Skip to main content
SpringerLink
Log in

Cytokines, Immunity and Schizophrenia with Emphasis on Underlying Neurochemical Mechanisms

  • Chapter
The Neuroimmunological Basis of Behavior and Mental Disorders

Abstract

This overview presents a hypothesis to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. In schizophrenia, a glutamatergic hypofunction is discussed to be crucially involved in dopaminergic dysfunction. This view is supported by findings of the neuregulin and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction is mediated by NMDA (N-methyl-d-aspartate) receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYN-A). KYN-A also blocks the nicotinergic acetylcholine receptor, i.e. increased KYN-A levels can explain psychotic symptoms and cognitive deterioration. KYN-A levels are described to be higher in the CSF and in critical CNS regions of schizophrenics. Another line of evidence suggests that the immune system in schizophrenic patients is characterized by an imbalance between the type-1 and the type-2 immune responses with a partial inhibition of the type-1 response, while the type-2 response is relatively over-activated. This immune constellation is associated with the inhibition of the enzyme indoleamine 2,3-dioxygenase (IDO), because type-2 cytokines are potent inhibitors of IDO. Due to the inhibition of IDO, tryptophan is predominantly metabolized by tryptophan 2,3-dioxygenase (TDO), which is located in astrocytes, but not in microglia cells. As indicated by increased levels of S100B, astrocytes are activated in schizophrenia. On the other hand, the kynurenine metabolism in astrocytes is restricted to the dead-end arm of KYN-A production. Accordingly, an increased TDO activity and an accumulation of KYN-A in the CNS of schizophrenics have been described. Thus, the immune-mediated glutamatergic– dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g. the use of anti-inflammatory cyclooxygenase-2 inhibitors, which are also able to directly decrease KYN-A, are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aloisi F, Ria F, Adorini L (2000) Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol Today 21: 141–147

    PubMed  CAS  Google Scholar 

  • Andreasen NC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, et al. (1992) Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiatry 49: 943–958

    PubMed  CAS  Google Scholar 

  • Avgustin B, Wraber B, Tavcar R (2005) Increased Th1 and Th2 immune reactivity with relative Th2 dominance in patients with acute exacerbation of schizophrenia. Croat Med J 46: 268–274

    PubMed  Google Scholar 

  • Bayer TA, Buslei R, Havas L, Falkai P (1999) Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 271: 126–128

    PubMed  CAS  Google Scholar 

  • Bechter K, Schreiner V, Herzog S, Breitinger N, Wollinsky KH, Brinkmeier H, et al. (2003) CSF filtration as experimental therapy in therapyresistant psychoses in borna disease virus-seropositive patients. Psychiatr Prax 30: 216–220

    PubMed  Google Scholar 

  • Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. (2004) Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 61: 774–780

    PubMed  Google Scholar 

  • Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH (2001) Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 58: 1032–1037

    PubMed  CAS  Google Scholar 

  • Carlsson A (1988) The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1: 179–186

    PubMed  CAS  Google Scholar 

  • Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41: 237–260

    PubMed  CAS  Google Scholar 

  • Carlsson A (2006) The neurochemical circuitry of schizophrenia. Pharmacopsychiatry 39(Suppl 1): S10–S14

    PubMed  CAS  Google Scholar 

  • Casolini P, Catalani A, Zuena AR, Angelucci L (2002) Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res 68: 337–343

    PubMed  CAS  Google Scholar 

  • Cazzullo CL, Scarone S, Grassi B, Vismara C, Trabattoni D, Clerici M, et al. (1998) Cytokines production in chronic schizophrenia patients with or without paranoid behaviour. Prog Neuropsychopharmacol Biol Psychiatry 22: 947–957

    PubMed  CAS  Google Scholar 

  • Ceresoli-Borroni G, Rassoulpour A, Wu HQ, Guidetti P, Schwarcz R (2006) Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J Neural Transm 113(10): 1355–1365

    PubMed  CAS  Google Scholar 

  • Chakos MH, Schobel SA, Gu H, Gerig G, Bradford D, Charles C, et al. (2005) Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia. Br J Psychiatry 186: 26–31

    PubMed  Google Scholar 

  • Chiang SSW, Riedel M, Müller N, Ackenheil M, Gruber R, Schwarz MJ (2004) Th2-shift in schizophrenia: primary findings from whole blood in vitro stimulation. Psychiatry Online

