Cited by 178Vagus Nerve Stimulation ResearchTreatment of Major DepressionDeep Brain Stimulation and Movement Disorders

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Two-Year Outcome of Vagus Nerve Stimulation in Treatment-Resistant Depression

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Bajbouj, Malek, Merkl, Angela, Schlaepfer, Thomas E., Frick, Caroline, Zobel, Astrid, Maier, Wolfgang, O'Keane, Veronica, Corcoran, Ciaran, Adolfsson, Rolf, Trimble, Michael, Rau, Harald, Hoff, Hans-Joachim, Padberg, Frank, Müller-Siecheneder, Florian, Audenaert, Kurt, van den Abbeele, Dirk, Matthews, Keith, Christmas, David, Eljamel, Sam, Heuser, Isabella·2010·Journal of Clinical Psychopharmacology

DOI 10.1097/jcp.0b013e3181db8831

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Abstract

One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms. Some of the previous studies of vagus nerve stimulation (VNS) have suggested antidepressant effects. Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant reduction (P < or = 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score, the primary outcome measure. After 2 years, 53.1% (26/49) of the patients fulfilled the response criteria (> or =50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scores < or = 10). The proportion of patients who fulfilled the remission criteria remained constant as the duration of VNS treatment increased. Voice alteration, cough, and pain were the most frequently reported adverse effects. Two patients committed suicide during the study; no other deaths were reported. No statistically significant differences were seen in the number of concomitant antidepressant medications. The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression.

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Rush, 2005, Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial., Biol Psychiatry, 58, 347, 10.1016/j.biopsych.2005.05.025 · DOI · Paper page

