Vagus nerve stimulation (VNS)

Article written and reviewed by Dr Luca Moretti

Vagus nerve stimulation (VNS) is an implantable neuromodulation therapy in which a subcutaneous generator sends electrical impulses to an electrode wrapped around the cervical vagus nerve, usually on the left. In depression, treatment is intended as a chronic adjunctive strategy for highly resistant forms, not as a rapid intervention to resolve an emergency.

In the United States, the VNS system received FDA approval in 2005 for the long term adjunctive treatment of chronic or recurrent depression in adults experiencing a major depressive episode who have not responded adequately to at least four adequate antidepressant treatments. Regulatory authorization is not the same as insurance coverage and does not imply that VNS is a first line choice. In Europe and individual healthcare systems, availability, reimbursement and operational indications may differ.

Implantable VNS should also be distinguished from transcutaneous vagus nerve stimulation, either cervical or auricular. Noninvasive techniques use different devices and parameters and have a different evidence base; results from surgical VNS cannot automatically be transferred to taVNS.

Functional anatomy and neuromodulation mechanism

Most vagus nerve fibers are afferent. Cervical stimulation sends signals toward the nucleus tractus solitarius and, through brainstem connections, modulates the locus coeruleus, raphe nuclei, thalamus, amygdala, hippocampus and cortical networks. These connections provide a rationale for influencing noradrenergic and serotonergic systems and circuits involved in affect regulation.

The antidepressant effect cannot be reduced to a linear increase in a single neurotransmitter. Imaging and neurophysiological studies suggest progressive changes in network connectivity and plasticity. The most clinically important feature is latency: when VNS works, benefit may accumulate over months, distinguishing it from ECT or ketamine/esketamine, which can act much more rapidly.

Selection of the left vagus partly derives from the organization of cardiac efferents and experience gained in epilepsy. However, the left nerve also contains efferent fibers and stimulation can produce laryngeal and respiratory effects; surgical anatomy and programming are therefore essential.

Cervical stimulation primarily involves afferent fibers projecting to the nucleus tractus solitarius and, through brainstem networks, modulates the locus coeruleus, raphe nuclei, thalamus, amygdala and prefrontal and limbic regions. Noradrenergic, serotonergic, inflammatory and plasticity related changes have been described, but no single pathway alone explains the antidepressant response in humans. The delay with which benefit often appears suggests that the clinical effect does not depend only on the immediate electrical response, but also on progressive network adaptations. This temporal profile distinguishes VNS from rapid acting therapies and directly influences patient selection.

Clinical indication and patient selection

The typical profile is a patient with highly treatment resistant chronic or recurrent depression, with numerous adequate pharmacological and psychotherapeutic treatments and, often, previous somatic strategies. VNS is generally not chosen when a response is needed within days: in the presence of severe imminent suicidality, catatonia, refusal of food or psychotic depression, ECT may have a more appropriate role because of its rapidity.

Assessment must systematically reconstruct previous treatments to distinguish true resistance from pseudoresistance due to insufficient dose, inadequate duration, poor adherence, incorrect diagnosis or untreated comorbidities. Bipolar disorder, substance use, personality disorders, neurological conditions, respiratory disorders and surgical risk must also be assessed.

Because treatment requires an implant and prolonged follow up, the ability to adhere to visits, understanding of the time course of response, willingness to maintain other treatment components and acceptance of possible effects on the voice are important. A realistic expectation is possible gradual improvement in a difficult to treat population, not guaranteed remission.

In the United States, the indication approved in 2005 concerns the long term adjunctive treatment of chronic or recurrent depression in adults aged at least 18 years who are experiencing a major depressive episode and have not achieved an adequate response to at least four adequate antidepressant treatments. The regulatory wording does not mean that every patient with four treatment failures should receive VNS: diagnosis, adequacy of previous treatments, comorbidities, surgical risk, expectations and willingness to engage in years of follow up must be reassessed. Because the effect may be slow, VNS is not an appropriate solution when the primary goal is immediate control of a life threatening condition.

Implantation, programming and follow up

The generator is implanted subcutaneously in the upper chest and connected by a lead to helical electrodes positioned on the left cervical vagus nerve. The procedure requires anesthesia and carries risks related to neck surgery and the generator pocket. After healing, the device is activated and programmed with stimulation cycles separated by off periods.

Parameters include current, frequency, pulse width, stimulation time and interval. Titration is gradual to balance efficacy and tolerability. Hoarseness or cough during the “on” phase may decrease with adaptation or parameter changes, but persist in some patients.

The device requires checks of impedance, battery status and function. Generator replacement is necessary when the battery is depleted; rechargeable models and battery life vary. Magnetic resonance imaging, diathermy and other electromedical procedures must be managed according to the specifications of the implanted system. Appropriate follow up integrates programming, psychiatric monitoring and management of comorbidities.

The implantable system generally uses an electrode wrapped around the left cervical vagus nerve connected to a generator positioned subcutaneously in the chest wall. After surgical healing, stimulation is activated and progressively titrated by changing current, pulse width, frequency and the on/off cycle according to tolerability and response. Follow up includes assessment of the wound and hardware, battery status, adverse events, depressive symptoms, functioning and suicidality. The need for repeated programming and possible generator replacement makes a center capable of providing continuity of care essential, not merely the initial procedure.

