Neurotoxicity Research

, Volume 10, Issue 2, pp 131–148

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Article

Abstract

This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulinand dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by theN-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor,i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO — located in astrocytes and microglial cells — is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences,e.g., the use of antiinflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

Keywords

Schizophrenia Inflammation Astrocytes Microglia Cyclo-oxygenase-2 inhibitors Type 1 immune response Type 2 immune response Kynurenic acid Indoleamine dioxygenase Tryptophan dioxygenase Glutamate Dopamine NMDA 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adler LE, A Olincy, M Waldo, JG Harris, J Griffith and K Stevens (1998) Schizophrenia, sensory gating, and nicotinic receptors.Schizophr. Bull. 24, 189–202.PubMedGoogle Scholar
  2. Aloisi F, G Penna, J Cerase, B Menendez Iglesias and L Adorini (1997) IL-12 production by central nervous system microglia is inhibited by astrocytes.J. Immunol. 159, 1604–1612.PubMedGoogle Scholar
  3. Aloisi F, F Ria and L Adorini (2000) Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes.Immunol. Today 21, 141–147.PubMedCrossRefGoogle Scholar
  4. Andreasen NC, K Kezai, R Alliger, VW Swayze II, M Flaum, P Kirchneret al., (1992) Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia.Arch. Gen. Psychiatry 49, 943–958.PubMedGoogle Scholar
  5. Ashdown H, Y Dumont, M Ng, S Poole, P Boksa and GN Luheshi (2006) The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia.Mol. Psychiatry 11, 47–55.PubMedCrossRefGoogle Scholar
  6. Banks WA, AJ Kastin and EG Gutierrez (1993) Interleukin-1α has direct access to cortical brain cells.Neurosci. Lett. 163, 41–44.PubMedCrossRefGoogle Scholar
  7. Bayer TA, R Buslei, L Havas and P Falkai (1999) Evidence for activation of microglia in patients with psychiatric illnesses.Neurosci. Lett. 27, 126–128.CrossRefGoogle Scholar
  8. Bechter K, V Schreiner, S Herzog, N Breitinger, KH Wollinsky, H Brinkmeier, P Aulkemeyer, F Weber and R Schuttler (2003) CSF filtration as experimental therapy in therapy-resistant psychoses in Borna disease virus-seropositive patients.Psychiatr. Prax. 30 (Suppl. 2), 216–220.PubMedGoogle Scholar
  9. Bessler H, Z Levental, L Karp, I Modai, M Djaldetti and A Weizman (1995) Cytokine production in drug-free and neuroleptic-treated schizophrenic patients.Biol. Psychiatry 38, 297–302.PubMedCrossRefGoogle Scholar
  10. Blackwell JM (2001) Genetics and genomics of infectious disease susceptibility.TIMM 7, 521–526.Google Scholar
  11. BleulerE (1911) Dementia praecox oder Gruppe der Schizophrenien, In:Handbuch der Psychiatrie (Aschaffenburg G, Ed.) (Deuticke: Leipzig, Wien).Google Scholar
  12. BoinF, R Zanardini, R Pioli, CA Altamura, M Maes and M Gennarelli (2001) Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia.Mol. Psychiatry 6, 79–82.PubMedCrossRefGoogle Scholar
  13. Brown AS, MD Begg, S Gravenstein, CA Schaefer, RJ Wyatt, M Bresnahan, VP Babulas and ES Susser (2004) Serologic evidence of prenatal influenza in the etiology of schizophrenia.Arch. Gen. Psychiatry 61, 774–780.PubMedCrossRefGoogle Scholar
  14. Buka SL, MT Tsuang, EF Torrey, MA Klebanoff, D Berstein and RH Yolken (2001) Maternal infections and subsequent psychosis in the offspring.Arch. Gen. Psychiatry 58, 1032–1037.PubMedCrossRefGoogle Scholar
  15. Buonanno A and GD Fischbach (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system.Curr. Opin. Neurobiol. 11(3), 287–296.PubMedCrossRefGoogle Scholar
  16. Cannon M, D Cotter, VP Coffey, PC Sham, N Takei, C Larkin, RM Murray and E O’Callaghan (1996) Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study.Br. J. Psychiatry 168, 368–371.PubMedCrossRefGoogle Scholar
  17. Cannon TD, TG van Erp, IM Rosso, M Huttunen, J Lonnqvist, T Pirkola, O Salonen, L Valanne, VP Poutanen and CG Standertskjold-Nordenstam (2002) Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls.Arch. Gen. Psychiatry 59(1), 35–41.PubMedCrossRefGoogle Scholar
  18. Cardno AG, EJ Marshall, B Coid, AM Macdonald, TR Ribchester, NJ Davies, P Venturi, LA Jones, SW Lewis, PC Sham, II Gottesman, AE Farmer, P McGuffin, AM Reveley and RM Murray (1999) Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.Arch. Gen. Psychiatry 56, 162–168.PubMedCrossRefGoogle Scholar
  19. Carlin JM, EC Borden, PM Sondel and GI Byrne (1989) Interferon-induced indoleamine 2,3-dioxygenase activity in human mono-nuclear phagocytes.J. Leukoc. Biol. 45, 29–34.PubMedGoogle Scholar
  20. Carlsson A (1978) Antipsychotic drugs, neurotransmitters, and schizophrenia.Am. J. Psychiatry 135, 165–173.PubMedGoogle Scholar
  21. Carlsson A (1988) The current status of the dopamine hypothesis of schizophrenia.Neuropsychopharmacol. 1, 179–186.CrossRefGoogle Scholar
  22. Carlsson A (1998) Schizophrenie und Neurotransmitterstöru ngen. Neue Perspektiven und therapeutischen Ansätze, In:Schizophrenie — Moderne Konzepte zu Diagnostik, Pathogenese und Therapie (Möller H-J and N Müller, Eds.) (Springer Verlag: Wien, NY),pp 93–116.Google Scholar
  23. Carlsson A, N Waters, S Holm-Waters, J Tedroff Jr, M Nilsson and ML Carlsson (2001) Interactions between monoamines, glutamate and GABA in schizophrenia: new evidence.Annu. Rev. Pharmacol. Toxicol. 41, 237–260.PubMedCrossRefGoogle Scholar
