Effectiveness of Clustered Versus Tapered Repetitive Transcranial Magnetic Stimulation (rTMS) as Maintenance Therapy Following Successful Acute rTMS Treatment in Patients With Depressive Syndrome

Repetitive transcranial magnetic stimulation (rTMS), including intermittent theta burst stimulation (iTBS), is an established treatment for depressive disorders. While the efficacy of acute treatment has been demonstrated in numerous clinical trials, a substantial proportion of patients experience symptom worsening or relapse following successful acute treatment if no maintenance therapy is provided. Several maintenance strategies have been proposed, including tapered treatment schedules with gradually decreasing treatment frequency and clustered treatment schedules consisting of repeated blocks of consecutive stimulation sessions. However, the available evidence is limited, and no randomized controlled trial has directly compared these two maintenance approaches using identical treatment duration and the same total number of stimulation sessions.

This prospective, randomized, controlled, two-center study aims to compare two maintenance treatment strategies following successful acute iTBS in adults with depressive syndrome. Patients who achieve response or remission after a standardized acute iTBS treatment course will be randomized in a 1:1 ratio to either a tapered maintenance protocol or a clustered maintenance protocol. Randomization will be stratified by study site and baseline depression severity. Because of the different treatment protocols, blinding of participants and treating clinicians is not feasible. MRI data analyses will be performed blinded to treatment allocation.

Both maintenance protocols include 20 stimulation sessions delivered over a 20-week maintenance period following a four-week stimulation-free interval after completion of the acute treatment phase. The treatment protocols differ only in the temporal distribution of maintenance sessions. The tapered protocol gradually reduces treatment frequency over time, whereas the clustered protocol delivers stimulation in four clusters of five consecutive daily sessions.

The primary objective is to compare the time to depressive relapse or clinically relevant symptom worsening during the 24-week follow-up period. Clinically relevant symptom worsening is defined using predefined changes in the Montgomery-Åsberg Depression Rating Scale (MADRS), and relapse is defined as the recurrence of at least moderate depressive symptoms together with loss of the previously achieved treatment response.

Secondary objectives include comparing longitudinal changes in depressive symptom severity, patient-reported depressive symptoms, global clinical status, and psychosocial functioning using the MADRS, Beck Depression Inventory (BDI), Clinical Global Impression (CGI), and Global Assessment of Functioning (GAF), respectively.

An additional objective of the study is to investigate neurobiological correlates of maintenance treatment using multimodal magnetic resonance imaging (MRI). At the Munich study site, participants will be offered optional multimodal MRI examinations. Participation in the MRI component is voluntary and is not required for participation in the clinical trial. MRI assessments include resting-state functional MRI, arterial spin labeling, diffusion imaging including NODDI, and quantitative MRI. These analyses aim to identify imaging biomarkers associated with maintenance of antidepressant effects, symptom worsening, and relapse risk following maintenance iTBS. Participation in the MRI component is optional and is not required for participation in the clinical trial.

• Change in Montgomery-Åsberg Depression Rating Scale Total Score [Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24]
• Change in Beck Depression Inventory II Total Score [Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24]
• Change in Global Assessment of Functioning Score (GAF) [Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24]
• Change in Clinical Global Impression Score (CGI) [Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24]
• Change in Resting-State Functional Connectivity [Time frame: During Maintenance rtMS Week 0-24]
• Change in Cerebral Perfusion Measured by Arterial Spin Labeling [Time frame: During maintenance treatment week 0-24]
• Change in Diffusion MRI Measures of Structural Connectivity and Microstructure [Time frame: during maintenance treatment week 0 to 24]
• Change in Quantitative MRI Parameters [Time frame: During maintenance treatment week 0-24]