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Systematic Review of Proinflammatory Cytokines in Obsessive-Compulsive Disorder

  • ANXIETY DISORDERS (DJ STEIN, SECTION EDITOR)
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Abstract

Several studies have examined levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. This meta-analysis was conducted to examine the association between obsessive-compulsive disorder (OCD) and plasma serum levels of proinflammatory cytokines. Twelve studies met inclusion criteria. The meta-analysis demonstrated a significant reduction in IL-1β levels in OCD. No significant difference in plasma levels of IL-6 or TNF-α was demonstrated. Stratified subgroup analysis revealed possible moderating effects of age and medication use on IL-6 levels. Studies including children on psychotropic medication had lower plasma IL-6 levels. Stratified subgroup analysis revealed a moderating effect of comorbid depression on TNF-α levels. Elevated TNF-α levels were reported in studies that included individuals with comorbid depression. Future studies examining immune function in OCD should adjust for potential confounding due to medication use and comorbid depression. Further studies assessing cerebrospinal fluid cytokine levels in OCD are also needed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.

    Article  PubMed  Google Scholar 

  2. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15:53–63.

    Article  PubMed  CAS  Google Scholar 

  3. DuPont RL, Rice DP, Shiraki S, Rowland CR. Economic costs of obsessive-compulsive disorder. Med Interface. 1995;8:102–9.

    PubMed  CAS  Google Scholar 

  4. First MB. Diagnostic and statistical manual of mental disorders. 4th ed. Washington: American Psychiatric Association; 2000.

    Google Scholar 

  5. • de Oliveira S, Pelajo C. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS): a controversial diagnosis. Curr Infect Dis Rep. 2010;12:103–9. This review highlights important criticism of the PANDAS hypothesis..

    Article  PubMed  Google Scholar 

  6. da Rocha FF, Correa H, Teixeira AL. Obsessive-compulsive disorder and immunology: a review. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1139–46.

    Article  PubMed  Google Scholar 

  7. Swedo SE, Grant PJ. Annotation: PANDAS: a model for human autoimmune disease. J Child Psychol Psychiatry. 2005;46:227–34.

    Article  PubMed  Google Scholar 

  8. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155:264–71.

    PubMed  CAS  Google Scholar 

  9. • Murphy TK, Kurlan R, Leckman J. The immunobiology of Tourette’s disorder, pediatric autoimmune neuropsychiatric disorders associated with streptococcus, and related disorders: a way forward. J Child Adolesc Psychopharmacol. 2010;20:317–31. This review provides an overview of PANDAS, including diagnostic criteria and evidence supporting the PANDAS hypothesis..

    Article  PubMed  Google Scholar 

  10. Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460:108–12.

    Article  PubMed  CAS  Google Scholar 

  11. Shulman ST. Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update. Curr Opin Pediatr. 2009;21:127.

    Article  PubMed  Google Scholar 

  12. • Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57. This article demonstrates that cytokine levels are altered by mood disorders, which are highly comorbid in OCD..

    Article  PubMed  CAS  Google Scholar 

  13. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9:853–8.

    Article  PubMed  CAS  Google Scholar 

  14. Penninx BWJH, Kritchevsky SB, Yaffe K, et al. Inflammatory markers and depressed mood in older persons: results from the health, aging and body composition study. Biol Psychiatry. 2003;54:566–72.

    Article  PubMed  CAS  Google Scholar 

  15. Empana JP, Sykes DH, Luc G, et al. Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men. Circulation. 2005;111:2299–305.

    Article  PubMed  CAS  Google Scholar 

  16. Kim YK, Suh IB, Kim H, et al. The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry. 2002;7:1107.

    Article  PubMed  CAS  Google Scholar 

  17. Jones AL, Mowry BJ, Pender MP, Greer JM. Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol. 2005;83:9–17.

    Article  PubMed  CAS  Google Scholar 

  18. Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun. 2006;27:71–80.

    Article  PubMed  CAS  Google Scholar 

  19. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801–8.

    Article  PubMed  CAS  Google Scholar 

  20. • Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. 2011;36:2452–9. This article demonstrates that psychotropic medication alters inflammatory cytokine levels in major depressive disorder..

    Article  PubMed  CAS  Google Scholar 

  21. Murphy K, Travers P, Walport M. Janeway’s immunobiology. 7th ed. New York: Garland Science; 2008.

    Google Scholar 

  22. Steinke JW, Borish L. 3. Cytokines and chemokines. J Allergy Clin Immunol. 2006;117:S441–5.

    Article  PubMed  CAS  Google Scholar 

  23. Brough D, Tyrrell PJ, Allan SM. Regulation of interleukin-1 in acute brain injury. Trends Pharmacol Sci. 2011;32:617–22.

