Abstract
OBJECTIVE: Major depressive disorder (MDD) is a debilitating condition that inflicts significant personal and economic burdens and affects approximately 8% of the US population. Approximately 30% of patients with MDD do not respond to conventional antidepressant and psychotherapeutic treatments. Current treatment options for refractory MDD include transcranial magnetic stimulation (TMS) and invasive surgical procedures such as surgical ablation, vagus nerve stimulation, and deep brain stimulation. In this context, therapeutic ultrasound emerges as a promising alternative for treating refractory MDD, which has the unique advantage of combining noninvasiveness with selective targeting. Over the past ten years, there has been growth in focused ultrasound research, leading to an exponential increase in interest in the technology. To support the future development of ultrasound for treating MDD, we conducted a systematic review following Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. MATERIALS AND METHODS: We identified 86 relevant studies from 1975 through June 2025. Our inclusion criteria were peer-reviewed prospective cohort studies, case-control studies, and randomized controlled trials that report ultrasound efficacy for treating depression in humans or depressive-like behaviors in animal models (International Prospective Register of Systematic Reviews registration number: CRD42024626093); 23 studies met all the inclusion criteria. We summarized ultrasonic techniques for treating depression and their efficacy. RESULTS: We identified two focused ultrasound techniques used to treat depression, including magnetic resonance-guided focused ultrasound (MRgFUS) for capsulotomy and low-intensity focused ultrasound (LIFUS) neuromodulation. MRgFUS capsulotomy causes permanent lesioning, whereas LIFUS is nonlesional and believed to have temporary effects. In human trials, the response rate (≥50% improvement in depression score from baseline) was 41.7% at 12 months postoperatively for MRgFUS capsulotomy and 56.3% for LIFUS neuromodulation, respectively. The odds ratio for LIFUS neuromodulation was 5.8. In addition, LIFUS neuromodulation had a large effect (|Cohen's d| > 0.8) on reducing standard depression scale scores in humans or resolving depressive-like behaviors in rodents. The certainty of evidence is moderate for human trials and low for rodent models. MRgFUS capsulotomy had inconsistent lesioning success and a limited response rate, whereas LIFUS neuromodulation lacked systematic exploration of the parameter space and clear delineation of the underlying mechanisms. Future work should refine patient selection for MRgFUS capsulotomy and optimize the parameters for individualized functional targeting. CONCLUSIONS: LIFUS neuromodulation achieved a large reduction in depressive behaviors in both rodent models and human trials. We conclude that LIFUS neuromodulation is a promising, noninvasive option for treating refractory MDD.