¹Gray Faculty of Medical & Health Sciences, Tel Aviv Jaffa, Israel, ²Mayanei Hayeshuhai Medical Center, Adult Psychiatry Department, Bnei Brak, Israel, ³Lev-Hasharon Mental Health Center, Adult Psychiatry Department, Tzur-Moshe, Israel, ⁴Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv Jaffa, Israel, ⁵Tel Aviv Sourasky Medial Center, Department of Neurosurgery, Tel Aviv Jaffa, Israel, ⁶Sheba Medical Center, Department of Neurosurgery, Tel Hashomer, Ramat Gan, Israel, ⁷Sheba Medical Center IS, The Advanced Treatments for TRD Clinic, Adult Psychiatry Department, Tel Hashomer, Ramat Gan, Israel, ⁸Sheba Medical Center, Department of Psychiatry, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Ramat Gan, Israel, ⁹The Academic College of Tel Aviv-Yaffo, School of Behavioral Sciences, Tel Aviv Jaffa, Israel

Background: Major depressive disorder (MDD) is a leading cause of disability. Despite multiple treatment strategies, a substantial proportion of patients do not achieve adequate symptom relief. This subgroup is known as treatment-resistant depression (TRD) and poses clinical and challenges. Among them, individuals with higher-grade TRD (HG-TRD)—defined as failure of at least four adequate treatment interventions—have limited treatment options. Vagus nerve stimulation (VNS) has emerged as a promising intervention for this population.

Aims & 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 real-world program, focusing on depressive severity, suicidality, safety, tolerability, and rates of response and remission.

Method: A prospective naturalistic 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.

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.

Discussion & Conclusions: In this national real-world 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.