Schizophrenia, a multifactorial mental disorder with polygenic inheritance as well as environmental influences, encompasses a characteristic group of symptoms. Negative and cognitive symptoms which respond poorly to currently available antipsychotics remain a great clinical challenge. Aggressive studies are ongoing to explore the etiological mechanisms of this disease. Among them, one of the primary causal factors is dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors.
This article reviews the clinical manifestations of the disease, limitations of current antipsychotics and reconceptualization of the nature of disease and treatment modalities based on the evidence provided by drug models, genetic studies, and clinical trials. The NMDA receptor (NMDAR) model plays a critical role in the revolution of pharmaceutical industry as a new set of drug targets is proposed. Investigations on the modulation of glutamatergic system, particularly the intrinsic NMDA glycine modulatory site, exhibit encouraging results. A group of “NMDA-enhancing agents” either acts directly or indirectly on the glycine modulatory site, showing therapeutic efficacy in preclinical and early clinical trials. A new generation of therapeutic agents targeting the NMDAR shows promise as the next wave of drug development for schizophrenia.
Keywords: Schizophrenia, NMDA receptor hypofunction, NMDA-enhancing agents, negative symptoms, cognitive function.