[Immunology in schizophrenic disorders].
This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.
Müller
N
N
Klinik für Psychiatrie und Psychotherapie, Ludwig-Maximilians-Universität, Nussbaumstrasse 7, 80336 München. Norbert.Mueller@med.uni-muenchen.de
Schwarz
M J
MJ
D001921:Brain / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004660:Encephalitis / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018448:Models, Immunological; D008959:Models, Neurological; D008960:Models, Psychological; D011598:Psychoneuroimmunology / Q000639:trends; D012559:Schizophrenia / Q000276:immunology*; D012565:Schizophrenic Psychology
D016207:Cytokines