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Individuals with bipolar disorder spend significantly more time depressed than manic, and treatment alternatives for treatment-resistant patients are greatly needed. Although the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) intermittent theta-burst stimulation (iTBS) protocol has shown efficacy in unipolar depression, its utility in bipolar depression remains largely unexplored. This study aims to assess the feasibility and safety of SAINT in patients with bipolar I depression that have failed to respond to a first-line treatment and examine underlying neural mechanisms of treatment response.

Ten participants with bipolar I disorder underwent a modified SAINT protocol in this open-label study. Depressive and manic symptoms were assessed throughout. Personalized left dorsolateral prefrontal cortex (DLPFC) stimulation targets exhibiting negative resting-state connectivity with the subgenual anterior cingulate cortex (sgACC) were generated using resting-state functional MRI. We then investigated changes in resting-state (DLPFC and sgACC) seed-to-whole brain connectivity, and its relationship to treatment response.

Immediately post-treatment, depressive symptoms decreased by an average of 56.7 (SD=19.7%)%. Following treatment, participants exhibited increased connectivity between sgACC and two bilateral frontal pole clusters. Greater reductions in depressive severity were significantly associated with increased negative connectivity between left DLPFC target seed and four clusters in prefrontal and temporal cortices.

SAINT iTBS was well-tolerated in a bipolar I depression sample and associated with sgACC functional connectivity changes. Increased negative connectivity between the DLPFC target and prefrontal/temporal cortex was associated with treatment response. Larger, sham-controlled studies are needed to confirm these findings and explore predictors of treatment response in bipolar depression.