Durability of Implanted Cervical Vagus Nerve Stimulation in Treatment-resistant Major Depression: Summary of Findings and Potential Mechanisms of Action

Abstract Purpose of Review Treatment-resistant depression (TRD), major depressive disorder (MDD) characterized by inadequate response to a series of antidepressant treatments, is a major clinical challenge. Implanted vagus nerve stimulation (VNS), surgical placement of a pulse generator with an electrical lead attached to the cervical vagus nerve, provides intermittent electrical stimulation 24/7. VNS for TRD was approved by the US FDA in 2005. This review summarizes the evidence for durability of the antidepressant effects of VNS and examines potential mechanisms that may explain this durability. Recent Findings Since the approval of VNS for TRD, numerous studies have demonstrated sustained durability of antidepressant responses up to 2 years. Most recently, the large, multicenter RECOVER VNS trial demonstrated very strong sustained durability (~ 80% at 2 years; ~70% at three years) across a wide range of depression outcomes including depressive symptoms, clinical impression, quality of life, and daily function in severe, unipolar, markedly TRD patients (mean lifetime years in depression 27; mean failed lifetime antidepressant treatments trials 13). We summarize multiple lines of current exploration in this area including: engagement of multiple neurotransmitter systems (monoamines and others), anti-inflammatory effects, impact on brain networks/regions associated with depression, evidence of neuroplasticity in brain circuits, modulation of the autonomic nervous system, a unique brainstem entryway into the central nervous system (nucleus tractus solitarius), and possible synergistic effects with other treatments. Summary VNS shows very strong durability of response in severe TRD. Several plausible mechanisms are supported by existing evidence; further research is needed to improve understanding.