Comparative effects of intermittent theta-burst stimulation and sequential bilateral rTMS on depression and emotion regulation in major depressive disorder: a randomized controlled trial

Background Major depressive disorder (MDD) is associated with dysfunction in prefrontal–limbic circuits, particularly involving deficits in emotion regulation. Non-invasive brain stimulation, including sequential bilateral repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS), targets these circuits, but comparative efficacy and mechanistic underpinnings remain unclear. Methods In this randomized controlled trial, 114 patients with MDD were recruited, and 106 completed the study. Participants were randomly assigned (1:1) to receive either sequential bilateral rTMS ( n = 50) or iTBS ( n = 56) over 2 weeks. Primary outcome was change in Hamilton depression rating scale (HAMD) scores. Secondary outcomes included changes in cognitive reappraisal, expressive suppression, anhedonia (SHAPS), anxiety (HAMA), and other psychobehavioral measures. Bonferroni correction was applied to adjust for multiple comparisons across secondary outcome measures. All change scores were calculated as baseline minus post-treatment values. Associations between changes in cognitive reappraisal and depressive symptoms were assessed using generalized linear models. Results Baseline demographic and clinical characteristics were comparable between groups. Following treatment, iTBS elicited significantly greater reductions in depressive symptoms (HAMD: 14.88 ± 5.25 vs. 7.88 ± 5.26; P < 0.001) and improvements in cognitive reappraisal (−10.36 ± 6.49 vs. −3.54 ± 4.41; P < 0.001, significant after Bonferroni correction) compared with sequential bilateral rTMS. iTBS also produced larger decreases in expressive suppression and anxiety. In the iTBS group, improvements in cognitive reappraisal were significantly associated with reductions in depressive symptoms ( B = −0.324, P = 0.001), whereas no such association was observed in the sequential bilateral rTMS group. Conclusion Intermittent theta-burst stimulation targeting the left dorsolateral prefrontal cortex induces more pronounced improvements in depressive symptoms and cognitive reappraisal than sequential bilateral rTMS, likely associated with potentiation of left prefrontal emotion-regulatory circuits. Sequential bilateral rTMS also provides therapeutic benefit, possibly through restoring interhemispheric balance.