  24. Casolini P, A Catalani, AR Zuena and L Angelucci (2002) Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioural impairments in the rat.J. Neurosci. Res. 68, 337–343.PubMedCrossRefGoogle Scholar
  25. Cazzullo CL, S Scarone, B Grassi, C Vismara, D Trabattoni and M Clerici (1998) Cytokines production in chronic schizophrenia patients with or without paranoid behavior.Prog. Neuro-Psychopharmacol. Biol. Psychiatry 22, 947–957.CrossRefGoogle Scholar
  26. Ceresoli-Borroni G, HQ Wu, P Guidetti, A Rassoulpour, AC Roberts and R Schwarcz (1999) Chronic haloperidole administration decreases kynurenic acid levels in rat brain.Soc. Neurosci. Abstr. 25, 7278.Google Scholar
  27. Ceresoli-Borroni G, A Rassoulpour, HQ Wu, P Guidetti and R Schwarcz (2006) Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain.J. Neural Transm. E-pub, February 9.Google Scholar
  28. Chiarugi A, R Carpenedo and F Moroni (1996) Kynurenine disposition in blood and brain of mice: effects of selective inhibitors of kynurenine hydroxylase and kynureninase.J. Neurochem. 67, 692–698.PubMedGoogle Scholar
  29. Clunie M, LA Crone, L Klassen and R Yip (2003) Psychiatric side effects of indomethacin in parturients.Can. J. Anaesth. 50, 586–588.PubMedGoogle Scholar
  30. Collier DA and T Li (2003) The genetics of schizophrenia: glutamate not dopamine.Eur. J. Pharmacol. 480, 177–184.PubMedCrossRefGoogle Scholar
  31. Cook GS and AV Hill (2001) Genetics of susceptibility to human infectious disease.Nat. Rev. Genetics 2, 967–977.CrossRefGoogle Scholar
  32. Cornblatt BI, M Obuchowski, S Roberts, S Pollack and E Erlenmeyer-Kimling (1999) Cognitive and behavioural precursors of schizophrenia.Dev. Psychopathol. 11, 487–508.PubMedCrossRefGoogle Scholar
  33. Das I and NS Khan (1998) Increased arachidonic acid induced platelet chemoluminiscence indicates cyclooxygenase overactivity in schizophrenic subjects.Prostaglandins, Leukot. Essent. Fatty Acids 58, 165–168.CrossRefGoogle Scholar
  34. Dean K and RM Murray (2005) Environmental risk factors for psychosis.Dialogues Clin. Neurosci. 7, 69–80.PubMedGoogle Scholar
  35. DeLisi LE, S Goodman, LM Neckers and RJ Wyatt (1982) An analysis of lymphocyte subpopulations in schizophrenic patients.Biol. Psychiatry 17, 1003–1009.PubMedGoogle Scholar
  36. Erhardt S and G Engberg (2002) Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid.Acta Physiol. Scand. 175(1), 45–53.PubMedCrossRefGoogle Scholar
  37. Erhardt S K Blennow, C Nordin, E Skogh, LH Lindstrom and G Engberg (2001a) Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia.Neurosci. Lett. 313, 96–98.PubMedCrossRefGoogle Scholar
  38. Erhardt S, H Oberg, JM Mathe and G Engberg (2001b) Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons.Amino Acids 20(4), 353–362.PubMedCrossRefGoogle Scholar
  39. Erhardt S, L Schwieler and G Engberg (2003) Kynurenic acid and schizophrenia.Adv. Exp. Med. Biol. 527, 155–165.PubMedGoogle Scholar
  40. Espey MG, ON Chernyshev, JJ Reinhard, MA Namboodiri and CA Colton (1997) Activated human microglia produce the excitotoxin quinolinic acid.Neuroreport 8, 431–434.PubMedCrossRefGoogle Scholar
  41. Farber NB, DF Wozniak, MT Price, J Labruyere, J Huss, H St Peter and JW Olney (1995) Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia?Biol. Psychiatry 38(12), 788–796.PubMedCrossRefGoogle Scholar
  42. Fearon P, P Cotter and RM Murray (2000) Is the association between obstretic complications and schizophrenia mediated by glutaminergic excitotoxic damage of the foetal/neonatal brain? In:Psychopharmacology of Schizophrenia (Revely M and B Deacon, Eds.) (Chapman and Hall:London), pp 21–40.Google Scholar
  43. Fortier M-E, R Joober, GN Luheshi and P Boksa (2004) Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring.J. Psychiatr. Res. 38, 335–345.PubMedCrossRefGoogle Scholar
  44. Frommberger UH, J Bauer, P Haselbauer, A Fraulin, D Riemann and M Berger (1997) Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission.Eur. Arch. Psychiatry Clin. Neurosci. 247, 228–233.PubMedCrossRefGoogle Scholar
  45. Furukawa H, A del Rey, G Monge-Arditi and HO Besedovsky (1998) Interleukin-1, but not stress, stimulates glucocorticoid output during early postnatal life in mice. Ann.NY Acad. Sci. 840, 117–122.CrossRefGoogle Scholar
  46. Gal EM (1974) Cerebral tryptophan-2,3-dioxygenase (pyrrolase) and its induction in rat brain.J. Neurochem. 22, 861–863.PubMedCrossRefGoogle Scholar
  47. Ganguli R, BS Rabin, RH Kelly, M Lyte and U Ragu (1987) Clinical and laboratory evidence of autoimmunity in acute schizophrenia.Ann. NY Acad. Sci. 496, 676–685.PubMedCrossRefGoogle Scholar
  48. Ganguli R, Z Yang, G Shurin, R Chengappa, JS Brar, AV Gubbi and BS Rabin (1994) Serum interleukin-6 concentration in schizophrenia: elevation associated with duration of illness.Psychiatry Res. 51, 1–10.PubMedCrossRefGoogle Scholar
  49. Ganguli R, JS Brar, KR Chengappa, M DeLeo, ZW Yang, G Shurin and B Rabin (1995) Mitogen-stimulated interleukin 2 production in never-medicated, first episode schizophrenics — the influence of age of onset and negative symptoms.Arch. Gen. Psychiatry 52, 668–672.PubMedGoogle Scholar
  50. Gattaz WF, AL Abrahao and R Foccacia (2004) Childhood meningitis, brain maturation and the risk of psychosis.Eur. Arch. Psychiatry Clin. Neurosci. 254, 9–13.CrossRefGoogle Scholar
