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.