Long-Term Benefit in the Most Difficult Cases of Depression: New Evidence Supporting Vagus Nerve Stimulation

By Joao L. de Quevedo, MD, PhD, Director, Center for Interventional Psychiatry UTHealth Houston
January 20, 2026

Achieving improvement in treatment-resistant depression (TRD) is difficult—but maintaining that improvement over time is often even harder. Patients with marked levels of treatment resistance not only respond less frequently to antidepressant interventions, but when they do respond, relapse rates are high. This challenge has long limited the real-world impact of many available treatments.

A newly published report from the RECOVER trial, titled “Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression,” provides some of the most substantial evidence to date that adjunctive vagus nerve stimulation (VNS) offers not only clinical benefit—but exceptional durability of benefit over two years, even in patients with profound chronicity and resistance to multiple prior treatments.

Why Durability Matters in TRD

In highly treatment-resistant major depressive disorder, relapse is the rule rather than the exception. Data from extensive studies such as STAR*D have shown that after multiple failed treatments, the likelihood of maintaining remission for one year with additional medications is well under 5%. Even with effective acute treatments such as electroconvulsive therapy (ECT), approximately half of patients relapse within months.

For this reason, durability of benefit—not just initial response—is a critical outcome when evaluating interventions for markedly TRD.

The RECOVER Trial: A Long-Term Perspective

The RECOVER study followed 214 adults with markedly treatment-resistant major depression, each with at least four failed antidepressant trials in the current episode, many of whom had also failed ECT and TMS. After completing one year of blinded adjunctive VNS, participants continued open-label active VNS for an additional year and were followed for outcomes at 18 and 24 months.

Importantly, outcomes were assessed across multiple clinically meaningful domains, including:

  • Depressive symptoms
  • Daily functioning
  • Quality of life
  • A composite “tripartite” measure integrating all three

This multidimensional approach reflects what truly matters to patients—how they feel, function, and live.

Key Findings: Sustained and Emerging Benefit

The results are striking:

  • Approximately 80% of participants who achieved meaningful benefit at 12 months maintained that benefit at both 18 and 24 months, across symptom, function, and quality-of-life measures.
  • Among those with substantial benefit or remission at 12 months, durability rates were even higher, with over 90% maintaining meaningful benefit at two years.
  • Relapse rates were consistently low, particularly among those who achieved stronger responses.
  • Notably, benefit continued to emerge over time: among participants with no meaningful benefit at 12 months, roughly 30–40% went on to achieve meaningful improvement by 24 months.

These improvements were not explained by changes in medications, ECT, TMS, or ketamine/esketamine use, underscoring that the sustained benefit was attributable to continued VNS therapy rather than treatment intensification.

A Unique Feature of VNS: Slow Onset, Strong Durability

Unlike many antidepressant treatments that act quickly but relapse early, VNS follows a different therapeutic trajectory. Clinical benefit often builds gradually over months, with peak effects sometimes emerging after a year or longer. The RECOVER data confirm that this slow onset is paired with remarkable long-term stability, making VNS particularly well-suited for patients with chronic, highly resistant depression.

What This Means for Patients and Clinicians

For individuals who have exhausted standard pharmacologic and neuromodulation options, these findings are highly consequential. They suggest that VNS is not merely another acute intervention but a long-term, disease-modifying strategy capable of producing sustained improvement in symptoms, function, and quality of life.

From a clinical perspective, this study reinforces the importance of setting appropriate expectations with patients: VNS is not a rapid fix, but for the right patient, it offers a realistic chance at durable recovery where other treatments have failed.

Looking Ahead

The RECOVER trial represents one of the most comprehensive evaluations of long-term outcomes in markedly treatment-resistant depression. Its findings support a broader role for VNS within advanced TRD programs and highlight the need to prioritize durability over short-term response when defining treatment success.

At UTHealth Houston Center for Interventional Psychiatry, these results align closely with our mission: to deliver evidence-based, innovative, and sustainable treatments for patients facing the most severe and refractory forms of depression.

Reference
Conway CR, Rush AJ, Aaronson ST, et al. Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report. International Journal of Neuropsychopharmacology. 2026;29(1):pyaf080. doi:10.1093/ijnp/pyaf080

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Disclaimer
This article was created with the assistance of artificial intelligence (AI) to enhance clarity and readability. All medical and scientific content has been reviewed and approved by Joao L. de Quevedo, MD, PhD, Director, UTHealth Houston Center for Interventional Psychiatry. This information is intended for educational purposes only and should not replace professional medical advice.