  51. Gholson RK, LV Hankes and LM Henderson (1960) 3- Hydroxyanthranilic acid as an intermediate in the oxidation of the indole nucleus of tryptophan.J. Biol. Chem. 235, 132–135.PubMedGoogle Scholar
  52. Green MF and KH Nuechterlein (1999) Should schizophrenia be treated as a neurocognitive disorder?Schizophr. Bull. 25, 309–319.PubMedGoogle Scholar
  53. Grishin AA, P Bequet and U Gerber (2005) Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase.Neuropharmacology 49, 328–337.PubMedCrossRefGoogle Scholar
  54. Grohmann U, F Fallarino and P Puccetti (2003) Tolerance, DCs and tryptophan: much ado about IDO.Trends Immunol. 24, 242–248.PubMedCrossRefGoogle Scholar
  55. Grosskopf A, N Müller, A Malo and R Wank (1998) Potential role for the narcolepsy- and multiple sclerosis-associated allele DQB1*0602 in schizophrenia subtypes.Schizophr. Res. 30, 187–189.PubMedCrossRefGoogle Scholar
  56. Grotta J (1994) Safety and tolerability of the glutamate receptor antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke.Stroke 26, 602–605.Google Scholar
  57. Guillemin GJ, SJ Kerr, GA Smythe, DG Smith, V Kapoor, PJ Armati, J Croitoru and BJ Brew (2003) Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection.J. Neural Transm. 110, 1–14.Google Scholar
  58. Haack M, D Hinze-Selch, T Fenzel, T Kraus, M Kuhn, A Schuld and T Pollmacher (1999) Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.J. Psychiatr. Res. 33, 407–418.PubMedCrossRefGoogle Scholar
  59. Haber R, D Bessette, B Hulihan-Giblin, MJ Durcan and D Goldman (1993) Identification of tryptophan-2,3-dioxygenase RNA in rodent brain.J. Neurochem. 60, 1159–1162.PubMedCrossRefGoogle Scholar
  60. Harris SG, J Padilla, L Koumas, D Ray and RP Phipps (2002) Prostaglandins as modulators of immunity.Trends Immunol. 23, 144–150.PubMedCrossRefGoogle Scholar
  61. Harrison PJ and DR Weinberger (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.Mol. Psychiatry 10, 40–68.PubMedCrossRefGoogle Scholar
  62. Hashimoto PH (1991) Aspects of normal cerebrospinal fluid circulation and circumventricular organs.Prog. Brain Res. 91, 439–443.CrossRefGoogle Scholar
  63. Heresco-Levy U (2003) Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality.Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 1113–1123.PubMedCrossRefGoogle Scholar
  64. Heresco-Levy U, DC Javitt, M Ermilov, C Mordel, G Silipo and M Lichtenstein (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.Arch. Gen. Psychiatry 56, 29–36.PubMedCrossRefGoogle Scholar
  65. Herrling PL (1994) D-CPPene (SDZ EAA 494), a competitive NMDA receptor antagonist: results from animal models and first results in humans.Neuropsychopharmacol. 10 (3S) 591S.Google Scholar
  66. Heyes MP, CL Achim, CA Wiley, EO Major, K Saito and SP Markey (1996) Human microglia convert L-tryptophan into the neurotoxin quinolinic acid.Biochem. J. 320, 595–597.PubMedGoogle Scholar
  67. Heyes MP, CY Chen, EO Major and K Saito (1997a) Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types.Biochem. J. 326, 351–356.PubMedGoogle Scholar
  68. Heyes MP, K Saito, CY Chen, MG Proescholdt, TS Nowak, J Li, KE Beagles, MA Proescholdt, MA Zito, K Kawai and SP Markey (1997b) Species heterogeneity between gerbils and rats: quino-linate production by microglia and astrocytes and accumulations in response to ischemic brain injury and systemic immune activation.J. Neurochem. 69, 1519–1529.PubMedCrossRefGoogle Scholar
  69. Hilkens CM, A Snijders, FG Snijdewint, EA Wierenga and ML Kapsenberg (1996) Modulation of T-cell cytokine secretion by accessory cell-derived products.Eur. Respir. J. Suppl.22, 90s-94s.Google Scholar
  70. Hill AV (1999) Genetics of infectious disease resistance.Curr. Opin. Genet. Dev. 6, 348–353.CrossRefGoogle Scholar
  71. Hilmas C, EF Pereira, M Alkondon, A Rassoulpour, R Schwarcz and EX Albuquerque (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.PubMedGoogle Scholar
  72. Hinson RM, JA Williams and E Shacter (1996) Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.Proc. Natl. Acad. Sci. USA 93, 4885–4890.PubMedCrossRefGoogle Scholar
  73. Hornberg M, V Arolt, I Wilke, A Kruse and H Kirchner (1995) Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia.Schizophr. Res. 15, 237–242.PubMedCrossRefGoogle Scholar
  74. Huber G (1983) Das Konzept substratnaher Basissymptome und seine Bedeutung für Theorie und Therapie schizophrener Erkrankungen.Nervenarzt. 54, 23–32.PubMedGoogle Scholar
  75. Hyde TM and JM Crook (2001) Cholinergic systems and schizophrenia: primary pathology or epiphenomena?J. Chem. Neuroanat. 22, 53–63.PubMedCrossRefGoogle Scholar
  76. Jablensky A (2000) Epidemiology of schizophrenia: the global burden of disease and disability.Eur. Arch. Psychiatry Clin. Neurosci. 250, 274–285.PubMedCrossRefGoogle Scholar
  77. Jentsch JD and RH Roth (1999) The neuropharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.Neuropsychopharmacology 20, 201–224.PubMedCrossRefGoogle Scholar
  78. KabierschA, H Furukawa, A del Rey and HO Besedovsky (1998) Administration of interleukin-1 at birth affects dopaminergic neurons in adult mice. Ann.NY Acad. Sci. 840, 123–127.CrossRefGoogle Scholar
  79. Kaiya H, M Uematsu, M Ofuji, A Nishida, K Takeuchi, M Nozaki and E Idaka (1989) Elevated plasma prostaglandin E2 levels in schizophrenia.J. Neural Transm. 77, 39–46.PubMedCrossRefGoogle Scholar
  80. Kallmann FJ and D Reisner (1943) Twin studies on the genetic variation in resistance to tuberculosis.J. Heredity 34.Google Scholar
