An observational study in Treatment Resistant Depression (TRD), Depression - Major Depressive Disorder and Bipolar Depression, sponsored by Dr.Yoav Domany. Completed at 2 sites in Israel. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-08-05.
Sponsored by Dr.Yoav Domany · Observational
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
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:
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.
461 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 148 are open to participants now.
This study's enrollment of 19 is below the median of 64 across 50 observational studies indexed under Depressive Disorder, Treatment-Resistant.
Browse Depressive Disorder, Treatment-Resistant studies →This is the only study on the registry with Dr.Yoav Domany as lead sponsor.
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Participants were recruited under the care of the participating physician investigators, from the Advanced Treatments for TRD Clinics at Sheba Medical Center (n=10, 62.5% of participants), or and Lev-Hasharon mental health center (n=6, 37.5% of participants).
Exclusion Criteria:
Participants were recruited under the care of the participating physician investigators, from the Advanced Treatments for Treatment Resistant Depression (TRD) Clinics at Sheba Medical Center, or Lev-Hasharon mental health center , who underwent VNS implantation procedure. Inclusion criteria were age ≥ 18 years; Diagnose of chronic and recurrent depressive episode lasting at least two years (persistent depressive disorder) or a history of at least three depressive episodes, including the current episode, according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria; Resistance to treatment was defined as failure to respond to at least four antidepressant treatments, including pharmacotherapy (administered at therapeutic dosages for at least four weeks), psychotherapy, ECT, or esketamine meaning HD-TRD; Baseline scores \>20 according to the Montgomery-Åsberg Depression Rating Scale (MADRS)(indicating moderate (20-34) to severe (\>34) depression).
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.
Also known as: VNS
Change in Depression Severity (MADRS Total Score)
Change in depressive symptom severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The scale consists of 10 clinician-rated items, each scored from 0 to 6, with total scores ranging from 0 (no symptoms) to 60 (severe depression). A reduction in score indicates clinical improvement. Depression severity was assessed at baseline and at predefined follow-up visits (6, 12, 18, and 24 months post-implantation). The primary outcome reflects the magnitude and trajectory of change in MADRS scores over time following vagus nerve stimulation (VNS) implantation.
Time frame: Baseline to 24 months post-implantation
Change in Suicidality (MADRS Item 10 Score)
Change in suicidality as measured by item 10 of the Montgomery-Åsberg Depression Rating Scale (MADRS), which assesses suicidal thoughts and behaviors on a 0-6 scale. A reduction in score indicates clinical improvement. The outcome captures both point-in-time and cumulative reductions in suicidality over the course of 24 months following vagus nerve stimulation (VNS) implantation.
Time frame: Baseline to 24 months post-implantation
Rates of Remission, Response, and Partial Response
Proportion of participants achieving clinical improvement at predefined follow-up timepoints (6, 12, 18, and 24 months) and cumulatively (i.e., best outcome achieved at any point during follow-up), based on changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score: * Remission: MADRS total score ≤12 * Response: ≥50% reduction in MADRS total score from baseline * Partial Response: 30%-49% reduction in MADRS total score from baseline Each participant was categorized based on the highest level of improvement attained at each timepoint. These outcomes reflect clinically meaningful levels of symptom reduction following vagus nerve stimulation (VNS) implantation.
Time frame: 6 to 24 months post-implantation
Safety - Incidence and Nature of Adverse Events
Incidence, type, severity, and time course of adverse events related to VNS implantation and stimulation, including surgical complications and stimulation-related side effects. Adverse events were documented throughout the 24-month follow-up period and categorized by clinical severity (e.g., mild, moderate, serious), duration, and management strategies (e.g., stimulation adjustment, discontinuation).
Time frame: Baseline to 24 months post-implantation
Change in Psychiatric Hospitalization Days
Change in the number of psychiatric inpatient hospitalization days before and after VNS implantation. Hospitalization burden was calculated for each participant across three time intervals: (1) 12 months pre-implantation, (2) first 12 months post-implantation, and (3) second 12 months post-implantation. Mean hospitalization days per period were compared to assess potential reductions in inpatient care burden following VNS therapy.
Time frame: 1 year pre-implantation to 2 years post-implantation
Plan to share: Undecided — Individual participant data (IPD) might not be shared due to concerns regarding participant confidentiality and the sensitive nature of the clinical data. The study involves a small cohort of individuals with severe, treatment-resistant depression, and the risk of re-identification cannot be fully mitigated, even with de-identification procedures.
This study is completed, as verified in Jul 2025. You cannot join it, but the record below documents what was studied.
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