Two-Year Clinical Outcomes of Vagus Nerve Stimulation for Higher-Grade Treatment-Resistant Depression: A Prospective Open-Label Multicenter Cohort Study.

OBJECTIVES: To assess 24-month clinical outcomes of vagus nerve stimulation (VNS) in individuals with higher-grade treatment-resistant depression (HG-TRD) treated within a national open-label program, focusing on depressive severity, suicidality, safety, tolerability, and rates of response and remission. METHODS: A prospective, open-label, multicenter cohort study was conducted on 19 patients who underwent VNS implantation between 2020 and 2023. Clinical assessments were performed at baseline and at 6, 12, 18, and 24 months. Depressive symptoms were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS), including item 10 for suicidality. Outcomes included mean percentage change in MADRS scores, rates of response, remission, partial response, adverse events, and adherence. Sixteen participants completed the 24-month follow-up. All analyses were exploratory. RESULTS: MADRS scores decreased significantly by 6 months (P<0.001) and remained improved throughout follow-up, with a mean reduction of 48% in 24 months. Cumulatively, 87.5% of participants experienced a clinically defined response during the 24-month period. Suicidality (MADRS item-10 scores) decreased significantly (P<0.001) and this improvement persisted throughout follow-up. No serious safety concerns were identified. Tolerability and long-term adherence were high, with most patients continuing active device use throughout the study period. CONCLUSIONS: In this open-label, multicenter cohort of individuals with HG-TRD, VNS was associated with substantial and durable reductions in depressive severity and suicidality over 24 months. Despite limitations related to sample size and lack of a control group, the magnitude and persistence of clinical benefit support VNS as a viable long-term treatment for carefully selected patients with severe, highly resistant depression.