Chemokines in bipolar disorder: Trait or state?

  • Izabela Guimarães Barbosa
  • Natália Pessoa Rocha
  • Moisés Evandro Bauer
  • Aline Silva de Miranda
  • Rodrigo Barreto Huguet
  • Helton José Reis
  • Patricia A. Zunszain
  • Mark A. Horowitz
  • Carmine M. Pariante
  • Antônio Lúcio TeixeiraEmail author
Original Paper


Recent evidence has suggested that inflammatory and immune mechanisms may play a role in the pathophysiology of bipolar disorder (BD). Only a few studies have assessed the profile of chemokines, a family of chemotactic cytokines related to the recruitment of leukocytes, in BD. The objective of our study was to evaluate the plasma levels of chemokines in BD patients in different mood states in comparison with healthy controls. Seventy BD type I patients (35 in euthymia and 35 in mania), and 50 healthy controls matched by age, gender, and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of CCL2, CCL3, CCL11, CCL24, CXCL8, and CXCL10 were measured by enzyme-linked immunosorbent assay. BD patients presented higher plasma levels of CCL11 (1.69-fold increase; p < 0.001), CCL24 (1.40-fold increase; p = 0.02), CXCL10 (1.45-fold increase; p < 0.001) and decreased plasma levels of CXCL8 (8.68-fold decrease p < 0.001). Logistic regression stressed the main effect of increased plasma levels of CXCL10 (OR = 1.009, 95 % CI = 1.000–1.018, p = 0.042) and CCL11 (OR = 1.002, 95 % CI = 1.001–1.003, p = 0.003) and decreased plasma levels of CXCL8 (OR = 0.995, 95 % CI = 0.990–0.999, p = 0.013) to BD. This study reinforces the view that BD is associated with an immune dysfunction.


Bipolar disorder Chemokines Immunology Inflammation Mania 



This work was funded by the Brazilian funding agencies Fapemig and CNPq. Dr. Barbosa was the recipient of a CAPES scholarship during her sandwich doctorate in the Institute of Psychiatry, London.