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“Other common symptoms reported are nausea, dizziness, shortness of breath, pain, and anxiety (Bajbouj et al., 2010; Cristancho et al., 2011).”
Background
Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: A potential marker for response?
Conway, C. R., Chibnall, J. T., Gangwani, S., Mintun, M. A., Price, J. L., Hershey, T. G., Giuffra, L. A., Bucholz, R. D., Christensen, J. J., & Sheline, Y. I. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.02.007 · Cited by 41
Direct and Transcutaneous Vagus Nerve Stimulation for Treatment of Tinnitus: A Scoping Review
Yakunina, N., & Nam, E. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.680590 · Cited by 41
A Systematic Review of Non-Invasive Brain Stimulation Therapies and Cardiovascular Risk: Implications for the Treatment of Major Depressive Disorder
Sampaio, L. A. N. P. C., Fráguas, R., Lotufo, P. A., Benseñor, I. M., & Brunoni, A. R. (2012) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2012.00087 · Cited by 38
“Further, it also seems to be a safe therapy from a cardiovascular perspective, according to a recent long-term follow-up in depressed patients (Bajbouj et al., 2010).”
Background
Current source density analysis of resting state EEG in depression: a review
Koo, P. C., Thome, J., Berger, C., Foley, P. B., & Hoeppner, J. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1432-2 · Cited by 38
Therapeutic Modalities for Treatment Resistant Depression: Focus on Vagal Nerve Stimulation and Ketamine
Shah, A. P., Carreno, F. R., & Frazer, A. (2014) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2014.12.2.83 · Cited by 36
The allure of transcutaneous vagus nerve stimulation as a novel therapeutic modality
Carreno, F. R., & Frazer, A. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.11.016 · Cited by 34
Hippocampal Gray Volumes Increase in Treatment-Resistant Depression Responding to Vagus Nerve Stimulation
Perini, G., Toffanin, T., Pigato, G., Ferri, G., Follador, H., Zonta, F., Pastorelli, C., Piazzon, G., Denaro, L., Rolma, G., et al. (2017) · Journal of Ect · doi:10.1097/yct.0000000000000424 · Cited by 34
“Moreover, an increase in VNS response rate over time has been reported from 3 months to 1 and 2 years, suggesting that VNS is effective in the acute treatment of TRD, but it may also prove more useful in the long-term maintenance treatment, because approximately 65% of the VNS responsive patients at 1 year maintained…”
Result
Neurostimulation for depression in epilepsy
Conway, C. R., Anita, U., & Schachter, S. C. (2018) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2018.06.007 · Cited by 36
Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD)
D, M. F. M., Freeman, M. P., Flynn, M., Hoeppner, B. B., Shelton, R. C., Iosifescu, D. V., Murrough, J. W., Mischoulon, D., Cusin, C., Rapaport, M. H., et al. (2017) · Brain stimulation · doi:10.1016/j.brs.2017.09.010 · Cited by 30
“In addition, only three nonpharmacological therapies have been approved for TRD: transcranial magnetic stimulation [10], vagus nerve stimulation [11], and electroconvulsive therapy [12].”
Background
The Association Between Vascular Inflammation and Depressive Disorder. Causality, Biomarkers and Targeted Treatment
Kalkman, H. O. (2020) · Pharmaceuticals · doi:10.3390/ph13050092 · Cited by 32
Activation of signaling pathways downstream of the brain-derived neurotrophic factor receptor, TrkB, in the rat brain by vagal nerve stimulation and antidepressant drugs
Carreno, F. R., & Frazer, A. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713000977 · Cited by 30
Novel attempts to optimize vagus nerve stimulation parameters on serotonin neuronal firing activity in the rat brain
Manta, S., Mansari, M. E., & Blier, P. (2011) · Brain stimulation · doi:10.1016/j.brs.2011.04.005 · Cited by 28
“The most recent open label multicenter study on 74 patients with treatment-resistant depression showed a 53% response rate and a 33% remission rate after 1 year of treatment.1 Moreover, there are reports showing a progressive improvement of response and remission rates after the initiation of VNS.2,3 Inversely, depres…”
BackgroundInfluential
Neuroendocrine homeostasis after vagus nerve stimulation in rats
Thrivikraman, K. V., Zejnelovic, F., Bonsall, R. W., & Owens, M. J. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.10.015 · Cited by 28
Vagus nerve stimulation therapy in treatment‐resistant depression: A series report
Tisi, G., Franzini, A., Messina, G., Savino, M., & Gambini, O. (2014) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12166 · Cited by 27
“Bajbouj et al.7 evaluated 74 patients over a follow-up period of 2 years, and remarked that the proportion of patients who fulfilled remission criteria remained constant over time.”
Background
Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP
Kalkman, H. O. (2019) · Pharmaceuticals · doi:10.3390/ph12030113 · Cited by 32
Vagus nerve stimulation for treatment-resistant mood disorders: a long-term naturalistic study
Albert, U., Maina, G., Aguglia, A., Vitalucci, A., Bogetto, F., Fronda, C., Ducati, A., & Lanotte, M. (2015) · BMC Psychiatry · doi:10.1186/s12888-015-0435-8 · Cited by 28
“2-57%); moreover, response rates increase from 3 months to 1 or 2 years [5,17-34].”
Background
A Systematic Review of Neuromodulation Treatment Effects on Suicidality
Kucuker, M. U., Almorsy, A. G., Sonmez, A. I., Ligezka, A. N., Doruk Camsari, D., Lewis, C. P., & Croarkin, P. E. (2021) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2021.660926 · Cited by 25
“In a cohort study of 74 patients with TRD who were treated with VNS, two patients had completed suicide by the end of the 2 year follow-up (Bajbouj et al., 2010).”
Background
Advances in the Management of Treatment-Resistant Depression
Holtzheimer, P. E. (2010) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.8.4.foc488 · Cited by 25
Suicide Prevention Interventions and Referral/Follow-Up Services: A Systematic Review
O'Neil, M. E., Peterson, K., Low, A., Carson, S., Denneson, L. M., Haney, E. M., Shiroma, P. R., & Kansagara, D. L. (2012) · Cited by 22
Vagus nerve stimulation as immunomodulatory therapy for stroke: A comprehensive review
Jelinek, M., Lipková, J., & Ďuriš, K. (2023) · Experimental Neurology · doi:10.1016/j.expneurol.2023.114628 · Cited by 23
“Furthermore, in 2005 VNS was approved by the FDA for treatment of chronic or recurring depression (Bajbouj et al., 2010; Johnson and Wilson, 2018).”
Transcutaneous vagus nerve stimulation as a pain modulator in knee osteoarthritis: a randomized controlled clinical trial
