Purpose of Review
Here, we propose to review the immuno-inflammatory hypothesis in OCD given the concurrent incidence of autoimmune comorbidities, infectious stigma, and raised levels of inflammatory markers in a significant subset of patients. A better understanding of the immune dysfunction in OCD may allow stratifying the patients in order to design personalized pharmaco/psychotherapeutic strategies.
A persistent low-grade inflammation involving both innate and adaptive immune system with coexisting autoimmune morbidities and stigma of infectious events has been prominently observed in OCD. Hence, specific treatments targeting inflammation/infection are a feasible alternative in OCD.
This review highlights that OCD is associated with low-grade inflammation, neural antibodies, and neuro-inflammatory and auto-immune disorders. In some subset of OCD patients, autoimmunity is likely triggered by specific bacterial, viral, or parasitic agents with overlapping surface epitopes in CNS. Hence, subset-profiling in OCD is warranted to benefit from distinct immune-targeted treatment modalities.
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• Gray SM, Bloch MH. Systematic review of proinflammatory cytokines in obsessive-compulsive disorder. Curr Psychiatry Rep. 2012;14(3):220–8. An inaugural important review of immuno-inflammatory markers involved in OCD.
Fontenelle LF, Barbosa IG, Luna JV, de Sousa LP, Abreu MNS, Teixeira AL. A cytokine study of adult patients with obsessive-compulsive disorder. Compr Psychiatry. 2012;53(6):797–804.
Cappi C, Muniz RK, Sampaio AS, Cordeiro Q, Brentani H, Palácios SA, et al. Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder. Arq Neuropsiquiatr. 2012;70(2):87–90.
Rodríguez N, Morer A, González-Navarro EA, Serra-Pages C, Boloc D, Torres T, et al. Inflammatory dysregulation of monocytes in pediatric patients with obsessive-compulsive disorder. J Neuroinflammation. 2017;14(1):261.
Şimşek Ş, Yüksel T, Çim A, Kaya S. Serum cytokine profiles of children with obsessive-compulsive disorder shows the evidence of autoimmunity. Int J Neuropsychopharmacol. 2016;19(8):pyw027.
• Rao NP, Venkatasubramanian G, Ravi V, Kalmady S, Cherian A, Yc JR. Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive-compulsive disorder. Psychiatry Res. 2015;229(3):949–52. This study showed significantly greater plasma levels of IL-2, IL-4, IL-6, IL-10 and TNF-α levels in patients with OCD.
Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155(2):264–71.
Singer HS, Mascaro-Blanco A, Alvarez K, Morris-Berry C, Kawikova I, Ben-Pazi H, et al. Neuronal antibody biomarkers for Sydenham’s chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. PLoS One. 2015;10(3):e0120499.
Cox CJ, Zuccolo AJ, Edwards EV, Mascaro-Blanco A, Alvarez K, Stoner J, et al. Antineuronal antibodies in a heterogeneous group of youth and young adults with tics and obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2015;25(1):76–85.
Dale RC, Heyman I, Giovannoni G, Church AWJ. Incidence of anti-brain antibodies in children with obsessive-compulsive disorder. Br J Psychiatry. 2005;187:314–9.
Morer A, Lázaro L, Sabater L, Massana J, Castro J, Graus F. Antineuronal antibodies in a group of children with obsessive-compulsive disorder and Tourette syndrome. J Psychiatr Res. 2008;42(1):64–8.
Bhattacharyya S, Khanna S, Chakrabarty K, Mahadevan A, Christopher R, Shankar SK. Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder. Neuropsychopharmacology. 2009;34(12):2489–96.
Maina G, Albert U, Bogetto F, Borghese C, Berro AC, Mutani R, et al. Anti-brain antibodies in adult patients with obsessive-compulsive disorder. J Affect Disord. 2009;116(3):192–200.
Gause C, Morris C, Vernekar S, Pardo-Villamizar C, Grados MA, Singer HS. Antineuronal antibodies in OCD: comparisons in children with OCD-only, OCD+chronic tics and OCD+PANDAS. J Neuroimmunol. 2009;214(1–2):118–24.
• Pearlman DM, Vora HS, Marquis BG, Najjar S, Dudley LA. Anti-basal ganglia antibodies in primary obsessive-compulsive disorder: systematic review and meta-analysis. Br J Psychiatry. 2014;205(1):8–16. A meta-analysis involving anti-basal ganglia antibodies in OCD with a strong but non specific association.
Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. 2003;9(7):914–20.
Kirvan CA, Swedo SE, Snider LA, Cunningham MW. Antibody-mediated neuronal cell signaling in behavior and movement disorders. J Neuroimmunol. 2006;179(1–2):173–9.
Kirvan CA, Cox CJ, Swedo SE, Cunningham MW. Tubulin is a neuronal target of autoantibodies in Sydenham’s chorea. J Immunol. 2007;178(11):7412–21.
