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Adjunctive Vagus Nerve Stimulation for Treatment-Resistant Depression: a Quantitative Analysis

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Abstract

Vagus nerve stimulation (VNS) has been increasingly studied in treating treatment-resistant depression (TRD), but the findings have been mixed. This updated meta-analysis was conducted to examine the efficacy and safety of adjunctive VNS for TRD. Controlled studies reporting on the efficacy and safety of adjunctive VNS for TRD were screened, identified and analyzed. Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were analyzed using RevMan version 5.3. Three controlled studies with a total of 1048 patients with TRD compared VNS (n = 622) with control (n = 426) groups. Only one study was rated as ‘high quality’ using the Jadad scale. Adjunctive VNS was significantly superior to the control group regarding study-defined response [SMD:1.96 (95%CI:1.60, 2.40), P < 0.00001, I2 = 0%]. Patient-reported voice alteration occurred more frequently with adjunctive VNS for patients with TRD. No significant group differences were found regarding discontinuation due to any reason [RR:0.50 (95%CI:0.12, 2.09), P = 0.34, I2 = 85%]. Adjunctive VNS appeared to be effective and relatively safe treatment for TRD. Further randomized controlled trials are needed to confirm the efficacy and safety of VNS for TRD.

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References

  1. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3(2):171–8. https://doi.org/10.1016/s2215-0366(15)00505-2.

    Article  PubMed  Google Scholar 

  2. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–59. https://doi.org/10.1016/s0006-3223(03)00231-2.

    Article  PubMed  Google Scholar 

  3. Galling B, Calsina Ferrer A, Abi Zeid Daou M, Sangroula D, Hagi K, Correll CU. Safety and tolerability of antidepressant co-treatment in acute major depressive disorder: results from a systematic review and exploratory meta-analysis. Expert Opin Drug Saf. 2015;14(10):1587–608. https://doi.org/10.1517/14740338.2015.1085970.

    Article  CAS  PubMed  Google Scholar 

  4. Zhou X, Keitner GI, Qin B, Ravindran AV, Bauer M, Del Giovane C, et al. Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. Int J Neuropsychopharmacol. 2015;18(11):pyv060. https://doi.org/10.1093/ijnp/pyv060.

    Article  CAS  PubMed  Google Scholar 

  5. Edwards SJ, Hamilton V, Nherera L, Trevor N. Lithium or an atypical antipsychotic drug in the management of treatment-resistant depression: a systematic review and economic evaluation. Health Technol Assess (Winch. Engl.). 2013;17(54):1–190. https://doi.org/10.3310/hta17540.

    Article  CAS  Google Scholar 

  6. Zheng W, Zhou YL, Liu WJ, Wang CY, Zhan YN, Li HQ, et al. Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder. J Affect Disord. 2019;33(4):494–501. https://doi.org/10.1177/0269881119827811.

    Article  CAS  Google Scholar 

  7. Zheng W, Zhou YL, Liu WJ, Wang CY, Zhan YN, Li HQ, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression. J Psychopharmacol (Oxford, England). 2018;106:61–8. https://doi.org/10.1016/j.jpsychires.2018.09.013.

    Article  Google Scholar 

  8. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150–8. https://doi.org/10.1176/appi.ajp.2017.17040472.

    Article  PubMed  Google Scholar 

  9. Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459–72. https://doi.org/10.1017/s0033291716000064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and safety of intranasal Esketamine for the rapid reduction of symptoms of depression and Suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatr. 2018;175(7):620–30. https://doi.org/10.1176/appi.ajp.2018.17060720.

    Article  PubMed  Google Scholar 

  11. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2018;75(2):139–48. https://doi.org/10.1001/jamapsychiatry.2017.3739.

    Article  Google Scholar 

  12. Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and safety of fixed-dose Esketamine nasal spray combined with a new Oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019. https://doi.org/10.1093/ijnp/pyz039.

  13. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed Esketamine nasal spray combined with a newly initiated Oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–38. https://doi.org/10.1176/appi.ajp.2019.19020172.

