, Volume 231, Issue 7, pp 1315–1323 | Cite as

Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial, randomized, controlled trial

  • André R. BrunoniEmail author
  • Rodrigo Machado-Vieira
  • Carlos A. Zarate
  • Leandro Valiengo
  • Erica LM Vieira
  • Isabela M Benseñor
  • Paulo A. Lotufo
  • Wagner F. Gattaz
  • Antonio L Teixeira
Original Investigation



The inflammatory hypothesis of depression states that increased levels of pro-inflammatory cytokines triggered by external and internal stressors are correlated to the acute depressive state. This hypothesis also suggests that pharmacotherapy partly acts in depression through anti-inflammatory effects. Transcranial direct current stimulation (tDCS) is a novel, promising, non-invasive somatic treatment for depression, although its antidepressant mechanisms are only partly understood.


We explored the effects of tDCS and sertraline over the immune system during an antidepressant treatment trial.


In a 6-week, double-blind, placebo-controlled trial, 73 antidepressant-free patients with unipolar depression were randomized to active/sham tDCS and sertraline/placebo (2 × 2 design). Plasma levels of several cytokines (IL-2, IL-4, IL-6, IL-10, IL-17a, IFN-γ, and TNF-α) were determined to investigate the effects of the interventions and of clinical response on them.


All cytokines, except TNF-α, decreased over time, these effects being similar across the different intervention-groups and in responders vs. non-responders.


tDCS and sertraline (separately and combined) acute antidepressant effects might not specifically involve normalization of the immune system. In addition, being one of the first placebo-controlled trials measuring cytokines over an antidepressant treatment course, our study showed that the decrease in cytokine levels during the acute depressive episode could involve a placebo effect, highlighting the need of further placebo-controlled trials and observational studies examining cytokine changes during depression treatment and also after remission of the acute depressive episode.


Major depressive disorder Transcranial direct current stimulation Sertraline Cytokines Interleukins Randomized Controlled trial Placebo response Placebo effect 



This study was partially funded by FAPESP (São Paulo Research Foundation, Grant number: 2009/05728-7), FAPEMIG and CNPq. ARB receives a research grant from FAPESP (2012/20911-5) and is recipient of a 2013 NARSAD Young Investigator Award. The sponsors played no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, and preparation, review or approval of the manuscript.

