Abstract
Major depressive disorder (MDD) affects 280 million people worldwide and is a major global health burden due to its link with suicide, physical comorbidities, and inadequate response to pharmacotherapy in many patients. The monoamine theory of depression has provided therapeutic targets, yet exploring additional mechanisms could enhance therapeutic outcomes and increase remission rates. This review examines the potential role of the vagus nerve in depression. Vagus Nerve Stimulation (VNS) has shown promising results in treating refractory depression and has been FDA-approved for MDD since 2005. Clinical and preclinical evidence suggests that vagotomy or vagus nerve ablation can both induce and alleviate depressive symptoms, depending on the context. Furthermore, we propose that structural and biochemical compromise of the vagus nerve may contribute to affective disorders, including depression, bipolar disorder, and anxiety phenotypes. To test this hypothesis, the intervention in question would involve performing vagotomy in rodents and the subsequent investigation for depression and anxiety phenotypes in the affected animals.