Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification.
Schizophrenia is a severe neuropsychiatric disorder for which there is no adequate current treatment. Recent theories about the molecular basis of schizophrenia focus on disturbances of glutamatergic neurotransmission, particularly at NMDA-type glutamate receptors (NMDARs). NMDARs are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine transporter type 1 (GlyT1), which serves to maintain low subsaturating glycine levels in the vicinity of the NMDAR. Therefore, one proposed approach to the treatment of schizophrenia is via the inhibition of GlyT1-mediated transport. During the past decade, several well-tolerated, high-affinity glycine transport inhibitors (GTIs) have been developed that demonstrate the ability to potentiate NMDAR-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GTI. Issues related to clinical proof-of-concept studies with high-affinity GTIs in schizophrenia are discussed in this review.
Javitt
Daniel C
DC
Nathan Kline Institute for Psychiatric Research/New York University Langone School of Medicine, Orangeburg, NY 10962, USA. javitt@nki.rfmh.org
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D002986:Clinical Trials as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005998:Glycine / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C493268:SLC6A9 protein, human; D005998:Glycine