Underactivity of A/-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission may play a critical role in schizophrenia (SZ) and, in particular, may underlie persistent negative symptoms and cognitive dysfunction. NMDA receptors are regulated in vivo by the amino acids glycine and D-serine, which bind to a modulatory site on the NMDA receptor complex. Studies using full agonists (glycine and D~serine) and a partial agonist (D-cycloserine) of the NMDA receptor added to conventional or atypical antipsychotics have yielded encouraging, but mixed, results due in part to limitations in the pharamacokinetic/pharmacodynamic properties of the compounds themselves. An alternative approach to raising brain glycine levels is administering compounds that block synaptic glycine reuptake in brain via glycine (GLYT1) transporters. GLYT1 transporters are co-localized with NMDA receptors in the brain and function to limit glycine levels in the immediate vicinity of NMDA receptors. Glycine transport inhibitors have proven effective in numerous animal models of SZ. Although high-affinity glycine transport inhibitors have been developed by several pharmaceutical companies, clinical data are, as yet, unavailable. Sarcosine (A/-methylglycine) is a naturally occurring glycine type I (GLYT1) transport inhibitor that has been reported to improve negative symptoms and cognition in both chronic and acutely decompensated patients in studies conducted in Taiwan, but remains unavailable in the US. In this project, we will perform a randomized, placebo-controlled study of sarcosine as add-on treatment to anti-psychotics in first episode schizophrenia patients in Israel. Use of sarcosine has been approved in Israel based upon the successful clinical trials that were conducted in Taiwan. Studies in Israel will be conducted in accordance with FDA GCP and GLP guidelines and will be supported by Data Management/Biostatistic core (Core C). Neurophysiological outcome measures will be incorporated into the study and will be supported by the Patient Assessment/Recruitment core (Core B). The study will also take advantage of the Israeli Draft Board Registry, which provides objective premorbid data on participating subjects. It is hypothesized that impaired premorbid function will predict more severe neurocognitive and neurophysiological deficit, and greater benefit from an NMDA-based approach.

Public Health Relevance

Schizophrenia is a major mental disorder. Neurocognitive dysfunction is a core component of schizophrenia and a major determinant of poor long-term outcome. This project is part of a Center application to determine brain mechanisms underlying neurocognitive dysfunction in schizophrenia with particular emphasis on sensory processing dysfunction. This project will evaluate the effects of the glycine transport inhibitor sarcosine on persistent neurocognitive deficits in schizophrenia. If successful, it will support a new treatment approach for schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-F)
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Columbia University (N.Y.)
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