Clinical and neural effects of a hybrid accelerated–maintenance iTBS protocol in adolescents with major depressive disorder

Intermittent theta burst stimulation (iTBS) has emerged as a safe and effective intervention for adolescents with major depressive disorder (MDD). While accelerated iTBS can induce rapid clinical improvement, intensive multi-day treatment schedules may present practical challenges for adolescents and their families, potentially affecting treatment adherence. This underscores the need for more flexible and feasible treatment strategies. This study evaluated the clinical efficacy of a hybrid accelerated–maintenance iTBS protocol, further explored treatment-related neural effects, and additionally examined the effects of accelerated iTBS beyond nonspecific factors. A total of 32 adolescents with MDD underwent a two-day accelerated phase followed by a four-week maintenance phase. Clinical and neuroimaging assessments were performed at baseline, after the accelerated phase, and at study completion, with 34 age- and sex-matched healthy controls (HCs) providing baseline data for comparison. The results showed that Montgomery–Åsberg Depression Rating Scale (MADRS) scores decreased significantly following treatment in adolescents with MDD ( F (2,85) = 33.50, p < 0.001), with response and remission rates reaching 62.5 and 54.2%, respectively. Neuroimaging analyses at baseline revealed widespread alterations in amplitude of low-frequency fluctuations and functional connectivity across large-scale brain networks in adolescents with MDD. Following treatment, most alterations changed significantly and were no longer significantly different from those in HCs. In addition, supplementary analyses indicated significantly greater reductions in MADRS scores with active accelerated iTBS than with sham stimulation. These findings provide preliminary evidence for the utility of a hybrid accelerated–maintenance iTBS protocol in adolescents with MDD and insights into the neuroimaging mechanisms underlying treatment response.