Conflict of interest



  1. Alonzo A, Chan G, Martin D, Mitchell PB, Loo C (2013) Transcranial direct current stimulation (tDCS) for depression: Analysis of response using a three-factor structure of the Montgomery-Asberg depression rating scale. J Affect Disord 150(1):91–95PubMedCrossRefGoogle Scholar
  2. Amorim P (2000) Mini International Neuropsychiatric Interview (MINI): validation of a short structured diagnostic psychiatric interview. Rev Bras Psiquiatr 22:106–115CrossRefGoogle Scholar
  3. Baharav E, Bar M, Taler M, Gil-Ad I, Karp L, Weinberger A, Weizman A (2012) Immunomodulatory effect of sertraline in a rat model of rheumatoid arthritis. Neuroimmunomodulation 19:309–18PubMedCrossRefGoogle Scholar
  4. Bai S, Loo C, Dokos S (2013) A review of computational models of transcranial electrical stimulation. Crit Rev Biomed Eng 41:21–35PubMedCrossRefGoogle Scholar
  5. Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trend Pharmacol Sci 34:167–77CrossRefGoogle Scholar
  6. Brunoni AR, Ferrucci R, Bortolomasi M, Scelzo E, Boggio PS, Fregni F, Dell'Osso B, Giacopuzzi M, Altamura AC, Priori A (2012a) Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the major depressive episode: findings from a naturalistic study. Eur Psychiatry 28(6):356–361CrossRefGoogle Scholar
  7. Brunoni AR, Ferrucci R, Bortolomasi M, Vergari M, Tadini L, Boggio PS, Giacopuzzi M, Barbieri S, Priori A (2011a) Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35:96–101PubMedCrossRefGoogle Scholar
  8. Brunoni AR, Kemp AH, Dantas EM, Goulart AC, Nunes MA, Boggio PS, Mill JG, Lotufo PA, Fregni F, Benseñor IM (2013a) Heart rate variability is a trait marker of major depressive disorder: evidence from the sertraline vs. electric current therapy to treat depression clinical study. Int J Neuropsychopharmacol 16(9):1937–1949CrossRefGoogle Scholar
  9. Brunoni AR, Nitsche MA, Bolognini N, Bikson M, Wagner T, Merabet L, Edwards DJ, Valero-Cabre A, Rotenberg A, Pascual-Leone A, Ferrucci R, Priori A, Boggio PS, Fregni F (2012b) Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul 5:175–95PubMedCentralPubMedCrossRefGoogle Scholar
  10. Brunoni AR, Valiengo L, Baccaro A, Zanao TA, de Oliveira JF, Vieira GP, Bueno VF, Goulart AC, Boggio PS, Lotufo PA, Bensenor IM, Fregni F (2011b) Sertraline vs. Electrical Current Therapy for Treating Depression Clinical Trial–SELECT TDCS: design, rationale and objectives. Contemp Clin Trials 32:90–8PubMedCrossRefGoogle Scholar
  11. Brunoni AR, Valiengo L, Baccaro A, Zanao TA, Oliveira AC, Goulart AC, Boggio PS, Lotufo PA, Bensenor IJ, Fregni F (2013b) The Sertraline versus Electrical Current Therapy for Treating Depression Clinical Study: results from a factorial, randomized, controlled trial. JAMA Psychiatry 70:383–91PubMedCrossRefGoogle Scholar
  12. Brunoni AR, Vanderhasselt MA, Boggio PS, Fregni F, Dantas EM, Mill JG, Lotufo PA, Bensenor IJ (2013c) Polarity- and valence-dependent effects of prefrontal transcranial direct current stimulation on heart rate variability and salivary cortisol. Psychoneuroendocrinology 38:58–66PubMedCrossRefGoogle Scholar
  13. Chen Y, Jiang T, Chen P, Ouyang J, Xu G, Zeng Z, Sun Y (2011) Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res 188:224–30PubMedCrossRefGoogle Scholar
  14. DaSilva AF, Volz MS, Bikson M, Fregni F (2011) Electrode positioning and montage in transcranial direct current stimulation. J Vis Exp 51:2744. doi: 10.3791/2744 PubMedGoogle Scholar
  15. Dell'Osso B, Mundo E, D'Urso N, Pozzoli S, Buoli M, Ciabatti M, Rosanova M, Massimini M, Bellina V, Mariotti M, Altamura AC (2009) Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression. Bipolar Disord 11:76–81PubMedCrossRefGoogle Scholar
  16. DellaGioia N, Hannestad J (2010) A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci Biobehav Rev 34:130–43PubMedCentralPubMedCrossRefGoogle Scholar
  17. Eller T, Vasar V, Shlik J, Maron E (2009) The role of IL-2 and soluble IL-2R in depression and antidepressant response. Curr Opin Investig Drugs 10:638–43PubMedGoogle Scholar
