Individualized Connectivity-Guided Versus Conventional Targeting of Accelerated Theta-Burst Stimulation in Depression: A Randomized, Double-Blind, Parallel-Design Trial
In brief
Connectivity-guided iTBS reduces depression scores about 9% more than standard targeting
In a double-blind trial of 119 adults with major depressive or bipolar II depression, structural-connectivity guided iTBS lowered Hamilton Depression scores roughly 9 percentage points more than the conventional 5-cm scalp rule after two weeks, with similar safety. The advantage persisted at six weeks but faded by three months, suggesting a short-term benefit that needs longer-term confirmation.
- Journal
- The American journal of psychiatry (Q1)
- Published
- 12 August 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Mingzhu Li, Zijia Wu, Xuefeng Lu, Andrew Zalesky, Xinle Cheng, Yuyanan Zhang, et al.
- PMID
- 42581396
- DOI
- 10.1176/appi.ajp.20251084
Why clinicians should know about it
- Picked for Psychiatry and Mental Health (top studies of the week, 16 August 2026): RCT of connectivity‑guided TMS for depression, but focuses on neuromodulation
Abstract
OBJECTIVE: Scalp-based repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) does not account for interindividual variability. This trial was designed to determine whether individualized connectivity-guided intermittent theta-burst stimulation (iTBS) improves antidepressant outcomes compared with 5-cm targeting. METHODS: In this single-center, randomized, double-blind, three-arm trial (February 2023-March 2025), adults ages 18-65 years with major depressive disorder or bipolar II depression (≥1 antidepressant failure) were randomly assigned to receive 20 sessions of iTBS over 2 weeks using robotic neuronavigation with one of three targeting strategies: 5-cm rule, functional connectivity (FC)-guided targeting showing negative resting-state connectivity with the subgenual anterior cingulate cortex (sgACC), or structural connectivity (SC)-guided sites defined by probabilistic tractography to the sgACC. The primary outcome was percentage reduction in 17-item Hamilton Depression Rating Scale (HAM-D) score at week 2. Secondary outcomes included HAM-D score reduction at weeks 6 and 12, response or remission, self-reported symptoms, performance on a cognitive battery, and adverse events. RESULTS: Of 123 randomized participants, 119 were included in the modified intention-to-treat analyses (5-cm, N=40; SC-guided, N=39; FC-guided, N=40). SC-guided iTBS produced significantly greater HAM-D score reduction than the 5-cm rule at week 2 (least squares mean difference [LSMD]=8.79 percentage points, 95% CI=2.19, 15.40; Cohen's d=0.70). At week 6, both SC-guided and FC-guided groups showed significantly greater improvement than the 5-cm group (SC-guided LSMD=12.87 percentage points, 95% CI=6.21, 19.54; Cohen's d=1.03; and FC-guided LSMD=9.41 percentage points, 95% CI=2.84, 15.98; Cohen's d=0.75). By week 12, between-group differences were no longer significant. Adverse events were comparable across groups, with no seizures or mania. CONCLUSIONS: SC-guided iTBS produced promising preliminary evidence of improved antidepressant response compared with 5-cm targeting, supporting sgACC-based connectivity-guided precision neuromodulation in depression.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.