Meta-regression insights for optimizing accelerated neuromodulation protocols in major depression

Accelerated neuromodulation, which involves multiple daily sessions of repetitive transcranial magnetic stimulation (rTMS), is increasingly recognized as a time-efficient and clinically effective treatment for major depressive episodes, including treatment-resistant and bipolar depression. Given the considerable variability in stimulation parameters and therapeutic outcomes, this study aims to provide preliminary insights to optimize accelerated excitatory rTMS protocols for enhanced clinical efficacy. We performed a meta-regression analysis including controlled and uncontrolled trials reporting the effect of high-frequency prefrontal cortex accelerated rTMS (arTMS) and intermittent Theta Burst Stimulation (aiTBS) on depression response rate in patients diagnosed with major depressive disorder, treatment-resistant depression and bipolar depression (both men and women, all ages). The systematic search identified 25 arTMS/aiTBS interventions in depression studies with 5 or more participants, totaling 810 participants and 722 stimulation sessions. Meta-regression analysis revealed a significant dose-response relationship in clinical outcomes. Both a higher number of pulses and a greater total number of sessions (i.e., more than 20) were associated with enhanced antidepressant effects. Additionally, longer intersession intervals (≥50 min) appeared to positively influence treatment effectiveness. No significant differences emerged between stimulation modalities (iTBS vs. arTMS) or methods of target localization. Despite some limitations, these findings provide preliminary evidence of the significant impact that parameter settings in accelerated rTMS protocols have on clinical outcomes, offering valuable guidance for the future optimization of neuromodulation strategies in the treatment of depression.