Vagus Nerve Stimulation (VNS)

Definition and Mechanism of Action

Vagus Nerve Stimulation (VNS) is a semi-invasive neuromodulation technique involving the surgical implantation of a subcutaneous pulse generator connected to an electrode wrapped around the left vagus nerve in the neck. It is approved for the treatment of treatment-resistant major depression in patients who do not respond adequately to conventional therapies.

The vagus nerve is the tenth cranial nerve and a major afferent pathway of the parasympathetic nervous system. Its stimulation produces widespread effects on the central nervous system, as vagal afferent fibers project to deep brain structures such as the locus coeruleus, nucleus of the solitary tract, amygdala, and medial prefrontal cortex, which are all key areas involved in affective regulation.

The hypothesized antidepressant mechanisms of VNS include:

• Increased central release of norepinephrine and serotonin;
• Modulation of limbic and cortical activity, particularly with increased metabolism in the orbitofrontal and cingulate cortices;
• Activation of cholinergic anti-inflammatory pathways and regulation of the hypothalamic-pituitary-adrenal (HPA) axis;
• Induction of neuroplasticity mediated by neurotrophic factors such as BDNF.

Compared to other neuromodulation techniques, VNS is characterized by slow but progressive effects: clinical benefits may appear weeks or months after activation but tend to persist over time.

Clinical Indications in Depression

VNS is indicated in patients with treatment-resistant major depression, defined as a failure to respond to at least four antidepressant treatments (including psychotherapy, medications, and in some cases, ECT). It is reserved for selected individuals in whom the severity of the clinical condition justifies surgical intervention and a long-term therapeutic strategy.

Main indications include:

• Chronic non-psychotic major depression lasting more than two years;
• High risk of relapse or frequent recurrences after initially effective treatment;
• Partial response to ECT or rTMS with contraindications for repeated sessions;
• Persistent anhedonia, apathy, and psychomotor slowing;
• No significant response to multiple adequate pharmacological and psychotherapeutic interventions.

VNS may also be considered in patients with psychosomatic comorbidities and autonomic dysfunctions, where a marked dysregulation of autonomic balance is observed.

Technique and Treatment Management

VNS implantation is performed by a neurosurgical team under general anesthesia. The generator (similar to a pacemaker) is placed in the left infraclavicular region, with an electrode encircling the left vagus nerve in the neck. After approximately 2–4 weeks, the device is activated and programmed by a psychiatrist or neurologist.

Stimulation parameters (intensity, frequency, pulse duration) are gradually adjusted based on clinical response and tolerability. Treatment is chronic and continuous, with regular clinical evaluations. In cases of significant response, symptom reduction can last for years, with sustained antidepressant effects over time.

Side Effects and Tolerability

VNS is generally a well-tolerated procedure, though it may cause a series of local and systemic side effects related to both the surgical implant and chronic vagus nerve stimulation.

The most common side effects include:

• Hoarseness or vocal changes due to laryngeal nerve stimulation;
• Dry cough, dyspnea, or throat tightness during active stimulation;
• Pain or discomfort at the implant site, especially in the early postoperative days;
• Mild dysphagia or foreign body sensation in the throat;
• Drowsiness, headache, paresthesias less commonly reported.

Most symptoms are dose-dependent and tend to diminish with gradual adjustment of stimulation parameters. Patients are trained to use a magnetic controller that allows temporary suspension of stimulation in case of adverse events.

Contraindications

VNS is contraindicated in patients with:

• Vascular malformations or previous cervical surgery affecting the vagus nerve pathway;
• Severe arrhythmic cardiac conditions, such as untreated second- or third-degree atrioventricular block;
• Severe obstructive pulmonary diseases, due to potential worsening of dyspnea;
• Previous infections at the surgical site or high risk of implant-related complications.

In addition, VNS is not recommended for patients with active psychosis, severe cognitive impairment, or reduced life expectancy, where the invasiveness of the procedure outweighs the expected benefit.

Effectiveness and Recommendations

The antidepressant efficacy of VNS has been documented in several observational and controlled studies. Long-term response rates (12 months) are approximately 30–40%, with remission rates up to 20% in carefully selected patients. A distinguishing feature of VNS is its progressive action over time, often with cumulative improvements months after treatment initiation.

According to major international guidelines (APA, CANMAT), VNS is considered a therapeutic option for unipolar or bipolar treatment-resistant depression in patients who have failed to respond to at least four previous interventions. It is proposed as an alternative to ECT in individuals who refuse or cannot undergo repeated courses.

Despite its initial cost and invasiveness, VNS provides continuous chronic stimulation, with minimal maintenance once the effective dose is established. Available data also suggest improved quality of life and reduced hospitalization rates in responder patients.

References
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