  81. Kilidireas K, N Latov, DH Strauss, DG Aviva, GA Hashim, JM Gorman and SA Sadiq (1992) Antibodies to human 60 KD hear-shock protein in patients with schizophrenia.Lancet 340, 569–572.PubMedCrossRefGoogle Scholar
  82. Kim JS, HH Kornhuber, W Schmid-Burgk and B Holzmuller (1980) Low cerebrospinal fluid glutamate in schizophrenia patients and a new hypothesis of glutamatergic neuronal dysfunction.Neurosci. Lett. 20, 379–382.PubMedCrossRefGoogle Scholar
  83. Kiss C, G Ceresoli-Borroni, P Guidetti, CL Zielke, HR Zielke and R Schwarcz (2003) Kynurenate production by cultured human astrocytes.J. Neural Transm. 110, 1–14.PubMedGoogle Scholar
  84. Koponen H, P Rantakallio, J Veijola, P Jones, J Jokelainen and M Isohanni (2004) Childhood central nervous system infections and risk for schizophrenia.Eur. Arch. Psychiatry Clin. Neurosci. 254, 9–13.PubMedCrossRefGoogle Scholar
  85. Kornhuber J, J Wiltfang and S Bleich (2004) The etiopathogenesis of schizophrenia.Pharmacopsychiatr. 37 Suppl. 2, S103-S112.CrossRefGoogle Scholar
  86. Körschenhausen D, H Hampel, M Ackenheil, R Penning and N Müller (1996) Fibrin degradation products in post mortem brain tissue of schizophrenics: a possible marker for underlying inflammatory processes.Schizophr. Res. 19, 103–109.PubMedCrossRefGoogle Scholar
  87. Kotake Y and T Masayama (1937) Über den Mechanismus der Kynurein-Bildung aus Tryptophan.Hoppe-Seyler’s Z. Physiol. Chem. 243, 237–244.Google Scholar
  88. Kraepelin E(1899) Psychiatrie.Ein Lehrbuch für Studierende und Ärzte, Vol. 6 (Barth:Leipzig).Google Scholar
  89. Kristensen JD, B Svensson and T Gordh (1992) The NMDA receptor antagonist CPP abolishes neurogenig ‘wind-up’ after intrathecal administration in humans.Pain 51, 249–253.PubMedCrossRefGoogle Scholar
  90. Krönig H, M Riedel, MJ Schwarz, M Strassnig, HJ Möller, M Ackenheil and N Müller (2005) ICAM G241A polymorphism and soluble ICAM-1 serum levels — evidence for an active immune process in schizophrenia.Neuroimmunomodulation 12, 54–59.PubMedCrossRefGoogle Scholar
  91. Krystal JH, LP Karper, JP Seibyl, R Delaney, JD Bremner, MB Bowers Jr, DS Charney (1993) Dose related effects of the NMDA antagonist, ketamine, in healthy humans.Schizophr. Res. 9, 240–241.CrossRefGoogle Scholar
  92. Krystal JH, LP Karper, JP Seibyl, GK Freeman, R Delaney, JD Bremner, GR Heninger, MB Bowers Jr and DS Charney (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.Arch. Gen. Psychiatry 51(3), 199–214.PubMedGoogle Scholar
  93. Kuhlman P, VT Moy, BA Lollo and AA Brian (1991) The accessory function of murine intercellular adhesion molecule-1 in T-lymphocyte activation: contribution of adhesion and co-activation. J.Immunol. 146, 1773–1782.Google Scholar
  94. Laruelle M, A Abi-Dargham, CH van Dyck, R Gil, CD D’Souza, J Erdos, E McCance, W Rosenblatt, C Fingado, SS Zoghbi, RM Baldwin, JP Seibyl, JH Krystal, DS Charney and RB Innis (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.Proc. Natl. Acad. Sci. USA 93, 9235–9240.PubMedCrossRefGoogle Scholar
  95. Laumbacher B, N Müller, B Bondy, B Schlesinger, S Gu, B Fellerhoff and R Wank (2003) Significant frequency deviation of the class I polymorphism HLA-A10 in schizophrenic patients.J. Med. Genet. 40, 217–219.PubMedCrossRefGoogle Scholar
  96. Leiderman E, I Zylberman, SR Zukin, TB Cooper and DC Javitt (1996) Preliminary investigation of high-dose oral glycine on serum levels and negative symptoms in schizophrenia: an open-label trial.Biol. Psychiatry 39, 213–215.PubMedCrossRefGoogle Scholar
  97. Leweke FM, CW Gerth, D Koethe, J Klosterkotter, I Ruslanova, B Krivogorsky, EF Torrey and RH Yolken (2004) Antibodies to infectious agents in individuals with recent onset schizophrenia.Eur. Arch. Psychiatry Clin. Neurosci. 254, 4–8.PubMedCrossRefGoogle Scholar
  98. Lin A, G Kenis, S Bignotti, GJB Tura, R De Jong, E Bosmans, R Pioli, C Altamura, S Scharpé and M Maes (1998) The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6.Schizophr. Res. 32, 9–15.PubMedCrossRefGoogle Scholar
  99. Litherland SA, XT Xie, AD Hutson, C Wasserfall, DS Whittaker, JX She, A Hofig, MA Dennis, K Fuller, R Cook, D Schztz, LL Moldawer and MJ Clare-Salzier (1999) Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus.J. Clin. Invest. 104, 515–523.PubMedCrossRefGoogle Scholar
  100. Lodge D, JA Aram, J Church, SN Davies, D Martin, CT ’Shoughnessy, ZS Zeman (1987) Excitatory amino acids and phencyclidine-like drugs, In:Excitatory Amino Acid Transmission (Hicks TP, D Lodge and H McLennan, Eds.), (Alan R Liss Inc: New York, NY), pp 83–90.Google Scholar
  101. Lohr JB and K Flynn (1992) Smoking and schizophrenia.Schizophr. Res. 8, 93–102.PubMedCrossRefGoogle Scholar
  102. Mach DM, C Schütt and I Börner (1983) Schizophrenie und B- Lymphozytenalteration — eine Hypothese.Psychiatrie, Neurologie und Medizinische Psychologie 35, 390–397.Google Scholar
  103. Maes M, E Bosmans, J Calabrese, R Smith and HY Meltzer (1995) Interleukin-2 and Interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood-stabilizers.J. Psychiatr. Res. 29, 141–152.CrossRefGoogle Scholar
  104. Maes M, E Bosmans, G Kenis, R De Jong, RS Smith and HY Meltzer (1997)In vivo immunomodulatory effects of clozapine in schizophrenia.Schizophr. Res. 26, 221–225.PubMedCrossRefGoogle Scholar
