Am J Psychiatry 158:1367-1377, September 2001
© 2001 American Psychiatric Association
The Emerging Role of Glutamate in the Pathophysiology and Treatment of Schizophrenia
Donald C. Goff, M.D., and
Joseph T. Coyle, M.D.
OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. CONCLUSIONS: Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.
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34(4):
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[Full Text]
[PDF]
|
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|
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|
|
|
P. J. Harrison
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|
|
|
|
|
|
|
C. Villmann and C.-M. Becker
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December 1, 2007;
13(6):
594 - 615.
[Abstract]
[PDF]
|
|
|
|
|
|
|
H. Goforth
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J Neuropsychiatry Clin Neurosci,
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19(4):
480 - 481.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P.R. Corlett, G.K. Murray, G.D. Honey, M.R.F. Aitken, D.R. Shanks, T.W. Robbins, E.T. Bullmore, A. Dickinson, and P.C. Fletcher
Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions
Brain,
September 1, 2007;
130(9):
2387 - 2400.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Large
Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs?
J Psychopharmacol,
May 1, 2007;
21(3):
283 - 301.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. S. Brown, T. Bottiglieri, C. A. Schaefer, C. P. Quesenberry Jr, L. Liu, M. Bresnahan, and E. S. Susser
Elevated Prenatal Homocysteine Levels as a Risk Factor for Schizophrenia
Arch Gen Psychiatry,
January 1, 2007;
64(1):
31 - 39.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. McGlashan
Schizophrenia in Translation: Is Active Psychosis Neurotoxic?
Schizophr Bull,
October 1, 2006;
32(4):
609 - 613.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Pomarol-Clotet, G. D. Honey, G. K. Murray, P. R. Corlett, A. R. Absalom, M. Lee, P. J. McKenna, E. T. Bullmore, and P. C. Fletcher
Psychological effects of ketamine in healthy volunteers: Phenomenological study
The British Journal of Psychiatry,
August 1, 2006;
189(2):
173 - 179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. W. McDaniel, D. R. Spiegel, and A. K. Sahota
Topiramate Effect in Catatonia: A Case Series
J Neuropsychiatry Clin Neurosci,
May 1, 2006;
18(2):
234 - 238.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Hofmann, A. E. Meuret, J. A. J. Smits, N. M. Simon, M. H. Pollack, K. Eisenmenger, M. Shiekh, and M. W. Otto
Augmentation of exposure therapy with d-cycloserine for social anxiety disorder.
Arch Gen Psychiatry,
March 1, 2006;
63(3):
298 - 304.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. THOMAS
Memantine and Catatonic Schizophrenia
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March 1, 2005;
162(3):
626 - 626.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Morey, S. Inan, T. V. Mitchell, D. O. Perkins, J. A. Lieberman, and A. Belger
Imaging Frontostriatal Function in Ultra-High-Risk, Early, and Chronic Schizophrenia During Executive Processing
Arch Gen Psychiatry,
March 1, 2005;
62(3):
254 - 262.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Kim, H. Aizawa, P. S. Kim, A. S. Huang, S. R. Wickramasinghe, A. H. Kashani, R. K. Barrow, R. L. Huganir, A. Ghosh, and S. H. Snyder
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February 8, 2005;
102(6):
2105 - 2110.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Centonze, A. Usiello, C. Costa, B. Picconi, E. Erbs, G. Bernardi, E. Borrelli, and P. Calabresi
Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors
J. Neurosci.,
September 22, 2004;
24(38):
8214 - 8222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. C. Goff, T. Bottiglieri, E. Arning, V. Shih, O. Freudenreich, A. E. Evins, D. C. Henderson, L. Baer, and J. Coyle
Folate, Homocysteine, and Negative Symptoms in Schizophrenia
Am J Psychiatry,
September 1, 2004;
161(9):
1705 - 1708.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T.-U. W. Woo, J. P. Walsh, and F. M. Benes
Density of Glutamic Acid Decarboxylase 67 Messenger RNA-Containing Neurons That Express the N-Methyl-D-Aspartate Receptor Subunit NR2A in the Anterior Cingulate Cortex in Schizophrenia and Bipolar Disorder
Arch Gen Psychiatry,
July 1, 2004;
61(7):