    Google Scholar 

  • Chiarugi A, Carpenedo R, Moroni F (1996) Kynurenine disposition in blood and brain of mice: effects of selective inhibitors of kynurenine hydroxylase and of kynureninase. J Neurochem 67: 692–698

    PubMed  CAS  Google Scholar 

  • Collier DA, Li T (2003) The genetics of schizophrenia: glutamate not dopamine? Eur J Pharmacol 480: 177–184

    PubMed  CAS  Google Scholar 

  • Cook GS, Hill DR (2001) Genetics of susceptibility to human infectious disease. Nat Rev Genet 2: 967–977

    Google Scholar 

  • Das I, Khan NS (1998) Increased arachidonic acid induced platelet chemiluminescence indicates cyclooxygenase overactivity in schizophrenic subjects. Prostaglandins Leukot Essent Fatty Acids 58: 165–168

    PubMed  CAS  Google Scholar 

  • Dean K, Murray RM (2005) Environmental risk factors for psychosis. Dialogues Clin Neurosci 7: 69–80

    PubMed  Google Scholar 

  • Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS (2006) Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 20: 532–545

    PubMed  CAS  Google Scholar 

  • Erhardt S, Blennow K, Nordin C, Skogh E, Lindstrom LH, Engberg G (2001a) Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 313: 96–98

    CAS  Google Scholar 

  • Erhardt S, Oberg H, Mathe JM, Engberg G (2001b) Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons. Amino Acids 20: 353–362

    CAS  Google Scholar 

  • Erhardt S, Schwieler L, Engberg G (2003) Kynurenic acid and schizophrenia. Adv Exp Med Biol 527: 155–165

    PubMed  CAS  Google Scholar 

  • Farber NB, Wozniak DF, Price MT, Labruyere J, Huss J, St PH, et al. (1995) Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia? Biol Psychiatry 38: 788–796

    PubMed  CAS  Google Scholar 

  • Fearon P, Cotter P, Murray RM (2000) Is the association between obstretic complications and schizophrenia mediated by glutaminergic excitotoxic damage of the foetal/neonatal brain? In: Revely M, Deacon B, eds. Psychopharmacology of Schizophrenia. London: Chapman and Hall 21–40

    Google Scholar 

  • Ganguli R, Rabin BS, Kelly RH, Lyte M, Ragu U (1987) Clinical and laboratory evidence of autoimmunity in acute schizophrenia. Ann N Y Acad Sci 496: 676–685

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Abrahao AL, Foccacia R (2004) Childhood meningitis, brain maturation and the risk of psychosis. Eur Arch Psychiatry Clin Neurosci 254: 23–26

    PubMed  Google Scholar 

  • Grohmann U, Fallarino F, Puccetti P (2003) Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 24: 242–248

    PubMed  CAS  Google Scholar 

  • Guidetti P, Luthi-Carter RE, Augood SJ, Schwarcz R (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis 17: 455–461

    PubMed  CAS  Google Scholar 

  • Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armati PJ, et al. (2001) Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 78: 842–853

    PubMed  CAS  Google Scholar 

  • Harris SG, Padilla J, Koumas L, Ray D, Phipps RP (2002) Prostaglandins as modulators of immunity. Trends Immunol 23: 144–150

    PubMed  CAS  Google Scholar 

  • Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56: 29–36

    PubMed  CAS  Google Scholar 

  • Heyes MP, Chen CY, Major EO, Saito K (1997) Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J 326: 351–356

    PubMed  CAS  Google Scholar 

  • Hill AV (1996) Genetics of infectious disease resistance. Curr Opin Genet Dev 6: 348–353

    PubMed  CAS  Google Scholar 

  • Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21: 7463–7473

    PubMed  CAS  Google Scholar 

  • Huber G (1983) Das Konzept substratnaher Basissymptome und seine Bedeutung für Theorie und THerapie schizophrener Erkrankungen [The concept of substrate-close basic symptoms and its significance for the theory and therapy of schizophrenic diseases]. Nervenarzt 54: 23–32

    PubMed  CAS  Google Scholar 

  • Jakob H, Beckmann H (1986) Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm 65: 303–326