Elsehrawy, G. G., Ibrahim, M. E., Moneim, N. H. A., Hefny, M., & El-Shaarawy, N. (2025) · BMC Musculoskeletal Disorders · doi:10.1186/s12891-025-08288-6 · Cited by 23
Neuromodulation therapies and treatment-resistant depression
Qureshi, N. A., & Harbi, K. A. (2012) · Medical Devices Evidence and Research · doi:10.2147/mder.s33198 · Cited by 24
“This 2-year open-label trial of VNS suggested a clinical response and a benign adverse-effect profile among patients with TRD. 67 In a recent study of 15 consecutive outpatients with TRD, VNS significantly decreased Beck Depression Inventory (BDI) scores compared to baseline at 6 and 12 months,…”
Vagus nerve stimulation in treating depression: A tale of two stories.
Yuan, T., Li, A., Sun, X., Arias-Carrión, Ó., & Machado, S. E. D. C. (2016) · Current Molecular Medicine · doi:10.2174/1566524016666151222143609 · Cited by 21
The potential role of vagus-nerve stimulation in the treatment of HIV-associated depression: a review of literature
Nicholson, W., Kempf, M., Moneyham, L. D., & Vance, D. (2017) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s136065 · Cited by 19
Toward Closed-Loop Electrical Stimulation of Neuronal Systems: A Review
Tanskanen, J. M. A., Ahtiainen, A., & Hyttinen, J. (2020) · Bioelectricity · doi:10.1089/bioe.2020.0028 · Cited by 20
Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles
Kalkman, H. O. (2023) · Biomedicines · doi:10.3390/biomedicines11030806 · Cited by 18
A Preclinical Study of Laryngeal Motor-Evoked Potentials as a Marker Vagus Nerve Activation
Grimonprez, A., Raedt, R., Taeye, L. D., Larsen, L. E., Delbeke, J., Boon, P., & Vonck, K. E. J. (2015) · International Journal of Neural Systems · doi:10.1142/s0129065715500343 · Cited by 17
Stimulation du nerf vague dans le traitement de la dépression
Senova, S., Rabu, C., Beaumont, S., Michel, V., Palfi, S., Mallet, L., & Domenech, P. (2019) · La Presse Médicale · doi:10.1016/j.lpm.2019.10.019 · Cited by 20
Mania following vagus nerve stimulation: A case report and review of the literature
Gerson, R. S., Murray, E. D., Price, B. H., Frankel, M., Douglass, L. M., & Cunningham, M. G. (2010) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2010.11.005 · Cited by 18
“Suicidality (completed, attempted, or ideation) has occurred very rarely in studies of VNS for unipolar or bipolar depression [6,18,21], and it is often suggested that suicidality after VNS is due to the underlying affective illness.”
Increased Concentrations of Circulating Interleukins following Non-Invasive Vagus Nerve Stimulation: Results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects
Veiz, E., Kieslich, S.-K., Czesnik, D., Herrmann‐Lingen, C., Meyer, T., & Staab, J. (2022) · NeuroImmunoModulation · doi:10.1159/000524646 · Cited by 16
Transcutaneous auricular vagal nerve stimulation inhibits limbic-regional P2X7R expression and reverses depressive-like behaviors in Zucker diabetic fatty rats
Yu, Y., He, X., Wang, Y., Zhang, J., Tang, C., & Rong, P. (2022) · Neuroscience Letters · doi:10.1016/j.neulet.2022.136562 · Cited by 16
Vagus Nerve Stimulation has Antidepressant Effects in the Kainic Acid Model for Temporal Lobe Epilepsy
Grimonprez, A., Raedt, R., Dauwe, I., Mollet, L., Larsen, L. E., Meurs, A., Herdt, V. D., Wadman, W. J., Delbeke, J., Vonck, K. E. J., et al. (2014) · Brain stimulation · doi:10.1016/j.brs.2014.09.013 · Cited by 16
Double Blinded Randomized Trial of Subcutaneous Trigeminal Nerve Stimulation as Adjuvant Treatment for Major Unipolar Depressive Disorder
Gorgulho, A. A., Fernandes, F. D. S., Damiani, L. P., Barbosa, D. A. N., Cury, A., Lasagno, C. M., Bueno, P. R. T., Santos, B. F. O., Santos, R. H. N., Berwanger, O. B., et al. (2018) · Neurosurgery · doi:10.1093/neuros/nyy420 · Cited by 16
The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders
Sackeim, H. A., Dibué, M., Bunker, M. T., & Rush, A. J. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s286977 · Cited by 15
Bibliometric analysis of publication trends and research hotspots in vagus nerve stimulation: A 20-year panorama
Li, R., Hu, H., Luo, N., & Fang, J. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.1045763 · Cited by 17
Setting Up a Successful Vagus Nerve Stimulation Service for Patients With Difficult-to-Treat Depression
Kraus, C., Quach, D., Sholtes, D. M., Kavakbasi, E., De Zwaef, R., Dibué, M., Zajecka, J., & Baune, B. T. (2022) · Neuromodulation: Technology at the Neural Interface · doi:10.1016/j.neurom.2021.12.010 · Cited by 14
Advances in Cardiac Pacing: Arrhythmia Prediction, Prevention and Control Strategies
Patel, M. H., Sampath, S., Kapoor, A., Damani, D. N., Chellapuram, N., Challa, A. B., Kaur, M. P., Walton, R. D., Stavrakis, S., Arunachalam, S. P., et al. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.783241 · Cited by 14
Complications of Implanted Vagus Nerve Stimulation: A Systematic Review and Meta-Analysis
Kalagara, R., Chennareddy, S., Reford, E., Bhimani, A. D., Cummins, D. D., Downes, M., Tosto, J., Bederson, J. B., Mocco, Putrino, D. F., et al. (2024) · Cerebrovascular Diseases · doi:10.1159/000536362 · Cited by 14
Effects of chronic vagal nerve stimulation in the treatment of β-amyloid-induced neuropsychiatric symptoms
Yeşiltepe, M., Çimen, B., & Sara, Y. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175179 · Cited by 16
Vagus Nerve Stimulation for Major Depressive Episodes
Eljamel, S. (2015) · Progress in neurological surgery · doi:10.1159/000434655 · Cited by 13
Self-citation
Vagus nerve stimulation for treatment-resistant depression: is this therapy distinct from other antidepressant treatments?
Vlaicu, A., & Vlaicu, M. B. ̆. (2020) · International Journal of Psychiatry in Clinical Practice · doi:10.1080/13651501.2020.1779751 · Cited by 12
Vagus nerve stimulation in pregnant rats and effects on inflammatory markers in the brainstem of neonates
Judkins, A. J., Johnson, R. L., Murray, S. T., Yellon, S. M., & Wilson, C. G. (2017) · Pediatric Research · doi:10.1038/pr.2017.265 · Cited by 12
“It has also been implicated in the anti-inflammatory response observed in other studies of VNS (27,28).”
Vagus Nerve Stimulation for Epilepsy and Depression
Conway, C. R., Colijn, M. A., & Schachter, S. C. (2015) · Brain stimulation · doi:10.1002/9781118568323.ch17 · Cited by 12
Long-term efficacy and safety of vagus nerve stimulation in treatment-resistant depression: A systematic review
Rosson, S., Bresolin, N., D’Amico, A., Denaro, L., Landi, A., Sambataro, F., & Pigato, G. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120483 · Cited by 12