  18. Enck P, Benedetti F, Schedlowski M (2008) New insights into the placebo and nocebo responses. Neuron 59:195–206PubMedCrossRefGoogle Scholar
  19. Ferrucci R, Bortolomasi M, Vergari M, Tadini L, Salvoro B, Giacopuzzi M, Barbieri S, Priori A (2009) Transcranial direct current stimulation in severe, drug-resistant major depression. J Affect Disord 118:215–9PubMedCrossRefGoogle Scholar
  20. Fidalgo TM, Morales-Quezada JL, Muzy GS, Chiavetta NM, Mendonca ME, Santana MV, Goncalves OF, Brunoni AR, Fregni F (2013) Biological markers in noninvasive brain stimulation trials in major depressive disorder: a systematic review. J ECT. In press.Google Scholar
  21. Fruscella P, Sottocorno M, Di Braccio M, Diomede L, Piccardi N, Cagnotto A, Grossi G, Romano M, Mennini T, Roma G (2001) 1,5-Benzodiazepine tricyclic derivatives exerting anti-inflammatory effects in mice by inhibiting interleukin-6 and prostaglandin E(2) production. Pharmacol Res: Off J Ital Pharmacol Soc 43:445–52CrossRefGoogle Scholar
  22. Gandiga PC, Hummel FC, Cohen LG (2006) Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol 117:845–50PubMedCrossRefGoogle Scholar
  23. Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, Canbay AE, Michel MC, Heemann U, Schedlowski M (2002) Behavioral conditioning of immunosuppression is possible in humans. FASEB J: Off Publ Fed Am Soc Exp Biol 16:1869–73CrossRefGoogle Scholar
  24. Gorenstein C, Andrade LHSG, Zuardi AW (2000) Escalas de Avaliação Clínica em Psiquiatria e Psicofarmacologia, Sao PauloGoogle Scholar
  25. Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 36:2452–9CrossRefGoogle Scholar
  26. Hiles SA, Baker AL, de Malmanche T, Attia J (2012) A meta-analysis of differences in IL-6 and IL-10 between people with and without depression: exploring the causes of heterogeneity. Brain Behav Immun 26:1180–8PubMedCrossRefGoogle Scholar
  27. Kupfer DJ, Frank E, Phillips ML (2012) Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 379:1045–55PubMedCentralPubMedCrossRefGoogle Scholar
  28. Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW (2013) Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Molecular psychiatry 18:692–9PubMedCrossRefGoogle Scholar
  29. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 22:370–9CrossRefGoogle Scholar
  30. Liu Y, Ho RC, Mak A (2012) Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 139:230–9PubMedCrossRefGoogle Scholar
  31. Loo CK, Alonzo A, Martin D, Mitchell PB, Galvez V, Sachdev P (2012) Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br J Psychiatry 200:52–59PubMedCrossRefGoogle Scholar
  32. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M (2009) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24:27–53PubMedCrossRefGoogle Scholar
  33. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–43PubMedCrossRefGoogle Scholar
  34. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA (2002) The functional neuroanatomy of the placebo effect. Am J Psychiatry 159:728–37PubMedCrossRefGoogle Scholar
  35. Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP (2001) Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Archives of neurology 58:1081–6PubMedCrossRefGoogle Scholar
  36. Myint AM, Leonard BE, Steinbusch HW, Kim YK (2005) Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 88:167–73PubMedCrossRefGoogle Scholar
  37. Nemeroff CB, Goldschmidt-Clermont PJ (2012) Heartache and heartbreak-the link between depression and cardiovascular disease. Nat Rev Cardiol 9:526–39PubMedCrossRefGoogle Scholar
  38. Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A (2008) Transcranial direct current stimulation: state of the art 2008. Brain Stimul 1:206–23PubMedCrossRefGoogle Scholar
  39. Nitsche MA, Paulus W (2000) Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 527(Pt 3):633–9PubMedCentralPubMedCrossRefGoogle Scholar
  40. Nwe SM, Champlain AH, Gordon KB (2013) Rationale and early clinical data on IL-17 blockade in psoriasis. Expert Rev Clin Immunol 9:677–82PubMedCrossRefGoogle Scholar
