Sequential bilateral rTMS combined with fluoxetine for anhedonic depression in adolescents: clinical efficacy and peripheral inflammatory profiles.

OBJECTIVE: Adolescent anhedonic depression often fails to respond fully to fluoxetine monotherapy, driven by chronic peripheral inflammation and dysfunctional reward circuits. This study aimed to compare clinical efficacy and inflammatory signatures of fluoxetine alone versus sequential bilateral rTMS plus fluoxetine in adolescents with anhedonic major depression. METHODS: This single-centre 4-week randomised controlled trial recruited 86 Han Chinese adolescents aged 13-18 years meeting DSM-5 major depression with prominent anhedonia, allocated 1:1 to combination (active bilateral rTMS + fluoxetine) and control (sham rTMS + fluoxetine) groups. Eighty-one participants completed treatment. The primary endpoint was the change in ASA-C score; secondary endpoints included changes in HAMD-24 total score, WCST cognitive indices, and plasma IL-1β, IL-6, and TNF-α levels. ANCOVA adjusted for baseline values for intergroup comparisons, with Pearson correlation analysing symptom-cytokine relationships. Adverse events were prospectively monitored. RESULTS: Both groups presented significant within-group improvements in depressive/anhedonic symptoms, cognition and proinflammatory cytokines post-treatment. After baseline adjustment, the combination group showed superior reductions in ASA-C, HAMD-24 and all three cytokines, as well as better executive function (all P < 0.001). Symptom relief magnitudes moderately correlated with cytokine declines in the combination arm. All adverse events were mild and transient; overall event rates did not differ statistically between groups (P = 0.079). CONCLUSION: Adjunct sequential bilateral rTMS yields synergistic benefits for adolescent anhedonic depression by ameliorating core symptoms, restoring executive function and attenuating systemic inflammation. Peripheral IL-1β, IL-6 and TNF-α are viable biomarkers for therapeutic monitoring, and this combined regimen is safe for adolescents with residual anhedonia after fluoxetine monotherapy.