Authors: Bajbouj, M., Merkl, A., Schlaepfer, T. E., Frick, C., Zobel, A., Maier, W., O'Keane, V., Corcoran, C., Adolfsson, R., Trimble, M., Rau, H., Hoff, H.-J., Padberg, F., Müller-Siecheneder, F., Audenaert, K., van den Abbeele, D., Matthews, K., Christmas, D., Eljamel, S., & Heuser, I.
Affiliations: University Hospital of Umeå (SE)
University of Dundee (GB)
University Hospital Bonn (DE)
National Hospital for Neurology and Neurosurgery (GB)
University Hospital of Bern (CH)
Ghent University Hospital (BE)
Corresponding author: Bajbouj, Malek
Merkl, Angela
Adolfsson, Rolf
Heuser, Isabella
ORCID: Bajbouj, Malek
Merkl, Angela
Schlaepfer, Thomas E.
Adolfsson, Rolf
Trimble, Michael
Rau, Harald
Padberg, Frank
Audenaert, Kurt
Matthews, Keith
Christmas, David
Eljamel, Sam
Heuser, Isabella
Venue: Journal of Clinical Psychopharmacology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2010-06
Volume: 30
Issue: 3
Pages: 273-281
ISSN: 0271-0749 (ISSN-L)
DOI: 10.1097/jcp.0b013e3181db8831
OpenAlex: W1987908185
Cited by: 178
References: 29
Citations by year: 2026: 8 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 17 · 2021: 7 · 2020: 12 · 2019: 13 · 2018: 10 · 2017: 13 · 2016: 7 · 2015: 15 · 2014: 12 · 2013: 8 · 2012: 21
FWCI: 8.34
Type: journal article
Language: en
Open access: green
biblio.ugent.be
Licence: other-oa
Locations: Journal of Clinical Psychopharmacology (publishedVersion)
PubMed (publishedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
Topics: Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
Keywords: vagus nerve stimulation, treatment-resistant depression, major depressive disorder, long-term efficacy, remission, antidepressant response, adverse effects, voice change, suicide
MeSH terms: Adult, Aged, Depressive Disorder, Major, Major Depressive Disorder, Electric Stimulation Therapy, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Time Factors, Cohort Studies, Treatment Outcome, Vagus Nerve Stimulation, Young Adult

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Two-Year Outcome of Vagus Nerve Stimulation in Treatment-Resistant Depression

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