Inflammation and the glutamate system in schizophrenia: implications for therapeutic targets and drug development

Background: Despite the progress in antipsychotic therapy for schizophrenia, the effects are still not satisfactory. There is a high percentage of therapy-resistant patients and the overall course of the disease is unfavourable in many affected individuals. Therefore, other therapeutic targets than dopaminergic and serotonergic neurotransmitters are being considered. Objective: Glutamatergic hypofunction, mediated mainly by NMDA receptor blockade, is suggested to be indirectly responsible for dopaminergic dysfunction in schizophrenia. Increased levels of kynurenic acid (KYN-A), an endogenous NMDA receptor antagonist, resulting from disturbed tryptophan/kynurenine metabolism can explain psychotic symptoms and cognitive deterioration. Methods: The role of the immune system in the production of KYN-A and therapeutic targets in the immune and glutamate systems are outlined. Conclusions: Therapeutic consequences are discussed. Glutamate modulators that particularly influence the NMDA co-transmitters glycine and serine, including inhibitors of glycine transporters, are described and initial clinical evidence is discussed. Another target of the glutamate system is the metabotropic mGlu2/3 receptor; Preliminary clinical results of a study with a mGlu2/3 receptor agonist in schizophrenia are mentioned.