Copenhagen Magnetic Personalized Accelerated Brain Circuit Therapy (CoMPACT) trial: study protocol for a randomized, double-blinded, sham-controlled, three-armed, parallel-group trial of transcranial magnetic stimulation for treatment-resistant depression.

Background: Treatment-resistant depression (TRD), characterized by poor response to conventional antidepressant therapies, remains a major clinical challenge. Repetitive transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (dlPFC) has emerged as a promising alternative. Employing intermittent theta burst stimulation (iTBS), TMS protocols have yielded rapid antidepressant effects in recent accelerated treatment studies. These findings warrant further investigation in larger samples to confirm efficacy and in-depth investigation into the underlying mechanisms. Moreover, other cortical sites may also represent suitable targets for accelerated iTBS treatment of TRD. Methods: This randomized, double-blind, sham-controlled trial will assess the efficacy, feasibility and mechanisms of a novel, personalized, and accelerated iTBS protocol for TRD, targeting two left hemispheric regions, the left dlPFC and inferior parietal lobule (IPL), both characterized by anticorrelated functional connectivity with the subgenual anterior cingulate cortex. 78 adults (aged 18-95 years) will be recruited from Danish mental health centers and randomly assigned to one of three groups: (1) active iTBS of the left dlPFC, (2) active iTBS targeting of the left IPL, or (3) sham iTBS at either site. The intervention includes five daily sessions over five consecutive days. Targeting informed by group-level functional connectivity will be combined with individualized coil placement and stimulation dosing using electric field modeling based on whole-brain anatomical magnetic resonance imaging (MRI). Antidepressant efficacy will be evaluated using the 6-item Hamilton Depression Rating Scale as the primary outcome, assessed at an early post-intervention follow-up (F1) within three days after the final stimulation session. Multimodal post-treatment assessments, including MRI, will be conducted within five days after the intervention (T1). A four-week follow-up (T2) will assess the durability of clinical and cognitive outcomes. Neurophysiological mechanisms will be investigated using electroencephalography as well as structural and functional MRI. Discussion: By testing a novel stimulation protocol and evaluating the efficacy of a new parietal target, this study will help advance the development of innovative, circuit-based interventions for TRD, with potential implications for broader applications across neuropsychiatry. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT06895863.