Non-ablative stereotactic radiosurgery for subgenual cingulate neuromodulation in treatment-resistant depression: a randomized dose-seeking pilot trial

<jats:p> The subgenual anterior cingulate cortex (sgACC) is a key node in treatment-resistant depression (TRD), but precise non-invasive neuromodulation of this target is challenging. Preclinical studies of non-ablative stereotactic radiosurgery (SRS) have shown neuromodulatory ("radiomodulation") effects. In this single-center, double-masked, randomized, dose-seeking pilot trial, nine adults with TRD were randomly assigned to bilateral sgACC radiomodulation at a dose of either 15, 20, or 25 Gy per hemispheric target. Primary endpoints were safety and feasibility; the efficacy endpoint was week-4 change in the Montgomery-Asberg Depression Rating Scale (MADRS). Both primary endpoints were met: the only treatment-related adverse event was transient grade 1 dizziness, with no structural MRI abnormality through week 12. Mean MADRS fell from 33.0 to 17.0 (48.5% reduction); 67% responded and 44% remitted, with benefit sustained to week 12. Resting-state fMRI revealed regional connectivity changes correlating with clinical improvement, with tractography showing streamline counts differing by response status. These first-in-human findings support a larger randomized controlled trial of sgACC radiomodulation for TRD. ClinicalTrial.gov registration: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT07274917">NCT07274917</jats:ext-link> . </jats:p>