Molecular Neurobiology

, Volume 56, Issue 7, pp 4751–4759 | Cite as

Immune Aberrations in Obsessive-Compulsive Disorder: a Systematic Review and Meta-analysis

  • Theodore D. Cosco
  • Toby Pillinger
  • Hadeer Emam
  • Marco Solmi
  • Sanjay Budhdeo
  • A. Matthew Prina
  • Michael Maes
  • Dan J. Stein
  • Brendon Stubbs
  • Andre F. CarvalhoEmail author


Some lines of evidence have indicated that immune dysregulation could play a role in the pathophysiology of obsessive-compulsive disorder (OCD). However, results have been inconsistent across studies. Thus, a systematic review and meta-analysis of studies measuring immune mediators in participants with OCD compared to healthy controls (HC) was conducted. The PubMed/MEDLINE, PsycINFO, and EMBASE electronic databases were systematically searched from inception through June 21, 2018. Sixteen studies met inclusion criteria comprising data from 1001 participants (538 with OCD and 463 were HCs). Levels of TNF-α, IL-6, IL-1β, IL-4, IL-10, and interferon-γ did not significantly differ between participants with OCD and healthy controls. In addition, the ex vivo production of TNF-α and IL-6 by isolated macrophages did not significantly differ between participants with OCD and HCs. Nevertheless, included studies have varied in methodological quality with the enrollment of samples that differed regarding medication status, the proper matching of OCD participants and HCs, age groups, and the presence of psychiatric comorbidities. In conclusion, an association between immune dysregulation and OCD remains unproven. Future studies should consider enrolling larger and more homogeneous samples with OCD.


Obsessive-compulsive disorder Meta-analysis Review Cytokines Chemokines Inflammation 


Compliance with Ethical Standards

Conflict of Interest

DJS is supported by the Medical Research Council of South Africa and has received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah, and Wyeth. The other authors declare no conflict of interest.

Supplementary material

12035_2018_1409_MOESM1_ESM.xlsx (31 kb)
ESM 1 (XLSX 31 kb)
12035_2018_1409_MOESM2_ESM.docx (80 kb)
ESM 2 (DOCX 79 kb)


