Abstract
Despite many pharmacological and psychosocial treatment options, schizophrenia remains a debilitating disorder. Thus, new treatment strategies rooted in the pathophysiology of the disorder are needed. Recently, vagus nerve stimulation (VNS) has been proposed as a potential treatment option for various neuropsychiatric disorders including schizophrenia. The objective of this study was to investigate for the first time the feasibility, safety and efficacy of transcutaneous VNS in stable schizophrenia. A bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. We could not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in our 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.
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References
Addington D, Addington J, Maticka-Tyndale E (1993) Assessing depression in schizophrenia: the calgary depression scale. Br J Psychiatry (Suppl 22):39–44
Andreasen NC (1983) Scale for the assessment of negative symptoms. University of Iowa Press, Iowa City
Aschenbrenner S, Tucha O, Lange KW (2000) Regensburger wortflüssigkeits-test (rwt): Handanweisung. In: Hogrefe, Verlag für Psychologie., Göttingen
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571
Berch DB, Krikorian R, Huha EM (1998) The corsi block-tapping task: methodological and theoretical considerations. Brain Cogn 38:317–338
Boon P, Moors I, De Herdt V, Vonck K (2006) Vagus nerve stimulation and cognition. Seizure 15:259–263
Brunelin J, Mondino M, Gassab L, Haesebaert F, Gaha L, Suaud-Chagny MF, Saoud M, Mechri A, Poulet E (2012) Examining transcranial direct-current stimulation (tdcs) as a treatment for hallucinations in schizophrenia. Am J Psychiatry 169:719–724
Buchanan RW (2007) Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull 33:1013–1022
Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W, Schizophrenia Patient Outcomes Research T (2010) The 2009 schizophrenia port psychopharmacological treatment recommendations and summary statements. Schizophr Bull 36:71–93
de Haan L, Weisfelt M, Dingemans PM, Linszen DH, Wouters L (2002) Psychometric properties of the subjective well-being under neuroleptics scale and the subjective deficit syndrome scale. Psychopharmacology 162:24–28
Dietrich S, Smith J, Scherzinger C, Hofmann-Preiss K, Freitag T, Eisenkolb A, Ringler R (2008) A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional mri. Biomed Technik Biomed Eng 53:104–111
Dlabac-de Lange JJ, Knegtering R, Aleman A (2010) Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis. J Clin Psychiatry 71:411–418
Englot DJ, Chang EF, Auguste KI (2011) Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J Neurosurg 115:1248–1255
Fagerstrom KO (1978) Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 3:235–241
Furukawa TA, Levine SZ, Tanaka S, Goldberg Y, Samara M, Davis JM, Cipriani A, Leucht S (2015) Initial severity of schizophrenia and efficacy of antipsychotics: participant-level meta-analysis of 6 placebo-controlled studies. JAMA Psychiatry 72:14–21
Gerlach J, Korsgaard S, Clemmesen P, Lauersen AM, Magelund G, Noring U, Povlsen UJ, Bech P, Casey DE (1993) The st. Hans rating scale for extrapyramidal syndromes: reliability and validity. Acta Psychiatr Scand 87:244–252
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Moller HJ (2012) World federation of societies of biological psychiatry (wfsbp) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13:318–378
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Moller HJ, Schizophrenia WTFoTGf (2015) World federation of societies of biological psychiatry (wfsbp) guidelines for biological treatment of schizophrenia part 3: update 2015 management of special circumstances: depression, suicidality, substance use disorders and pregnancy and lactation. World J Biol Psychiatry 16:142–170
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Moller HJ, World Federation of Societies of Biological Psychiatry Task Force on Treatment Guidelines for S (2012) World federation of societies of biological psychiatry (wfsbp) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13:318–378
He W, Jing X, Wang X, Rong P, Li L, Shi H, Shang H, Wang Y, Zhang J, Zhu B (2013) Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. Epilepsy Behav E&B 28:343–346
Hein E, Nowak M, Kiess O, Biermann T, Bayerlein K, Kornhuber J, Kraus T (2013) Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm 120:821–827
Helmstaedter C, Lendt M, Lux S (2000) Testhandbuch verbaler lern- und merkfähigkeitstest. Hogrefe Verlag, Göttingen
Henry TR, Bakay RA, Pennell PB, Epstein CM, Votaw JR (2004) Brain blood-flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: ii. Prolonged effects at high and low levels of stimulation. Epilepsia 45:1064–1070
Homan P, Kindler J, Hauf M, Hubl D, Dierks T (2012) Cerebral blood flow identifies responders to transcranial magnetic stimulation in auditory verbal hallucinations. Transl Psychiatry 2:e189
Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (panss) for schizophrenia. Schizophr Bull 13:261–276
Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR (2006) The nimh-matrics consensus statement on negative symptoms. Schizophr Bull 32:214–219
Kraus T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C (2007) Bold fmri deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J Neural Transm 114:1485–1493
Kraus T, Kiess O, Hosl K, Terekhin P, Kornhuber J, Forster C (2013) Cns bold fmri effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal—a pilot study. Brain Stimul 6:798–804
Kreuzer PM, Landgrebe M, Husser O, Resch M, Schecklmann M, Geisreiter F, Poeppl TB, Prasser SJ, Hajak G, Langguth B (2012) Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Front Psychiatry 3:70
Kreuzer PM, Landgrebe M, Resch M, Husser O, Schecklmann M, Geisreiter F, Poeppl TB, Prasser SJ, Hajak G, Rupprecht R, Langguth B (2014) Feasibility, safety and efficacy of transcutaneous vagus nerve stimulation in chronic tinnitus: an open pilot study. Brain Stimul 7:740–747
Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L (2014) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 125:2150–2206. doi:10.1016/j.clinph.2014.05.021
Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382:951–962
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987) The uku side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 334:1–100
Martin JL, Martin-Sanchez E (2012) Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Eur Psychiatry 27:147–155
Mojtabai R, Lavelle J, Gibson PJ, Sohler NL, Craig TJ, Carlson GA, Bromet EJ (2002) Gaps in use of antipsychotics after discharge by first-admission patients with schizophrenia, 1989 to 1996. Psychiatr Serv 53:337–339
Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389
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 31:1345–1355
Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353:487–497
Perez SM, Carreno FR, Frazer A, Lodge DJ (2014) Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia. J Neurosci 34:9261–9267
Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, Kane JM, Sanghani S, Goldberg TE, John M, Mendelowitz A (2015) Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry 172:52–58
Prikryl R, Kucerova HP (2013) Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia? J ECT 29:67–74
Rosenquist PB, Miller B, Pillai A (2014) The antipsychotic effects of ect: a review of possible mechanisms. J ECT 30:125–131
Sackeim HA, Keilp JG, Rush AJ, George MS, Marangell LB, Dormer JS, Burt T, Lisanby SH, Husain M, Cullum CM, Oliver N, Zboyan H (2001) The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsychiatry Neuropsychol Behav Neurol 14:53–62
Schaub D, Juckel G (2011) PSP scale: german version of the personal and social performance scale: valid instrument for the assessment of psychosocial functioning in the treatment of schizophrenia. Der Nervenarzt 82:1178–1184
Schmidt KH (1992) Der wortschatztest (wst). Beltz Test GmbH, Weinheim
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The mini-international neuropsychiatric interview (m.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for dsm-iv and icd-10. J Clin Psychiatry 59(Suppl. 20):22–33 (quiz 34-57)
Shi C, Yu X, Cheung EF, Shum DH, Chan RC (2013) Revisiting the therapeutic effect of rtms on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Res 215:505–513
Slotema CW, Blom JD, van Lutterveld R, Hoek HW, Sommer IE (2014) Review of the efficacy of transcranial magnetic stimulation for auditory verbal hallucinations. Biol Psychiatry 76:101–110
Stefan H, Kreiselmeyer G, Kerling F, Kurzbuch K, Rauch C, Heers M, Kasper BS, Hammen T, Rzonsa M, Pauli E, Ellrich J, Graf W, Hopfengartner R (2012) Transcutaneous vagus nerve stimulation (t-vns) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia 53:e115–e118
Tombaugh TN (2004) Trail making test a and b: normative data stratified by age and education. Arch Clin Neuropsychol 19:203–214
Wani A, Trevino K, Marnell P, Husain MM (2013) Advances in brain stimulation for depression. Ann Clin Psychiatry 25:217–224
Wobrock T, Guse B, Cordes J, Wolwer W, Winterer G, Gaebel W, Langguth B, Landgrebe M, Eichhammer P, Frank E, Hajak G, Ohmann C, Verde PE, Rietschel M, Ahmed R, Honer WG, Malchow B, Schneider-Axmann T, Falkai P, Hasan A (2015) Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial. Biol Psychiatry 77:979–988
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We would like to thank Ms Louise Marshall for English editing.
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The study was sponsored by CerboMed GmbH, Erlangen, Germany. The authors deny any conflict of interest in relation to the subject of this report.
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Alkomiet Hasan and Claus Wolff-Menzler have contributed equally to this work.
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Hasan, A., Wolff-Menzler, C., Pfeiffer, S. et al. Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. Eur Arch Psychiatry Clin Neurosci 265, 589–600 (2015). https://doi.org/10.1007/s00406-015-0618-9
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DOI: https://doi.org/10.1007/s00406-015-0618-9