Vagus Nerve Stimulation for Depression: What the Evidence Shows
Introduction: The Neurobiology of Depression
Major depressive disorder (MDD) is among the most prevalent and disabling conditions worldwide, affecting an estimated 280 million people globally (World Health Organisation, 2023). While pharmacotherapy and psychotherapy remain first-line treatments, roughly one-third of patients with MDD fail to achieve remission after multiple treatment trials — a condition known as treatment-resistant depression (TRD).
The search for alternatives has led researchers to neuromodulation, a broad category of therapies that use electrical or magnetic stimulation to alter brain activity. Vagus nerve stimulation (VNS) has been at the forefront of this research since the early 2000s, when clinical observations revealed that patients receiving VNS for epilepsy often reported unexpected improvements in mood.
This article reviews the current evidence for VNS — both implanted and transcutaneous — as a treatment for depression, examining the mechanisms, clinical trial data, and outstanding questions in this rapidly evolving field.
How VNS May Influence Depression
Neuroanatomical Pathways
The vagus nerve projects to the nucleus tractus solitarius (NTS) in the brainstem, which in turn relays signals to several brain regions implicated in mood regulation:
- Locus coeruleus — the primary source of noradrenaline in the brain, a neurotransmitter central to arousal and mood
- Dorsal raphe nucleus — the principal source of serotonin, the target of most antidepressant medications
- Amygdala and hippocampus — structures involved in emotional processing and memory
- Prefrontal cortex — involved in executive function and cognitive control of emotion
Animal studies have demonstrated that VNS increases the firing rate of noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe nucleus (Manta et al., 2009; Dorr & Debonnel, 2006), mimicking the neurochemical effects of conventional antidepressants but through a distinct mechanism.
The Default Mode Network
Functional neuroimaging studies have provided additional insight into how VNS may exert its antidepressant effects. Fang et al. (2016) demonstrated that transcutaneous auricular VNS (taVNS) modulated functional connectivity within the default mode network (DMN) — a network of brain regions associated with self-referential thinking and rumination, both of which are elevated in depression. After four weeks of taVNS, patients with MDD showed normalised connectivity patterns in the DMN alongside significant reductions in depression scores.
More recently, Guo et al. (2024) used fMRI to show that taVNS altered the topological architecture of functional brain networks in patients with MDD, with changes in network organisation correlating with clinical improvement.
Neuroplasticity and BDNF
Emerging evidence suggests that VNS may also promote neuroplasticity — the brain's ability to form new neural connections. Preclinical studies have shown that VNS increases the expression of brain-derived neurotrophic factor (BDNF), a protein critical for neuronal growth and survival that is often reduced in patients with depression (Follesa et al., 2007). This neuroplastic mechanism may help explain why the antidepressant effects of VNS often develop gradually over weeks to months, rather than immediately.
Implanted VNS for Treatment-Resistant Depression
FDA Approval and Early Trials
In 2005, the US Food and Drug Administration (FDA) approved implanted VNS (iVNS) as an adjunctive long-term treatment for chronic or recurrent depression in adults who had not responded to four or more adequate antidepressant treatments. The approval was based on a body of evidence showing that VNS could produce meaningful improvements in a subset of severely treatment-resistant patients.
The pivotal randomised controlled trial by Rush et al. (2005) compared active VNS to sham stimulation over a 10-week acute phase in 235 patients with TRD. While the primary endpoint did not reach statistical significance — a 15.2% response rate in the active group versus 10.0% in the sham group — the study was followed by open-label extension data that showed more encouraging results.
Long-Term Outcomes
The most compelling evidence for iVNS in depression comes from long-term observational data. Aaronson et al. (2017) reported 5-year follow-up data from the largest VNS registry, comparing patients who received VNS plus treatment as usual (TAU) with those receiving TAU alone. The VNS group demonstrated significantly higher cumulative response rates (67.6% vs 40.9%) and remission rates (43.3% vs 25.7%) over the five-year period.
This progressive improvement over time is a distinctive feature of VNS that distinguishes it from most other treatments for depression, where efficacy typically plateaus or diminishes. The mechanism underlying this gradual improvement is not fully understood but may relate to slow-onset neuroplastic changes in mood-regulating circuits.
The RECOVER Trial
The largest ongoing randomised controlled trial of iVNS for depression is the RECOVER trial (NCT03887715), which began enrolling in 2019 with an estimated completion date of 2030. This study represents a significant advancement in study design, featuring a large sample size, one year of controlled comparison, and the use of percent time in response as the primary outcome measure — acknowledging the fluctuating course of chronic depression.
Transcutaneous VNS for Depression
The Case for Non-Invasive Stimulation
While iVNS has shown promise over the long term, its requirement for surgical implantation, associated risks, and high cost have limited its accessibility. Transcutaneous auricular VNS (taVNS) has emerged as a non-invasive alternative that stimulates the auricular branch of the vagus nerve through electrodes placed on the ear — specifically the cymba conchae or tragus, where vagal afferent fibres are accessible on the skin surface.
The rationale is that stimulating these auricular vagal afferents should activate the same brainstem-to-cortex pathways as implanted VNS, but without the need for surgery. Neuroimaging studies have confirmed that taVNS activates the NTS and connected brain regions in a pattern similar to iVNS (Frangos et al., 2015; Yakunina et al., 2017).
