2-Year Study of Vagus Nerve Stimulation for Higher-Grade Treatment-Resistant Depression: Clinical Outcomes and Policy Recommendation
NCT ID: NCT07097025
Last Updated: 2025-08-05
Study Results
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Basic Information
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COMPLETED
19 participants
OBSERVATIONAL
2020-01-01
2025-06-30
Brief Summary
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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
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Detailed Description
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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
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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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).
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.
Interventions
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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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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).
Exclusion Criteria
* Lifetime history of rapid-cycling bipolar disorder.
18 Years
ALL
No
Sponsors
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Lev HaSharon Mental Health Center
UNKNOWN
Maaynei Hayesha Medical Center
OTHER
Dr.Yoav Domany
OTHER
Responsible Party
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Dr.Yoav Domany
Psychiatrist, Department Manager
Locations
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Maaynei Hayeshua medical center
Bnei Brak, , Israel
Lev Hasharon Medical Center
Netanya, , Israel
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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0371-23-SMC
Identifier Type: -
Identifier Source: org_study_id
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