    PubMed  CAS  Google Scholar 

  • Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20: 201–225

    PubMed  CAS  Google Scholar 

  • Job DE, Whalley HC, McIntosh AM, Owens DG, Johnstone EC, Lawrie SM (2006) Grey matter changes can improve the prediction of schizophrenia in subjects at high risk. BMC Med 4: 29

    PubMed  Google Scholar 

  • Kabiersch A, Furukawa H, del RA, Besedovsky HO (1998) Administration of interleukin-1 at birth affects dopaminergic neurons in adult mice. Ann N Y Acad Sci 840: 123–127

    PubMed  CAS  Google Scholar 

  • Kaiya H, Uematsu M, Ofuji M, Nishida A, Takeuchi K, Nozaki M, et al. (1989) Elevated plasma prostaglandin E2 levels in schizophrenia. J Neural Transm 77: 39–46

    PubMed  CAS  Google Scholar 

  • Kegeles LS, bi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, et al. (2000) Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 48: 627–640

    PubMed  CAS  Google Scholar 

  • Kessler M, Terramani T, Lynch G, Baudry M (1989) A glycine site associated with N-methyld- aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 52: 1319–1328

    PubMed  CAS  Google Scholar 

  • Kilidireas K, Latov N, Strauss DH, Gorig AD, Hashim GA, Gorman JM, et al. (1992) Antibodies to the human 60 kDa heat-shock protein in patients with schizophrenia. Lancet 340: 569–572

    PubMed  CAS  Google Scholar 

  • Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmuller B (1980) Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett 20: 379–382

    PubMed  CAS  Google Scholar 

  • Kim YK, Suh IB, Kim H, Han CS, Lim CS, Choi SH, et al. (2002) The plasma levels of interleukin- 12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 7: 1107–1114

    PubMed  CAS  Google Scholar 

  • Kiss C, Ceresoli-Borroni G, Guidetti P, Zielke CL, Zielke HR, Schwarcz R (2003) Kynurenate production by cultured human astrocytes. J Neural Transm 110: 1–14

    PubMed  CAS  Google Scholar 

  • Koponen H, Rantakallio P, Veijola J, Jones P, Jokelainen J, Isohanni M (2004) Childhood central nervous system infections and risk for schizophrenia. Eur Arch Psychiatry Clin Neurosci 254: 9–13

    PubMed  Google Scholar 

  • Körschenhausen DA, Hampel HJ, Ackenheil M, Penning R, Müller N (1996) Fibrin degradation products in post mortem brain tissue of schizophrenics: a possible marker for underlying inflammatory processes. Schizophr Res 19: 103–109

    PubMed  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51: 199–214

    PubMed  CAS  Google Scholar 

  • Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, et al. (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93: 9235–9240

    PubMed  CAS  Google Scholar 

  • Laruelle M, Frankle WG, Narendran R, Kegeles LS, bi-Dargham A (2005) Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther 27(Suppl A): S16–S24

    PubMed  CAS  Google Scholar 

  • Laumbacher B, Müller N, Bondy B, Schlesinger B, Gu S, Fellerhoff B, et al. (2003) Significant frequency deviation of the class I polymorphism HLA-A10 in schizophrenic patients. J Med Genet 40: 217–219

    PubMed  CAS  Google Scholar 

  • Leweke FM, Gerth CW, Koethe D, Klosterkotter J, Ruslanova I, Krivogorsky B, et al. (2004) Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 254: 4–8

    PubMed  Google Scholar 

  • Litherland SA, Xie XT, Hutson AD, Wasserfall C, Whittaker DS, She JX, et al. (1999) Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulindependent diabetes mellitus. J Clin Invest 104: 515–523

    PubMed  CAS  Google Scholar 

  • Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY (1997) In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 26: 221–225

    PubMed  CAS  Google Scholar 

  • Marshall BE, Longnecker DE (1990) General anesthetics. In: Goodman LS, Gilman A, Rall TW, et al., eds. The pharmacological basis of therapeutics. Elmsford, NY: Pergamon Press 285–310

    Google Scholar 

  • Meira-Lima IV, Pereira AC, Mota GF, Floriano M, Araujo F, Mansur AJ, et al. (2003) Analysis of a polymorphism in the promoter region of the tumor necrosis factor alpha gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia. Mol Psychiatry 8: 718–720

