Cited by 83Amino Acid Enzymes and MetabolismSchizophrenia research and treatmentNeuroscience and Neuropharmacology Research

Glycine transport inhibitors in the treatment of schizophrenia

Javitt, Daniel C.·2012·Handbook of experimental pharmacology

Abstract

Schizophrenia is a severe neuropsychiatric disorder without adequate current treatment. Recent theories of schizophrenia focus on disturbances of glutamatergic neurotransmission particularly at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine type I (GlyT1) transporters, which serve to maintain low subsaturating glycine levels in the vicinity of the NMDA receptor. A proposed approach to treatment of schizophrenia, therefore, is inhibition of GlyT1-mediated transport. Over the past decade, several well tolerated, high affinity GlyT1 inhibitors have been developed and shown to potentiate NMDA receptor-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GlyT1 inhibitor, and with the high affinity compound RG1678. Although definitive trials remain ongoing, encouraging results to date have been reported.

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Crossref · 10.1007/978-3-642-25758-2_12

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  • Trials of drugs aimed at glutamatergic, immune, or antioxidant targets have yielded mixed findings, some encouraging and others inconclusive.

    “To date, clinical trials using molecules targeting either the glutamatergic system (mGluR5, mGluR2/3, glycine site of NMDARs) (Javitt, 2012; Kantrowitz and Javitt, 2012; Poels et al., 2014; Vinson and Conn, 2012), the immune (Leza et al., 2014; Muller et al., 2013), or antioxidant systems (Leza et al., 2014; Reddy and Reddy, 2011) have produced mixed results, some encouraging and others inconclusi”

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Authors
Javitt, D. C.
Affiliations
Nathan Kline Institute for Psychiatric Research (US)
Corresponding author
Javitt, Daniel C.
Venue
Handbook of experimental pharmacology
Published
2012
Issue
213
Pages
367-399
ISSN
  • 0171-2004 (ISSN-L)
  • 1865-0325
OpenAlex
W161931321
Cited by
83
References
197
Citations by year
2026: 1 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 9 · 2015: 13 · 2014: 14 · 2013: 14 · 2012: 3
FWCI
28.09
Type
book chapter
Language
en
Open access
closed
Locations
  • Handbook of experimental pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Pfizer
  • National Institute of Mental Health (R37MH049334, P50MH086385, U01MH074356)
  • National Institute on Drug Abuse (R01DA03383, R01DA003383)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
schizophrenia, glycine transporter 1, NMDA receptor, glutamatergic neurotransmission, sarcosine, D-serine, glycine, NMDA receptor potentiation
MeSH terms
Animals, Glycine, Humans, Piperazines, Schizophrenia, Sulfones, Receptors, N-Methyl-D-Aspartate, Glycine Plasma Membrane Transport Proteins

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