Skip to main content
    • Aa
    • Aa

Vagus nerve stimulation for depression: efficacy and safety in a European study

  • T. E. Schlaepfer (a1) (a2) (a3), C. Frick (a1) (a2), A. Zobel (a2), W. Maier (a2), I. Heuser (a4), M. Bajbouj (a4), V. O'Keane (a5), C. Corcoran (a5), R. Adolfsson (a6), M. Trimble (a7), H. Rau (a8) (a9), H.-J. Hoff (a8), F. Padberg (a10), F. Müller-Siecheneder (a10), K. Audenaert (a11), D. Van den Abbeele (a11), K. Matthews (a12), D. Christmas (a12), Z. Stanga (a1) and M. Hasdemir (a13)...

Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression.


An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically.


The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (⩾50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%).


VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

Corresponding author
*Address for correspondence: T. E. Schlaepfer, M.D., Department of Psychiatry/University Hospital, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. (Email:
Hide All
Andrews JM, Nemeroff CB (1994). Contemporary management of depression. American Journal of Medicine 97, 24S32S.
Ben-Menachem E (2001). Vagus nerve stimulation, side effects, and long-term safety. Journal of Clinical Neurophysiology 18, 415418.
Ben-Menachem E, Manon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W, Tarver WB, Wernicke JF (1994). Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group. Epilepsia 35, 616626.
Carpenter LL, Moreno FA, Kling MA, Anderson GM, Regenold WT, Labiner DM, Price LH (2004). Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients. Biological Psychiatry 56, 418426.
Chae JH, Nahas Z, Lomarev M, Denslow S, Lorberbaum JP, Bohning DE, George MS (2003). A review of functional neuroimaging studies of vagus nerve stimulation (VNS). Journal of Psychiatric Research 37, 443455.
Conway CR, Sheline YI, Chibnall JT, George MS, Fletcher JW, Mintun MA (2006). Cerebral blood flow changes during vagus nerve stimulation for depression. Psychiatry Research 146, 179184.
Dago P, Quitkin F (1995). Role of the placebo response in the treatment of depressive disorders. CNS Drugs 4, 335340.
Dorr AE, Debonnel G (2006). Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. Journal of Pharmacology and Experimental Therapeutics 318, 890898.
Dunner D, Rush A, Russell J, Burke M, Woodard S, Wingard P, Allen J (2006). Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. Journal of Clinical Psychiatry 67, 688695.
Elger G, Hoppe C, Falkai P, Rush A, Elger C (2000). Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Research 42, 203210.
FDA (1995). COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms. US Department of Health and Human Services, Center for Drug Evaluation and Research, Food and Drug Administration, Center for Drugs and Biologics: Rockville, MD.
George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, Howland R, Kling MA, Moreno F, Rittberg B, Dunner D, Schwartz T, Carpenter L, Burke M, Ninan P, Goodnick P (2005). A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biological Psychiatry 58, 364373.
George MS, Sackeim HA, Rush AJ, Marangell LB, Nahas Z, Husain MM, Lisanby S, Burt T, Goldman J, Ballenger JC (2000). Vagus nerve stimulation: a new tool for brain research and therapy. Biological Psychiatry 47, 287295.
Groves DA, Brown VJ (2005). Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neuroscience and Biobehavioral Reviews 29, 493500.
Hamilton M (1967). Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology 6, 278296.
Handforth A, DeGiorgio C, Schachter S, Uthman B, Naritoku D, Tecoma E (1998). Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 51, 4855.
Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR (2000). A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy and Behavior 1, 9399.
Helmstaedter C, Hoppe C, Elger CE (2001). Memory alterations during acute high-intensity vagus nerve stimulation. Epilepsy Research 47, 3742.
Henry TR, Votaw JR, Pennell PB, Epstein CM, Bakay RAE, Faber TL, Grafton ST, Hoffman JM (1999). Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy. Neurology 52, 11661173.
Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RM, Shea T (1992). Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Archives of General Psychiatry 49, 809816.
Kosel M, Schlaepfer TE (2002). Mechanisms and state of the art of vagus nerve stimulation. Journal of ECT 18, 189192.
Kosel M, Schlaepfer TE (2003). Beyond the treatment of epilepsy: new applications of vagus nerve stimulation (VNS) in psychiatry. CNS Spectrums 8, 515521.
Lyketsos CG, DelCampo L, Steinberg M, Miles Q, Steele CD, Munro C, Baker AS, Sheppard JM, Frangakis C, Brandt J, Rabins PV (2003). Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Archives of General Psychiatry 60, 737746.
Mann JJ (2005). The medical management of depression. New England Journal of Medicine 353, 18191834.
Mason BL, Pariante CM (2006). The effects of antidepressants on the hypothalamic–pituitary–adrenal axis. Drug News and Perspectives 19, 603608.
Montgomery SA, Rasmussen JG, Tanghoj P (1993). A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression. International Clinical Psychopharmacology 8, 181188.
Morris GL 3rd, Mueller WM (1999). Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 53, 17311735.
Naritoku DK, Terry WJ, Helfert RH (1995). Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Research 22, 5362.
Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, George MS, Charney DS, Brannan SK (2006). VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology 31, 13451355.
Nestler E (1998). Antidepressant treatments in the 21st century. Biological Psychiatry 44, 526533.
Prudic J, Sackeim HA, Devanand DP (1990). Medication resistance and clinical response to electroconvulsive therapy. Psychiatry Research 31, 287296.
Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RK, Goodmann R (2000). Vagus nerve stimulation (VNS) for treatment-resistant depression: a multicenter study. Biological Psychiatry 47, 276286.
Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG (2005 a). Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biological Psychiatry 58, 347354.
Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, Lavori P, Howland R, Kling MA, Rittberg B, Carpenter L, Ninan P, Moreno F, Schwartz T, Conway C, Burke M, Barry JJ (2005 b). Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biological Psychiatry 58, 355363.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry 163, 19051917.
Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, Johnson CR, Seidman S, Giller C, Haines S, Simpson RK, Goodman RR (2001). Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 25, 713728.
Schachter SC (2002). Vagus nerve stimulation therapy summary: five years after FDA approval. Neurology 59 (Suppl. 4), S15S20.
Schatzberg AF, Kraemer HC (2000). Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. Biological Psychiatry 47, 736744.
Schlaepfer TE, Kosel M (2004). Novel physical treatments for major depression: vagus nerve stimulation, transcranial magnetic stimulation and magnetic seizure therapy. Current Opinion in Psychiatry 17, 1520.
Shuchman M (2007). Approving the vagus-nerve stimulator for depression. New England Journal of Medicine 356, 16041607.
The Vagus Nerve Stimulation Study Group (1995). A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. Neurology 45, 224230.
Uthman BM (2000). Vagus nerve stimulation for seizures. Archives of Medical Research 31, 300303.
Zobel A, Joe A, Freymann N, Clusmann H, Schramm J, Reinhardt M, Biersack HJ, Maier W, Broich K (2005). Changes in regional cerebral blood flow by therapeutic vagus nerve stimulation in depression: an exploratory approach. Psychiatry Research 139, 165179.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 5
Total number of PDF views: 63 *
Loading metrics...

Abstract views

Total abstract views: 561 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd October 2017. This data will be updated every 24 hours.