    Article  PubMed  CAS  Google Scholar 

  24. Konuk N, Tek, #x131, et al. Plasma levels of tumor necrosis factor-alpha and interleukin-6 in obsessive compulsive disorder. Mediat Inflamm. 2007;2007.

  25. Pan W, Zadina JE, Harlan RE, Weber JT, Banks WA, Kastin AJ. Tumor necrosis factor-alpha: a neuromodulator in the CNS. Neurosci Biobehav Rev. 1997;21:603–13.

    Article  PubMed  CAS  Google Scholar 

  26. Schöbitz B, de Kloet ER, Sutanto W, Holsboer F. Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. Eur J Neurosci. 1993;5:1426–35.

    Article  PubMed  Google Scholar 

  27. Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC. Inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α impart neuroprotection to an excitotoxin through distinct pathways. J Immunol. 1999;163:3963–8.

    PubMed  CAS  Google Scholar 

  28. Hirano T, Yasukawa K, Harada H, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986;324:73–6.

    Article  PubMed  CAS  Google Scholar 

  29. Spooren A, Kolmus K, Laureys G, et al. Interleukin-6, a mental cytokine. Brain Res Rev. 2011;67:157–83.

    Article  PubMed  CAS  Google Scholar 

  30. Tadamitsu K. Interleukin-6 and its receptor in autoimmunity. J Autoimmun. 1992;5(Supplement A):123–32.

    Google Scholar 

  31. Xing Z, Gauldie J, Cox G, et al. IL-6 is an anti-inflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101:311–20.

    Article  PubMed  CAS  Google Scholar 

  32. Uyttenhove C, Coulie PG, Van Snick J. T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. J Exp Med. 1988;167:1417–27.

    Article  PubMed  CAS  Google Scholar 

  33. Lotz M, Jirik F, Kabouridis P, et al. B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med. 1988;167:1253–8.

    Article  PubMed  CAS  Google Scholar 

  34. Zheng H, Fletcher D, Kozak W, et al. Resistance to fever induction and impaired acute-phase response in interleukin-1β-deficient mice. Immunity. 1995;3:9–19.

    Article  PubMed  CAS  Google Scholar 

  35. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994;83:113–8.

    PubMed  CAS  Google Scholar 

  36. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.

    Article  PubMed  CAS  Google Scholar 

  37. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87:2095–147.

    PubMed  CAS  Google Scholar 

  38. Marlin SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell. 1987;51:813–9.

    Article  PubMed  CAS  Google Scholar 

  39. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986;137:245–54.

    PubMed  CAS  Google Scholar 

  40. Sironi M, Breviario F, Proserpio P, et al. IL-1 stimulates IL-6 production in endothelial cells. J Immunol. 1989;142:549–53.

    PubMed  CAS  Google Scholar 

  41. Wang CC, Fu CL, Yang YH, et al. Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma. Gene Ther. 2006;13:1414–21.

    Article  PubMed  CAS  Google Scholar 

  42. Nakae S, Asano M, Horai R, Iwakura Y. Interleukin-1β, but not interleukin-1α, is required for T-cell-dependent antibody production. Immunology. 2001;104:402–9.

    Article  PubMed  CAS  Google Scholar 

  43. Pfeffer K. Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev. 2003;14:185–91.

    Article  PubMed  CAS  Google Scholar 

  44. McCoy M, Tansey M. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflamm. 2008;5:1–13.

    Article  Google Scholar 

  45. Cairns CB, Panacek EA, Harken AH, Banerjee A. Bench to bedside tumor necrosis factor-alpha: from inflammation to resuscitation. Acad Emerg Med. 2000;7:930–41.

    Article  PubMed  CAS  Google Scholar 

  46. Graham AL, Allen JE, Read AF. Evolutionary causes and consequences of immunopathology. Annu Rev Ecol Evol Syst. 2005;36:373–97.

    Article  Google Scholar 

  47. Deeks J, Higgins J, Altman D. Cochrane reviewer’s handbook 4.2.2 [Updated March 2004] In: The Cochrane library. Chinchester: Wiley; 2004.

  48. Brambilla F, Perna G, Bellodi L, et al. Plasma interleukin-1β and tumor necrosis factor concentrations in obsessive-compulsive disorders. Biol Psychiatry. 1997;42:976–81.