Chiaie RD, Caronti B, Macrì F, Campi S, Marino M, Corrado A, et al. Anti-purkinje cell and natural autoantibodies in a group of psychiatric patients. Evidences for a correlation with the psychopathological status. Clin Pract Epidemiol Ment Health. 2012;8:81–90.
Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev. 2005;57(2):217–52.
Hamdani N, Doukhan R, Kurtlucan O, Tamouza R, Leboyer M. Immunity, inflammation, and bipolar disorder: diagnostic and therapeutic implications. Curr Psychiatry Rep. 2013;15(9):387.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691–705.
Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268–75.
Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci. 2013;16(5):543–51.
Frick L, Pittenger C. Microglial dysregulation in OCD, Tourette syndrome, and PANDAS. J Immunol Res. 2016;8606057:1–8. https://doi.org/10.1155/2016/8606057.
Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014;17(3):400–6.
•• Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, et al. Inflammation in the Neurocircuitry of obsessive-compulsive disorder. JAMA Psychiatry. 2017;74(8):833–40. An original study demonstrating inflammation within the neurocircuitry of OCD (beyond the basal ganglia to include the cortico-striato-thalamo-cortical circuit).
Frick LR, Williams K, Pittenger C. Microglial dysregulation in psychiatric disease. Clin Dev Immunol. 2013;2013:608654.
Adam Y, Meinlschmidt G, Gloster AT, Lieb R. Obsessive-compulsive disorder in the community: 12-month prevalence, comorbidity and impairment. Soc Psychiatry Psychiatr Epidemiol. 2012;47(3):339–49.
Witthauer C. T Gloster A, Meyer AH. Lieb R Physical diseases among persons with obsessive compulsive symptoms and disorder: a general population study Soc Psychiatry Psychiatr Epidemiol déc. 2014;49(12):2013–22.
Fullana MA, Vilagut G, Rojas-Farreras S, Mataix-Cols D, de Graaf R, Demyttenaere K, et al. Obsessive-compulsive symptom dimensions in the general population: results from an epidemiological study in six European countries. J Affect Disord. 2010;124(3):291–9.
Härter MC, Conway KP, Merikangas KR. Associations between anxiety disorders and physical illness. Eur Arch Psychiatry Clin Neurosci. 2003;253(6):313–20.
Sareen J, Jacobi F, Cox BJ, Belik S-L, Clara I, Stein MB. Disability and poor quality of life associated with comorbid anxiety disorders and physical conditions. Arch Intern Med. 2006;166(19):2109–16.
Roy-Byrne PP, Davidson KW, Kessler RC, Asmundson GJG, Goodwin RD, Kubzansky L, et al. Anxiety disorders and comorbid medical illness. Gen Hosp Psychiatry. 2008;30(3):208–25.
•• Isomura K, Brander G, Chang Z, Kuja-Halkola R, Rück C, Hellner C, et al. Metabolic and cardiovascular complications in obsessive-compulsive disorder: a Total population, sibling comparison study with long-term follow-up. Biol Psychiatry. 2018;84(5):324–31. A recent study that showed a dramatic association between OCD and metabolic or cardiovascular complications.
•• Mataix-Cols D, Frans E, Pérez-Vigil A, Kuja-Halkola R, Gromark C, Isomura K, et al. A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette’s/chronic tic disorders. Mol Psychiatry. 2018 Jul;23(7):1652–8. This study suggests a familial link between autoimmune diseases in general, not limited to Streptococcus-related conditions, and OCD.
Murphy TK, Storch EA, Turner A, Reid JM, Tan J, Lewin AB. Maternal history of autoimmune disease in children presenting with tics and/or obsessive-compulsive disorder. J Neuroimmunol. 2010;229(1–2):243–7.
Giedd JN, Rapoport JL, Kruesi MJ, Parker C, Schapiro MB, Allen AJ, et al. Sydenham’s chorea: magnetic resonance imaging of the basal ganglia. Neurology. 1995;45(12):2199–202.
• Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev mars. 2018;86:51–65. A comprehensive review which describes a large panel of treatments for patients suffering from PANDAS and PANS.
Swedo SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatrics & Therapeutics. 2012;2(2):1–8.
Cox CJ, Sharma M, Leckman JF, Zuccolo J, Zuccolo A, Kovoor A, et al. Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease. J Immunol. 2013;191(11):5524–41.
Brimberg L, Benhar I, Mascaro-Blanco A, Alvarez K, Lotan D, Winter C, et al. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012;37(9):2076–87.
Ben-Pazi H, Stoner JA, Cunningham MW. Dopamine receptor autoantibodies correlate with symptoms in Sydenham’s chorea. PLoS One. 2013;8(9):e73516.
