary greatly from patient to patient, on average, bipolar disorder patients are in the “depressive phase” of the illness between 70% to 80% of the time, and a significant number do not respond satisfactorily or cannot tolerate drug therapies which include mood stabilizers, antidepressants, and antipsychotic medicines. There is also the issue of testing potential drug therapies one by one to see by trial and error which (if any) are effective. Each trial takes weeks and costs the patient more time.

The emerging evidence regarding use of rapid-acting non-invasive brain stimulation to treat bipolar depression is of particular importance given the greatly elevated risk of suicide among adults with BD (estimated at 10% - 15% or higher). The new evidence is about a protocol called SAINT (Stanford Accelerated Intelligent Neuromodulation Therapy), pioneered by BBRF grantee and prize winner Nolan R. Williams, M.D., of Stanford University.

As Dr. Williams and colleagues reported beginning in 2018, SAINT, non-invasively delivering 90,000 magnetic pulses to modify cortical activity over the course of only 5 days, has had remarkable efficacy in small initial trials, enabling a majority of patients with severe, refractory depression to achieve remission in just days. SAINT was approved for commercialization by the FDA for use in depression early in 2024.

SAINT uses an accelerated form of iTBS (aiTBS: accelerated intermittent theta-burst stimulation), which delivers five times as many magnetic pulses to patients than conventional TMS (transcranial magnetic stimulation) in a course of therapy. TMS, pioneered by BBRF Scientific Council member and past grantee Mark S. George, M.D. and others and approved by the FDA in 2009, is usually given five times a week in 38-minute sessions over 4-6 weeks. In SAINT, over a 5-day course, ten stimulation sessions are given each day separated by about an hour.

SAINT is individually targeted. A resting-state functional MRI scan of the patient’s brain made prior to treatment provides an optimized location at which to focus the stimulation. Dr. Williams and colleagues aim the pulses at a spot on the scalp above the left dorsolateral prefrontal cortex (DLPFC) that, when stimulated, generates a specific neural response in a brain area much farther below the scalp called the subgenual anterior cingulate cortex (sgACC). Precise targeting, Dr. Williams and colleagues believe, can enhance the therapeutic impact in patients receiving SAINT.

The approach has been highly effective in treating patients with unipolar depression (i.e., patients with a major depression diagnosis, as opposed to BD, which also involves episodes of mania/hypomania).

In July, BBRF Scientific Council member and three-time grantee Yvette I. Sheline, M.D., and colleagues at the University of Pennsylvania, reported on a randomized, blinded aiTBS clinical trial involving 24 patients currently experiencing a depressive bipolar episode that had not responded to prior treatment attempts. That trial generated “a large antidepressant effect” in patients who received the therapy, whose depression scores “were significantly lower” after 5 days of treatment. Five of 12 patients receiving the active treatment had achieved a remission at that point. That trial utilized an identical aiTBS stimulation approach to SAINT and a similar resting-state fMRI targeting approach.

Now, in the Journal of Affective Disorders, Dr. Williams and colleagues at Stanford and Johns Hopkins Universities have reported similarly impressive results with SAINT in treatment-resistant bipolar depression. SAINT was not paired in this “open-label” trial with an alternate or placebo treatment; all 10 patients knew the treatment they were receiving. Each patient was carefully monitored for possible “emergent” mania symptoms, which in past conventional rTMS trials had been observed in rare cases.

All of the patients were able to receive all of the planned treatment sessions over the 5 days of the trial. There were no serious adverse side effects including an absence of emergent mania symptoms, and no negative impact on cognition. Importantly, SAINT appeared to work just as powerfully as it had in the past for unipolar depression patients.

The participants, who were rated with moderate to severe bipolar depression that had resisted treatment in the current episode, had an average reduction of about 17 points on a depression scale called MADRS. (The typical participant had entered the trial with a score of about 30.) Immediately following the end of the 5-day course of treatment, half the participants had experienced a response (defined as a reduction in depression symptoms of 50% or more); 40% qualified for remission (in essence, the absence of depression symptoms). The remission rate grew to 60% one month following the completion of treatments.

All of the participants in the SAINT trial were diagnosed with bipolar I depression—they had been diagnosed on the basis of experiences of depression and full mania. Several months earlier, another small open-label SAINT study conducted by Dr. Williams and Stanford and Johns Hopkins colleagues included 2 patients with bipolar I (depression and mania) as wells as 5 patients diagnosed with bipolar II (depression and hypomania—a less intense form of mania). As reported in the journal Brain Stimulation, this study also generated impressive results: large decreases in depression scores, remissions in some patients, and an absence of severe side effects, including an absence of emergent hypo/mania.

Having now shown powerful preliminary results (in terms of safety, tolerability, feasibility, and efficacy) with individuals with moderate and severe bipolar depression—patients with both bipolar I and bipolar II diagnoses—Dr. Williams and colleagues in both recent publications say the time is right for much larger, double-blind, placebo-controlled trials for SAINT in bipolar depression, with larger and more diverse patient samples needed to confirm both efficacy and safety.

While there are “a few first-line treatment options for bipolar depression,” they noted in one of their recent papers, “none are rapid-acting.” SAINT, if one day approved for depression in BD, would address both “the time constraints posed by 4-6 week conventional rTMS course and the need for fast-acting treatments for acute suicidality in high-risk populations,” they noted.

In addition to Dr. Williams, who is the BBRF 2024 Colvin Prize winner for Outstanding Achievement in Mood Disorders Research, 2019 BBRF Klerman Prize winner for Exceptional Clinical Research, and a 2018 and 2016 BBRF Young Investigator, the team in the Journal of Affective Disorders paper included Peter Zandi, Ph.D., MPH, MHS, a 2004 BBRF Young Investigator. First author on that paper was Dr. Kevin Li, of Johns Hopkins. First author on the Brain Stimulation publication was Dr. Kristin S. Raj.