Efficacy and Safety of Acute Followed by Maintenance rTMS in Treatment Resistant Depression: A Randomized Controlled Trial

Treatment-resistant depression (TRD) is a major cause of disability and is associated with persistent symptoms, reduced quality of life, increased healthcare utilization, and a high risk of relapse despite evidence-based treatment. Although repetitive transcranial magnetic stimulation (rTMS) is an established treatment for TRD, many patients experience recurrence of depressive symptoms after completion of the acute treatment course. At present, there is no universally accepted maintenance strategy following successful acute rTMS.

Maintenance rTMS has shown promise in reducing relapse; however, existing randomized studies have primarily compared maintenance rTMS with sham stimulation, antidepressants, or lithium. No randomized controlled trial has directly compared maintenance accelerated intermittent theta burst stimulation (aiTBS) with quetiapine augmentation, despite quetiapine having Level 1 evidence as an augmentation strategy for TRD in the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines. This represents an important gap in evidence for long-term management following acute neuromodulation.

The present study is a hospital-based, investigator-initiated, randomized, open-label, rater-blinded, parallel-group clinical trial conducted at the Department of Psychiatry, AIIMS Bhubaneswar. All participants will receive an acute course of accelerated intermittent theta burst stimulation while continuing treatment as usual (TAU). Following completion of the acute phase, participants will be randomly allocated to receive either maintenance aiTBS or quetiapine augmentation in addition to TAU. This design allows direct comparison of two evidence-based maintenance approaches after a common acute neuromodulation intervention.

The study will evaluate whether maintenance aiTBS provides sustained clinical benefit comparable or superior to quetiapine augmentation while maintaining an acceptable safety profile. In addition to clinical assessments, the study will examine changes in serum brain-derived neurotrophic factor (BDNF), a biomarker associated with neuroplasticity, to explore its relationship with treatment response during the maintenance phase.

The findings from this trial are expected to provide evidence regarding the comparative effectiveness and safety of maintenance neuromodulation versus pharmacological augmentation after acute rTMS in treatment-resistant depression. The results may help inform future maintenance treatment strategies and improve long-term outcomes for individuals with TRD.