  105. Maino K, R Gruber, M Riedel, N Seitz, MJ Schwarz and N Müller (2006) T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment.Psychiatry Res. (in press).Google Scholar
  106. Marshall BE and DE Longnecker (1990) General anesthetics, In:The Pharmacological Basis of Therapeutics (Goodman LS, A Gilman, TW Rall, AS Nies P Taylor, Eds.) (Pergamon Press: Elmsford NY), pp 285–310.Google Scholar
  107. Marshall B, DB Keskin and AL Mellor (2001) Regulation of prostaglandin synthesis and cell adhesion by a tryptophan catabolizing enzyme.BMC Biochemistry 2, 5.PubMedCrossRefGoogle Scholar
  108. Martin LF, WR Kem and R Freedman (2004) Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.Psychopharmacol. (Berl.) 174, 54–64.CrossRefGoogle Scholar
  109. Mattsson A, E Lindqvist, SO Ogran and L Olson (2005) Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.Neuroreport. 16(16), 1815–1819.PubMedCrossRefGoogle Scholar
  110. McAllister CG, MH Rapaport, D Pickar and SM Paul (1989) Effects of short-term administration of antipsychotic drugs on lymphocyte subsets in schizophrenic patients.Arch. Gen. Psychiatry 46, 956–957.PubMedGoogle Scholar
  111. McNeil TF, E Cantor-Graae and DR Weinberger (2000) Relationship of abstretic complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia.Am. J. Psychiatry 157, 203–212.PubMedCrossRefGoogle Scholar
  112. Mednick SA, RA Machon, MO Huttunen and D Bonett (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic.Arch. Gen. Psychiatry 45, 817–824.Google Scholar
  113. Meira-Lima IV, AC Pereira, GF Mota, M Floriano, F Araujo, AJ Mansur, JE Krieger and H Vallada (2003) Analysis of a polymorphism in the promoter region of the tumor necrosis factor-α gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia.Mol. Psychiatry 8, 718–720.PubMedCrossRefGoogle Scholar
  114. Miller CL, IC Llenos, JR Dulay, MM Barillo, RH Yolken and S Weis (2004) Expression of the kynurenine pathway enzyme tryptophane 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia.Neurobiol. Dis. 15, 618–629.PubMedCrossRefGoogle Scholar
  115. Miller DW and ED Abercrombie (1996) Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured within vivo microdialysis in awake rats.Brain Res. Bull. 40, 57–62.PubMedCrossRefGoogle Scholar
  116. Miller R and G Chouinard (1993) Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia.Biol. Psychiatry 34, 713–38.PubMedCrossRefGoogle Scholar
  117. Mills CD, K Kincaid, JM Alt, MJ Heilman and AM Hill (2000) Macrophages and the Th1/Th2 paradigm.J. Immunol. 164, 6166–6173.PubMedGoogle Scholar
  118. Mittleman BB, FX Castellanos, LK Jacobson, JL Rapoport, SE Swedo and GM Shearer (1997) Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease.J. Immunol. 159, 2994–2999.PubMedGoogle Scholar
  119. Molholm HB (1942) Hyposensitivity to foreign protein in schizophrenic patients.Psychiatr. Quart. 16, 565–571.Google Scholar
  120. Moller HJ (2003) Management of the negative symptoms of schizophrenia: new treatment options.CNS Drugs 17, 793–823.PubMedCrossRefGoogle Scholar
  121. Müller N(2004) Immunological and infectious aspects of schizophrenia (Editorial).Eur. Arch. Psychiatry Clin. Neurosci. 254, 1–3.PubMedCrossRefGoogle Scholar
  122. Müller N and M Ackenheil (1995) Immunoglobulin and albumin contents of cerebrospinal fluid in schizophrenic patients: the relationship to negative symptomatology.Schizophr. Res. 14, 223–228.PubMedCrossRefGoogle Scholar
  123. Müller N and M Ackenheil (1998) Psychoneuroimmunology, the cytokine network in the CNS, and the implications for psychiatric disorders.Progr. Neuro-Psychopharmacol. Biol. Psychiatry 22, 1–31.CrossRefGoogle Scholar
  124. Müller N, M Ackenheil, E Hofschuster, W Mempel and R Eckstein (1991) Cellular immunity in schizophrenic patients before and during neuroleptic therapy.Psychiatry Res. 37, 147–160.PubMedCrossRefGoogle Scholar
  125. Müller N, M Empel, M Riedel, MJ Schwarz and M Ackenheil (1997a) Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia.Eur. Arch. Psychiatry Clin. Neurosci. 247, 308–313.PubMedCrossRefGoogle Scholar
  126. Müller N, P Dobmeier, M Empel, M Riedel, M Schwarz and M Ackenheil (1997b) Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients.Eur. Psychiatry 12, 294–299.CrossRefPubMedGoogle Scholar
  127. Müller N, M Riedel, M Schwarz, R Gruber and M Ackenheil (1997c) Immunomodulatory effects of neuroleptics to the cytokine system and the cellular immune system in schizophrenia, In:Current Update in Psychoimmunology (Wieselmann G, Ed.) (Springer Verlag:Wien, NY), pp 57–67.Google Scholar
  128. Müller N, BC Schlesinger, M Hadjamu, M Riedel, MJ Schwarz, J Primbs, M Ackenheil, R Wank and R Gruber (1998) Cytotoxic gamma/delta cells (g/d+CD8+) are elevated in unmedicated schizophrenic patients and related to the blood-brain barrier and the HLA allele DPA 02011.Schizophr. Res. 12, 69–71.CrossRefGoogle Scholar
  129. Müller N, M Hadjamu, M Riedel, J Primbs, M Ackenheil and R Gruber (1999) The adhesion-molecule receptor expression on T helper cells increases during treatment with neuroleptics and is related to the blood-brain barrier permeability in schizophrenia.Am. J. Psychiatry 156, 634–636.PubMedGoogle Scholar
  130. Müller N, M Riedel, M Ackenheil and MJ Schwarz (2000) Cellular and humoral immune system in schizophrenia: a conceptual reevaluation.World J. Biol. Psychiatry 1, 173–179.PubMedCrossRefGoogle Scholar
