Glycine Site Modulators and Glycine Transporter-1 Inhibitors as Novel Therapeutic Targets for the Treatment of Schizophrenia

Current antipsychotic medications are efficacious for the positive symptoms of schizophrenia. However, there remains a significant unmet need for alternate strategies that could result in improved tolerability and/or efficacy for negative and cognitive symptoms. A growing body of research suggests that NMDA mediated neuronal activity is involved in the etiology of schizophrenia. Glycine binds to a modulatory glycineB strychnine-insensitive binding site on the NR1 subunit of the NMDA receptor complex and acts necessary co-agonist for activation of the NMDA receptor. Thus, several approaches have emerged aimed towards modulating this glycine binding site. To date, the glycineB site agonists glycine and D-serine, the partial agonist, D-cycloserine and the glycine reuptake inhibitor, sarcosine, have been shown to provide relief to schizophrenic patients. These clinical findings, combined with a growing body of preclinical literature, support the notion that enhancing synaptic glycineB activity leads to an increase in the effectiveness of normal glutamatergic signaling at the NMDA receptor complex and provides efficacy for schizophrenic patients. Accordingly, the present review examines the role of glycineB site modulation as a therapeutic approach for the treatment of schizophrenia.