DOI: 10.1196/annals.1300.020. Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia

Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia

10.1196/annals.1300.020

Crossref journal-article

Wiley

Annals of the New York Academy of Sciences (311)

Abstract

Abstract: Numerous clinical studies demonstrate that subanesthetic doses of dissociative anesthetics, which are noncompetitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms, and brain functional abnormalities of schizophrenia. Postmortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo‐controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that hypofunction of a subset of NMDA receptors may contribute to the symptomatic features of schizophrenia.

Bibliography

COYLE, J. T., TSAI, G., & GOFF, D. (2003). Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia. Annals of the New York Academy of Sciences, 1003(1), 318â327. Portico.

Authors 3

JOSEPH T. COYLE (first)
GUOCHUAN TSAI (additional)
DONALD GOFF (additional)

References 53 Referenced 353

10.1176/appi.ajp.158.9.1367
10.1016/S0140-6736(03)12379-3
10.1016/S0006-3223(99)00289-9
10.1176/ajp.138.4.460
10.1185/03007999709113338
10.1177/070674376701200217
10.1001/archneurpsyc.1959.02340150095011
10.1176/ajp.148.10.1301
10.1001/archpsyc.1994.03950030035004
10.1016/S0893-133X(97)00036-5
10.1016/S0893-133X(98)00067-0
10.1016/S0006-3223(01)01242-2
10.1176/appi.ajp.159.9.1490
10.1016/S0924-977X(96)00039-9
10.1523/JNEUROSCI.17-08-02921.1997
{'issue': '7', 'key': 'e_1_2_9_17_2', 'first-page': '627', 'article-title': 'Modulation of amphetamine‐induced striatal dopamine release by ketamine in humans: implications for schizophrenia', 'volume': '48', 'author': 'Kegeles L.S.', 'year': '2000', 'journal-title': 'Proc. Natl. Acad. Sci. USA'} / Proc. Natl. Acad. Sci. USA / Modulation of amphetamine‐induced striatal dopamine release by ketamine in humans: implications for schizophrenia by Kegeles L.S. (2000)
10.1016/S0959-4388(00)00070-2
10.1073/pnas.97.9.4926
{'issue': '4', 'key': 'e_1_2_9_20_2', 'first-page': '608', 'article-title': 'Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes', 'volume': '45', 'author': 'Kim K.M.', 'year': '1994', 'journal-title': 'Mol. Pharmacol.'} / Mol. Pharmacol. / Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes by Kim K.M. (1994)
10.1073/pnas.95.26.15730
10.1152/jn.1998.80.6.3336
10.1152/jn.00680.2002
10.1016/S0006-3223(01)01078-2
10.1002/(SICI)1096-9861(19991206)415:1<52::AID-CNE4>3.0.CO;2-K
10.1001/archpsyc.1995.03950220039008
10.1073/pnas.081071198
10.1152/jn.2001.85.3.1097 / J. Neurophysiol. / beta‐NAAG rescues LTP from blockade by NAAG in rat dentate gyrus via the type 3 metabotropic glutamate receptor by Lea P.M. (2001)
10.1002/ajmg.1624
10.1073/pnas.182412499
10.1001/archpsyc.60.6.572
10.1016/S0959-4388(00)00210-5
10.1086/342734
10.3109/10673229609017192
10.1523/JNEUROSCI.16-06-02034.1996 / J. Neurosci. / NMDA‐dependent modulation of CA1 local circuit inhibition by Grunze H.C. (1996)
10.1016/0006-3223(95)00046-1
10.1523/JNEUROSCI.22-08-03070.2002 / J. Neurosci. / NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: a potential mechanism of neurotoxicity by Li Q. (2002)
10.1001/archpsyc.57.11.1061
10.1001/archpsyc.57.3.237
10.1176/appi.ajp.158.2.256
10.1093/cercor/12.10.1063
10.1016/0306-4522(96)00328-4
10.1002/jnr.10509
10.2174/1568007024606212
10.1016/S0006-3223(98)00237-6
10.1001/archpsyc.56.1.29
10.1016/S0006-3223(98)00279-0
10.1016/S0028-3908(01)00073-9
10.1074/jbc.M111814200
10.1176/ajp.152.8.1213
10.1001/archpsyc.56.1.21
10.1176/appi.ajp.159.3.480
{'key': 'e_1_2_9_53_2', 'article-title': 'Transporter I inhibitor, N‐methylglycine (sarcosine), added to antipsychotics for treatment of schizophrenia', 'author': 'Tsai G.', 'year': '2003', 'journal-title': 'Biol. Psychiatry'} / Biol. Psychiatry / Transporter I inhibitor, N‐methylglycine (sarcosine), added to antipsychotics for treatment of schizophrenia by Tsai G. (2003)
10.1001/archpsyc.60.8.766

Dates

Type	When
Created	21 years, 7 months ago (Jan. 14, 2004, 8:04 p.m.)
Deposited	1 year, 11 months ago (Sept. 25, 2023, 7:44 a.m.)
Indexed	1 week, 4 days ago (Aug. 23, 2025, 9:41 p.m.)
Issued	21 years, 10 months ago (Nov. 1, 2003)
Published	21 years, 10 months ago (Nov. 1, 2003)
Published Online	19 years, 7 months ago (Jan. 24, 2006)
Published Print	21 years, 10 months ago (Nov. 1, 2003)

Funders 0

None

BibTeX

@article{COYLE_2003, title={Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia}, volume={1003}, ISSN={1749-6632}, url={http://dx.doi.org/10.1196/annals.1300.020}, DOI={10.1196/annals.1300.020}, number={1}, journal={Annals of the New York Academy of Sciences}, publisher={Wiley}, author={COYLE, JOSEPH T. and TSAI, GUOCHUAN and GOFF, DONALD}, year={2003}, month=nov, pages={318–327} }

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