  131. Müller N, M Riedel, C Scheppach, B Brandstätter, S Sokkullu, K Krampe, M Ulmschneider, H-J Möller and M Schwarz (2002) Beneficial anti-psychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.Am. J. Psychiatry 159, 1029–1034.PubMedCrossRefGoogle Scholar
  132. Müller N, M Ulmschneider, C Scheppach, MJ Schwarz, M Ackenheil, H-J Möller, R Gruber and M Riedel (2004a) 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.PubMedCrossRefGoogle Scholar
  133. Müller N, M Riedel and MJ Schwarz (2004b) Psychotropic effects of COX-2 inhibitors — a possible new approach for the treatment of psychiatric disorders.Pharmacopsychiatr. 37, 266–269.CrossRefGoogle Scholar
  134. Müller N, M Riedel, MJ Schwarz and RR Engel (2005) Clinical effects of COX-2 inhibitors on cognition in schizophrenia.Eur. Arch. Psychiatry Clin. Neurosci. 255, 149–151.PubMedCrossRefGoogle Scholar
  135. Murray RM and SW Lewis (1987) Is schizophrenia a neurodevel-opmental disorder?BMJ 295, 681–682.PubMedCrossRefGoogle Scholar
  136. Neidhart M, F Pataki and K Fehr (1995) Increased soluble endothelial adhesion molecules in rheumatoid arthritis correlate with circulating cytokines and depletion of CD45R0+ T-lymphocytes from blood stream.Schweiz. Med. Wochenschr. 125, 424–428.PubMedGoogle Scholar
  137. Nilsson LK, L Schwieler, G Engberg, KR Linderholm and S Erhardt (2005) Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms.Int. J. Neuropsychopharmacol. 8(3):329–339. E-pub Feb 18.PubMedCrossRefGoogle Scholar
  138. Nishino S, E Mignot, KL Benon and VP Zarcone Jr (1998) Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture.Psychiatry Res. 78, 141–150.PubMedCrossRefGoogle Scholar
  139. Numakawa T, Y Yagasaki, T Ishimoto, T Okada, T Suzuki, N Iwata, N Ozaki, T Taguchi, M Tatsumi, K Kamijima, RE Straub, DR Weinberger, H Kunugi and R Hashimoto (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia.Hum. Mol. Genet. 13, 2699–2708.PubMedCrossRefGoogle Scholar
  140. Olney JW and NB Farber (1995) Glutamate receptor dysfunction and schizophrenia.Arch. Gen. Psychiatry 52, 998–1007.PubMedGoogle Scholar
  141. Ozawa K, K Hashimoto, T Kishimoto, E Shimizu, H Ishikura and M Iyo (2006) Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.Biol. Psychiatry 59(6), 546–554. E-pub 2005 Oct 26.PubMedCrossRefGoogle Scholar
  142. Özek M, K Toreci, I Akkok and Z Genever (1971) [Influence of therapy on antibody-formation].Psychopharmacologia 21, 401–412.PubMedCrossRefGoogle Scholar
  143. Paludan SR (1998) Interleukin-4 and interferon-gamma: the quintessence of a mutual antagonistic relationship.Scand. J. Immunol. 48, 459–468.PubMedCrossRefGoogle Scholar
  144. Parsons CG, W Danysz, G Quack, S Hartmann, B Lorenz, C Wollenburg, L Baran, E Przegalinski, W Kostowski, P Krzascik, B Chizh and PM Headley (1997). Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization.J. Pharmacol. Exp. Ther. 283, 1264–1275.PubMedGoogle Scholar
  145. Pearce BD (2001) Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms.Mol. Psychiatry 6, 634–646.PubMedCrossRefGoogle Scholar
  146. Picciotto MR, BJ Caldarone, SL King and V Zachariou (2000) Nicotinic receptors in the brain. Links between molecular biology and behavior.Neuropsychopharmacology 22, 451–465.PubMedCrossRefGoogle Scholar
  147. Pollmächer T, D Hinze-Selch and J Mullington (1996) Effects of clozapine on plasma cytokine and soluble cytokine receptor levels.J. Clin. Pharmacol. 16, 403–409.Google Scholar
  148. Pyeon D, FJ Diaz and GA Splitter (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.PubMedCrossRefGoogle Scholar
  149. Ramchand R, J Wei, CN Ramchand and GP Hemmings (1994) Increased serum IgE in schizophrenic patients who responded poorly to neuroleptic treatment.Life Sci. 54, 1579–1584.PubMedCrossRefGoogle Scholar
  150. Rantakallio P, P Jones, J Moring and L von Wendt (1997) Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up.Int. J. Epidemiol. 26, 837–843.PubMedCrossRefGoogle Scholar
  151. Rapaport MH and N Müller (2001) Immunological states associated with schizophrenia, In:Psychoneuroimmunolgy, 3rd Edition, Vol. 2 (Chapter 48) (Ader A, DL Felten and N Cohen, Eds.) (Academic Press:San Diego, NY), pp 373–382.Google Scholar
  152. Riedel M. H Krönig, MJ Schwarz, RR Engel, KU Kühn, CH Sikorski, S Sokullu, M Ackenheil, HJ Möller and N Müller (2002) No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia.Eur. Arch. Psychiatry Clin. Psychiatr. 252, 232–234.CrossRefGoogle Scholar
  153. Riedel M, M Strassnig, I Spellmann, CH Sikorski, MJ Schwarz, HJ Möller and N Müller (2006) Decreased T cellular immune response in schizophrenic patients.J. Psychiatr. Res. Jan. 21, E-pub ahead of print.Google Scholar
  154. Romagnani S (1995) Biology of human TH1 and TH2 cells.J. Clin. Immunol. 15, 121–129.PubMedCrossRefGoogle Scholar
  155. Rothermundt M, V Arolt, C Weitzsch, D Eckhoff and H Kirchner (1996) Production of cytokines in acute schizophrenic psychosis.Biol Psychiatry 40(12), 1294–1297.PubMedCrossRefGoogle Scholar
  156. Rothermundt M, G Ponath and V Arolt (2004a) S100B in schizophrenic psychosis.Int. Rev. Neurobiology 59, 445–470.CrossRefGoogle Scholar
  157. Rothermundt M, P Falkai, G Ponath, S Abel, H Bürkle, M Diedrich, G Hetzel, M Peters, A Siegmund, A Pedersen, W Maier, J Schramm, T Suslow, P Ohrmann and V Arolt (2004b) Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF.Mol. Psychiatry 9, 897–899.PubMedCrossRefGoogle Scholar
