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VNS Therapy in Treatment-Resistant Depression: Clinical Evidence and Putative Neurobiological Mechanisms
Abstract
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 System 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 System, 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.
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“Whether by activating nerves through electrical stimulation or by reading their electrical signals, nerve neuroprosthetics offer a myriad of applications such as the control of bladder function (Brindley et al., 1982), management of depression (Nemeroff et al., 2006), and restoration of sensory perception in amputees (D'Anna et al., 2019).”
From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Nemeroff et al., 2006
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“Through direct or indirect anatomic connections via the NTS, the vagus nerve has structural connections with several mood regulating limbic and cortical brain areas (82).”
From Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders (2018) · cites this paper as [82]
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Metadata
- Authors
- Nemeroff, C. B., Mayberg, H. S., Krahl, S. E., McNamara, J., Frazer, A., Henry, T. R., George, M. S., Charney, D. S., & Brannan, S. K.
- Affiliations
- Emory University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Duke Medical Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Medical University of South Carolina (US)
- VA Greater Los Angeles Healthcare System (US)
- Corresponding author
- Nemeroff, Charles B
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2006-04-19
- Volume
- 31
- Issue
- 7
- Pages
- 1345-1355
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2094533610
- Cited by
- 496
- References
- 70
- Citations by year
- 2026: 29 · 2025: 34 · 2024: 37 · 2023: 45 · 2022: 33 · 2021: 26 · 2020: 10 · 2019: 24 · 2018: 27 · 2017: 16 · 2016: 28 · 2015: 25 · 2014: 14 · 2013: 17 · 2012: 22
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Update notices
- erratum (2006-07-31)
- Open access
- closed
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- vagus nerve stimulation, treatment-resistant depression, drug-resistant epilepsy, nucleus tractus solitarius, serotonergic projections, noradrenergic projections, mood regulation, neurostimulation, treatment efficacy and safety
- MeSH terms
- Animals, Major Depressive Disorder, Drug Resistance, Electric Stimulation Therapy, Evaluation Studies as Topic, Humans, Neurobiology, Time Factors, Vagus Nerve
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