Neuropsychopharmacology (2006) 31, 1345–1355. doi:10.1038/sj.npp.1301082; published online 19 April 2006

VNS Therapy in Treatment-Resistant Depression: Clinical Evidence and Putative Neurobiological Mechanisms

Charles B Nemeroff1,2, Helen S Mayberg2, Scott E Krahl3, James McNamara4, Alan Frazer5, Thomas R Henry2, Mark S George6, Dennis S Charney7 and Stephen K Brannan8

  1. 1Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
  2. 2Emory University School of Medicine, Atlanta, GA, USA
  3. 3Mt. Sinai School of Medicine, New York, NY, USA
  4. 4Duke University Medical Center, Durham, NC, USA
  5. 5The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
  6. 6Medical University of South Carolina, Charleston, SC, USA
  7. 7VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
  8. 8Cyberonics Inc., Houston, TX, USA

Correspondence: Dr CB Nemeroff, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322, USA. Tel: +1 404 727 8382; Fax: +1 404 727 3233; E-mail:

Received 17 October 2005; Revised 9 March 2006; Accepted 10 March 2006; Published online 19 April 2006.



Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation modality. The VNS Therapy SystemTM has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy SystemTM, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment-resistant depression remain obscure. Suggestions for future research directions are described.


vagus nerve stimulation, treatment-resistant depression, mechanism of action, vagus nerve, neuroimaging, research



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