Key Insights from a Landmark Study Exploring Vagus Nerve Stimulation for Treatment-Resistant Depression

February 24, 2025

Written by Joao L. de Quevedo, MD, PhD

Introduction

Treatment-resistant depression (TRD) remains one of the most challenging conditions in psychiatry. With limited options for patients who do not respond to conventional treatments, researchers continue to explore novel interventions. One such promising therapy is Vagus Nerve Stimulation (VNS). A recent one-year, randomized, sham-controlled trial published in Brain Stimulation has provided compelling insights into the safety and efficacy of VNS in TRD patients.

What is Vagus Nerve Stimulation?

VNS is a neuromodulation technique that delivers intermittent electrical impulses to the left vagus nerve via a surgically implanted pulse generator. Initially developed for drug-resistant epilepsy, VNS received FDA approval in 2005 as an adjunctive therapy for patients with chronic or recurrent major depressive disorder (MDD) who had not responded to at least four prior antidepressant treatments.

Study Overview

The UTHealth Houston Center for Interventional Psychiatry was one of the top centers enrolling patients for this study, contributing significantly to the trial’s success.

This 12-month, multicenter, double-blind trial enrolled 493 adults with severe treatment-resistant depression. Participants were randomized into two groups:

  • Active VNS group (VNS ON + treatment as usual [TAU])
  • Sham group (VNS OFF + TAU)

The study aimed to evaluate the antidepressant effects of VNS by measuring the percent time in response (≥50% improvement on the Montgomery-Åsberg Depression Rating Scale [MADRS]) from months 3–12.

Key Findings

1. Efficacy Results

  • There was no significant difference in the primary outcome (MADRS response rate): Active VNS did not significantly outperform sham VNS in terms of the time spent in full response.
  • Significant improvements in secondary measures:
    • Clinician-rated Clinical Global Impression–improvement (CGI-I) showed a higher response rate with active VNS (P = 0.004).
    • Patient-rated Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR) also showed a modest but significant improvement (P = 0.049).
    • Partial response (≥30% symptom reduction) was significantly higher in the VNS group (P < 0.001), suggesting meaningful clinical benefits.

2. Safety and Tolerability

  • High completion rate: 88.4% of participants completed the study.
  • No new adverse events were identified.
  • Side effects: Dyspnea (difficulty breathing) was significantly more common in the VNS group (P = 0.035), a known side effect of VNS.
  • Suicidal ideation and depression worsening were reported in both groups, reflecting the severity of TRD rather than a treatment effect.

Implications for TRD Treatment

While VNS did not significantly outperform sham treatment in the primary outcome, the consistent improvement in secondary measures suggests that VNS may provide meaningful benefits for TRD patients. Importantly, VNS demonstrated long-term safety and potential for improving quality of life in this difficult-to-treat population.

Future Directions

  • Longer-term follow-up: The study included a 4-year observational phase, which may provide more insights into the durability of VNS benefits.
  • Refining patient selection: Identifying the TRD subgroups that benefit most from VNS could improve its clinical application.
  • Optimizing VNS parameters: Adjustments beyond the initial two months might enhance effectiveness.

Conclusion

For patients suffering from marked TRD, vagus nerve stimulation remains a viable adjunctive treatment with demonstrated safety and potential long-term benefits. While further research is needed, this study provides valuable evidence supporting its continued use and refinement in clinical practice.

If you or someone you know is struggling with treatment-resistant depression, consult a mental health professional to explore whether VNS could be an option for you.

Reference

Conway, C. R., Aaronson, S. T., Sackeim, H. A., George, M. S., Zajecka, J., Bunker, M. T., Duffy, W., Stedman, M., Riva-Posse, P., Allen, R. M., Quevedo, J., Berger, M., Alva, G., Malik, M. A., Dunner, D. L., Cichowicz, I., Banov, M., Manu, L., Nahas, Z., Macaluso, M., Mickey, B. J., Sheline, Y., Kriedt, C. L., Lee, Y. C., Gordon, C., Shy, O., Tran, Q., Yates, L., & Rush, A. J. (2024). Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial. Brain Stimulation. https://doi.org/10.1016/j.brs.2024.12.1191

How do you refer a patient or request an appointment to the UTHealth Houston Center for Interventional Psychiatry?

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