    Article  PubMed  CAS  Google Scholar 

  49. Maes M, Meltzer HY, Bosmans E. Psychoimmune investigation in obsessive-compulsive disorder: assays of plasma transferrin, IL-2 and IL-6 receptor, and IL-1β and IL-6 concentrations. Neuropsychobiology. 1994;30:57–60.

    Article  PubMed  CAS  Google Scholar 

  50. Monteleone P, Catapano F, Fabrazzo M, Tortorella A, Maj M. Decreased blood levels of tumor necrosis factor-alpha in patients with obsessive-compulsive disorder. Neuropsychobiology. 1998;37:182–5.

    Article  PubMed  CAS  Google Scholar 

  51. Leckman JF, Katsovich L, Kawikova I, et al. Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette’s syndrome. Biol Psychiatry. 2005;57:667–73.

    Article  PubMed  CAS  Google Scholar 

  52. Gabbay V, Coffey BJ, Guttman LE, et al. A cytokine study in children and adolescents with Tourette’s disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:967–71.

    Article  PubMed  CAS  Google Scholar 

  53. Bos-Veneman NGP, Bijzet J, Limburg PC, Minderaa RB, Kallenberg CG, Hoekstra PJ. Cytokines and soluble adhesion molecules in children and adolescents with a tic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1390–5.

    Article  PubMed  CAS  Google Scholar 

  54. Weizman R, Laor N, Barber Y, et al. Cytokine production in obsessive-compulsive disorder. Biol Psychiatry. 1996;40:908–12.

    Article  PubMed  CAS  Google Scholar 

  55. Denys D, Fluitman S, Kavelaars A, Heijnen C, Westenberg H. Decreased TNF-α and NK activity in obsessive-compulsive disorder. Psychoneuroendocrinology. 2004;29:945–52.

    Article  PubMed  CAS  Google Scholar 

  56. Denys D, Fluitman S, Kavelaars A, Heijnen C, Westenberg HGM. Effects of paroxetine and venlafaxine on immune parameters in patients with obsessive compulsive disorder. Psychoneuroendocrinology. 2006;31:355–60.

    Article  PubMed  CAS  Google Scholar 

  57. Fluitman S, Denys D, Vulink N, Schutters S, Heijnen C, Westenberg H. Lipopolysaccharide-induced cytokine production in obsessive-compulsive disorder and generalized social anxiety disorder. Psychiatry Res. 2010;178:313–6.

    Article  PubMed  CAS  Google Scholar 

  58. Fluitman SBAHA, Denys DAJP, Heijnen CJ, Westenberg HGM. Disgust affects TNF-alpha, IL-6 and noradrenalin levels in patients with obsessive-compulsive disorder. Psychoneuroendocrinology. 2010;35:906–11.

    Article  PubMed  CAS  Google Scholar 

  59. Carpenter LL, Heninger GR, McDougle CJ, Tyrka AR, Epperson CN, Price LH. Cerebrospinal fluid interleukin-6 in obsessive-compulsive disorder and trichotillomania. Psychiatry Res. 2002;112:257–62.

    Article  PubMed  CAS  Google Scholar 

  60. Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol. 1997;159:2994–9.

    PubMed  CAS  Google Scholar 

  61. Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci. 2002;966:290–303.

    Article  PubMed  CAS  Google Scholar 

  62. Vgontzas AN, Bixler EO, Lin HM, Prolo P, Trakada G, Chrousos GP. IL-6 and Its Circadian Secretion in Humans. Neuroimmunomodulation. 2005;12:131–40.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the National Institute of Mental Health support of the Yale Child Study Center Research Training Program (Dr. Bloch), the National Institutes of Health (NIH) 1K23MH091240 (Dr. Bloch), the APIRE/Eli Lilly Psychiatric Research Fellowship (Dr. Bloch), the AACAP/Eli Lilly Junior Investigator Award (Dr. Bloch), the Trichotillomania Learning Center (Dr. Bloch), NARSAD (Dr. Bloch), and UL1 RR024139 from the National Center for Research Resources, a component of the NIH, and NIH roadmap for Medical Research (Dr. Bloch).

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  1. Child Study Center, Yale University School of Medicine, P.O. Box 2070900, New Haven, CT, 06520, USA

    Simon M. Gray & Michael H. Bloch

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  2. Michael H. Bloch
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Correspondence to Michael H. Bloch.

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Gray, S.M., Bloch, M.H. Systematic Review of Proinflammatory Cytokines in Obsessive-Compulsive Disorder. Curr Psychiatry Rep 14, 220–228 (2012). https://doi.org/10.1007/s11920-012-0272-0

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