Transcutaneous auricular vagus nerve stimulation for major depressive disorder: current evidence and future research directions.

Major depressive disorder (MDD) causes a significant global disease burden, yet existing pharmacological treatments are often limited by side effects and poor adherence. Transcutaneous auricular vagus nerve stimulation (taVNS), a promising non-invasive neuromodulation technique, offers a safe and accessible therapeutic alternative. This narrative review synthesizes current clinical evidence, explores potential mechanisms of action, and outlines future research directions for taVNS in MDD. Clinical studies consistently indicate that taVNS significantly alleviates depressive symptoms. Its therapeutic effects are mediated through multiple pathways, including anti-inflammatory regulation, autonomic modulation, neurotransmitter restoration, functional brain network reorganization, and the gut-brain axis. Despite these promising findings, clinical translation is hindered by methodological heterogeneity, small sample sizes, and a lack of long-term follow-up data. To advance clinical application, future research should prioritize establishing standardized stimulation protocols to reduce methodological heterogeneity, integrating multi-omics approaches to systematically decipher the "neuro-immune-endocrine-gut-brain" regulatory axis, and leveraging machine learning algorithms to identify multimodal predictive biomarkers for precision medicine. By integrating these advanced approaches, taVNS has the potential to become a robust, first-line therapeutic option for depression.