  41. Okada K, Matsunaga K, Yuhi T, Kuroda E, Yamashita U, Tsuji S (2002) The long-term high-frequency repetitive transcranial magnetic stimulation does not induce mRNA expression of inflammatory mediators in the rat central nervous system. Brain research 957:37–41PubMedCrossRefGoogle Scholar
  42. Pizzagalli DA (2011) Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 36:183–206CrossRefGoogle Scholar
  43. Pizzi C, Mancini S, Angeloni L, Fontana F, Manzoli L, Costa GM (2009) Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease. Clin Pharmacol Ther 86:527–32PubMedCrossRefGoogle Scholar
  44. Roumestan C, Michel A, Bichon F, Portet K, Detoc M, Henriquet C, Jaffuel D, Mathieu M (2007) Anti-inflammatory properties of desipramine and fluoxetine. Respir Res 8:35PubMedCentralPubMedCrossRefGoogle Scholar
  45. Sampaio LA, Fraguas R, Lotufo PA, Bensenor IM, Brunoni AR (2012) A systematic review of non-invasive brain stimulation therapies and cardiovascular risk: implications for the treatment of major depressive disorder. Front Psychiatry 3:87PubMedCentralPubMedCrossRefGoogle Scholar
  46. Schestatsky P, Simis M, Freeman R, Pascual-Leone A, Fregni F (2013) Non-invasive brain stimulation and the autonomic nervous system. Clin Neurophysiol 124(9):1716–1728PubMedCrossRefGoogle Scholar
  47. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H (1995) Cytokine production and serum proteins in depression. Scand J Immunol 41:534–8PubMedCrossRefGoogle Scholar
  48. Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, Wiktorowicz K (1996) Indicators of immune activation in major depression. Psychiatry Res 64:161–7PubMedCrossRefGoogle Scholar
  49. Song C, Halbreich U, Han C, Leonard BE, Luo H (2009) Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry 42:182–8PubMedCrossRefGoogle Scholar
  50. Spezia Adachi LN, Caumo W, Laste G, Fernandes Medeiros L, Ripoll Rozisky J, de Souza A, Fregni F, Torres IL (2012) Reversal of chronic stress-induced pain by transcranial direct current stimulation (tDCS) in an animal model. Brain research 1489:17–26PubMedCrossRefGoogle Scholar
  51. Taupin V, Gogusev J, Descamps-Latscha B, Zavala F (1993) Modulation of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interleukin-8, and granulocyte/macrophage colony-stimulating factor expression in human monocytes by an endogenous anxiogenic benzodiazepine ligand, triakontatetraneuropeptide: evidence for a role of prostaglandins. Mol Pharmacol 43:64–9PubMedGoogle Scholar
  52. Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M, Weihe E, Weidenfeld J (2001) Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 24:531–44CrossRefGoogle Scholar
  53. Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Katsuki A, Atake K, Nakamura J (2013) Plasma levels of interleukin-6 and selective serotonin reuptake inhibitor response in patients with major depressive disorder. Hum Psychopharmacol 28(5):466–470PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • André R. Brunoni
    • 1
    • 5
    Email author
  • Rodrigo Machado-Vieira
    • 2
    • 3
  • Carlos A. Zarate
    • 3
  • Leandro Valiengo
    • 1
    • 2
    • 5
  • Erica LM Vieira
    • 4
  • Isabela M Benseñor
    • 1
  • Paulo A. Lotufo
    • 1
  • Wagner F. Gattaz
    • 2
  • Antonio L Teixeira
    • 4
  1. 1.Center for Clinical and Epidemiological Research and Interdisciplinary Center for Applied Neuromodulation (CINA)University Hospital, University of São PauloSão PauloBrazil
  2. 2.Laboratory of Neuroscience (LIM27), Department and Institute of PsychiatryUniversity of São PauloSão PauloBrazil
  3. 3.Experimental Therapeutics and Pathophysiology Branch, Intramural Research ProgramNational Institute of Mental Health (NIMH), NIHBethesdaUSA
  4. 4.Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine of Minas GeraisBelo HorizonteBrazil
  5. 5.Service of Interdisciplinary Neuromodulation (SIN), Department and Institute of PsychiatryUniversity of São PauloSão PauloBrazil

Personalised recommendations