NCT07097025

2-Year Study of Vagus Nerve Stimulation for Higher-Grade Treatment-Resistant Depression: Clinical Outcomes and Policy Recommendation

Efficacy and Safety of Vagus Nerve Stimulation Treatment in Treatment Resistant Depression

• Status: Completed
• Phase: —
• Study type: Observational
• Enrollment: 19 (actual)
• Sponsor: Dr.Yoav Domany · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The goal of this observational study is to evaluate whether vagus nerve stimulation (VNS) intervention can reduce depressive symptoms and suicidality in adults with higher-grade treatment-resistant depression (HG-TRD)-individuals who have not responded to at least four prior depression treatments. The main questions it aims to answer are: does VNS lead to a meaningful and sustained reduction in depression severity over 24 months? and does VNS reduce suicidal thoughts and behaviors in this population? Participants in this study were adults (age ≥ 18) with chronic or recurrent depression and at least four failed prior treatments, including medication, psychotherapy, electroconvulsive therapy (ECT), or esketamine. They underwent surgical implantation of a VNS device and their depressive symptoms and suicidality assessed at baseline, and then again at 6, 12, 18, and 24 months using the Montgomery-Åsberg Depression Rating Scale (MADRS). The study includes continous follow-upvisits and VNS device adjustments for 2 years post implantation. with outcomes including treatment response, remission, changes in suicidal ideation, and psychiatric hospitalization days over the study period

Detailed description

This prospective, multi-center observational study aimed to evaluate the long-term real-world effectiveness, safety, and clinical utility of vagus nerve stimulation (VNS) in individuals diagnosed with higher-grade treatment-resistant depression (HG-TRD), defined by failure to respond to at least four adequate therapeutic interventions. The study was conducted in three Israeli psychiatric centers between 2020 and 2025. Vagus nerve stimulation (VNS) is a neuromodulation therapy involving the surgical implantation of a device that delivers electrical stimulation to the vagus nerve, targeting brain regions associated with mood regulation. While VNS is approved in several countries for treatment-resistant depression (TRD), real-world data outside of structured clinical trials for TRD remain limited. This study sought to fill that gap, particularly in the Israeli healthcare context. Study Population and Procedures Eligible participants were adults with chronic or recurrent major depressive episodes, who had previously failed at least four depression treatments (e.g., pharmacotherapy, Electro-Convulsive Treatment (ECT), esketamine, psychotherapy). Participants underwent VNS implantation and were followed prospectively for 24 months. Follow-up assessments were conducted at 6, 12, 18, and 24 months, evaluating depression severity, suicidality, and adverse effects using standardized clinical tool, the Montgomery-Åsberg Depression Rating Scale (MADRS). Device programming and stimulation adjustments were conducted biweekly in the early phases post-implantation and subsequently as clinically indicated. Stimulation parameters were titrated based on clinical response and tolerability. Data were collected in dedicated TRD specialty clinics and recorded by trained raters using structured clinical forms. All assessments were performed in-person during scheduled follow-up visits. The study was approved by the institutional Helsinki committees at all participating sites. Written informed consent was obtained from all participants. Statistical Plan and Handling of Data: * Sample Size: The final sample included 16 participants who completed 24-month follow-up and were eligible for efficacy analyses. All 19 implanted patients were included in safety analyses. * Primary analysis involved repeated measures ANOVA to examine changes in MADRS total scores over time. * Categorical outcomes (response, remission, partial response) were computed at each time-point and cumulatively (best outcome achieved at any time). * Suicidality was analyzed via MADRS item 10, both as a continuous and categorical outcome (≥50% or ≥30% reduction). * Hospitalization burden was analyzed as an exploratory outcome, comparing inpatient days during three time intervals (pre-implantation, year 1 post-implantation, year 2 post-implantation). * Missing data: Participants who permanently deactivated the device within the first 6 months were excluded from efficacy analyses but retained for safety reporting. Missing values in the MADRS and item 10 of this tool (suicidality) were imputed using the last observation carried forward method. Imputation was performed in the case of a missing value between two measurement points, but was not done after the last measurement point (for example, if a participant had values up to month 12, imputing was not done for month 18). Safety Assessment: Adverse events were monitored throughout the study and including voice alteration, throat discomfort, and coughing, as well as rarer complications such as dysphagia or transient vocal cord paresis. All adverse events were documented in accordance with clinical research guidelines.

Conditions

• Treatment Resistant Depression (TRD)
• Depression - Major Depressive Disorder
• Bipolar Depression

Interventions

Type	Name	Description
DEVICE	vagus nerve stimulation	VNS is a neuromodulatory treatment involving implantation of a subcutaneous device that delivers intermittent electrical stimulation to the vagus nerve, modulating central pathways associated with mood regulation.

Timeline

• Start date: 2020-01-01
• Primary completion: 2025-06-30
• Completion: 2025-06-30
• First posted: 2025-07-31
• Last updated: 2025-08-05

Locations

2 sites across 1 country: Israel

Regulatory

• FDA-regulated device study