{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:34:00Z","timestamp":1789702440742,"version":"4.0.1"},"posted":{"date-parts":[[2026,1,13]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,4]]},"abstract":"<jats:p>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 \u226550% reduction in the Montgomery-\u00c5sberg 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.<\/jats:p>","DOI":"10.64898\/2026.01.11.26343900","type":"posted-content","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T17:05:13Z","timestamp":1768323913000},"source":"Crossref","is-referenced-by-count":3,"title":["Efficacy of Personalized Connectivity-Guided Accelerated Brain Stimulation in a Naturalistic Treatment-Resistant Depression Population"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-0329","authenticated-orcid":false,"given":"Ru","family":"Kong","sequence":"first","affiliation":[{"name":"National University of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-3418","authenticated-orcid":false,"given":"Xiao Wei","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Mental Health;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7907-8594","authenticated-orcid":false,"given":"Aihuiping","family":"Xue","sequence":"additional","affiliation":[{"name":"National University of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3546-4580","authenticated-orcid":false,"given":"Leon Qi Rong","family":"Ooi","sequence":"additional","affiliation":[{"name":"National University of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih Ee","family":"Goh","sequence":"additional","affiliation":[{"name":"Institute of Mental Health;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan Jie","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Mental Health;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4376-5765","authenticated-orcid":false,"given":"Jingwen","family":"Cheng","sequence":"additional","affiliation":[{"name":"National University of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3732-4768","authenticated-orcid":false,"given":"Trevor Wei Kiat","family":"Tan","sequence":"additional","affiliation":[{"name":"National University of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Si Yun","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Mental Health;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1498-909X","authenticated-orcid":false,"given":"Jovi Zheng Jie","family":"Koh","sequence":"additional","affiliation":[{"name":"Institute of Mental Health;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasvinjit Kaur Gulwant","family":"Singh","sequence":"additional","affiliation":[{"name":"Institute of Mental Health;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6884-1863","authenticated-orcid":false,"given":"Jia Hui","family":"Chai","sequence":"additional","affiliation":[{"name":"Singapore Clinical Research Institute;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6828-5856","authenticated-orcid":false,"given":"Luming","family":"Shi","sequence":"additional","affiliation":[{"name":"Singapore Clinical Research Institute;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0967-9289","authenticated-orcid":false,"given":"Shan","family":"Siddiqi","sequence":"additional","affiliation":[{"name":"Harvard Medical School;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-3276","authenticated-orcid":false,"given":"B.T. Thomas","family":"Yeo","sequence":"additional","affiliation":[{"name":"National University of Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-3030","authenticated-orcid":false,"given":"Phern-Chern","family":"Tor","sequence":"additional","affiliation":[{"name":"National University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.11.26343900","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T00:00:13Z","timestamp":1775347213000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.01.11.26343900"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.01.11.26343900","relation":{},"subject":[],"published":{"date-parts":[[2026,1,13]]},"subtype":"preprint"}}