    PubMed  CAS  Google Scholar 

  • Miller DW, Abercrombie ED (1996) Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats. Brain Res Bull 40: 57–62

    PubMed  CAS  Google Scholar 

  • Miller CL, Llenos IC, Dulay JR, Barillo MM, Yolken RH, Weis S (2004) Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis 15: 618–629

    PubMed  CAS  Google Scholar 

  • Miller CL, Llenos IC, Dulay JR, Weis S (2006) Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res 1073–1074: 25–37

    PubMed  Google Scholar 

  • Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/ Th2 paradigm. J Immunol 164: 6166–6173

    PubMed  CAS  Google Scholar 

  • Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM (1997) Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 159: 2994–2999

    PubMed  CAS  Google Scholar 

  • Molholm HB (1942) Hyposensitivity to foreign protein in schizophrenic patients. Psychiatr Quarterly 16: 565–571

    Google Scholar 

  • Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R (1991) Cellular immunity in schizophrenic patients before and during neuroleptic treatment. Psychiatry Res 37: 147–160

    PubMed  Google Scholar 

  • Müller N, Ackenheil M (1995) Immunoglobulin and albumin content of cerebrospinal fluid in schizophrenic patients: relationship to negative symptomatology. Schizophr Res 14: 223–228

    PubMed  Google Scholar 

  • Müller N, Empl M, Riedel M, Schwarz M, Ackenheil M (1997a) Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin Neurosci 247: 308–313

    Google Scholar 

  • Müller N, Riedel M, Schwarz MJ, et al. (1997b) Immunomodulatory effects of neuroleptics to the cytokine system and the cellular immune system in schizophrenia. In: Wieselmann G, ed. Current Update in Psychoimmunology. Wien, NY: Springer 57–67

    Google Scholar 

  • Müller N, Ackenheil M (1998) Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 22: 1–33

    PubMed  Google Scholar 

  • Müller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R (1999) Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia. Am J Psychiatry 156: 634–636

    PubMed  Google Scholar 

  • Müller N, Riedel M, Ackenheil M, Schwarz MJ (2000) Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry 1: 173–179

    PubMed  Google Scholar 

  • Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, et al. (2002) Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 159: 1029–1034

    PubMed  Google Scholar 

  • Müller N (2004a) Immunological and infectious aspects of schizophrenia. Eur Arch Psychiatry Clin Neurosci 254: 1–3

    Google Scholar 

  • Müller N, Riedel M, Schwarz MJ (2004b) Psychotropic effects of COX-2 inhibitors – a possible new approach for the treatment of psychiatric disorders. Pharmacopsychiatry 37: 266–269

    Google Scholar 

  • Müller N, Ulmschneider M, Scheppach C, Schwarz MJ, Ackenheil M, Möller HJ, et al. (2004c) COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci 254: 14–22

    Google Scholar 

  • Müller N, Riedel M, Schwarz MJ, Engel RR (2005) Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 255: 149–151

    PubMed  Google Scholar 

  • Murray RM, Lewis SW (1987) Is schizophrenia a neurodevelopmental disorder? Br Med J (Clin Res Ed) 295: 681–682

    CAS  Google Scholar 

  • Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata N, et al. (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13: 2699–2708

    PubMed  CAS  Google Scholar 

  • Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52: 998–1007

    PubMed  CAS  Google Scholar 

  • Ozek M, Toreci K, Akkok I, Guvener Z (1971) Influence of therapy on antibody-formation. Psychopharmacologia 21: 401–412

    PubMed  CAS  Google Scholar 

  • Pearce BD (2001) Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms. Mol Psychiatry 6: 634–646

    PubMed  CAS  Google Scholar 

  • Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, et al. (2006) First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 11: 118–119

    PubMed  CAS  Google Scholar 

  • Pyeon D, Diaz FJ, Splitter GA (2000) Prostaglandin E(2) increases bovine leukemia virus tax and pol mRNA levels via cyclooxygenase 2: regulation by interleukin-2, interleukin-10, and bovine leukemia virus. J Virol 74: 5740–5745

    PubMed  CAS  Google Scholar 

  • Rapaport MH, Müller N (2001) Immunological states associated with schizophrenia. In: Ader A, Felten DL, Cohnen N, eds. Psychoneuroimmunology, vol 2, 3rd ed. San Diego, CA: Academic Press 373–382

