The RECOVER Trial of Vagus Nerve Stimulation in Markedly Treatment-Resistant Depression: Critical Findings, Lessons...

This review summarizes the RECOVER trial's key findings and their clinical and research implications. RECOVER was a 12-month triple-blind randomized trial in adults with markedly treatment-resistant major depressive disorder (N=493; at least four failed trials in the current episode) that compared adjunctive active and sham vagus nerve stimulation (VNS) in effects on symptoms, function, and quality of life (QoL). Durability of benefit during the second year of active VNS was also evaluated. Participants had profoundly treatment-resistant illness, averaging 13.3 lifetime antidepressant treatments and a duration of 17.8 years for the current episode. The prespecified primary outcome (percent time in Montgomery-Åsberg Depression Rating Scale response) did not differentiate the treatment groups, while other outcomes for symptoms (Quick Inventory of Depressive Symptomatology-Clinician Rated: 39.6% vs. 30.7%; Clinical Global Impressions improvement scale: 53.8% vs. 39.8%), function (item 6 on the Work Productivity and Activity Impairment Questionnaire: 43.3% vs. 37.5%), and QoL (7-item subset of the Quality of Life Enjoyment and Satisfaction Questionnaire: 45.4% vs. 37.1%) and a tripartite metric combining these three outcome domains significantly favored active stimulation. Over 80% of participants who achieved meaningful benefit in symptom, function, or QoL measures after 12 months of active VNS retained these benefits at the 18- and 24-month assessments, demonstrating remarkable durability in participants expected to relapse at high rates. Approximately 30% of participants without benefit at 12 months improved meaningfully in the second year. In markedly treatment-resistant depression, adjunctive active VNS was more effective, in multiple measures, than a sham intervention administered over the course of 1 year. Continued treatment with active VNS was associated with durable improvement. Challenges and optimal methods for evaluating outcomes in samples with markedly treatment-resistant depression are discussed.