Increased proinflammatory markers like cytokines have been described in the blood and cerebrospinal fluid of patients suffering from schizophrenia. Animal models have shown that a hit in early life to the immune system might trigger a lifelong increased immune reactivity. Many epidemiological and clinical studies show the role of various infectious agents as risk factors for schizophrenia with overlap to other psychoses. The first large-scale epidemiological study in psychiatry from Denmark clearly demonstrates severe infections and autoimmune disorders during lifetime to be risk factors for schizophrenia. Genetic studies have shown the strongest signal for schizophrenia on chromosome 6p22.1, in a region related to the major histocompatibility complex and other immune functions. The vulnerability-stress-inflammation model is important as stress may increase proinflammatory cytokines and even contribute to a lasting proinflammatory state. The immune system itself is considered an important further piece in the puzzle, as in autoimmune disorders in general, which are always linked to three factors: genes, the environment and the immune system. Alterations of dopaminergic, serotonergic, noradrenergic and glutamatergic neurotransmission have been shown with low-level neuroinflammation and may directly be involved in the generation of schizophrenic symptoms. Loss of central nervous system volume and microglial activation has been demonstrated in schizophrenia in neuroimaging studies, which supports the assumption of a low-level neuroinflammatory process. Further support comes from the therapeutic benefit of anti-inflammatory medications in specific studies and the anti-inflammatory and immunomodulatory intrinsic effects of antipsychotics.

O'Neill LA: How frustration leads to inflammation. Science 2008;320:619-620.
Hohlfeld R, Kerschensteiner M, Meinl E: Dual role of inflammation in CNS disease. Neurology 2007;68:S58-S63.
Hanson DR, Gottesman II: Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet 2005;6:7.
Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H: Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705-2712.
Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R: Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci 2008;274:42-44.
Kerschensteiner M, Meinl E, Hohlfeld R: Neuro-immune crosstalk in CNS diseases. Neuroscience 2009;158:1122-1132.
Anderson G, Berk M, Dodd S, Bechter K, Altamura AC, Dell'osso B, Kanba S, Monji A, Fatemi SH, Buckley P, Debnath M, Das UN, Meyer U, Muller N, Kanchanatawan B, Maes M: Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013;42:1-4.
Felgenhauer K: Psychiatric disorders in the encephalitic form of multiple sclerosis. J Neurol 1990;237:11-18.
Chiveri L, Sciacco M, Prelle A: Schizophreniform disorder with cerebrospinal fluid PCR positivity for herpes simplex virus type 1. Eur Neurol 2003;50:182-183.
Oommen KJ, Johnson PC, Ray CG: Herpes simplex type 2 virus encephalitis presenting as psychosis. Am J Med 1982;73:445-448.
Hiroshi H, Seiji K, Toshihiro K, Nobuo K: An adult case suspected of recurrent measles encephalitis with psychiatric symptoms (in Japanese). Seishin Shinkeigaku Zasshi 2003;105:1239-1246.
Mercadante MT, Busatto GF, Lombroso PJ, Prado L, Rosario-Campos MC, do VR, Marques-Dias MJ, Kiss MH, Leckman JF, Miguel EC: The psychiatric symptoms of rheumatic fever. Am J Psychiatry 2000;157:2036-2038.
Teixeira AL Jr, Maia DP, Cardoso F: Psychosis following acute Sydenham's chorea. Eur Child Adolesc Psychiatry 2007;16:67-69.
Kerbeshian J, Burd L, Tait A: Chain reaction or time bomb: a neuropsychiatric-developmental/neurodevelopmental formulation of tourettisms, pervasive developmental disorder, and schizophreniform symptomatology associated with PANDAS. World J Biol Psychiatry 2007;8:201-207.
Bechter K, Bindl A, Horn M, Schreiner V: Therapy-resistant depression with fatigue: a case of presumed streptococcal-associated autoimmune disorder (in German). Nervenarzt 2007;78:338, 340-338, 341.
Müller N, Gizycki-Nienhaus B, Günther W, Meurer M: Depression as a cerebral manifestation of scleroderma: immunological findings in serum and cerebrospinal fluid. Biol Psychiatry 1992;31:1151-1156.
Müller N, Gizycki-Nienhaus B, Botschev C, Meurer M: Cerebral involvement of scleroderma presenting as schizophrenia-like psychosis. Schizophr Res 1993;10:179-181.
van Dam AP: Diagnosis and pathogenesis of CNS lupus. Rheumatol Int 1991;11:1-11.
Nikolich-Zugich J: Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 2008;8:512-522.
Dantzer R: Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 2001;15:7-24.
Perry VH: Stress primes microglia to the presence of systemic inflammation: implications for environmental influences on the brain. Brain Behav Immun 2007;21:45-46.
Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH: Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005;25:9275-9284.
Godbout JP, Johnson RW: Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin North Am 2009;29:321-337.
Sparkman NL, Johnson RW: Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation 2008;15:323-330.
Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF: Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 2007;21:47-59.
Furukawa H, del Rey A, Monge-Arditi G, Besedovsky HO: Interleukin-1, but not stress, stimulates glucocorticoid output during early postnatal life in mice. Ann NY Acad Sci 1998;840:117-122.
Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS: Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 1993;133:2523-2530.
Anisman H, Merali Z: Cytokines, stress and depressive illness: brain-immune interactions. Ann Med 2003;35:2-11.
Hayley S, Wall P, Anisman H: Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor-α: peripheral and central mechanisms. Eur J Neurosci 2002;15:1061-1076.
Nair A, Bonneau RH: Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 2006;171:72-85.
Zubin J, Spring B: Vulnerability - a new view of schizophrenia. J Abnorm Psychol 1977;86:103-126.
Raison CL, Miller AH: The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry 2013;18:15-37.
Claes S, Myint AM, Domschke K, Del-Favero J, Entrich K, Engelborghs S, De Deyn P, Mueller N, Baune B, Rothermundt M: The kynurenine pathway in major depression: haplotype analysis of three related functional candidate genes. Psychiatry Res 2011;188:355-360.
Körschenhausen DA, Hampel HJ, Ackenheil M, Penning R, Müller N: Fibrin degradation products in post mortem brain tissue of schizophrenics: a possible marker for underlying inflammatory processes. Schizophr Res 1996;19:103-109.
Wildenauer DB, Körschenhausen D, Hoechtlen W, Ackenheil M, Kehl M, Lottspeich F: Analysis of cerebrospinal fluid from patients with psychiatric and neurological disorders by two-dimensional electrophoresis: identification of disease-associated polypeptides as fibrin fragments. Electrophoresis 1991;12:487-492.
Müller N, Schwarz MJ: Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders. Exp Ref Neurotherapeutics 2006;6:1017-1038.
Müller N, Schwarz MJ: Immune System and Schizophrenia. Curr Immunol Rev 2010;6:213-220.
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E: Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 2008;63:801-808.
Carlsson A: The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988;1:179-186.
Ling ZD, Potter ED, Lipton JW, Carvey PM: Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 1998;149:411-423.
Kabiersch A, Furukawa H, del Rey A, Besedovsky HO: Administration of interleukin-1 at birth affects dopaminergic neurons in adult mice. Ann NY Acad Sci 1998;840:123-127.
Potter ED, Ling ZD, Carvey PM: Cytokine-induced conversion of mesencephalic-derived progenitor cells into dopamine neurons. Cell Tissue Res 1999;296:235-246.
Jarskog LF, Xiao H, Wilkie MB, Lauder JM, Gilmore JH: Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro. Int J Dev Neurosci 1997;15:711-716.
Winter C, Djodari-Irani A, Sohr R, Morgenstern R, Feldon J, Juckel G, Meyer U: Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia. Int J Neuropsychopharmacol 2009;12:513-524.
Rouse BT, Sehrawat S: Immunity and immunopathology to viruses: what decides the outcome? Nat Rev Immunol 2010;10:514-526.
Müller N, Schwarz MJ: The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J Neurotransmission 2007;72:269-280.
Stone TW: Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 1993;45:309-379.
Müller N, Myint AM, Schwarz MJ: Kynurenine pathway in schizophrenia: pathophysiological and therapeutic aspects. Curr Pharm Des 2011;17:130-136.
Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, Kastner A, Skalej M, Jordan W, Schiltz K, Klingbeil C, Wandinger KP, Bogerts B, Stoecker W: Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 2013;70:271-278.
Vincent A, Bien CG: Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. Lancet Neurol 2008;7:1074-1075.
Erhardt S, Blennow K, Nordin C, Skogh E, Lindstrom LH, Engberg G: Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 2001;313:96-98.
Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, Samuelsson M, Erhardt S: Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull 2012;38:426-432.
Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC: Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 2001;50:521-530.
Sathyasaikumar KV, Stachowski EK, Wonodi I, Roberts RC, Rassoulpour A, McMahon RP, Schwarcz R: Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull 2011;37:1147-1156.
Olsson SK, Andersson AS, Linderholm KR, Holtze M, Nilsson-Todd LK, Schwieler L, Olsson E, Larsson K, Engberg G, Erhardt S: Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia. Int J Neuropsychopharmacol 2009;12:501-512.
Condray R, Dougherty GG, Keshavan MS, Reddy RD, Haas GL, Montrose DM, Matson WR, McEvoy J, Kaddurah-Daouk R, Yao JK: 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia. Int J Neuropsychopharmacol 2011;14:756-767.
Myint AM, Schwarz MJ, Verkerk R, Mueller HH, Zach J, Scharpe S, Steinbusch HW, Leonard BE, Kim YK: Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication- naive and medication-free schizophrenic patients. Brain Behav Immun 2011;25:1576-1581.
Ceresoli-Borroni G, Rassoulpour A, Wu HQ, Guidetti P, Schwarcz R: Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J Neural Transm 2006;113:1355-1365.