Orefici G, Cardona F, Cox CJ, Cunningham MW. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). In: Ferretti JJ, Stevens DL, Fischetti VA, eds. Streptococcus pyogenes : Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016.
Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354(9185):1153–8.
Cunningham MW. Streptococcus and rheumatic fever. Curr Opin Rheumatol. 2012;24(4):408–16.
Cunningham MW, Cox CJ. Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond. Acta Physiol. 2016;216(1):90–100.
Lin H, Williams KA, Katsovich L, Findley DB, Grantz H, Lombroso PJ, et al. Streptococcal upper respiratory tract infections and psychosocial stress predict future tic and obsessive-compulsive symptom severity in children and adolescents with Tourette syndrome and obsessive-compulsive disorder. Biol Psychiatry. 2010;67(7):684–91.
Murphy TK, Storch EA, Lewin AB, Edge PJ, Goodman WK. Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Pediatr. f2012;160(2):314–319.
Cardona F, Orefici G. Group a streptococcal infections and tic disorders in an Italian pediatric population. J Pediatr. 2001;138(1):71–5.
Leslie DL, Kozma L, Martin A, Landeros A, Katsovich L, King RA, et al. Neuropsychiatric disorders associated with streptococcal infection: a case-control study among privately insured children. J Am Acad Child Adolesc Psychiatry. 2008;47(10):1166–72.
Mell LK, Davis RL, Owens D. Association between streptococcal infection and obsessive-compulsive disorder, Tourette’s syndrome, and tic disorder. Pediatrics. 2005;116(1):56–60.
Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156(4):356–61.
Macerollo A, Martino D. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an evolving concept. Tremor other Hyperkinet Mov. N Y. 2013:3.
Luo F, Leckman JF, Katsovich L, Findley D, Grantz H, Tucker DM, et al. Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections. Pediatrics. 2004;113(6):e578–85.
Kurlan R, Johnson D, Kaplan EL. Tourette syndrome study group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics. 2008;121(6):1188–97.
Leckman JF, King RA, Gilbert DL, Coffey BJ, Singer HS, Dure LS, et al. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011;50(2):108–118.e3.
Murphy TK, Sajid M, Soto O, Shapira N, Edge P, Yang M, et al. Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. Biol Psychiatry. 2004;55(1):61–8.
Schrag A, Gilbert R, Giovannoni G, Robertson MM, Metcalfe C, Ben-Shlomo Y. Streptococcal infection, Tourette syndrome, and OCD: is there a connection? Neurology. 2009;73(16):1256–63.
Ercan TE, Ercan G, Severge B, Arpaozu M, Karasu G. Mycoplasma pneumoniae infection and obsessive-compulsive disease: a case report. J Child Neurol. 2008;23(3):338–40.
Yaramiş A, Hergüner S, Kara B, Tatli B, Tüzün U, Ozmen M. Cerebral vasculitis and obsessive-compulsive disorder following varicella infection in childhood. Turk J Pediatr. 2009;51(1):72–5.
Dietrich DE, Zhang Y, Bode L, Münte TF, Hauser U, Schmorl P, et al. Brain potential amplitude varies as a function of Borna disease virus-specific immune complexes in obsessive-compulsive disorder. Mol Psychiatry. 2005;10(6):515, 519–20.
Miman O, Mutlu EA, Ozcan O, Atambay M, Karlidag R, Unal S. Is there any role of toxoplasma gondii in the etiology of obsessive-compulsive disorder? Psychiatry Res. 2010;177(1–2):263–5.
Cong W, Dong W, Bai L, Wang X-Y, Ni X-T, Qian A-D, et al. Seroprevalence and associated risk factors of toxoplasma gondii infection in psychiatric patients: a case-control study in eastern China. Epidemiol Infect. 2015;143(14):3103–9.
Akaltun İ, Kara SS, Kara T. The relationship between toxoplasma gondii IgG antibodies and generalized anxiety disorder and obsessive-compulsive disorder in children and adolescents: a new approach. Nord J Psychiatry. 2018;72(1):57–62.
• Flegr J, Horáček J. Toxoplasma-infected subjects report an obsessive-compulsive disorder diagnosis more often and score higher in obsessive-compulsive inventory. Eur Psychiatry. 2017;40:82–7. An original study associating OCD with T. gondii.
Garvey MA, Perlmutter SJ, Allen AJ, Hamburger S, Lougee L, Leonard HL, et al. A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;45(12):1564–71.
Snider LA, Lougee L, Slattery M, Grant P, Swedo SE. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biol Psychiatry. 2005;57(7):788–92.
Murphy TK, Brennan EM, Johnco C, Parker-Athill EC, Miladinovic B, Storch EA, et al. A double-blind randomized placebo-controlled pilot study of azithromycin in youth with acute-onset obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2017;27(7):640–51.
