fMRI-guided V1-targeted rTMS improves depressive symptoms in adolescents and young adults with bipolar disorder: a double-blind randomized controlled trial

Background Bipolar depression (BD-D) in adolescents and young adults is associated with disrupted neural circuits underlying affective regulation, particularly those involving the orbitofrontal cortex (OFC). Despite the promise of repetitive transcranial magnetic stimulation (rTMS) as a non-invasive intervention, effective targeting strategies that engage these dysfunctional circuits remain insufficiently explored. This study investigates the clinical efficacy of a novel rTMS protocol targeting the primary visual cortex (V1) node of the V1-OFC functional circuit in adolescents and young adults with BD-D. Methods We conducted a double-blind randomized controlled trial. Fifty-two adolescents and young adults BD-D participants were randomized to active rTMS group (10 Hz, 100% RMT) or sham rTMS group (20% RMT) targeting the V1 region that exhibited the strongest functional connectivity with the OFC (MNI: − 12, − 81, 6). rTMS was administered over 3 weeks (5 sessions/week, 15 sessions in total), with all participants receiving adjunctive lurasidone (40–80 mg/day). The primary outcome was the change in depressive symptoms measured by the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline, week 3, and week 8. Secondary outcomes included HAMD-24, QIDS-SR, and HAMA. Resting-state fMRI was performed at baseline and after the 3-week intervention to examine changes in functional connectivity related to rTMS. Results A total of 43 participants completed a 3-week intervention, and 37 completed the 8-week follow-up. Compared with the sham group, the active rTMS group showed significantly greater reductions in depressive symptoms. Between-group differences were significant on the primary outcome MADRS at week 8 (t(35) = − 3.595, pFDR < 0.01), with a parallel effect detected for the secondary outcome on the QIDS-SR (t(35) = − 3.653, pFDR < 0.01). HAMD-24 scores also differed significantly at week 3 (t(35) = − 3.921, pFDR < 0.01). No significant changes were found in anxiety symptoms. Resting-state fMRI indicated altered connectivity in the anterior cingulate cortex and right superior occipital gyrus, suggesting modulation of mood-related visual circuits. No severe adverse effects were reported in all participants. Conclusions The study preliminarily demonstrated that the navigated rTMS precisely targeting the V1-OFC circuit may be a safe and potentially effective intervention for adolescents and young adults with BD-D. Trial registration ClinicalTrials.gov identifier: NCT05929183.