BRAIN STIMULATION: Basic, Translational, and Clinical Research in Neuromodulation
Volume 1, Issue 2 , Pages 112-121 , April 2008

A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders

  • Mark S. George, MD

      Affiliations

    • Department of Psychiatry, Medical University of South Carolina, Charleston, South Carolina
    • Corresponding Author InformationAddress reprints requests to: Dr. Mark S. George, 502N, IOP, Medical University of South Carolina, 67 President Street, Charleston, SC 29425.
    • ,
  • Herbert E. Ward Jr., MD

      Affiliations

    • Department of Psychiatry, University of Florida School of Medicine, Gainesville, Florida
    • ,
  • Philip T. Ninan, MD

      Affiliations

    • Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
    • ,
  • Mark Pollack, MD

      Affiliations

    • Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
    • ,
  • Ziad Nahas, MD

      Affiliations

    • Department of Psychiatry, Medical University of South Carolina, Charleston, South Carolina
    • ,
  • Berry Anderson, RN

      Affiliations

    • Department of Psychiatry, Medical University of South Carolina, Charleston, South Carolina
    • ,
  • Samet Kose, MD

      Affiliations

    • Department of Psychiatry, Medical University of South Carolina, Charleston, South Carolina
    • ,
  • Robert H. Howland, MD

      Affiliations

    • Western Psychiatric Institute, Pittsburgh, Pennsylvania
    • ,
  • Wayne K. Goodman, MD

      Affiliations

    • Department of Psychiatry, University of Florida School of Medicine, Gainesville, Florida
    • ,
  • James C. Ballenger, MD

      Affiliations

    • Department of Psychiatry, Medical University of South Carolina, Charleston, South Carolina

Received 25 August 2007 ,Revised 22 January 2008 ,Accepted 19 February 2008.

References 

  1. Sheehan DV, Sheehan KH. Current approaches to the pharmacologic treatment of anxiety disorders. Psychopharmacol Bull. 2007;40(1):98–109
  2. Kessler RC. The global burden of anxiety and mood disorders: putting the European Study of the Epidemiology of Mental Disorders (ESEMeD) findings into perspective. J Clin Psychiatry. 2007;68(Suppl 2):10–19
  3. Olatunji BO, Cisler JM, Tolin DF. Quality of life in the anxiety disorders: a meta-analytic review. Clin Psychol Rev. 2007;27(5):572–581
  4. Friedman BH. An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone. Biol Psychol. 2007;74(2):185–199
  5. George MS, Sackeim HA, Rush AJ, et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry. 2000;47(4):287–295
  6. George MS, Nahas Z, Bohning DE, et al. Vagus nerve stimulation: a research update. Neurology. 2002;54(Suppl 4):S56–S61
  7. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology. 2002;59(Suppl 4):S15–S20
  8. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure attenuating effects of vagus nerve stimulation. Epilepsia. 1998;39:709–714
  9. Smith MA, Makino S, Altemus M, et al. Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus. Proc Natl Acad Sci U S A. 1995;92(19):8788–8792
  10. Hirata H, Aston-Jones G. A novel long-latency response of locus coeruleus neurons to noxious stimuli: mediation by peripheral C-fibers. J Neurophysiol. 1994;71(5):1752–1761
  11. Kapur S, Austin MC, Underwood MD, Arango V, Mann JJ. Electroconvulsive shock increases tyrosine hydroxylase and neuropeptide Y gene expression in the locus coeruleus. Brain Res Mol Brain Res. 1993;18(1-2):121–126
  12. Nakamura S. Axonal sprouting of noradrenergic locus coeruleus neurons following repeated stress and antidepressant treatment. Prog Brain Res. 1991;88:587–598
  13. Delgado PL, Goodman WK, Price LH, Heninger GR, Charney DS. Fluvoxamine/pimozide treatment of concurrent Tourette's and obsessive-compulsive disorder. Br J Psychiatry. 1990;157:762–765
  14. Goodman WK, Price LH, Rasmussen SA, Heninger GR, Charney DS. Fluvoxamine as an antiobsessional agent. Psychopharmacol Bull. 1989;25:31–35
  15. Ben-Menachem E, Hamberger A, Hedner T, et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res. 1995;20:221–227
  16. Chae JH, Nahas Z, Lomarev M, et al. A review of functional neuroimaging studies of vagus nerve stimulation (VNS). J Psychiatr Res. 2003;37(6):443–455
  17. Bohning DE, Lomarev MP, Denslow S, Nahas Z, Shastri A, George MS. Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI. Invest Radiol. 2001;36(8):470–479
  18. Lomarev M, Denslow S, Nahas Z, Chae JH, George MS, Bohning DE. Vagus nerve stimulation (VNS) synchronized BOLD fMRI suggests that VNS in depressed adults has frequency/dose dependent effects. J Psychiatr Res. 2002;36(4):219–227
  19. Mu Q, Bohning DE, Nahas Z, et al. Acute vagus nerve stimulation using different pulse widths produces varying brain effects. Biol Psychiatry. 2004;55(8):816–825
  20. Nahas Z, Teneback C, Chae JH, et al. Serial vagus nerve stimulation functional MRI (VNS/fMRI) in Treatment resistant depression. Neuropsychopharmacol. 2007;32(2):1–12
  21. Krahl SE, Senanayake SS, Handforth A. Seizure suppression by systemic epinephrine is mediated by the vagus nerve. Epilepsy Res. 2000;38:171–175
  22. Krahl SE, Senanayake SS, Handforth A. Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression. Epilepsia. 2001;42:586–589
  23. Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry. 2000;47(4):276–286
  24. Sackeim HA, Keilp JG, Rush AJ, et al. The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14(1):53–62
  25. Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacol. 2001;25(5):713–728
  26. Nahas Z, Marangell LB, Husain MM, et al. Two-year outcome of vagus nerve stimulation (VNS) therapy for major depressive episodes. J Clin Psychiatry. 2005;66:1097–1104
  27. George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58(5):364–373
  28. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58(5):347–354
  29. Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58(5):355–363
  30. Post RM, Ballenger JC, Uhde TW, Bunney WEJ. Efficacy of carbamazepine in manic-depressive illness: implications for underlying mechanisms. In:  Post RM,  Ballenger JC editor. Neurobiology of Mood Disorders. Baltimore: Williams and Wilkins; 1984;p. 777–816
  31. Post RM, Uhde TW, Ballenger JC, Squillace KM. Prophylactic efficacy of carbamazepine in manic-depressive illness. Am J Psychiatry. 1983;140:1602–1604
  32. Ballenger JC, Post RM. Anticonvulsants in psychiatric disease: when are they effective?. Drug Therapy. 1985;15:144–156
  33. Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J Clin Psychopharmacol. 2007;27(3):263–272
  34. Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. Vagus nerve stimulation for treatment of partial seizures: 1, a controlled study of effect on seizures. Epilepsia. 1994;35:616–626
  35. George R, Salinsky M, Kuzniecky R, et al. Vagus nerve stimulation for treatment of partial seizures: 2, long-term follow-up on first 67 patients exiting a controlled study. Epilepsia. 1994;35:637–643
  36. Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry. 2000;47:276–286
  37. Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacol. 2001;25(5):713–728
  38. Trivedi MH, Rush AJ, Ibrahim HM, et al. The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med. 2004;34(1):73–82
  39. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435
  40. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I, conceptual framework and item selection. Med Care. 1992;30:473–483
  41. Greenberg BD, Price LH, Rauch SL, et al. Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues. Neurosurg Clin N Am. 2003;14(2):199–212
  42. Greenberg BD, Malone DA, Friehs GM, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. [erratum appears in Neuropsychopharmacol 2006 Nov;31(11):2394] Neuropsychopharmacol. 2006;31(11):2384–2393
  43. James W. What is an emotion?. Mind. 1884;9:188–205