Clinical Evidence for taVNS in Depression
The Rong et al. (2016) pilot study was among the first to formally test taVNS for depression. In this controlled pilot study of 160 patients with MDD, four weeks of taVNS significantly reduced Hamilton Depression Rating Scale (HAMD) scores compared to sham stimulation, with a response rate of 37.5% versus 12.5% in controls. While not a full randomised controlled trial, this study established the feasibility and preliminary efficacy of taVNS for depression.
The Hein et al. (2013) RCT was an early randomised controlled pilot study of auricular transcutaneous electrical nerve stimulation in depressed patients. The study found significant improvements in depression scores in the active stimulation group compared to sham over a two-week period, providing initial controlled evidence for the approach.
Neuroimaging confirmation: Fang et al. (2016) demonstrated that the clinical improvements seen with taVNS were accompanied by measurable changes in brain connectivity. Using resting-state fMRI, they showed that four weeks of taVNS normalised functional connectivity in the default mode network of patients with MDD — providing a neurobiological correlate for the antidepressant effects.
The Tan et al. (2023) Meta-Analysis
A systematic review and meta-analysis by Tan et al. (2023) evaluated the efficacy and safety of taVNS for depression across randomised controlled trials. The pooled analysis found that taVNS significantly reduced depression scores compared to sham stimulation, with moderate effect sizes. The authors concluded that taVNS shows promise as a non-invasive treatment for depression but called for larger, multi-centre trials with standardised stimulation parameters.
Recent Developments
The field is moving rapidly. In 2025, the iWAVE open-label pilot trial explored accelerated taVNS protocols in an inpatient psychiatric setting, investigating whether more intensive stimulation schedules could produce faster antidepressant effects. This represents a shift toward optimising treatment delivery rather than simply demonstrating efficacy.
Liu et al. (2024) published a double-blind, randomised, placebo-controlled trial specifically examining taVNS for post-stroke depression, finding significant improvements in depression scores — expanding the potential applications of taVNS beyond primary MDD.
Mechanisms of Action: What We Know and Don't Know
Established Mechanisms
The evidence supports several pathways through which VNS may exert antidepressant effects:
1. Neurotransmitter modulation — VNS increases noradrenaline and serotonin transmission through direct activation of brainstem nuclei (Manta et al., 2009; Dorr & Debonnel, 2006)
2. Network-level brain changes — VNS normalises functional connectivity in the default mode network, reducing the neural substrate of rumination (Fang et al., 2016)
3. Anti-inflammatory effects — Depression is associated with elevated levels of pro-inflammatory cytokines, and VNS activates the cholinergic anti-inflammatory pathway (Tracey, 2002; Bonaz et al., 2016), potentially addressing the inflammatory component of depression
4. Neuroplasticity — VNS promotes BDNF expression and may enhance the brain's capacity for adaptive change (Follesa et al., 2007)
Outstanding Questions
Despite two decades of research, several critical questions remain unanswered:
- Optimal stimulation parameters — There is no consensus on the ideal frequency, intensity, pulse width, or treatment duration for either iVNS or taVNS in depression. Different studies have used widely varying protocols, making comparison difficult.
- Patient selection — It remains unclear which patients are most likely to benefit from VNS. The progressive improvement seen over months to years suggests that patient commitment and sustained use are important factors.
- Mechanism specificity — Whether taVNS truly engages the same therapeutic pathways as iVNS at sufficient intensity to produce comparable clinical effects is still debated.
Safety Profile
Implanted VNS
The safety of iVNS has been established over decades of use in epilepsy and depression. The most common side effects are stimulation-related and include voice alteration, cough, and throat discomfort during stimulation periods. These effects are generally mild and tend to diminish over time (Ben-Menachem, 2002). Surgical risks include infection and, rarely, vocal cord paralysis.
Transcutaneous VNS
A comprehensive systematic review and meta-analysis by Kim et al. (2022) assessed the safety of taVNS across 177 studies involving 6,322 subjects. The analysis found that taVNS was generally well-tolerated, with side effects limited to mild, transient skin irritation or tingling at the stimulation site. Serious adverse events were rare and not clearly attributable to the stimulation itself.
Clinical Implications and Future Directions
The evidence for VNS in depression sits at an interesting juncture. For iVNS, the long-term data are encouraging — particularly the progressive improvement over years — but the surgical requirement and cost limit its use to the most severely treatment-resistant patients. For taVNS, the evidence is growing but has not yet reached the level of large, multi-centre randomised trials that would be needed for regulatory approval.
Several developments to watch include:
- The RECOVER trial — This large-scale RCT of iVNS will provide the most definitive evidence to date when results are available
- Accelerated protocols — Exploring whether intensive taVNS schedules can produce faster antidepressant effects
- Biomarker-guided treatment — Using neuroimaging or heart rate variability to predict which patients will respond to VNS
- Combination therapies — Investigating whether VNS can enhance the effects of psychotherapy or pharmacotherapy when used in combination
Key Takeaways
VNS for depression remains a field of active investigation rather than an established first-line treatment. The strongest evidence exists for iVNS in treatment-resistant depression, where long-term data suggest progressive improvement over years. taVNS offers a non-invasive alternative with a favourable safety profile, supported by preliminary clinical trials and neuroimaging evidence, but larger definitive trials are needed.
For patients and clinicians, the key message is one of cautious optimism: VNS represents a genuinely different approach to depression that works through distinct neurobiological mechanisms, and the research trajectory is encouraging.
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