The role of inflammation in schizophrenia

Norbert Müller, Elif Weidinger, Bianka Leitner, Markus J. Schwarz

High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.