Conflict of interest



  1. 1.
    Altamura AC, Serati M, Albano A, Paoli RA, Glick ID, Dell’Osso B (2011) An epidemiologic and clinical overview of medical and psychopathological comorbidities in major psychoses. Eur Arch Psychiatry Clin Neurosci 261:489–508PubMedCrossRefGoogle Scholar
  2. 2.
    Barbosa IG, Huguet RB, Mendonça VA, Sousa LP, Neves FS, Bauer ME, Teixeira AL (2011) Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder. Eur Arch Psychiatry Clin Neurosci 261:139–143PubMedCrossRefGoogle Scholar
  3. 3.
    Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PV, Amminger P, McGorry P, Malhi GS (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35:804–817PubMedCrossRefGoogle Scholar
  4. 4.
    Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS (2009) Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 70:1078–1090PubMedCrossRefGoogle Scholar
  5. 5.
    Kim YK, Myint AM, Lee BH, Han CS, Lee SW, Leonard BE, Steinbusch HW (2004) T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients. Psychiatry Res 129(3):267–272PubMedCrossRefGoogle Scholar
  6. 6.
    Liu HC, Yang YY, Chou YM, Chen KP, Shen WW, Leu SJ (2004) Immunologic variables in acute mania of bipolar disorder. J Neuroimmunol 150:116–122PubMedCrossRefGoogle Scholar
  7. 7.
    Drexhage RC, Hoogenboezem TH, Versnel MA, Berghout A, Nolen WA, Drexhage HA (2011) The activation of monocyte and T cell networks in patients with bipolar disorder. Brain Behav Immun 25(6):1206–1213PubMedCrossRefGoogle Scholar
  8. 8.
    Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 23(2):87–94PubMedCrossRefGoogle Scholar
  9. 9.
    Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621PubMedCrossRefGoogle Scholar
  10. 10.
    Gonzalez-Perez O, Jauregui-Huerta F, Galvez-Contreras AY (2010) Immune system modulates the function of adult neural stem cells. Curr Immunol Rev 6:167–173PubMedCrossRefGoogle Scholar
  11. 11.
    Adler MW, Rogers TJ (2005) Are chemokines the third major system in the brain? J Leukoc Biol 78:1204–1209PubMedCrossRefGoogle Scholar
  12. 12.
    Altamura AC, Mundo E, Cattaneo E, Pozzoli S, Del’Osso B, Vergani C, Trabattoni D, Arosio B, Clerici M (2010) The MCP-1 gene (SCYA2) and mood disorders preliminary results of a case-control association study. NeuroImmunoModulation 17:126–131PubMedCrossRefGoogle Scholar
  13. 13.
    Nakatani N, Hattori E, Ohnishi T, Dean B, Iwayama Y, Matsumoto I, Kato T, Osumi N, Higuchi T, Niwa S, Yoshikawa T (2006) Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation. Hum Mol Genet 15:1949–1962PubMedCrossRefGoogle Scholar
  14. 14.
    O’Brien SM, Scully P, Scott LV, Dinan TG (2006) Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord 90:263–267PubMedCrossRefGoogle Scholar
  15. 15.
    Brietzke E, Kauer-Sant’anna M, Teixeira AL, Kapczinski F (2009) Abnormalities in serum chemokine levels in euthymic patients with bipolar disorder. Brain Behav Immun 23:1079–1082PubMedCrossRefGoogle Scholar
  16. 16.
    Amorim P (2000) Mini International Neuropsychiatric Interview (MINI): validação de entrevista breve para diagnóstico de transtornos mentais. Rev Bras Psiquiatr 22:106–115CrossRefGoogle Scholar
  17. 17.
    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 59:4–57Google Scholar
  18. 18.
    Hamilton M (1967) Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278–296PubMedCrossRefGoogle Scholar
  19. 19.
    Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435PubMedCrossRefGoogle Scholar
  20. 20.
    Teixeira AL, Reis HJ, Nicolato R, Brito-Melo G, Correa H, Teixeira MM, Romano-Silva MA (2008) Increased serum levels of CCL11/eotaxin in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32(3):710–714PubMedCrossRefGoogle Scholar
  21. 21.
    Scalzo P, de Miranda AS, Guerra Amaral DC, de Carvalho Vilela M, Cardoso F, Teixeira AL (2011) Serum levels of chemokines in Parkinson’s disease. NeuroImmunoModulation 18:240–244PubMedCrossRefGoogle Scholar
  22. 22.
    Munro BH (2005) Statistical methods for health care research, 5th edn. Lippincott/Raven Publishers, PhiladelphiaGoogle Scholar
  23. 23.
    Brietzke E, Stertz L, Fernandes BS, Kauer-Sant’anna M, Mascarenhas M, Escosteguy Vargas A, Chies JA, Kapczinski F (2009) Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord 116(3):214–217PubMedCrossRefGoogle Scholar
  24. 24.
    Ortiz-Domínguez A, Hernández ME, Berlanga C, Gutiérrez-Mora D, Moreno J, Heinze G, Pavón L (2007) Immune variations in bipolar disorder: phasic differences. Bipolar Disord 9(6):596–602PubMedCrossRefGoogle Scholar
  25. 25.
    Rothenberg ME, Hogan SP (2006) The eosinophil. Annu Rev Immunol 24:147–174PubMedCrossRefGoogle Scholar
  26. 26.
    Ellman LM, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Kern DM, Tsai WY, Schaefer CA, Brown AS (2010) Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr Res 121(1–3):46–54PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC (2004) Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry 65(7):940–947PubMedCrossRefGoogle Scholar
  28. 28.
    Semple BD, Kossmann T, Morganti-Kossmann MC (2010) Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 30(3):459–473PubMedCrossRefGoogle Scholar
  29. 29.
    Langan C, McDonald C (2009) Neurobiological trait abnormalities in bipolar disorder. Mol Psychiatry 14(9):833–846PubMedCrossRefGoogle Scholar
  30. 30.
    Cavčić A, Tešović G, Gorenec L, Grgić I, Benić B, Lepej SZ (2011) Concentration gradient of CXCL10 and CXCL11 between the cerebrospinal fluid and plasma in children with enteroviral aseptic meningitis. Eur J Paediatr Neurol 15(6):502–507PubMedCrossRefGoogle Scholar
  31. 31.
    Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA (2010) The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 10(1):59–76PubMedCrossRefGoogle Scholar
  32. 32.
    Kim YK, Jung HG, Myint AM, Kim H, Park SH (2007) Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord 104:91–95PubMedCrossRefGoogle Scholar
  33. 33.
    Su KP, Leu SJ, Yang YY, Shen WW, Chou YM, Tsai SY (2002) Reduced production of interferon-gamma but not interleukin-10 in bipolar mania and subsequent remission. J Affect Disord 71:205–209PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Izabela Guimarães Barbosa
    • 1
    • 2
  • Natália Pessoa Rocha
    • 2
  • Moisés Evandro Bauer
    • 3
  • Aline Silva de Miranda
    • 2
  • Rodrigo Barreto Huguet
    • 1
  • Helton José Reis
    • 1
  • Patricia A. Zunszain
    • 4
  • Mark A. Horowitz
    • 4
  • Carmine M. Pariante
    • 4
  • Antônio Lúcio Teixeira
    • 1
    • 2
    • 5
    Email author
  1. 1.Programa de Pós-Graduação em NeurociênciasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Laboratório de Imunofarmacologia, Instituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  3. 3.Laboratório de Imunologia do Envelhecimento, Instituto de Pesquisas BiomédicasPontifícia Católica Universidade do Rio Grande do SulPorto AlegreBrazil
  4. 4.Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology (SPI-lab), Department of Psychological Medicine, Institute of PsychiatryKing’s College LondonLondonUK
  5. 5.Departamento de Clínica Médica da Faculdade de Medicina da UFMGBelo HorizonteBrazil

Personalised recommendations