Wearable vagus nerve stimulation for depression: mechanisms, devices, and the road toward personalized neuromodulation

Major depressive disorder remains a leading cause of global disability, with a substantial fraction of patients exhibiting inadequate response to conventional pharmacological and psychotherapeutic treatments. Vagus nerve stimulation has emerged as an effective neuromodulation strategy for treatment-resistant depression, yet implantable systems are limited by surgical risk, cost, and restricted scalability. Recent advances in non-invasive, wearable vagus nerve stimulation technologies, particularly transcutaneous auricular and cervical approaches, offer a promising pathway toward accessible, home-based neuromodulation. This Review synthesizes the anatomical and physiological rationale underlying wearable non-invasive VNS and critically evaluates mechanistic evidence spanning monoaminergic modulation, neuroplasticity, neuroimmune regulation, autonomic control, and large-scale brain network reorganization. We further summarize clinical findings from implantable and non-invasive trials and discuss key engineering considerations, including electrode–skin interfaces, stimulation parameters, wearability, and safety. Finally, we highlight major challenges and future opportunities, emphasizing the integration of flexible bioelectronics, multimodal sensing, and Artificial Intelligence-driven closed-loop control to enable personalized, scalable neuromodulation for depression.