    Article  PubMed  Google Scholar 

  14. Zheng W, Zhang QE, Cai DB, Yang XH, Qiu Y, Ungvari GS, et al. N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2018;137(5):391–400. https://doi.org/10.1111/acps.12862.

    Article  CAS  PubMed  Google Scholar 

  15. Zheng W, Zhu XM, Zhang QE, Cheng G, Cai DB, He J, et al. Adjunctive minocycline for major mental disorders: a systematic review. J Psychopharmacol (Oxford, England). 2019;33(10):1215–26. https://doi.org/10.1177/0269881119858286.

    Article  CAS  Google Scholar 

  16. Ross EL, Zivin K, Maixner DF. Cost-effectiveness of electroconvulsive therapy vs pharmacotherapy/psychotherapy for treatment-resistant depression in the United States. JAMA Psychiat. 2018;75(7):713–22. https://doi.org/10.1001/jamapsychiatry.2018.0768.

    Article  Google Scholar 

  17. Iwabuchi SJ, Auer DP, Lankappa ST, Palaniyappan L. Baseline effective connectivity predicts response to repetitive transcranial magnetic stimulation in patients with treatment-resistant depression. Eur Neuropsychopharmacol. 2019;29(5):681–90. https://doi.org/10.1016/j.euroneuro.2019.02.012.

    Article  CAS  PubMed  Google Scholar 

  18. Moffa AH, Martin D, Alonzo A, Bennabi D, Blumberger DM, Bensenor IM, et al. Efficacy and acceptability of transcranial direct current stimulation (tDCS) for major depressive disorder: an individual patient data meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry. 2019;109836. https://doi.org/10.1016/j.pnpbp.2019.109836.

  19. Martin JL, Martin-Sanchez E. Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Eur Psychiatry. 2012;27(3):147–55. https://doi.org/10.1016/j.eurpsy.2011.07.006.

    Article  CAS  PubMed  Google Scholar 

  20. Cimpianu CL, Strube W, Falkai P, Palm U, Hasan A. Vagus nerve stimulation in psychiatry: a systematic review of the available evidence. J Neural Transm (Vienna, Austria : 1996). 2017;124(1):145–58. https://doi.org/10.1007/s00702-016-1642-2.

    Article  CAS  Google Scholar 

  21. Schachter SC. Vagus nerve stimulation therapy summary: five years after FDA approval. Neurology. 2002;59(6 Suppl 4):S15–20. https://doi.org/10.1212/wnl.59.6_suppl_4.s15.

    Article  PubMed  Google Scholar 

  22. Helmers SL, Begnaud J, Cowley A, Corwin HM, Edwards JC, Holder DL, et al. Application of a computational model of vagus nerve stimulation. Acta Neurol Scand. 2012;126(5):336–43. https://doi.org/10.1111/j.1600-0404.2012.01656.x.

    Article  CAS  PubMed  Google Scholar 

  23. Berry SM, Broglio K, Bunker M, Jayewardene A, Olin B, Rush AJ. A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckland, N.Z.). 2013;6:17–35. https://doi.org/10.2147/mder.s41017.

    Article  Google Scholar 

  24. Martinez JM, Zboyan HA. Vagus nerve stimulation therapy in a patient with treatment-resistant depression: a case report of long-term follow-up and battery end-of-service. CNS Spectr. 2006;11(2):143–7. https://doi.org/10.1017/s1092852900010683.

    Article  PubMed  Google Scholar 

  25. Critchley HD, Lewis PA, Orth M, Josephs O, Deichmann R, Trimble MR, et al. Vagus nerve stimulation for treatment-resistant depression: behavioral and neural effects on encoding negative material. Psychosom Med. 2007;69(1):17–22.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dell'Osso B, Oldani L, Palazzo MC, Balossi I, Ciabatti M, Altamura AC. Vagus nerve stimulation in treatment-resistant depression: acute and follow-up results of an italian case series. J ECT. 2013;29(1):41–4. https://doi.org/10.1097/YCT.0b013e3182735ef0.

    Article  PubMed  Google Scholar 

  27. Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study ∗. Biol Psychiatry. 2001;47(4):1–4.