  1. 1.
    Ruscio AM, Stein DJ, Chiu WT, Kessler RC (2010) The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 15(1):53–63. CrossRefPubMedGoogle Scholar
  2. 2.
    APA (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub,Google Scholar
  3. 3.
    Dell'Osso B, Benatti B, Hollander E, Fineberg N, Stein DJ, Lochner C, Nicolini H, Lanzagorta N et al (2016) Childhood, adolescent and adult age at onset and related clinical correlates in obsessive-compulsive disorder: a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). Int J Psychiatry Clin Pract 20(4):210–217. CrossRefPubMedGoogle Scholar
  4. 4.
    Swedo SE, Rapoport JL, Cheslow DL, Leonard HL, Ayoub EM, Hosier DM, Wald ER (1989) High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. Am J Psychiatry 146(2):246–249. CrossRefPubMedGoogle Scholar
  5. 5.
    Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S et al (1998) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155(2):264–271. CrossRefPubMedGoogle Scholar
  6. 6.
    Teixeira AL, Rodrigues DH, Marques AH, Miguel EC, Fontenelle LF (2014) Searching for the immune basis of obsessive-compulsive disorder. Neuroimmunomodulation 21(2–3):152–158. CrossRefPubMedGoogle Scholar
  7. 7.
    Swedo S, Leckman J, Rose N (2012) From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatr Therapeut 2(2):113CrossRefGoogle Scholar
  8. 8.
    Gray SM, Bloch MH (2012) Systematic review of proinflammatory cytokines in obsessive-compulsive disorder. Current psychiatry reports 14(3):220–228. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fontenelle LF, Barbosa IG, Luna JV, de Sousa LP, Abreu MN, Teixeira AL (2012) A cytokine study of adult patients with obsessive-compulsive disorder. Compr Psychiatry 53(6):797–804. CrossRefPubMedGoogle Scholar
  10. 10.
    Colak Sivri R, Bilgic A, Kilinc I (2018) Cytokine, chemokine and BDNF levels in medication-free pediatric patients with obsessive-compulsive disorder. Eur Child Adoles Psychiatry 27:977–984. CrossRefGoogle Scholar
  11. 11.
    Leckman JF, Katsovich L, Kawikova I, Lin H, Zhang H, Kronig H, Morshed S, Parveen S et al (2005) Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette’s syndrome. Biol Psychiatry 57(6):667–673. CrossRefPubMedGoogle Scholar
  12. 12.
    Bos-Veneman NG, Bijzet J, Limburg PC, Minderaa RB, Kallenberg CG, Hoekstra PJ (2010) Cytokines and soluble adhesion molecules in children and adolescents with a tic disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 34(8):1390–1395. CrossRefGoogle Scholar
  13. 13.
    Brambilla F, Perna G, Bellodi L, Arancio C, Bertani A, Perini G, Carraro C, Gava F (1997) Plasma interleukin-1 beta and tumor necrosis factor concentrations in obsessive-compulsive disorders. Biol Psychiatry 42(11):976–981CrossRefGoogle Scholar
  14. 14.
    Monteleone P, Catapano F, Fabrazzo M, Tortorella A, Maj M (1998) Decreased blood levels of tumor necrosis factor-alpha in patients with obsessive-compulsive disorder. Neuropsychobiology 37(4):182–185. CrossRefPubMedGoogle Scholar
  15. 15.
    Denys D, Fluitman S, Kavelaars A, Heijnen C, Westenberg H (2004) Decreased TNF-alpha and NK activity in obsessive-compulsive disorder. Psychoneuroendocrinology 29(7):945–952. CrossRefPubMedGoogle Scholar
  16. 16.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical research ed) 339:b2700. CrossRefGoogle Scholar
  17. 17.
    santé Omdl, Organization WH, WHO (1992) The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines, vol 1. World Health Organization,Google Scholar
  18. 18.
    Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, Stubbs B, Solmi M et al (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 135(5):373–387. CrossRefPubMedGoogle Scholar
  19. 19.
    Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5:13. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127(9):820–826CrossRefGoogle Scholar
  21. 21.
    Patsopoulos NA, Evangelou E, Ioannidis JP (2009) Heterogeneous views on heterogeneity. Int J Epidemiol 38(6):1740–1742. CrossRefPubMedGoogle Scholar
  22. 22.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188CrossRefGoogle Scholar
  23. 23.
    Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G et al (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ (Clinical research ed) 343:d4002. CrossRefGoogle Scholar
  24. 24.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed) 315(7109):629–634CrossRefGoogle Scholar
  25. 25.
    Carvalho AF, Kohler CA, Brunoni AR, Miskowiak KW, Herrmann N, Lanctot KL, Hyphantis TN, Quevedo J et al (2016) Bias in peripheral depression biomarkers. Psychother Psychosom 85(2):81–90. CrossRefPubMedGoogle Scholar
  26. 26.
    Carvalho AF, Kohler CA, Fernandes BS, Quevedo J, Miskowiak KW, Brunoni AR, Machado-Vieira R, Maes M et al (2016) Bias in emerging biomarkers for bipolar disorder. Psychol Med 46(11):2287–2297. CrossRefPubMedGoogle Scholar
  27. 27.
    Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56(2):455–463CrossRefGoogle Scholar
  28. 28.
    Higgins JP, Thompson SG (2004) Controlling the risk of spurious findings from meta-regression. Stat Med 23(11):1663–1682. CrossRefPubMedGoogle Scholar
  29. 29.
    Maes M, Meltzer HY, Bosmans E (1994) Psychoimmune investigation in obsessive-compulsive disorder: assays of plasma transferrin, IL-2 and IL-6 receptor, and IL-1 beta and IL-6 concentrations. Neuropsychobiology 30(2–3):57–60. CrossRefPubMedGoogle Scholar
  30. 30.