Short and long term efficacy: interpretation of the studies

The initial randomized study in 2005 did not demonstrate a significant difference in the main acute outcome after a relatively short stimulation period. This result is consistent with VNS having a slow onset. Subsequent observational studies have shown that response and remission may increase over time and that, among responders, benefit can be relatively durable.

The five year observational registry reported better outcomes in the VNS plus treatment as usual group than with treatment as usual, but the nonrandomized design prevents complete elimination of selection bias and confounding. Meta analyses have found a favorable signal especially in long term assessments, although with heterogeneity and a predominance of uncontrolled studies.

The large RECOVER trial published in 2025 reopened the discussion with almost five hundred markedly treatment resistant patients randomized to active or sham stimulation for one year. The primary analysis and different outcomes require a nuanced interpretation: the trial showed signals of benefit on several clinical and functional measures, but does not justify considering all uncertainty about the specific effect resolved. The value of VNS remains primarily the possibility of gradual and durable benefit in a population with few alternatives.

Adverse effects, surgical risks and precautions

The most frequent stimulation related effects include hoarseness or voice changes, cough, pharyngeal or cervical discomfort, dyspnea, paresthesias and dysphagia. They are often more evident during the active phase of the cycle. Programming can reduce them, but individual tolerability varies.

Implantation risks include infection, hematoma, pain, nerve injury, wound complications and hardware problems. Intraoperative bradycardia or asystole are rare but recognized; the presence of heart disease requires appropriate assessment. Stimulation may worsen sleep related breathing disorders in some patients, and nocturnal symptoms or suspected apnea should be considered during follow up.

VNS does not replace suicide risk monitoring. Candidate patients have very severe depression and high baseline morbidity; partial improvement does not eliminate risk and must be accompanied by a comprehensive treatment plan. Emergence of activation or manic symptoms also requires diagnostic and therapeutic reassessment.

Stimulation related effects mainly include voice alteration, hoarseness, cough, pharyngeal discomfort, dyspnea or dysphagia, often more evident during the “on” phase and sometimes attenuated by programming. Implantation risks include pain, hematoma, infection, nerve injury and hardware complications; rarer events require individual assessment. Because VNS interacts with laryngeal and autonomic functions, respiratory conditions, swallowing disorders and future surgical or diagnostic procedures must be considered during follow up. Long term safety also depends on the ability to manage the battery, procedural compatibility and the need for revisions, in addition to psychiatric effects.

Role relative to other neuromodulation techniques

Within the treatment pathway for resistant depression, VNS is distinguished by being invasive but extracranial and by its chronic nature. rTMS is noninvasive and is used at less extreme stages of resistance; ECT is better suited when a rapid response is required; DBS is intracranial and remains experimental for depression.

VNS is most meaningful when the dominant problem is long lasting depression with relapses and numerous treatment failures, and when both patient and center accept a therapeutic horizon of months. Potential benefit must be weighed against surgery, effects on the voice, device management and local availability.

Future directions include response biomarkers, optimization of parameters and identification of subgroups more likely to benefit. Studies of noninvasive vagal stimulation are also increasing, but should be evaluated as a distinct line of research.

Compared with ECT and rTMS, VNS requires surgery but not repeated anesthesia sessions and can provide continuous chronic stimulation. Its potential advantage emerges mainly over the long term and in patients with highly resistant illness; its main limitation is the absence of a rapid effect and the need for a permanent implant. The choice should therefore be placed within a longitudinal strategy: ECT may be preferred when rapidity and a high probability of acute response are required, rTMS when a noninvasive technique is sought, and VNS when the central problem is a highly treatment resistant chronic or recurrent depression for which accepting surgery and prolonged follow up is reasonable.

Bibliography
1. Conway CR et al. Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial. Brain Stimul. 18(3), 2025: 676-689.
2. Aaronson ST et al. A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. Am J Psychiatry. 174(7), 2017: 640-648.
3. Rush AJ et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 58(5), 2005: 347-354.
4. Bottomley JM et al. Vagus nerve stimulation therapy in patients with treatment resistant depression: A systematic review and meta-analysis. Compr Psychiatry. 98, 2020: 152156.
5. Kalagara R et al. Complications of Implanted Vagus Nerve Stimulation: A Systematic Review and Meta-Analysis. Cerebrovasc Dis. 54(1), 2025: 112-120.
6. Nahas Z et al. Two-year outcome of vagus nerve stimulation for treatment of major depressive episodes. J Clin Psychiatry. 66(9), 2005: 1097-1104.
7. George MS et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 58(5), 2005: 364-373.
8. Cristancho P et al. Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J Clin Psychiatry. 72(10), 2011: 1376-1382.
9. Carreno FR et al. Vagal nerve stimulation for treatment-resistant depression. Neurotherapeutics. 14(3), 2017: 716-727.
10. McAllister-Williams RH et al. Assessment for vagus nerve stimulation in patients with difficult-to-treat depression: a model from the Newcastle Regional Affective Disorders Service. J Affect Disord. 280(Pt A), 2021: 315-325.
11. U.S. Food and Drug Administration. VNS Therapy System: Premarket Approval P970003/S050. 2005.