Enhancing effect of cognitive control training on rTMS treatment in depression: A study protocol for a multicenter randomized controlled trial

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), yet some patients only show partial or no response. Recent efforts to enhance rTMS efficacy have focused on combining rTMS with adjunctive interventions, such as psychotherapy, which may yield synergistic effects rather than merely additive effects. Cognitive control training (CCT) activates similar underlying neural circuits as rTMS and has demonstrated antidepressant potential. Given the time-intensive nature of rTMS, augmenting it with CCT may offer a pragmatic, time-efficient and potentially cost-effective solution to increase the therapeutic response of rTMS. This study aims to investigate whether rTMS augmented with CCT is more (cost-) effective in reducing depressive symptoms as opposed to rTMS alone. Methods: In this international multicenter clinical trial, 132 adult patients with depression will be randomized to receive rTMS either augmented with CCT or placebo task. The trial consists 30 rTMS sessions over eight weeks, followed by a follow-up period up to one year. The primary outcome is the change in depressive severity, assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17) after eight weeks of treatment. Secondary outcomes include an economic evaluation and response and remission after 8 weeks of treatment as well as during follow-up. Discussion: The present study aims to improve the (cost-)effectiveness of rTMS by concurrently combining rTMS with CCT. Findings may support the development of more cost-effective, personalized interventions for the treatment of depression. Trial registration: This trial is registered within the Overview of medical research in the Netherlands, OMON (code: NL-OMON57187, date: 18 December 2024).