    Google Scholar 

  28. Rush AJ, Sackeim HA, Marangell LB, George MS, Barry JJ. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58(5):355–63.

    Article  PubMed  Google Scholar 

  29. Christmas D, Steele JD, Tolomeo S, Eljamel MS, Matthews K. Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. J Affect Disord. 2013;150(3):1221–5. https://doi.org/10.1016/j.jad.2013.05.080.

    Article  PubMed  Google Scholar 

  30. Dunner DL, Rush AJ, Russell JM, Burke M, Woodard S, Wingard P, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry. 2006;67(5):688–95. https://doi.org/10.4088/jcp.v67n0501.

    Article  PubMed  Google Scholar 

  31. Aaronson ST, Sears P, Ruvuna F, Bunker M. A five year observational study of patients with treatment resistant depression treated with VNS therapy or treatment as usual: comparative response and remission rates, duration of response and remission. Biol Psychiatry. 2015;77(9):640–8.

    Google Scholar 

  32. Sperling W, Reulbach U, Kornhuber J. Clinical benefits and cost effectiveness of vagus nerve stimulation in a long-term treatment of patients with major depression. Pharmacopsychiatry. 2009;42(3):85–8. https://doi.org/10.1055/s-0028-1103294.

    Article  CAS  PubMed  Google Scholar 

  33. Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of Vagus nerve stimulation in treatment-resistant depression. A systematic review. J Affect Disord. 2008;110(1–2):1–15. https://doi.org/10.1016/j.jad.2008.02.012.

    Article  PubMed  Google Scholar 

  34. Lv H, Zhao YH, Chen JG, Wang DY, Chen H. Vagus nerve stimulation for depression: a systematic review. Front Psychol. 2019;10:64. https://doi.org/10.3389/fpsyg.2019.00064.

    Article  PubMed  PubMed Central  Google Scholar 

  35. McGirr A, Berlim MT. Clinical usefulness of therapeutic Neuromodulation for major depression: a systematic meta-review of recent meta-analyses. Psychiatr Clin North Am. 2018;41(3):485–503. https://doi.org/10.1016/j.psc.2018.04.009.

    Article  PubMed  Google Scholar 

  36. Hein E, Nowak M, Kiess O, Biermann T, Bayerlein K, Kornhuber J, et al. Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm (Vienna, Austria : 1996). 2013;120(5):821–7. https://doi.org/10.1007/s00702-012-0908-6.

    Article  Google Scholar 

  37. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ (Clinical research ed.). 2009;339:b2535. https://doi.org/10.1136/bmj.b2535.

    Article  Google Scholar 

  38. Higgins J, Higgins J. Cochrane handbook for systematic reviews of interventions: Wiley; 2008.

  39. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry J Ment Sci. 1979;134:382–9.

    Article  CAS  Google Scholar 

  40. Zhong BL, Wang Y, Chen HH, Wang XH. Reliability, validity and sensitivity of Montgomery-Åsberg depression rating scale for patients with current major depressive disorder [in Chinese]. Chin J Behav Med Brain Sci. 2011;20(1):85–7.

    Google Scholar 

  41. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xie GR, Shen QJ. Use of the Chinese version of the Hamilton rating scale for depression in general population and patients with major depression (In Chinese). Chinese Journal of Nervous and Mental Diseases. 1984;10:364.

    Google Scholar 

  43. Conway CR, Kumar A, Xiong W, Bunker M, Aaronson ST, Rush AJ. Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression. J Clin Psychiatry. 2018;79(5). https://doi.org/10.4088/JCP.18m12178.

  44. Kumar A, Bunker MT, Aaronson ST, Conway CR, Rothschild AJ, Mordenti G, et al. Durability of symptomatic responses obtained with adjunctive vagus nerve stimulation in treatment-resistant depression. Neuropsychiatr Dis Treat. 2019;15:457–68. https://doi.org/10.2147/ndt.s196665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang YY, Zheng W, Ng CH, Ungvari GS, Wei W, Xiang YT. Meta-analysis of randomized, double-blind, placebo-controlled trials of melatonin in Alzheimer's disease. Int J Geriatr Psychiatry. 2017;32(1):50–7. https://doi.org/10.1002/gps.4571.