    Google Scholar 

  • Riedel M, Krönig H, Schwarz MJ, Engel RR, Kuhn KU, Sikorski C, et al. (2002) No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia. Eur Arch Psychiatry Clin Neurosci 252: 232–234

    PubMed  Google Scholar 

  • Riedel M, Spellmann I, Schwarz MJ, Strassnig M, Sikorski C, Möller HJ, et al. (2007) Decreased T cellular immune response in schizophrenic patients. J Psychiatr Res 41:3–7

    PubMed  Google Scholar 

  • Rothermundt M, Arolt V, Bayer TA (2001) Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun 15: 319–339

    PubMed  CAS  Google Scholar 

  • Rothermundt M, Falkai P, Ponath G, Abel S, Burkle H, Diedrich M, et al. (2004a) Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF. Mol Psychiatry 9: 897–899

    CAS  Google Scholar 

  • Rothermundt M, Ponath G, Arolt V (2004b) S100B in schizophrenic psychosis. Int Rev Neurobiol 59: 445–470

    CAS  Google Scholar 

  • Schuld A, Hinze-Selch D, Pollmacher T (2004) Zytokinnetzwerke bei Patienten mit Schizophrenie und ihre Bedeutung für die Pathophysiologie der Erkrankung [Cytokine network in patients with schizophrenia and its significance for the pathophysiology of the illness]. Nervenarzt 75: 215–226

    PubMed  CAS  Google Scholar 

  • Schwab SG, Hallmayer J, Albus M, Lerer B, Eckstein GN, Borrmann M, et al. (2000) A genomewide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6. Mol Psychiatry 5: 638–649

    PubMed  CAS  Google Scholar 

  • Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50: 521–530

    PubMed  CAS  Google Scholar 

  • Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303: 1–10

    PubMed  CAS  Google Scholar 

  • Schwarz MJ, Riedel M, Gruber R, Ackenheil M, Müller N (1999) Antibodies to heat shock proteins in schizophrenic patients: implications for the mechanism of the disease. Am J Psychiatry 156: 1103–1104

    PubMed  CAS  Google Scholar 

  • Schwarz MJ, Riedel M, Ackenheil M, Müller N (2000) Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. Biol Psychiatry 47: 29–33

    PubMed  CAS  Google Scholar 

  • Schwarz MJ, Chiang S, Müller N, Ackenheil M (2001) T-helper-1 and T-helper-2 responses in psychiatric disorders. Brain Behav Immun 15: 340–370

    PubMed  CAS  Google Scholar 

  • Schwarz MJ, Kronig H, Riedel M, Dehning S, Douhet A, Spellmann I, et al. (2005) IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia. Eur Arch Psychiatry Clin Neurosci 256(2): 72–76

    PubMed  Google Scholar 

  • Schwieler L, Engberg G, Erhardt S (2004) Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex. Synapse 52: 114–122

    PubMed  CAS  Google Scholar 

  • Schwieler L, Erhardt S, Erhardt C, Engberg G (2005) Prostaglandin-mediated control of rat brain kynurenic acid synthesis – opposite actions by COX-1 and COX-2 isoforms. J Neural Transm 112: 863–872

    PubMed  CAS  Google Scholar 

  • Speciale C, Schwarcz R (1993) On the production and disposition of quinolinic acid in rat brain and liver slices. J Neurochem 60: 212–218

    PubMed  CAS  Google Scholar 

  • Speciale C, Wu HQ, Cini M, Marconi M, Varasi M, Schwarcz R (1996) (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur J Pharmacol 315: 263–267

    PubMed  CAS  Google Scholar 

  • Sperner-Unterweger B, Miller C, Holzner B, et al. (1999) Measurement of neopterin, kynurenine and tryptophan in sera of schizophrenic patients. In: Müller N, ed. Psychiatry, Psychoimmunology, and Viruses. Wien, NY: Springer 115–119

    Google Scholar 

  • Stolina M, Sharma S, Lin Y, Dohadwala M, Gardner B, Luo J, et al. (2000) Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164: 361–370

    PubMed  CAS  Google Scholar 

  • Stone TW (1993) Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 45: 309–379