  158. Rothermundt M, G Ponath, T Glaser, G Hetzel and V Arolt (2004c) S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia.Neuropsychopharmacol. 29, 1004–1011.CrossRefGoogle Scholar
  159. Sarter M, CL Nelson and JP Bruno (2005) Cortical cholinergic transmission and cortical information processing in schizophrenia.Schizophr. Bull. 31, 117–138.PubMedCrossRefGoogle Scholar
  160. Schwab SG, M Albus, J Hallmayer, S Honig, M Borrmann, D Lichtermann, RP Ebstein, M Ackenheil, B Lerer and N Risch (1995) Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.Nat. Genet. 11(3), 325–327.PubMedCrossRefGoogle Scholar
  161. Schwab SG, J Hallmayer, M Albus, B Lerer, GN Eckstein, M Borrmann, RH Segman, C Hanses, J Freymann, A Yakir, M Trixler, P Falkai, M Rietschel, W Maier and DB Wildenauer (2000) A genome-wide 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.PubMedCrossRefGoogle Scholar
  162. Schwab SG, M Knapp, S Mondabon, J Hallmayer, M Borrmann-Hassenbach, M Albus, B Lerer, M Rietschel, M Trixler, W Maier and DB Wildenauer (2003) Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families.Am. J. Hum. Genet. 72, 185–190.PubMedCrossRefGoogle Scholar
  163. Schwarcz R, A Rassoulpour, HQ Wu, D Medoff, CA Tamminga and RC Roberts (2001) Increased cortical kynurenate content in schizophrenia.Biol. Psychiatry 50, 521–530.PubMedCrossRefGoogle Scholar
  164. Schwarz MJ, M Riedel, R Gruber, M Ackenheil and N Müller (1999) Antibodies to heat-shock proteins in schizophrenic patients — implications for disease mechanism.Am. J. Psychiatry 156, 1103–1104.PubMedGoogle Scholar
  165. Schwarz MJ, M Riedel, M Ackenheil and N Müller (2000) Deceased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients.Biol. Psychiatry 47, 29–33.PubMedCrossRefGoogle Scholar
  166. Schwarz MJ, S Chiang, N Müller and M Ackenheil (2001) T-helper-1 and T-helper-2 responses in psychiatric disorders.Brain Behav. Immunol. 15, 340–370.CrossRefGoogle Scholar
  167. Schwarz MJ, H Krönig, M Riedel, S Dehning, A Douhet, I Spellmann, M Ackenheil, HJ Möller and N Müller (2005) IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia.Eur. Arch. Psychiatry Clin. Neurosci. 256(2), 72–76. E-pub Aug 17.PubMedCrossRefGoogle Scholar
  168. Schwieler L, G Engberg and S Erhardt(2004) Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex.Synapse 52, 114–122.PubMedCrossRefGoogle Scholar
  169. Schwieler L, S Erhardt, C Erhardt and G Engberg (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.PubMedCrossRefGoogle Scholar
  170. Seder RA and WE Paul (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells.Annu. Rev. Immunol. 12, 635–673.PubMedCrossRefGoogle Scholar
  171. Shayegan DM and SM Stahl (2004) Atypical antipsychotics: matching receptor profile to individual patient’s clinical profile.CNS Spectrum 10 (Suppl. 11) 6–14.Google Scholar
  172. Skok M, R Grailhe and JP Changeux (2005) Nicotinic receptors regulate B lymphocyte activation and immune response.Eur. J. Pharmacol. 517, 246–251.PubMedCrossRefGoogle Scholar
  173. Speciale C and R Schwarcz (1993) On the production and disposition of quinolinic acid in rat brain and liver slices.J. Neurochem. 60, 212–218.PubMedCrossRefGoogle Scholar
  174. Speciale C, HQ Wu, M Cini, M Marconi, M Varasi and R Schwarcz (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.PubMedCrossRefGoogle Scholar
  175. Sperner-Unterweger B, C Miller, B Holzner, B Widner, WW Fleischhacker and D Fuchs (1999) Measurement of neopterin, kynurenine and tryptophan in sera of schizophrenic patients, In:Psychiatry, Psychimmunology, and Viruses (Müller N, Ed.) (Springer:Wien, NY), pp 115–119.Google Scholar
  176. Stalder AK, A Pagenstecher, NC Yu, C Kincaid, CS Chiang, MV Hobbs, FE Bloom and IL Campbell (1997) Lipopolysaccharide-induced IL-12 expression in the central nervous system and cultured astrocytes and microglia.J. Immunol. 159, 1344–1351.PubMedGoogle Scholar
  177. Stefansson H, E Sigurdsson, V Steinthorsdottir, S Bjornsdottir, T Sigmundsson, S Ghosh, J Brynjolfsson, S Gunnarsdottir, O Ivarsson, TT Chou, O Hjaltason, B Birgisdottir, H Jonsson, VG Gudnadottir, E Gudmundsdottir, A Bjornsson, B Ingvarsson, A Ingason, S Sigfusson, H Hardardottir, RP Harvey, D Lai, M Zhou, D Brunner, V Mutel, A Gonzalo, G Lemke, J Sainz, G Johannesson, T Andresson, D Gudbjartsson, A Manolescu, ML Frigge, ME Gurney, A Kong, JR Gulcher, H Petursson and K Stefansson (2002) Neuregulin 1 and susceptibility to schizophrenia.Am. J. Hum. Genet. 71, 877–892.PubMedCrossRefGoogle Scholar
  178. Stefansson H, J Sarginson, A Kong, P Yates, V Steinthorsdottir, E Gudfinnsson, S Gunnarsdottir, N Walker, H Petursson, C Crombie, A Ingason, JR Gulcher, K Stefansson and D St Clair (2003) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population.Am. J. Hum. Genet. 72, 83–87.PubMedCrossRefGoogle Scholar
  179. Stolina M, S Sharma, Y Linet 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.PubMedGoogle Scholar
  180. Stone TW (1993) Neuropharmacology of quinolinic and kynurenine acids.Pharmacol. Rev. 43, 309–379.Google Scholar
  181. Straub RE, Y Jiang, CJ MacLean, Y Ma, BT Webb, MV Myakishev, C Harris-Kerr, B Wormley, H Sadek, B Kadambi, AJ Cesare, A Gibberman, X Wang, FA O’Neill, D Walsh and KS Kendler (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia.Am. J. Hum. Genet. 71, 337–348.PubMedCrossRefGoogle Scholar
  182. Sullivan PF, KS Kendler and MC Neale (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.Arch. Gen. Psychiatry 60, 1187–1192.PubMedCrossRefGoogle Scholar
