Low Intensity Ultrasound Neuromodulation for the treatment of Major Depressive Disorder: Systematic Review and Meta‑Analysis of Randomized Controlled Trials

Background Major depressive disorder (MDD) affects over 264 million individuals globally, yet about one‑third of patients fail to achieve remission with conventional therapies. Low‑intensity ultrasound neuromodulation (LIUN), which includes low‑intensity focused ultrasound (LIFU) and transcranial pulse stimulation (TPS), offers millimetre‑scale targeting and the ability to reach deep limbic regions without implants or strong electromagnetic fields. Objectives To conduct the first systematic review and meta‑analysis of randomized, sham‑controlled trials assessing the efficacy and safety of LIUN in adults with MDD. Methods We searched PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey through July 2025 for RCTs comparing active LIUN versus sham in MDD. Two reviewers independentlyscreened studies and extracted data. Depressive symptom change was pooled using a random‑effects model to calculate standardized mean differences (SMDs). Heterogeneity was quantified with the I² statistic. Adverse events were narratively summarized. Results Three RCTs (n = 78 randomized; 68 completers) met inclusion criteria—one LIFU trial (Oh et al., 2024) and two TPS trials (Cheung et al., 2022; QIN, 2025). LIUN yielded a small‑to‑moderate reduction in depressive symptoms compared to sham (SMD = –0.55; 95 % CI: − 1.07 to − 0.02; p = 0.04). Between‑stud heterogeneity was low (I² = 23 %). Adverse events—transient headache, scalp ingling, and skin redness—were generally mild and self‑limiting. Qin et al. reported higher rates of transient sensations in the active arm (92 % vs 42 %), whereas Cheung et al. and Oh et a. descrbed minimal or no adverse effects without treatment discontinuation. Conclusions Preliminary evidence suggests LIUN modestly reduces depressive symptoms in MDD with a benign safety profile. However, the small number of heterogeneous trials underscores the need for larger, parameter‑standardized RCTs to confirm efficacy, optimize sonication protocols, and establish long‑term safety.