    PubMed  CAS  Google Scholar 

  • Stoy N, Mackay GM, Forrest CM, Christofides J, Egerton M, Stone TW, et al. (2005) Tryptophan metabolism and oxidative stress in patients with Huntington’s disease. J Neurochem 93: 611–623

    PubMed  CAS  Google Scholar 

  • Sumiyoshi T, Anil AE, Jin D, Jayathilake K, Lee M, Meltzer HY (2004) Plasma glycine and serine levels in schizophrenia compared to normal controls and major depression: relation to negative symptoms. Int J Neuropsychopharmacol 7: 1–8

    PubMed  CAS  Google Scholar 

  • Sumiyoshi T, Jin D, Jayathilake K, Lee M, Meltzer HY (2005) Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia. Int J Neuropsychopharmacol 8: 451–455

    PubMed  CAS  Google Scholar 

  • Takikawa O, Yoshida R, Kido R, Hayaishi O (1986) Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem 261: 3648–3653

    PubMed  CAS  Google Scholar 

  • Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, et al. (2004) Dysbindin- 1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 113: 1353–1363

    PubMed  CAS  Google Scholar 

  • Tamminga CA, Cascella N, Fakouhl TD, et al. (1992) Enhancement of NMDA-mediated transmission in schizophrenia: effects of milacemide. In: Meltzer HY, ed. Novel Antipsychotic Drugs. New York: Raven Press 171–177

    Google Scholar 

  • Tanaka KF, Shintani F, Fujii Y, Yagi G, Asai M (2000) Serum interleukin-18 levels are elevated in schizophrenia. Psychiatry Res 96: 75–80

    PubMed  CAS  Google Scholar 

  • Torrey EF, Miller J, Rawlings R, Yolken RH (1997) Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 28: 1–38

    PubMed  CAS  Google Scholar 

  • van Kammen DP, McAllister-Sistilli CG, Kelley ME (1997) Relationship between immune and behavioral measures in schizophrenia. In: Wieselmann G, ed. Current Update in Psychoimmunology. Wien, NY: Springer 51–55

    Google Scholar 

  • Westergaard T, Mortensen PB, Pedersen CB, Wohlfahrt J, Melbye M (1999) Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence. Arch Gen Psychiatry 56: 993–998

    PubMed  CAS  Google Scholar 

  • Wilke I, Arolt V, Rothermundt M, Weitzsch C, Hornberg M, Kirchner H (1996) Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 246: 279–284

    PubMed  CAS  Google Scholar 

  • Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S, et al. (2003) Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 8: 485–487

    PubMed  CAS  Google Scholar 

  • Wu HQ, Rassoulpour A, Schwarcz R (2007) Kynurenic acid leads, dopamine follows: a new case of volume transmission in the brain? J Neural Transm 114:33–41

    PubMed  Google Scholar 

  • Xiao BG, Link H (1999) Is there a balance between microglia and astrocytes in regulating Th1/ Th2-cell responses and neuropathologies? Immunol Today 20: 477–479

    PubMed  CAS  Google Scholar 

  • Yokota O, Terada S, Ishihara T, Nakashima H, Kugo A, Ujike H, et al. (2004) Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28: 715–721

    PubMed  CAS  Google Scholar 

  • Yolken RH, Torrey EF (1995) Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 8: 131–145

    PubMed  CAS  Google Scholar 

  • Zuckerman L, Weiner I (2005) Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res 39: 311–323

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Hospital for Psychiatry and Psychotherapy, Nussbaumstrasse 7, D-80336 Munich, Germany

    Norbert Müller

Authors
  1. Norbert Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus J. Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Departments of Neurology and Neuroscience and Psychiatry, University of Medicine and Dentistry of New Jersey — NJ Medical School, Newark, NJ 07103, USA

    Allan Siegel

  2. University of Medicine and Dentistry of New Jersey — NJ Medical School, Newark, NJ 07103, USA

    Steven S. Zalcman

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Müller, N., Schwarz, M.J. (2009). Cytokines, Immunity and Schizophrenia with Emphasis on Underlying Neurochemical Mechanisms. In: Siegel, A., Zalcman, S.S. (eds) The Neuroimmunological Basis of Behavior and Mental Disorders. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-84851-8_15

Download citation

Publish with us

Policies and ethics

Search

Navigation