Adjunctive Vagus Nerve Stimulation Shows Durable Benefit in Treatment-Resistant Depression
Key Clinical Summary
- Sustained response: Approximately 80% of patients with treatment-resistant major depression who saw a meaningful or substantial treatment effect at 12 months maintained benefit through 24 months of adjunctive vagus nerve stimulation (VNS).
- Delayed benefit: Nearly one-third of patients without meaningful response at 12 months achieved benefit by 18–24 months.
- Broad outcomes: Improvements were observed across depressive symptoms, daily functioning, quality of life, and global clinical status.
Approximately 80% of patients with treatment-resistant major depression who saw a meaningful or substantial improvement in depressive symptoms after 12 months of adjunctive vagus nerve stimulation (VNS) maintained treatment benefit through 24 months of continued VNS, according to a long-term extension study published in the International Journal of Neuropsychopharmacology.
Study Design and Findings
The RECOVER study was a prospective, open-label, single-arm long-term extension conducted between September 2019 and April 2025 in an outpatient setting. It enrolled 214 adults with moderate to severe major depressive disorder (MDD) who had failed at least 4 antidepressant trials during the current depressive episode.
Participants initially received 12 months of blinded adjunctive VNS, followed by an additional 12 months of open-label VNS alongside usual psychotropic medications and, when applicable, other interventional treatments such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or ketamine/esketamine.
Durability of benefit was assessed at 18 and 24 months using 3 depression symptom scales, measures of daily function and quality of life (QoL), a tripartite composite outcome, and the Clinical Global Impression–Improvement (CGI-I) scale. Substantial benefit was predefined as at least a 50% reduction in symptoms or equivalent improvement across domains, while meaningful benefit reflected a ≥30% symptom reduction or comparable functional or QoL gains.
Among participants with substantial benefit at 12 months, a median of 78.8% at 18 months and 79.0% at 24 months maintained benefit across 5 measures. For those with at least meaningful benefit at 12 months, durability remained high, with medians of 83.1% at 18 months and 81.3% at 24 months across 7 measures.
Benefit also continued to emerge over time. Among participants without meaningful benefit at 12 months, a median of 30.6% achieved benefit at 18 months, increasing to 37.8% at 24 months. The researchers reported that sustained improvement was not explained by changes in medications or other interventional therapies.
Clinical Implications
High rates of relapse and loss of response are common with pharmacologic strategies in patients with severe, treatment-resistant MDD. The observed durability of VNS-associated benefit suggests a potential role for neuromodulation as a long-term adjunctive strategy rather than a short-term intervention.
The observed delayed emergence of benefit may also impact clinical decision-making. Patients who do not respond within the first year of VNS may still achieve meaningful improvement with continued therapy, which could support persistence with treatment when tolerated.
The consistency of benefit across symptom severity, function, and QoL also underscores the multidimensional impact of VNS, aligning outcomes with patient-centered goals. The low rates of loss of benefit, approximately 17% to 19% over 2 years, compare favorably with relapse rates reported for other interventions in highly resistant depression.
Expert Commentary
The researchers acknowledged that a possible alternative explanation for the sustained treatment benefit could be changes in concurrent treatment during the second year. “However, examination of the numbers and classes of medications added and subtracted during the second year, and specifically the receipt of ECT, TMS, and esketamine, did not yield a pattern suggesting impact on durability of benefit,” wrote Charles R Conway, MD, professor of psychiatry, Washington University in St Louis School of Medicine, St Louis, Missouri, and study coauthors. “These findings are consistent with the view that active VNS was an essential component to the durability of benefit.”
