Efficacy of Personalized Connectivity-Guided Accelerated Brain Stimulation in a Naturalistic Treatment-Resistant Depression Population

Personalized connectivity-guided accelerated intermittent theta burst stimulation (iTBS), like the Stanford Accelerated Intelligent Neuromodulation Therapy (SNT), shows high efficacy for treatment-resistant depression (TRD) in Western cohorts. However, generalizability to other demographics with substantial comorbidity remains unclear. Here, we evaluate connectivity-guided iTBS in a naturalistic Asian TRD population with high comorbidity burden. Twenty TRD participants received 50 sessions of TAO-TMS (Tree-based Algorithm for Optimized Transcranial Magnetic Stimulation) over 5 days. Participants averaged 1.6 psychiatric comorbidities, including personality disorders, autism and obsessive-compulsive disorder. TAO-TMS personalizes targets within attentional networks and maximize anti-correlation with the subgenual anterior cingulate cortex. Its near-scalp targets reduce stimulation intensity under the SNT protocol, improving patient comfort. Clinical response was defined as ≥50% reduction in the Montgomery-Åsberg Depression Rating Scale within four weeks of treatment. TAO-TMS yielded 70% response rate. Among patients who met typical randomized-trial eligibility criteria (N = 11), response rate was 83%. For context, non-accelerated BeamF3 TMS at the same hospital historically achieved response rate of 21%, indicating a patient population profile less responsive to TMS than those recruited in typical clinical trials. Post-hoc electric-field modeling showed that TAO-TMS improved network focality by 21% over BeamF3 targets. Functional connectivity changes were significant within every participant, but highly heterogeneous across participants. TAO-TMS was more cost-effective than electroconvulsive therapy (ECT), saving US$37,838 with higher quality-adjusted life years (QALYs 0.69 vs 0.65). These findings provide early evidence for the generalizability of connectivity-guided personalized TMS in a naturalistic Asian TRD population with substantial psychiatric comorbidities. TAO-TMS offers a cost-effective alternative to ECT, positioning it as a viable precision psychiatry intervention.