A 3-Month Follow-Up Pilot Study on Accelerated Intermittent Theta Burst Stimulation for Bipolar Depression.

backgroundApproximately 25% of patients with bipolar disorder are reported to have treatment-resistant bipolar depression (TRBD). Accelerated intermittent Theta Burst Stimulation (aiTBS) is an innovative form of repetitive transcranial magnetic stimulation (rTMS), delivering bursts of stimulation at theta wave frequencies, which are believed to enhance synaptic plasticity. This pilot study aimed to explore the safety, tolerability, and preliminary efficacy of aiTBS in individuals with treatment-resistant bipolar depression (TRBD).

methodsThis open-label pilot study (registered at Overview of Medical Research in the Netherlands (OMON), NL-OMON53634), conducted between July 2023 and September 2024, included patients aged 43-64 years who were diagnosed with bipolar I or II and were experiencing a current moderate-to-severe depressive episode. Patients were required to have treatment-refractory symptoms according to the Hidalgo-Mazzei criteria. All patients were receiving antidepressant medication. Patients received eight daily sessions of intermittent Theta Burst Stimulation (iTBS) over five consecutive days, with 50-min intervals between sessions. Stimulation targeted the left dorsolateral prefrontal cortex (DLPFC) using the BeamF3 targeting method. Outcomes included safety, tolerability, and efficacy and were assessed at day 3, day 5, week 2, week 4 and week 12 post-treatment. Safety was assessed by documentation of serious adverse events (SAEs) and adverse events (AEs); tolerability was evaluated based on reported side effects. Efficacy was measured by the mean reduction in depression symptoms using the 17-item Hamilton Depression Rating Scale (HDRS-17).

resultsEight patients were recruited, all of whom completed the treatment course. aiTBS was well tolerated and no SAEs occurred during the treatment week or during follow-up. The most frequently reported AEs were discomfort at the stimulation site and fatigue (87.5%). Although one patient experienced hypomanic symptoms (YMRS = 13) at the 3-month follow-up visit, this was considered unrelated to the study treatment due to the timing of onset, and because several significant psychosocial stressors were identified in the patient's life during that period. Mean HDRS scores decreased from 22.9 (SD = 4.4) at baseline to 16.6 (SD = 4.2) on day 3 of treatment (difference = 6.3 (95% CI, 1.6-10.9); 27.3% improvement, p = 0.01), 12.8 (SD = 4.1) on day 5 (difference = 10.1 (95% CI, 2.2-18.1); 44.3%, p = 0.02), 11.1 (SD = 3.8) at week 2 (difference = 11.8 (95% CI, 4.5-19.0); 51.4%, p = 0.004) and 13.5 (SD = 3.9) at week 4 (difference = 9.4 (95% CI, 1.0-17.7); 41.0% improvement, p = 0.03). At month 3, the mean HDRS score was 13.7 (SD = 6.9, difference compared to baseline = 9.1 (95% CI, -3.0 to 21.3); 40.0% improvement, p = 0.2).

conclusionThis pilot study extends prior evidence suggesting the antidepressant effects, safety, and tolerability of aiTBS in patients with TRBD; however, its durability may be limited. We recommend that future RCTs investigate relapse prevention following acute aiTBS and determine the optimal strategy for maintaining antidepressant effects.