The NMDA Receptor Hypofunction Hypothesis for Schizophrenia and Glycine Modulatory Sites on the NMDA Receptors as Potential Therapeutic Drugs

Multiple lines of evidence suggest that an abnormality of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia. Considering the NMDA receptor hypofunction hypothesis for schizophrenia, increasing NMDA receptor function by pharmacological manipulation could potentially be a new strategy for the management of schizophrenia. Currently, the NMDA receptor glycine modulatory site is the most attractive therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. It has been shown that glycine transporter-1 (GlyT-1) inhibitors and D-serine (an endogenous co-agonist at glycine modulatory site) could be potential drugs for treating schizophrenia, since the permeability of glycine into the brain is poor. In this article, the author reviews the NMDA receptor hypofunction hypothesis for schizophrenia, and the author discusses potential therapeutic drugs, including glycine transporter-1 (GlyT-1) inhibitors and D-serine.