649 - 657.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Tibbo, C. Hanstock, A. Valiakalayil, and P. Allen
3-T Proton MRS Investigation of Glutamate and Glutamine in Adolescents at High Genetic Risk for Schizophrenia
Am J Psychiatry,
June 1, 2004;
161(6):
1116 - 1118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Jackson, H. Homayoun, and B. Moghaddam
NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex
PNAS,
June 1, 2004;
101(22):
8467 - 8472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Pei, F. J. S. Lee, A. Moszczynska, B. Vukusic, and F. Liu
Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors
J. Neurosci.,
February 4, 2004;
24(5):
1149 - 1158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Theberge, Y. Al-Semaan, P. C. Williamson, R. S. Menon, R. W.J. Neufeld, N. Rajakumar, B. Schaefer, M. Densmore, and D. J. Drost
Glutamate and Glutamine in the Anterior Cingulate and Thalamus of Medicated Patients With Chronic Schizophrenia and Healthy Comparison Subjects Measured With 4.0-T Proton MRS
Am J Psychiatry,
December 1, 2003;
160(12):
2231 - 2233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Lenroot, J. R. Bustillo, J. Lauriello, and S. J. Keith
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Psychiatr Serv,
November 1, 2003;
54(11):
1499 - 1507.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. LARUELLE, L. S. KEGELES, and A. ABI-DARGHAM
Glutamate, Dopamine, and Schizophrenia: From Pathophysiology to Treatment
Ann. N.Y. Acad. Sci.,
November 1, 2003;
1003(1):
138 - 158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. COYLE, G. TSAI, and D. GOFF
Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia
Ann. N.Y. Acad. Sci.,
November 1, 2003;
1003(1):
318 - 327.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. I. Tarazi, R. J. Baldessarini, N. S. Kula, and K. Zhang
Long-Term Effects of Olanzapine, Risperidone, and Quetiapine on Ionotropic Glutamate Receptor Types: Implications for Antipsychotic Drug Treatment
J. Pharmacol. Exp. Ther.,
September 1, 2003;
306(3):
1145 - 1151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Clinton, V. Haroutunian, K. L. Davis, and J. H. Meador-Woodruff
Altered Transcript Expression of NMDA Receptor-Associated Postsynaptic Proteins in the Thalamus of Subjects With Schizophrenia
Am J Psychiatry,
June 1, 2003;
160(6):
1100 - 1109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hashimoto, T. Fukushima, E. Shimizu, N. Komatsu, H. Watanabe, N. Shinoda, M. Nakazato, C. Kumakiri, S.-i. Okada, H. Hasegawa, et al.
Decreased Serum Levels of D-Serine in Patients With Schizophrenia: Evidence in Support of the N-Methyl-D-Aspartate Receptor Hypofunction Hypothesis of Schizophrenia
Arch Gen Psychiatry,
June 1, 2003;
60(6):
572 - 576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Estacion, J. S. Weinberg, W. G. Sinkins, and W. P. Schilling
Blockade of maitotoxin-induced endothelial cell lysis by glycine and L-alanine
Am J Physiol Cell Physiol,
April 1, 2003;
284(4):
C1006 - C1020.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Miyamoto, A. S. LaMantia, G. E. Duncan, P. Sullivan, J. H. Gilmore, and J. A. Lieberman
Recent Advances in the Neurobiology of Schizophrenia
Mol. Interv.,
February 1, 2003;
3(1):
27 - 39.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Strous, R. Maayan, R. Lapidus, R. Stryjer, M. Lustig, M. Kotler, and A. Weizman
Dehydroepiandrosterone Augmentation in the Management of Negative, Depressive, and Anxiety Symptoms in Schizophrenia
Arch Gen Psychiatry,
February 1, 2003;
60(2):
133 - 141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kapur
Psychosis as a State of Aberrant Salience: A Framework Linking Biology, Phenomenology, and Pharmacology in Schizophrenia
Am J Psychiatry,
January 1, 2003;
160(1):
13 - 23.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Lewis
In Pursuit of the Pathogenesis and Pathophysiology of Schizophrenia: Where Do We Stand?
Am J Psychiatry,
September 1, 2002;
159(9):
1467 - 1469.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. C. Goff
A 23-Year-Old Man With Schizophrenia
JAMA,
June 26, 2002;
287(24):
3249 - 3257.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sawa and S. H. Snyder
Schizophrenia: Diverse Approaches to a Complex Disease
Science,
April 26, 2002;
296(5568):
692 - 695.
[Abstract]
[Full Text]
[PDF]
|
|
|
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