Abstract
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.
Highlights
We humans are constantly being assaulted by infectious agents, noxious chemicals, and physical traumata
The possible influence on the pathogenesis of schizophrenia of an immunological process resulting in inflammation has long been neglected
Increasing evidence for a role of proinflammatory cytokines in schizophrenia, the strong influence of proand anti-inflammatory cytokines on tryptophan/kynurenine metabolism, the related influence of cytokines on glutamatergic neurotransmission, the results of imaging studies, genetic findings and, last but not least, the therapeutic effect of antiinflammatory drugs all support the view that the recent increased focus of schizophrenia research on psychoneuroimmunology and inflammation is justified
Summary
We humans are constantly being assaulted by infectious agents, noxious chemicals, and physical traumata. A second stimulus (e.g., systemic inflammation, stress) led to immune activation, associated with cellular proliferation, and increased production and release of proinflammatory cytokines (Frank et al, 2007).
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