Durability of the Benefit of Vagus Nerve Stimulation in Markedly Treatment-Resistant Major Depression: A RECOVER Trial Report

ABSTRACT Importance Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability). Objective Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression. Design Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. Setting Outpatient. Participants Adults with moderate-severe MDD with ≥4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (N=214). Interventions VNS and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, ketamine/esketamine) were characterized over the 12-month extension. Main Outcomes and Measures The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression–Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori . Results Most participants with substantial benefit maintained their benefit (18-month median=78.8%; 24-month median=79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median=83.1%; 24-month median=81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median=30.6%) and 24 (median=37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatry modalities. Conclusions and Relevance Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year. Significance Statement Patients with markedly treatment-resistant major depression have low likelihood of benefiting from antidepressant treatments and high likelihood of rapid relapse if benefit is obtained. In 214 participants randomized in the RECOVER trial to active treatment with adjunctive Vagus Nerve Stimulation (VNS) therapy, outcomes after a second year of stimulation were examined for depressive symptom severity, function, and quality of life. Participants with meaningful benefit at 12 months maintained this level of benefit or better at 24 months at high rates (median ≥80% across all measures). Durability was strong for symptoms, function, and quality of life regardless of the threshold used to define benefit and was not attributable to changes in concomitant treatments. Moreover, a substantial proportion of participants had meaningful improvement at 24 months who did not at 12 months. In a sample characterized by profound chronicity and treatment resistance, active VNS was associated with exceptionally strong durability of benefit.