Murphy TK, Parker-Athill EC, Lewin AB, Storch EA, Mutch PJ. Cefdinir for recent-onset pediatric neuropsychiatric disorders: a pilot randomized trial. Journal of Child and Adolescent Psychopharmacology. 2014;25(1):57–64.
Calaprice D, Tona J, Murphy TK. Treatment of pediatric acute-onset neuropsychiatric disorder in a large survey population. J Child Adolesc Psychopharmacol. 2018;28(2):92–103.
Esalatmanesh S, Abrishami Z, Zeinoddini A, Rahiminejad F, Sadeghi M, Najarzadegan M-R, et al. Minocycline combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: a placebo-controlled, double-blind, randomized trial. Psychiatry Clin Neurosci. 2016;70(11):517–26.
Rodriguez CI, Bender J, Marcus SM, Snape M, Rynn M, Simpson HB. Minocycline augmentation of pharmacotherapy in obsessive-compulsive disorder: an open-label trial. J Clin Psychiatry. 2010;71(9):1247–9.
Stryjer R, Budnik D, Ebert T, Green T, Polak L, Weizman S, et al. Amantadine augmentation therapy for obsessive compulsive patients resistant to SSRIs-an open-label study. Clin Neuropharmacol. 2014;37(3):79–81.
Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry. 1999;32(2):47–55.
Brynska A, Tomaszewicz-Libudzic E, Wolanczyk T. Obsessive-compulsive disorder and acquired toxoplasmosis in two children. Eur Child Adolesc Psychiatry. 2001;10(3):200–4.
Spartz EJ, Freeman GM, Brown K, Farhadian B, Thienemann M, Frankovich J. Course of neuropsychiatric symptoms after introduction and removal of nonsteroidal anti-inflammatory drugs: a pediatric observational study. J Child Adolesc Psychopharmacol. 2017;27(7):652–9.
Brown KD, Farmer C, Freeman GM, Spartz EJ, Farhadian B, Thienemann M, et al. Effect of early and prophylactic nonsteroidal anti-inflammatory drugs on flare duration in pediatric acute-onset neuropsychiatric syndrome: an observational study of patients followed by an academic community-based pediatric acute-onset neuropsychiatric syndrome clinic. J Child Adolesc Psychopharmacol. 2017;27(7):619–28.
Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016;41(2):214–9.
Latimer ME, L’Etoile N, Seidlitz J, Swedo SE. Therapeutic plasma apheresis as a treatment for 35 severely ill children and adolescents with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):70–5.
Elia J, Dell ML, Friedman DF, Zimmerman RA, Balamuth N, Ahmed AA, et al. PANDAS with catatonia: a case report. Therapeutic response to lorazepam and plasmapheresis. J Am Acad Child Adolesc Psychiatry. 2005;44(11):1145–50.
Frankovich J, Thienemann M, Rana S, Chang K. Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):31–7.
Allen AJ, Leonard HL, Swedo SE. Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry. 1995;34(3):307–11.
Kovacevic M, Grant P, Swedo SE. Use of intravenous immunoglobulin in the treatment of twelve youths with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol. 2015;25(1):65–9.
Williams KA, Swedo SE, Farmer CA, Grantz H, Grant PJ, D’Souza P, et al. Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Am Acad Child Adolesc Psychiatry. 2016;55(10):860–867.e2.
Murphy TK, Lewin AB, Parker-Athill EC, Storch EA, Mutch PJ. Tonsillectomies and adenoidectomies do not prevent the onset of pediatric autoimmune neuropsychiatric disorder associated with group a streptococcus. Pediatr Infect Dis J. 2013;32(8):834–8.
Demesh D, Virbalas JM, Bent JP. The role of tonsillectomy in the treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). JAMA Otolaryngol Head Neck Surg. 2015;141(3):272–5.
Pavone P, Rapisarda V, Serra A, Nicita F, Spalice A, Parano E, et al. Pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection: the role of surgical treatment. Int J Immunopathol Pharmacol. 2014;27(3):371–8.
Lamothe H, Baleyte JM, Smith P, Pelissolo A, Mallet L. Individualized immunological data for precise classification of OCD patients. Brain Sci. 2018;9(8):8.
The editors would like to thank Dr. Leonardo Fontenelle for taking the time to review this manuscript.
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Mona Gerentes, Krishnamoorthy Rajagopal, Ryad Tamouza, and Nora Hamdani each declare no potential conflicts of interest.
Antoine Pelissolo is a section editor for Current Psychiatry Reports.
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Gerentes, M., Pelissolo, A., Rajagopal, K. et al. Obsessive-Compulsive Disorder: Autoimmunity and Neuroinflammation. Curr Psychiatry Rep 21, 78 (2019). https://doi.org/10.1007/s11920-019-1062-8