    Weizman R, Laor N, Barber Y, Hermesh H, Notti I, Djaldetti M, Bessler H (1996) Cytokine production in obsessive-compulsive disorder. Biol Psychiatry 40(9):908–912. CrossRefPubMedGoogle Scholar
  31. 31.
    Carpenter LL, Heninger GR, McDougle CJ, Tyrka AR, Epperson CN, Price LH (2002) Cerebrospinal fluid interleukin-6 in obsessive-compulsive disorder and trichotillomania. Psychiatry Res 112(3):257–262CrossRefGoogle Scholar
  32. 32.
    Konuk N, Tekin IO, Ozturk U, Atik L, Atasoy N, Bektas S, Erdogan A (2007) Plasma levels of tumor necrosis factor-alpha and interleukin-6 in obsessive compulsive disorder. Mediat Inflamm 2007:65704. CrossRefGoogle Scholar
  33. 33.
    Fluitman S, Denys D, Vulink N, Schutters S, Heijnen C, Westenberg H (2010) Lipopolysaccharide-induced cytokine production in obsessive-compulsive disorder and generalized social anxiety disorder. Psychiatry Res 178(2):313–316. CrossRefPubMedGoogle Scholar
  34. 34.
    Fluitman SB, Denys DA, Heijnen CJ, Westenberg HG (2010) Disgust affects TNF-alpha, IL-6 and noradrenalin levels in patients with obsessive-compulsive disorder. Psychoneuroendocrinology 35(6):906–911. CrossRefPubMedGoogle Scholar
  35. 35.
    Rao NP, Venkatasubramanian G, Ravi V, Kalmady S, Cherian A, Yc JR (2015) Plasma cytokine abnormalities in drug-naive, comorbidity-free obsessive-compulsive disorder. Psychiatry Res 229(3):949–952. CrossRefPubMedGoogle Scholar
  36. 36.
    Simsek S, Yuksel T, Cim A, Kaya S (2016) Serum cytokine profiles of children with obsessive-compulsive disorder shows the evidence of autoimmunity. Int J Neuropsychopharmacol 19(8):pyw027. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rodriguez N, Morer A, Gonzalez-Navarro EA, Serra-Pages C, Boloc D, Torres T, Garcia-Cerro S, Mas S et al (2017) Inflammatory dysregulation of monocytes in pediatric patients with obsessive-compulsive disorder. J Neuroinflammation 14(1):261. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Erbay LG, Kavuran NA, Taşkapan Ç, Lara Utku İ, Yoloğlu S, Temelli HG, Ünal S (2018) Serum IL-1, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ levels in drug-free, comorbidity-free obsessive-compulsive disorder patients. ANADOLU PSIKIYATRI DERGISI-Anatolian J Psychiatry 19(2):157–162Google Scholar
  39. 39.
    Kohler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, de Andrade NQ, Morris G, Fernandes BS, Brunoni AR, Herrmann N, Raison CL, Miller BJ, Lanctot KL, Carvalho AF (2018) Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Mol Neurobiol 55 (5):4195–4206. doi:
  40. 40.
    Maes M, Carvalho AF (2018) The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol 55:8885–8903. CrossRefPubMedGoogle Scholar
  41. 41.
    Walker FR (2013) A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology 67:304–317. CrossRefPubMedGoogle Scholar
  42. 42.
    de Melo LGP, Nunes SOV, Anderson G, Vargas HO, Barbosa DS, Galecki P, Carvalho AF, Maes M (2017) Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 78:34–50. CrossRefGoogle Scholar
  43. 43.
    Rom O, Avezov K, Aizenbud D, Reznick AZ (2013) Cigarette smoking and inflammation revisited. Respir Physiol Neurobiol 187(1):5–10. CrossRefPubMedGoogle Scholar
  44. 44.
    Dantzer R (2018) Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev 98(1):477–504. CrossRefPubMedGoogle Scholar
  45. 45.
    Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, Xu C, Richter MA et al (2017) Inflammation in the neurocircuitry of obsessive-compulsive disorder. JAMA psychiatry 74(8):833–840. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Theodore D. Cosco
    • 1
    • 2
  • Toby Pillinger
    • 3
  • Hadeer Emam
    • 4
  • Marco Solmi
    • 5
    • 6
  • Sanjay Budhdeo
    • 7
    • 8
  • A. Matthew Prina
    • 9
  • Michael Maes
    • 10
    • 11
  • Dan J. Stein
    • 12
  • Brendon Stubbs
    • 13
    • 14
    • 15
  • Andre F. Carvalho
    • 16
    • 17
    • 18
    Email author
  1. 1.Gerontology Research CenterSimon Fraser UniversityVancouverCanada
  2. 2.Oxford Institute of Population AgeingUniversity of OxfordOxfordUK
  3. 3.Department of Psychosis Studies, Institute of Psychiatry, Psychology and NeuroscienceKing’s College LondonLondonUK
  4. 4.Olin Neuropsychiatry Research CenterInstitute of LivingHartfordUSA
  5. 5.Neurosciences DepartmentUniversity of PaduaPaduaItaly
  6. 6.Padova Neuroscience CenterUniversity of PaduaPaduaItaly
  7. 7.National Hospital for Neurology and NeurosurgeryLondonUK
  8. 8.Institute of NeurologyUniversity College LondonLondonUK
  9. 9.Health Service and Population Research Department, Institute of Psychiatry, Psychology & NeuroscienceKing’s College LondonLondonUK
  10. 10.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  11. 11.IMPACT Strategic Research CenterDeakin UniversityGeelongAustralia
  12. 12.Department of Psychiatry and MRC Unit on Risk and Resilience in Mental Disorders, Faculty of Health SciencesUniversity of Cape Town and Groote Schuur HospitalCape TownSouth Africa
  13. 13.Physiotherapy DepartmentSouth London and Maudsley NHS Foundation TrustLondonUK
  14. 14.Department of Psychological Medicine, Institute of Psychiatry, Psychology and NeuroscienceKing’s College LondonLondonUK
  15. 15.Faculty of Health, Social Care and EducationAnglia Ruskin UniversityChelmsfordUK
  16. 16.Department of PsychiatryUniversity of TorontoTorontoCanada
  17. 17.Centre for Addiction and Mental Health (CAMH)TorontoCanada
  18. 18.Faculty of MedicineUniversity of TorontoTorontoCanada

Personalised recommendations