The role of inflammation in schizophrenia. (2015)

The role of inflammation in schizophrenia.

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.

Cyclooxygenase-2 (COX-2) inhibition as an anti-inflammatory therapeutic approach in schizophrenia

Modern anti-inflammatory agents have been explored in schizophrenia. The cyclooxygenase-2 (COX-2) inhibitor celecoxib was studied in a prospective, randomized, double-blind study of acute exacerbations of schizophrenia. The patients receiving celecoxib add-on to risperidone showed a statistically significantly better outcome than the patients receiving risperidone alone; the clinical effects of COX-2 inhibition in schizophrenia were especially pronounced in cognition (Müller et al., 2005). The efficacy of therapy with a COX-2 inhibitor seems most pronounced in the first years of the schizophrenic disease process (Müller, 2010; Müller et al., 2010). A recent study also demonstrated a beneficial effect of acetylsalicylic acid in schizophrenic spectrum disorders (Laan et al., 2010). A meta-analysis of the clinical effects of non-steroidal anti-inflammatory drugs in schizophrenia revealed significant effects on schizophrenic total, positive and negative symptoms (Sommer et al., 2012), while another meta-analysis found a significant benefit only in schizophrenia patients with a short duration of disease or in first manifestation schizophrenia (Nitta et al., 2013).

Further immune-related substances in the therapy of schizophrenia

Because of the role of microglia activation in inflammation, minocycline, an antibiotic and inhibitor of microglia activation, is an interesting substance for the treatment of schizophrenia. The improvement of cognition by minocycline has been described in animal models of schizophrenia (Mizoguchi et al., 2008) and in two double-blind, placebo-controlled add-on therapy trials in schizophrenia patients (Levkovitz et al., 2010; Chaudhry et al., 2012). In clinical studies, positive effects on schizophrenic negative symptoms were noted as well (Chaudhry et al., 2012). Case reports documented positive effects of minocycline on the whole symptom spectrum in schizophrenia (Ahuja and Carroll, 2007).

Acetylcysteine (ACC) and other substances, including omega-3 fatty acids, that have anti-inflammatory and other effects also provide some benefit to schizophrenia patients (overview: Sommer et al., 2014)

First pilot experiences with cytokine interferon gamma (IFN-γ), which stimulates the monocytic type 1 immune response, as a therapeutic approach in schizophrenia are encouraging (Grüber et al., 2014), although side effects, including unwanted immune effects, have to be carefully monitored and the results are only preliminary. On the other hand, such a hypothesis-driven therapeutic approach opens interesting perspectives for the development of therapeutic substances based on etiopathology.

‘Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression’ and first episode psychosis (FEP) ‘patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype’ [1]

Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons [2] and ‘lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders’

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