Vagus nerve stimulation shows lasting benefit in treatment-resistant depression

By Tarun Sai LomteReviewed by Lauren HardakerJan 16 2026

Two-year data show that adding VNS to standard care can produce lasting symptom, function, and quality-of-life benefits in one of the most difficult-to-treat depression populations.

Study: Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report. Image credit: BigBlueStudio/Shutterstock.com

In a recent study published in the International Journal of Neuropsychopharmacology, researchers characterized function, depressive symptoms, and quality of life (QoL) over two years of vagus nerve stimulation (VNS) in individuals with severe, chronic treatment-resistant depression (TRD).

High treatment resistance limits long-term depression outcomes

Most people with major depressive disorder improve with one to three attempts of antidepressant treatment, but 18 % to 33 % of patients do not. Individuals with difficult-to-treat depression or TRD have higher rates of hospitalization, relapse, disability, and suicide attempt than those responsive to treatment.

TRD presents two fundamental challenges: achieving and sustaining benefit, particularly in patients with long illness duration and multiple failed treatment trials.

The odds of achieving symptomatic improvement decrease with higher levels of treatment resistance. Likewise, the likelihood that the benefit is sustained decreases with increased levels of treatment resistance.

For TRD, evaluating the durability of the initial benefit is crucial for assessing the clinical impact of treatment in patients who are more likely to lose it due to chronic illness and prior nonresponse.

RECOVER trial tracks long-term outcomes during ongoing VNS

In the present study, researchers evaluated clinical outcomes after VNS in individuals with TRD. The first phase of the triple-blind, randomized RECOVER trial assessed the safety and efficacy of adjunctive VNS over 12 months in patients with TRD, assigning them to receive either adjunctive active or sham VNS therapy along with treatment as usual (TAU).

Following the 12-month blinded phase, all participants received open-label active VNS alongside TAU, and the analysis focuses on outcomes during ongoing treatment, without a control condition.

The current analysis included participants randomized to active VNS for the first 12 months. The severity of depressive symptoms was assessed by the clinician-rated and self-reported Quick Inventory of Depressive Symptomatology (QIDS) and the Montgomery, Åsberg Depression Rating Scale (MADRS).

For each scale, a partial response (PR) or response was defined as ≥30 % or ≥50 % decrease in the baseline score, respectively. A score ≤5 on the QIDS scale and ≤9 on the MADRS indicated remission.

For these scales, meaningful benefit (MB) equaled PR, and substantial benefit (SB) equaled response. The Clinical Global Impression, Improvement (CGI-I) scale was used to assess the general psychiatric status, with scores of ≤3, ≤2, and 1 indicating MB, SB, and remission, respectively.

A subset of the QoL Enjoyment and Satisfaction questionnaire was used to assess QoL, meeting the minimal clinically important difference (MCID) of an 11.89 % increase from baseline, indicating an MB.

The effect of depression on daily activities was assessed using item 6 of the Work Productivity and Activity Impairment questionnaire, with MB defined as a two-point reduction or more.

All measures were combined into a single, composite metric with a score of 0,3 based on the number of domains with an MB. A composite score of 0 indicated no meaningful benefit (NB), 1 indicated an MB, and 2 or 3 meant SB. The rates of each outcome measure were determined at 12, 18, and 24 months after randomization.

The durability of benefit was estimated as the proportion of participants with ≥MB at 12 months who retained at least that status at 18 and 24 months. In contrast, the proportion of participants with MB or SB at 12 months but NB at subsequent time points reflected the loss of benefit. In addition, the proportion of participants with SB at 12 months but NB at later time points indicated relapse. Benefit was also assessed in patients with NB at 12 months.

Most patients maintained meaningful benefit through two years

The study included 214 participants, with an average age of 55.2 years. Most participants were female (68 %) and unemployed (72 %). The study population spent 52.6 % of their lifetime in depressive illness, had failed multiple prior antidepressant and interventional treatments, had very poor QoL, and were functionally impaired.

At 12 months, 80 % of the sample achieved at least MB on the tripartite composite measure. At 18 and 24 months, 83.6 % and 82.4 % of the sample achieved at least MB, respectively.

Among participants who were in remission at 12 months, roughly 59 % to 66 % maintained remission at 18 months, and about 48 % to 70 % did so at 24 months. Across outcome measures, loss of benefit occurred in approximately 17 % of participants at 18 months and 19 % at 24 months.

The relapse rate was 6.7 % at 18 months and 7.8 % at 24 months. Furthermore, many participants with NB at 12 months achieved at least MB at subsequent time points, with approximately one-third achieving benefit by 18 months and nearly 38 % by 24 months.

VNS shows durable benefit in highly treatment-resistant depression

Together, a substantial proportion of individuals with TRD treated with TAU and VNS achieved benefit at 12 months across symptom, function, and QoL measures. Approximately 80 % of participants who achieved at least MB at 12 months retained at least MB over the subsequent 12 months while continuing adjunctive VNS.

A subset of participants (approximately 38 %) who did not achieve MB at 12 months had achieved this status by 24 months. Rates of loss of benefit were low, and relapse was rare.

The authors note that sustained and emergent benefits were not explained by changes in concomitant medications or exposure to other interventional treatments, supporting the durability of VNS-associated outcomes in a population with exceptionally high treatment resistance and illness chronicity.

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