Meyer U, Feldon J: Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia. Psychopharmacology (Berl) 2009;206:587-602.
Meyer U, Schwarz MJ, Müller N: Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacol Ther 2011;132:96-110.
Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH: Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001;58:1032-1037.
Westergaard T, Mortensen PB, Pedersen CB, Wohlfahrt J, Melbye M: Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence. Arch Gen Psychiatry 1999;56:993-998.
Pearce BD: Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms. Mol Psychiatry 2001;6:634-646.
Buka SL, Cannon TD, Torrey EF, Yolken RH: Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biol Psychiatry 2008;63:809-815.
Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, Babulas VP, Susser ES: Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004;61:774-780.
Brown AS, Cohen P, Susser ES, Greenwald MA: Nonaffective psychosis after prenatal exposure to rubella. Am J Psychiatry 2000;157:438-443.
Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA: Association between prenatal exposure to bacterial infection and risk of schizophrenia. Schizophr Bull 2009;35:631-637.
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS: Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry 2006;163:927-929.
Brown AS, Schaefer CA, Quesenberry CP Jr, Liu L, Babulas VP, Susser ES: Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J Psychiatry 2005;162:767-773.
Boksa P: Maternal infection during pregnancy and schizophrenia. J Psychiatry Neurosci 2008;33:183-185.
Gattaz WF, Abrahao AL, Foccacia R: Childhood meningitis, brain maturation and the risk of psychosis. Eur Arch Psychiatry Clin Neurosci 2004;254:23-26.
Brown AS: The risk for schizophrenia from childhood and adult infections. Am J Psychiatry 2008;165:7-10.
Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G, Lofving S, Rasmussen F, Wicks S, Karlsson H: Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry 2008;165:59-65.
Yolken RH, Torrey EF: Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 1995;8:131-145.
Leweke FM, Gerth CW, Koethe D, Klosterkotter J, Ruslanova I, Krivogorsky B, Torrey EF, Yolken RH: Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 2004;254:4-8.
Krause D, Matz J, Weidinger E, Wagner J, Wildenauer A, Obermeier M, Riedel M, Muller N: The association of infectious agents and schizophrenia. World J Biol Psychiatry 2010;11:739-743.
Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES: Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry 2004;161:889-895.
Ellman LM, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Kern DM, Tsai WY, Schaefer CA, Brown AS: Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr Res 2010;121:46-54.
Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB: Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry 2011;168:1303-1310.
Benros ME, Mortensen PB, Eaton WW: Autoimmune diseases and infections as risk factors for schizophrenia. Ann NY Acad Sci 2012;1262:56-66.
Gogtay N, Lu A, Leow AD, Klunder AD, Lee AD, Chavez A, Greenstein D, Giedd JN, Toga AW, Rapoport JL, Thompson PM: Three-dimensional brain growth abnormalities in childhood-onset schizophrenia visualized by using tensor-based morphometry. Proc Natl Acad Sci USA 2008;105:15979-15984.
Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA: Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry 2006;188:510-518.
Job DE, Whalley HC, McIntosh AM, Owens DG, Johnstone EC, Lawrie SM: Grey matter changes can improve the prediction of schizophrenia in subjects at high risk. BMC Med 2006;4:29.
Chakos MH, Schobel SA, Gu H, Gerig G, Bradford D, Charles C, Lieberman JA: Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia. Br J Psychiatry 2005;186:26-31.
Meisenzahl EM, Rujescu D, Kirner A, Giegling I, Kathmann N, Leinsinger G, Maag K, Hegerl U, Hahn K, Moller HJ: Association of an interleukin-1β genetic polymorphism with altered brain structure in patients with schizophrenia. Am J Psychiatry 2001;158:1316-1319.
Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, Achten E, Slegers G, Dierckx RA, Korf J: Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur Neurol 2003;50:39-47.
van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS: Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008;64:820-822.
Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC: Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009;50:1801-1807.
Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R, Okubo Y, Suhara T: Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C]DAA1106. Int J Neuropsychopharmacol 2010;13:943-950.
Müller N, Riedel M, Schwarz MJ, Engel RR: Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2005;255:149-151.
Müller N: COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs 2010;11:31-42.
Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, Möller HJ, Klauss V, Schwarz MJ, Riedel M: Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res 2010;121:119-124.
Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H: Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2010;71:520-527.
Sommer IE, de Witte L, Begemann M, Kahn RS: Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 2012;73:414-419.
Nitta M, Kishimoto T, Müller N, Weiser M, Davidson M, Kane JM, Correll CU: Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39:1230-1241.
Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, Ibi D, Kim HC, Yamada K: Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology (Berl) 2008;196:233-241.
Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S: A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 2010;71:138-149.
Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B: Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012;26:1185-1193.
Ahuja N, Carroll BT: Possible anti-catatonic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:968-969.
Hunter J: A treatise on the blood, inflammation and gun-shot wounds. Georg Nicol, London, 1794.
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