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Treatment Resistant Depression (TRD)VNS TRD HG-TRDNCT07097025

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

An observational study of Treatment Resistant Depression (TRD) and Depression - Major Depressive Disorder, run by Dr.Yoav Domany at 2 sites in Israel.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
vagus nerve stimulation
How many people
19 participants
Where
2 sitesIsrael
Study dates
1 Jan 2020to 30 Jun 2025
How long will I take part?
24 Months
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: 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).

Who may be able to join

  • 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, Electroconvulsive treatment (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).

Who cannot join

  • Lifetime history of psychotic disorders (e.g., schizophrenia, schizoaffective disorder and other) or psychotic features during the current depressive episode.
  • Lifetime history of rapid-cycling bipolar disorder.

Trial locations and contacts

2 sites in 1 country.

Israel2 sites

  • Maaynei Hayeshua medical center

    Bnei Brak, 5154475

  • Lev Hasharon Medical Center

    Netanya, 4281000

Other trials in Israel

About this study

Official title: Efficacy and Safety of Vagus Nerve Stimulation Treatment in Treatment Resistant Depression

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

Read the 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.

Being tested
vagus nerve stimulation
Keywords
TRD, VNS, MDD, Suicidality, depression, policy
Medical subject headings
Depressive Disorder, Treatment-Resistant, Bipolar Disorder, Suicidal Ideation, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • vagus nerve stimulationDevice

    Also called VNS

    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.

Study groups in NCT07097025
Study groupRoleWhat they receive
Treatment Resistant Depression (TRD) patientsParticipants 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).
Receives: Device: vagus nerve stimulation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline to 24 months post-implantation

Secondary outcomes (3)

  1. 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.

    Measured: Baseline to 24 months post-implantation

  2. 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.

    Measured: 6 to 24 months post-implantation

  3. 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).

    Measured: Baseline to 24 months post-implantation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jul 2025
  2. Study start1 Jan 2020
  3. Primary completion30 Jun 2025
  4. Study completion30 Jun 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
19 participants (actual)
Target duration
24 Months
IDs, dates and publications
ClinicalTrials.gov ID
NCT07097025
Sponsor's protocol ID
0371-23-SMC
Acronym
VNS TRD HG-TRD
Status last verified
Jul 2025
First submitted
24 Jul 2025
Last updated
5 Aug 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
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.

Publications

  • Rush AJ, Conway CR, Aaronson ST, George MS, Riva-Posse P, Dunner DL, Zajecka J, Bunker MT, Quevedo J, Allen RM, Alva G, Luing H, Nahas Z, Manu L, Bennett JI, Mickey BJ, Becker J, Sheline Y, Cusin C, Murrough JW, Reeves K, Rosenquist PB, Lee YL, Majewski S, Way J, Olin B, Sackeim HA. Effects of vagus nerve stimulation on daily function and quality of life in markedly treatment-resistant major depression: Findings from a one-year, randomized, sham-controlled trial. Brain Stimul. 2025 May-Jun;18(3):690-700. doi: 10.1016/j.brs.2024.12.1187. Epub 2024 Dec 18.

    PubMed 39701918

  • Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, Reimherr FW, Schwartz TL, Zajecka JM. A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. Am J Psychiatry. 2017 Jul 1;174(7):640-648. doi: 10.1176/appi.ajp.2017.16010034. Epub 2017 Mar 31.

    PubMed 28359201

  • Rush AJ, Conway CR, Aaronson ST. Cost-effectiveness of VNS therapy for difficult-to-treat depression: insights from the RECOVER trial. J Affect Disord. 2024. In Press.

  • Conway CR, Aaronson ST, Greenberg BD, Carpenter LL, Holbert RC, Bunker M, et al. RECOVER VNS Depression Study: One-year outcomes of a randomized, controlled trial. Biol Psychiatry. 2024. In Press.

  • Lynch F, Law CW, McIntyre RS. Vagus nerve stimulation for treatment-resistant depression: efficacy, side effects, and future prospects. CNS Drugs. 2022;36(10):1041-55.

  • Cusin C, Dougherty DD. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biol Mood Anxiety Disord. 2012 Aug 17;2:14. doi: 10.1186/2045-5380-2-14.

    PubMed 22901565

  • Strawbridge R, Carter B, Marwood L, Bandelow B, Tsapekos D, Nikolova VL, Taylor R, Mantingh T, de Angel V, Patrick F, Cleare AJ, Young AH. Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis. Br J Psychiatry. 2019 Jan;214(1):42-51. doi: 10.1192/bjp.2018.233. Epub 2018 Nov 20.

    PubMed 30457075

  • Rush AJ, Sackeim HA, Conway CR, Bunker MT, Hollon SD, Demyttenaere K, Young AH, Aaronson ST, Dibue M, Thase ME, McAllister-Williams RH. Clinical research challenges posed by difficult-to-treat depression. Psychol Med. 2022 Feb;52(3):419-432. doi: 10.1017/S0033291721004943. Epub 2022 Jan 7.

    PubMed 34991768

  • Lam RW, Milev R, Rotzinger S, Andreazza AC, Blier P, Brenner C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Difficult-to-treat depression. Can J Psychiatry. 2024;69(2):95-120.

  • McAllister-Williams RH, Arango C, Blier P, Demyttenaere K, Falkai P, Gorwood P, Hopwood M, Javed A, Kasper S, Malhi GS, Soares JC, Vieta E, Young AH, Papadopoulos A, Rush AJ. The identification, assessment and management of difficult-to-treat depression: An international consensus statement. J Affect Disord. 2020 Apr 15;267:264-282. doi: 10.1016/j.jad.2020.02.023. Epub 2020 Feb 7.

    PubMed 32217227

  • Perez-Sola V, Roca M, Alonso J, Gabilondo A, Hernando T, Sicras-Mainar A, Sicras-Navarro A, Herrera B, Vieta E. Economic impact of treatment-resistant depression: A retrospective observational study. J Affect Disord. 2021 Dec 1;295:578-586. doi: 10.1016/j.jad.2021.08.036. Epub 2021 Aug 27.

    PubMed 34509073

  • Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003 Apr 15;53(8):649-59. doi: 10.1016/s0006-3223(03)00231-2.

    PubMed 12706951

  • Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF. Major depressive disorder. Nat Rev Dis Primers. 2016 Sep 15;2:16065. doi: 10.1038/nrdp.2016.65.

    PubMed 27629598

Questions about this trial

What is this clinical trial studying?

An observational study of Treatment Resistant Depression (TRD) and Depression - Major Depressive Disorder, run by Dr.Yoav Domany at 2 sites in Israel.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Depression Severity (MADRS Total Score) (time frame: Baseline to 24 months post-implantation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07097025, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2025.

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