 This study was supported in part by grants from Cyberonics, Inc. Data were collected by Quintiles Transnational Corp. Statistical analyses were performed by Amara K. Jayewardene, MS, and John Allen, Jr., PhD, of Cyberonics, Inc., manufacturer of the VNS Therapy System and reviewed by the authors. Susan E. Siefert, ELS, CBC, also of Cyberonics, assisted with the development of the manuscript.

 Dr. George has received research grants from Cyberonics, and is on the Cyberonics Depression and Mechanism of Action Scientific Advisory Boards.

 Dr. Nahas has received research grants and speaking fees from Cyberonics.

 Dr. Robert H. Howland has received research support from Aspect Medical Systems; Bristol-Myers Squibb; Cyberonics; Forest; Cederroth; National Institutes of Mental Health; National Center for Complementary and Alternative Medicine. He has received speaking fees from Wyeth; Bristol-Myers Squibb; AstraZeneca; Cyberonics.

 Amara Jayewardene, MS, John Allen, Jr, PhD, and Susan E. Siefert, ELS, CBC, are employees of Cyberonics.

 Dr. Allen and Ms Siefert own Cyberonics stock. Dr. Ninan is now an employee of Wyeth Pharmaceuticals.

 Dr. Pollack is a paid adviser, consultant or speaker for AstraZeneca, Brain Cells Inc, Bristol Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Eli Lilly, Medavante, Neurocrine, Neurogen, Novartis, Otsuka Pharmaceuticals, Pfizer, Predix, Roche, Laboratories, Sanofi, Sepracor, Solvay, Tikvah Therapeutics, Transcept Inc, UCB Pharma, and Wyeth. He has equity stake in Medavante and Mensante Corporation. He has received research grants from Bristol Myers Squibb, Cephalon, Cyberonics, Forest Laboratories, GlaxoSmithKline, Janssen, Eli Lilly, NARSAD, NIDA NIMH, Pfizer, Sepracor, UCB Pharma, and Wyeth.

 Although Cyberonics sponsored the trial, the authors were involved in initial study design, data collection, manuscript writing, and have had full access to the data.

 Aspects of this trial have been previously reported in poster format at:

 George MS, et al: Vagus nerve stimulation (VNS) shows potential therapeutic benefit for severe anxiety disorders in an initial open trial. 41st American College of Neuropsychopharmacology Annual Meeting. December 2002.

 Ward H, et al: Treatment-refractory obsessive-compulsive disorder: potential benefit of VNS therapy. 23rd Annual Conference of the Anxiety Disorders Association of America. March 2003.

 George MS, et al: Open trial of VNS therapy in severe anxiety disorder. 156th American Psychiatric Association Annual Meeting. May 17-22, 2003, San Francisco, California.

PII: S1935-861X(08)00003-X

doi: 10.1016/j.brs.2008.02.001

BRAIN STIMULATION: Basic, Translational, and Clinical Research in Neuromodulation
Volume 1, Issue 2 , Pages 112-121 , April 2008

Article Tools

* Image Usage & Resolution