    Article  PubMed  Google Scholar 

  46. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  47. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. https://doi.org/10.1136/bmj.327.7414.557.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  50. Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet. 1997;350(9081):834–43.

    Article  CAS  PubMed  Google Scholar 

  51. George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58(5):364–73.

    Article  PubMed  Google Scholar 

  52. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ (Clinical research ed.). 2011;343:d4002. https://doi.org/10.1136/bmj.d4002.

    Article  Google Scholar 

  53. Husain MM, Stegman D, Trevino K. Pregnancy and delivery while receiving vagus nerve stimulation for the treatment of major depression: a case report. Ann General Psychiatry. 2005;4:16. https://doi.org/10.1186/1744-859x-4-16.

    Article  Google Scholar 

  54. Sackeim HA, Keilp JG, Rush AJ, George MS, Marangell LB, Dormer JS, 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.

    CAS  PubMed  Google Scholar 

  55. Solmi M, Murru A, Pacchiarotti I, Undurraga J, Veronese N, Fornaro M, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13:757–77. https://doi.org/10.2147/tcrm.s117321.

  56. Vancampfort D, Wampers M, Mitchell AJ, Correll CU, De Herdt A, Probst M, et al. A meta-analysis of cardio-metabolic abnormalities in drug naive, first-episode and multi-episode patients with schizophrenia versus general population controls. World Psychiatry. 2013;12(3):240–50. https://doi.org/10.1002/wps.20069.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Vancampfort D, Correll CU, Wampers M, Sienaert P, Mitchell AJ, De Herdt A, et al. Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variables. Psychol Med. 2014;44(10):2017–28. https://doi.org/10.1017/s0033291713002778.

    Article  CAS  PubMed  Google Scholar 

  58. Burke MJ, Husain MM. Concomitant use of vagus nerve stimulation and electroconvulsive therapy for treatment-resistant depression. J ECT. 2006;22(3):218–22. https://doi.org/10.1097/01.yct.0000230364.04240.52.

    Article  PubMed  Google Scholar 

  59. Carpenter LL, Moreno FA, Kling MA, Anderson GM, Regenold WT, Labiner DM, et al. Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients. Biol Psychiatry. 2004;56(6):418–26. https://doi.org/10.1016/j.biopsych.2004.06.025.

    Article  CAS  PubMed  Google Scholar 

  60. Muller HHO, Moeller S, Lucke C, Lam AP, Braun N, Philipsen A. Vagus nerve stimulation (VNS) and other augmentation strategies for therapy-resistant depression (TRD): review of the evidence and clinical advice for use. Front Neurosci. 2018;12:239. https://doi.org/10.3389/fnins.2018.00239.

    Article  PubMed  PubMed Central  Google Scholar 

  61. George MS, Sackeim HA, Marangell LB, Husain MM, Nahas Z, Lisanby SH, et al. Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr Clin North Am. 2000;23(4):757–83. https://doi.org/10.1016/s0193-953x(05)70196-9.

    Article  CAS  PubMed  Google Scholar 

  62. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ (Clinical research ed). 2008;336(7650):924–6. https://doi.org/10.1136/bmj.39489.470347.AD.

    Article  Google Scholar 

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Acknowledgements

The study was supported by Science and Technology Department of Guangdong Province (2017A020215008).

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  1. Department of Neurosurgery, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China

    Xun Zhang, Ming-Jun Qing & Ying-Hua Rao

  2. Department of Intensive Care Unit, The Third Affiliated of Guangzhou Medical University, Guangzhou, China

    Yan-Mei Guo

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Zhang, X., Qing, MJ., Rao, YH. et al. Adjunctive Vagus Nerve Stimulation for Treatment-Resistant Depression: a Quantitative Analysis. Psychiatr Q 91, 669–679 (2020). https://doi.org/10.1007/s11126-020-09726-5

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