Immunomodulation as Therapeutic Approach in Schizophrenia and Depression: State of the Art

Abstract

Inflammation has been discussed for decades as an underlying cause of psychiatric disorders such as major depression (MD) and schizophrenia. Almost a hundred years ago, an anti-inflammatory therapeutic approach, so-called vaccination therapy, was proposed by Wagner von Jauregg. In schizophrenia and MD, opposite patterns of the type-1 and type-2 immune response seem to be associated with differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in tryptophan-kynurenine metabolism. These differences are associated with an imbalance in glutamatergic neurotransmission, which may contribute to an excess of N-methyl-d-aspartate (NMDA) agonism in depression and NMDA antagonism in schizophrenia. In both schizophrenia and depression the immunological imbalance results in increased prostaglandin E2 (PE2) production and probably also in increased cyclooxygenase-2 (COX-2) expression. Although there is strong evidence for the view that the interactions of the immune system, IDO, serotonergic system and glutamatergic neurotransmission play a key role in schizophrenia and depression, several gaps remain that need to be closed by intense research. Accordingly, anti-inflammatory or immune-modulating substances might have beneficial effects in schizophrenia and MD. COX-2 inhibitors have shown encouraging results in animal models. Moreover, during the last decade many clinical studies have been performed with COX-2 inhibitors, mostly celecoxib, in schizophrenia and MD. For ethical reasons, all these studies used an add-on design, i.e. the COX-2 inhibitor was given adjunctive to either antipsychotics (in schizophrenia) or antidepressants (in MD). Although an add-on design is a methodological challenge, favourable effects of COX-2 inhibitors were observed in placebo-controlled double-blind studies in both indications. Meta-analytic studies proved a significant therapeutic effect of COX-2 inhibitors in MD and in early stages of schizophrenia. Other pharmacological approaches based on immunological effects are discussed. Anti-inflammatory and immune-modulating compounds are promising but still need careful further scientific evaluation, including clinical studies in larger samples of patients.