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

NCT07097025 | Completed FDA Device

• 1 other identifier: 0371-23-SMC
• Study Type: observational
• Target: 19
• Locations: 1 country
• Sites: 2

Brief 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

Conditions

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

Keywords

TRD; VNS; MDD; Suicidality; depression; policy

Outcome Measures

Primary Outcomes (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.

  Baseline to 24 months post-implantation

Secondary Outcomes (3)

• Change in Suicidality (MADRS Item 10 Score)

  Baseline to 24 months post-implantation

• Rates of Remission, Response, and Partial Response

  6 to 24 months post-implantation

• Safety - Incidence and Nature of Adverse Events

  Baseline to 24 months post-implantation

Other Outcomes (1)

• Change in Psychiatric Hospitalization Days

  1 year pre-implantation to 2 years post-implantation

Study Arms (1)

Treatment Resistant Depression (TRD) patients

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

Interventions

vagus nerve stimulation DEVICE

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

Treatment Resistant Depression (TRD) patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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).

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dr.Yoav Domany: lead
• Lev HaSharon Mental Health Center: collaborator
• Maaynei Hayesha Medical Center: collaborator

Study Sites (2)

Maaynei Hayeshua medical center

Bnei Brak, 5154475, Israel

Location

Lev Hasharon Medical Center

Netanya, 4281000, Israel

Location

Related Publications (13)

• 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.

  PMID: 39701918 BACKGROUND

• 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.

  PMID: 28359201 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 22901565 BACKGROUND

• 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.

  PMID: 30457075 BACKGROUND

• 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.

  PMID: 34991768 BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 32217227 BACKGROUND

• 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.

  PMID: 34509073 BACKGROUND

• 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.

  PMID: 12706951 BACKGROUND

• 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.

  PMID: 27629598 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Bipolar Disorder; Suicidal Ideation; Depression

Interventions

Vagus Nerve Stimulation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Bipolar and Related Disorders; Suicide; Self-Injurious Behavior; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 24 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Psychiatrist, Department Manager

Study Record Dates

• First Submitted: July 24, 2025
• First Posted: July 31, 2025
• Study Start: January 1, 2020
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: August 5, 2025

Record last verified: 2025-07

Locations

IL (2)