Advertisement

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

      Background

      Vagus nerve stimulation (VNS) is an effective anticonvulsant device and has shown antidepressant effects in chronic treatment resistant depression. Because the vagus nerve sends information to brain regions important in anxiety regulation (locus coeruleus, orbitofrontal cortex, insula, hippocampus and amygdala), this pathway might be involved in perceiving or manifesting various somatic and cognitive symptoms that characterize anxiety disorders. On the basis of this reasoning and reports of anxiolytic effects of VNS in patients treated for epilepsy and depression, we organized an open-label pilot acute trial of adjunctive VNS on top of stable medications, followed by long-term follow-up, to assess the safety and potential efficacy of VNS for patients with treatment resistant anxiety disorders.

      Methods

      Eleven adult outpatients with treatment resistant obsessive-compulsive disorder (OCD), panic disorder (PD), or posttraumatic stress disorder (PTSD) were recruited. Patients had failed several medication trials as well as cognitive behavioral therapy (CBT). All patients were rated with the Hamilton Anxiety Scale (HAM-A) and the clinical global impressions improvement scale (CGI-I). Patients with OCD were also rated with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Patients were maintained on their current psychotropic medications at fixed doses during the acute 12-week phase. Changes in medications and VNS stimulus parameters were allowed during the long-term follow-up. Response was defined as a 50% or greater improvement on the HAM-A for all patients and a 25% or greater improvement on the Y-BOCS for patients with OCD.

      Results

      Eleven patients were recruited. Seven patients had a primary diagnosis of OCD, two had PTSD, and one had PD. One OCD patient changed their mind and was never implanted. One patient with OCD withdrew consent before the end of the acute phase, so long-term results were available for nine patients. Three patients were acute responders, based on the HAM-A, and there was some improvement in anxiety ratings over time (with statistically significant improvements at 14 of 18 quarters during long-term follow-up). Of the seven patients with OCD who received stimulation, three were acute responders, based on the Y-BOCS, and there was some improvement in Y-BOCS scores over time (with statistically significant improvements at 7 of 18 quarters during long-term follow-up). VNS was relatively well tolerated. Four years after implantation, four patients (diagnoses two OCD, one PD, one PTSD) were still receiving VNS with continued and sustained improvement in anxiety scores compared with their baseline scores.

