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: 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.

Keywords: difficult-to-treat depression; durability; long-term extension; treatment-resistant depression; vagus nerve stimulation.