  183. Sumiyoshi T, AE Anil, D Jin, K Jayathilake, M Lee and HY Meltzer (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.PubMedCrossRefGoogle Scholar
  184. Sumiyoshi T, D Jin, K Jayathilake, M Lee and HJ Meltzer (2005) Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia.Int. J. Neuropsychopharmacol. 8, 1–5.CrossRefGoogle Scholar
  185. Suvisaari J, J Haukka, A Transkanen, T Hovi and J Lonnquist (1999) Association between prenatal exposure to poliovirus infection and adult schizophrenia.Am. J. Psychiatry 156, 1100–1102.PubMedGoogle Scholar
  186. Takai N, PB Mortensen, U Klaening, RM Murray, PC Sham, E O’Callaghan and P Munk-Jorgensen (1996) Relationship betweenin utero exposure to influenza epidemics and risk of schizophrenia in Denmark.Biol. Psychiatry 40, 817–824.CrossRefGoogle Scholar
  187. Takikawa O, R Yoshida, R Kido and O Hayaishi (1986) Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase.J. Biol. Chem. 261, 347–351.Google Scholar
  188. Talbot K, WL Eidem, CL Tinsley, MA Benson, EW Thompson, RJ Smith, CG Hahn, SJ Siegel, JQ Trojanowski, RE Gur, DJ Blake and SE Arnold (2004) Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.J. Clin. Invest. 113(9), 1353–1363.PubMedGoogle Scholar
  189. Tanaka KF, F Shintani, Y Fujii, G Yagi and M Asai (2000) Serum interleukin-18 levels are elevated in schizophrenia.Psychiatry Res. 96, 75–80.PubMedCrossRefGoogle Scholar
  190. Tharumaratnam D, S Bashford and SA Khan (2000) Indomethacin induced psychosis.Postgrad. Med. J. 76, 736–737.PubMedCrossRefGoogle Scholar
  191. Tohmi M, N Tsuda, Y Watanabe, A Kakita and H Nawa (2004) Perinatal inflammatory cytokine challenge results in distinct neurobehavioral alterations in rats: implication in psychiatric disorders of developmental origin.Neurosci. Res. 50, 67–75.PubMedCrossRefGoogle Scholar
  192. Torrey EF, J Miller, R Rawlings and RH Yolken (1997) Seasonality of births in schizophrenia and bipolar disorder: a review of the literature.Schizophr. Res. 28, 1–38.PubMedCrossRefGoogle Scholar
  193. Tracey KJ (2002) The inflammatory reflex.Nature 420, 853–859.PubMedCrossRefGoogle Scholar
  194. Tsai G, P Yang, LC Chung, N Lange and JT Coyle (1998) D-serine added to antipsychotics for the treatment of schizophrenia.Biol. Psychiatry 44, 1081–1089.PubMedCrossRefGoogle Scholar
  195. Van Kammen DP, CG McAllister-Sistilli and ME Kelley (1997) Relationship between immune and behavioral measures in schizophrenia, In:Current Update in Psychoimmunology (Wieselmann G, Ed.) (Springer Verlag:Wien, NY), pp 51–55.Google Scholar
  196. Van Westerloo DJ, IAJ Giebelen, S Florquin, J Daalhuisen, MJ Bruno, AF de Vos, KJ Tracey and T van der Poll (2005)J. Infect. Dis. 191, 2138–2148.PubMedCrossRefGoogle Scholar
  197. Villemain F, L Chatenoud, A Galinowski, F Homo Delarche, D Genestet, H Loo, E Zarifarain and JF Bach (1989) Aberrant T-cell-mediated immunity in untreated schizophrenic patients: deficient interleukin-2 production.Am. J. Psychiatry 146, 609–616.PubMedGoogle Scholar
  198. Vinogradov S, II Gottesman, HW Moises and S Nicol (1991) Negative association between schizophrenia and rheumatoid arthritis.Schizophr. Bull. 17, 669–678.PubMedGoogle Scholar
  199. Wang H, M Yu, M Ochani, CA Amelia, M Tanovic, S Susaria, JH Li, H Wang, H Yang, L Ulloa, Y Al-Abed, CJ Czura and KJ Tracey (2003) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation.Nature 421, 384–388.PubMedCrossRefGoogle Scholar
  200. Weickert TW and TE Goldberg (2000) The course of cognitive impairment in patients with schizophrenia, In:Cognition in Schizophrenia: Impairments, Importance and Treatment Strategies (Sharma T and P Harvey, Eds) (University Press: Oxford, NY), pp 3–15.Google Scholar
  201. Westergaard T, PB Mortensen, CB Pedersen, J Wohlfahrt and M Melbye (1999) Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenca prevalence.Arch. Gen. Psychiatry 56, 993–998.PubMedCrossRefGoogle Scholar
  202. Wilke I, V Arolt, M Rothermundt, CH Weitzsch, M Hornberg and H Kirchner (1996) Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients.Eur. Arch. Psychiatry Clin. Neurosci. 246, 279–284.PubMedCrossRefGoogle Scholar
  203. Williams NM, A Preece, G Spurlock, N Norton, HJ Williams, S Zammit, MC O’Donovan and M JOwen (2003) Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia.Mol. Psychiatry 8, 485–487.PubMedCrossRefGoogle Scholar
  204. Wu HO, SC Lee, HE Scharfman and R Schwarcz (2002) L-4-chlo-rokynurenine attenuates kainate-induced seizures and lesions in the rat.Exp. Neurol. 177, 222–232.PubMedCrossRefGoogle Scholar
  205. Xiao BG and H Link (1999) Is there a balance between microglia and astrocytes in regulating Th1/Th2-cell responses and neuropathologies?Immunology Today 20, 477–479.PubMedCrossRefGoogle Scholar
  206. Yolken RH and EF Torrey (1995) Viruses, schizophrenia, and bipolar disorder.Clin. Microbiol. Rev. 8, 131–145.PubMedGoogle Scholar
  207. Zimmer DB, EH Cornwall, A Landar and W Song (1995) The S100 protein family: history, function, and expression.Brain Res. Bull. 37, 417–429.PubMedCrossRefGoogle Scholar
  208. Zuckerman L and I Weiner (2005) Maternal immune activation leads to behavioural and pharmacological changes in the adult offspring.J. Psychiatr. Res. 39, 311–323.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  1. 1.Hospital for Psychiatry and PsychotherapyLudwig-Maximilians-UniversitätMünchenGermany

Personalised recommendations