Accelerated Intermittent Theta-Burst Stimulation and Treatment-Refractory Bipolar Depression

Importance Bipolar disorder (BD) is chronic and disabling, with depression accounting for the majority of time with illness. Recent research demonstrated a transformative advance in the clinical efficacy of transcranial magnetic stimulation for treatment-resistant major depressive disorder (MDD) using an accelerated schedule of intermittent theta-burst stimulation (aiTBS), but the effectiveness of this treatment for treatment-refractory BD is unknown. Objective To evaluate the effectiveness of aiTBS for treatment-refractory BD. Design, Setting, and Participants This randomized clinical trial, conducted from March 2022 to February 2024, included individuals with treatment-resistant BD with moderate to severe depressive episodes referred from the Penn Bipolar outpatient clinic. Included patients had 2 or more prior failed antidepressant trials by Antidepressant Treatment History Form criteria and no other primary psychiatric diagnosis, were receiving a mood stabilizer for 4 or more weeks, and had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher. Intervention Prior to treatment, resting-state functional magnetic resonance imaging was used to compute personalized left dorsolateral prefrontal cortex target by connectivity to subgenual anterior cingulate cortex. Patients were randomized 1:1 to 10 sessions per day of imaging-guided active or sham aiTBS for 5 days with 1 session per hour at 90% resting motor threshold for 90 000 pulses total. Main Outcome and Measures The main outcome was repeated MADRS scores before and after treatment. Results A total of 24 participants (12 50% female; 12 50% male; mean SD age, 43.3 16.9 years) were randomized to active (n = 12) or sham (n = 12) aiTBS. All participants completed treatment and 1-month follow-up. MADRS scores were significantly lower in the active group (mean SD, 30.4 4.8 at baseline; 10.5 6.7 after treatment) than in the sham group (28.0 5.4 at baseline; 25.3 6.7 after treatment) at treatment end (estimated difference, –14.75; 95% CI, –19.73 to –9.77; P lt; .001; Cohen d , –2.19). Conclusion and Relevance In this randomized clinical trial, aiTBS was more effective than sham stimulation for depressive symptom reduction in patients with treatment-resistant BD. Further trials are needed to determine aiTBS durability and to compare with other treatments. Trial Registration ClinicalTrials.gov Identifier: NCT05228457