Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report

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 Vagus nerve stimulation and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, and 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 measures 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 psychiatric 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. Highlights Over 80% of participants with clinically meaningful benefit (as measured with 7 scales) at 12 months of adjunctive active VNS treatment maintained that benefit at 18 and 24 months of continued active VNS treatment. Rates of loss of meaningful benefit were consistently low: at 18 and 24 months of active VNS, loss of treatment benefit medians were 16.9% and 18.8%, respectively. Benefit with active VNS continued to emerge through the second year of treatment: among participants with no meaningful benefit at 12 months, a median of 30.6% and 37.8% achieved benefit at 18 and 24 months, respectively. Across those measures having meaningful benefit (partial response) as an outcome (MADRS, QIDS-C, QIDS-SR, CGI-I, tripartite measure [combination of mood symptoms, function, and QoL]), achieving meaningful benefit at 12 months resulted in two-thirds of participants having sustained benefit at 24 months, with one-third moving to substantial (full response) benefit.