**9. Drug treatment that targets NMDA receptors**

Typically, drug treatment for schizophrenia patients consists of antipsychotics, such as clo‐ zapine, that target D2 receptors to relieve the positive symptoms. However, a significant portion of schizophrenia subjects do not respond well to D2 antagonists; moreover, the nega‐ tive and cognitive impairments are barely affected by treatment with antipsychotic drugs. As a result, medical professionals are testing new pharmacological agents that target NMDA receptors as a therapeutic option. Due to the observed glutamate hypofunction impairment in patients, investigative studies have focused on the enhancement of NMDA receptor function. Therefore, high doses of glycine agonists (60 g/day) that act upon the glycineB modulatory site are used to increase NMDA receptor function [13]. These agonists have been shown to mod‐ estly improve the negative and positive symptoms of schizophrenia and are currently being utilized as an adjunctive treatment to primary therapy with D2 antagonists. An alternative option is to target the glycine transporter‐1 (GlyT‐1) with the selective inhibitor, sarcosine, to increase glycine availability for NMDA receptor binding [14]. Sarcosine administered at 2 g/day have shown to improve negative and cognitive symptoms of schizophrenia. Other drugs include *d*‐Serine and *d‐*amino acid oxidase (DAAO) inhibitors to increase *d*‐Serine availability, as it is considered a co‐agonist to NR1. The effects of the inhibitor were shown to alleviate negative and cognitive impairments in patients when administered at high doses (>2 g/day) and as a supplement to antipsychotic treatments [14]. Kynurenine aminotransfer‐ ase II (KATII) inhibitors are used to block kynurenic acid (an endogenous antagonist at the NR1 glycineB site) used to improve negative symptoms. NR2 subtype selective modulators are still under drug development and could prove beneficial to a neurological disorder, such as schizophrenia. Other pharmacological drugs available that affect glutamate transmission are utilized to target AMPA receptors, mGlu5 receptors, and NMDA receptors on GABAergic interneurons. However, many of these new therapeutic interventions are still in clinical trials, whether they are more effective than the typical and atypical D2‐related antipsychotic drugs remains to be determined.
