Introduction and aim: Vagus Nerve Stimulation (VNS), including its non-invasive form transcutaneous auricular VNS (taVNS), has emerged as a promising treatment for Major Depressive Disorder (MDD), particularly treatment-resistant cases. The aim of this review is to provide a comprehensive review of VNS and taVNS, with a focus on their mechanisms, efficacy, and immunomodulatory effects in depression.
Methods: A systematic review of PubMed literature (2020-2025) was conducted using the terms "Depresion," and either "Transcutaneous Auricular Vagus Nerve Stimulation" or "taVNS" or "Vagus Nerve Stimulation" or "VNS" and “depression” or “Major Depressive Disorder” with studies manually screened for relevance and credibility.
Results: VNS modulates the brain’s monoaminergic systems by enhancing serotonergic and noradrenergic neurotransmission via afferent vagal projections. It also exerts anti-inflammatory effects by activating cholinergic anti-inflammatory pathways that reduce systemic and central neuroinflammation- which has been suggest as an underlying mechanism for the pathophysiology of depression. VNS also influences the microbiota–gut–brain axis, improving intestinal barrier integrity and restoring gut microbial balance. Dysbiosis may be one of the factors involved in the pathogenesis of depression. TaVNS, targeting the auricular branch of the vagus nerve, activates similar neural circuits and shows comparable antidepressant effects with fewer risks. Clinical trials and meta-analyses support its efficacy, especially when combined with pharmacotherapy.
Conclusion: VNS and taVNS represent effective adjunctive treatments for MDD by modulating neurochemical, immunological, and microbiota-related pathways. Further large-scale, controlled trials are needed to clarify optimal stimulation parameters and long-term outcomes