      Conclusions

      These patients with treatment-resistant anxiety disorders generally tolerated VNS treatment, and there was evidence of acute and long-term improvement in some patients. These open data suggest that further double-blind studies assessing the VNS role in treating anxiety disorders, particularly OCD, may be warranted.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Sheehan D.V.
        • Sheehan K.H.
        Current approaches to the pharmacologic treatment of anxiety disorders.
        Psychopharmacol Bull. 2007; 40: 98-109
        • Kessler R.C.
        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: 10-19
        • Olatunji B.O.
        • Cisler J.M.
        • Tolin D.F.
        Quality of life in the anxiety disorders: a meta-analytic review.
        Clin Psychol Rev. 2007; 27: 572-581
        • Friedman B.H.
        An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone.
        Biol Psychol. 2007; 74: 185-199
        • George M.S.
        • Sackeim H.A.
        • Rush A.J.
        • et al.
        Vagus nerve stimulation: a new tool for brain research and therapy.
        Biol Psychiatry. 2000; 47: 287-295
        • George M.S.
        • Nahas Z.
        • Bohning D.E.
        • et al.
        Vagus nerve stimulation: a research update.
        Neurology. 2002; 54: S56-S61
        • Henry T.R.
        Therapeutic mechanisms of vagus nerve stimulation.
        Neurology. 2002; 59: S15-S20
        • Krahl S.E.
        • Clark K.B.
        • Smith D.C.
        • Browning R.A.
        Locus coeruleus lesions suppress the seizure attenuating effects of vagus nerve stimulation.
        Epilepsia. 1998; 39: 709-714
        • Smith M.A.
        • 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: 8788-8792
        • 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: 1752-1761
        • Kapur S.
        • Austin M.C.
        • Underwood M.D.
        • Arango V.
        • Mann J.J.
        Electroconvulsive shock increases tyrosine hydroxylase and neuropeptide Y gene expression in the locus coeruleus.
        Brain Res Mol Brain Res. 1993; 18: 121-126
        • Nakamura S.
        Axonal sprouting of noradrenergic locus coeruleus neurons following repeated stress and antidepressant treatment.
        Prog Brain Res. 1991; 88: 587-598
        • Delgado P.L.
        • Goodman W.K.
        • Price L.H.
        • Heninger G.R.
        • Charney D.S.
        Fluvoxamine/pimozide treatment of concurrent Tourette's and obsessive-compulsive disorder.
        Br J Psychiatry. 1990; 157: 762-765
        • Goodman W.K.
        • Price L.H.
        • Rasmussen S.A.
        • Heninger G.R.
        • Charney D.S.
        Fluvoxamine as an antiobsessional agent.
        Psychopharmacol Bull. 1989; 25: 31-35
        • 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
        • Chae J.H.
        • Nahas Z.
        • Lomarev M.
        • et al.
        A review of functional neuroimaging studies of vagus nerve stimulation (VNS).
        J Psychiatr Res. 2003; 37: 443-455
        • Bohning D.E.
        • Lomarev M.P.
        • Denslow S.
        • Nahas Z.
        • Shastri A.
        • George M.S.
        Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI.
        Invest Radiol. 2001; 36: 470-479
        • Lomarev M.
        • Denslow S.
        • Nahas Z.
        • Chae J.H.
        • George M.S.
        • Bohning D.E.
        Vagus nerve stimulation (VNS) synchronized BOLD fMRI suggests that VNS in depressed adults has frequency/dose dependent effects.
        J Psychiatr Res. 2002; 36: 219-227
        • Mu Q.
        • Bohning D.E.
        • Nahas Z.
        • et al.
        Acute vagus nerve stimulation using different pulse widths produces varying brain effects.
        Biol Psychiatry. 2004; 55: 816-825
        • Nahas Z.
        • Teneback C.
        • Chae J.H.
        • et al.
        Serial vagus nerve stimulation functional MRI (VNS/fMRI) in Treatment resistant depression.
        Neuropsychopharmacol. 2007; 32: 1-12
        • Krahl S.E.
        • Senanayake S.S.
        • Handforth A.
        Seizure suppression by systemic epinephrine is mediated by the vagus nerve.
        Epilepsy Res. 2000; 38: 171-175
        • Krahl S.E.
        • Senanayake S.S.
        • Handforth A.
        Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression.
        Epilepsia. 2001; 42: 586-589
        • Rush A.J.
        • George M.S.
        • Sackeim H.A.
        • et al.
        Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.
        Biol Psychiatry. 2000; 47: 276-286
        • Sackeim H.A.
        • Keilp J.G.
        • Rush A.J.
        • et al.
        The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression.
        Neuropsychiatry Neuropsychol Behav Neurol. 2001; 14: 53-62
        • Sackeim H.A.
        • Rush A.J.
        • George M.S.
        • et al.
        Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.
        Neuropsychopharmacol. 2001; 25: 713-728
        • Nahas Z.
        • Marangell L.B.
        • Husain M.M.
        • et al.
        Two-year outcome of vagus nerve stimulation (VNS) therapy for major depressive episodes.
        J Clin Psychiatry. 2005; 66: 1097-1104
        • George M.S.
        • Rush A.J.
        • Marangell L.B.
        • et al.
        A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression.
        Biol Psychiatry. 2005; 58: 364-373
        • Rush A.J.
        • Marangell L.B.
        • Sackeim H.A.
        • et al.
        Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.
        Biol Psychiatry. 2005; 58: 347-354
        • Rush A.J.
        • Sackeim H.A.
        • Marangell L.B.
        • et al.
        Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study.
        Biol Psychiatry. 2005; 58: 355-363
        • Post R.M.
        • Ballenger J.C.
        • Uhde T.W.
        • Bunney W.E.J.
        Efficacy of carbamazepine in manic-depressive illness: implications for underlying mechanisms.
        in: Post R.M. Ballenger J.C. Neurobiology of Mood Disorders. Williams and Wilkins, Baltimore1984: 777-816
        • Post R.M.
        • Uhde T.W.
        • Ballenger J.C.
        • Squillace K.M.
        Prophylactic efficacy of carbamazepine in manic-depressive illness.
        Am J Psychiatry. 1983; 140: 1602-1604
        • Ballenger J.C.
        • Post R.M.
        Anticonvulsants in psychiatric disease: when are they effective?.
        Drug Therapy. 1985; 15: 144-156
        • Mula M.
        • Pini S.
        • Cassano G.B.
        The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence.
        J Clin Psychopharmacol. 2007; 27: 263-272
        • 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
        • 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
        • Rush A.J.
        • George M.S.
        • Sackeim H.A.
        • et al.
        Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.
        Biol Psychiatry. 2000; 47: 276-286
        • Sackeim H.A.
        • Rush A.J.
        • George M.S.
        • et al.
        Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.
        Neuropsychopharmacol. 2001; 25: 713-728
        • Trivedi M.H.
        • Rush A.J.
        • Ibrahim H.M.
        • 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: 73-82
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania: reliability, validity and sensitivity.
        Br J Psychiatry. 1978; 133: 429-435
        • Ware J.E.
        • Sherbourne C.D.
        The MOS 36-item short-form health survey (SF-36): I, conceptual framework and item selection.
        Med Care. 1992; 30: 473-483
        • Greenberg B.D.
        • Price L.H.
        • Rauch S.L.
        • et al.
        Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues.
        Neurosurg Clin N Am. 2003; 14: 199-212
        • Greenberg B.D.
        • Malone D.A.
        • Friehs G.M.
        • et al.
        Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder.
        Neuropsychopharmacol. 2006; 31 ([erratum appears in Neuropsychopharmacol 2006 Nov;31(11):2394]): 2384-2393
        • James W.
        What is an emotion?.
        Mind. 1884; 9: 188-205