Schizophr Bull 38(5): 920-926

NMDA Receptor and Schizophrenia: A Brief History

Department of Psychiatry and Neuroscience, Harvard Medical School, McLean Hospital, Belmont, MA

*To whom correspondence should be addressed; tel: 617-855-2101, fax: 617-855-2705, e-mail: ude.dravrah.smh@elyoc_hpesoJ

Accepted 2012 Apr 27.

Copyright © The Author 2012. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com

Abstract

Although glutamate was first hypothesized to be involved in the pathophysiology of schizophrenia in the 1980s, it was the demonstration that N-methyl-D-aspartate (NMDA) receptor antagonists, the dissociative anesthetics, could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects that placed the “NMDA receptor hypofunction hypothesis” on firm footing. Additional support came from the demonstration that a variety of agents that enhanced NMDA receptor function at the glycine modulatory site significantly reduced negative symptoms and variably improved cognition in patients with schizophrenia receiving antipsychotic drugs. Finally, persistent blockade of NMDA receptors recreates in experimental animals the critical pathologic features of schizophrenia including downregulation of parvalbumin-positive cortical GABAergic neurons, pyramidal neuron dendritic dysgenesis, and reduced spine density.

Key words: NMDA receptor, Glutamic Acid, Dopamine, GABA, Schizophrenia, Bipolar Disorder

Abstract

“History is written by the victors.” Winston Churchill

Acknowledgments

Conflict of Interest statement: J.T.C. holds a patent on the use of D-serine for the treatment of schizophrenia that is owned by Partners Healthcare, and he has consulted with Abbott, Bristol Meyer Squibb, Janssen, EnVivo, PureTech, and Eli Lilly on drug discovery.

Acknowledgments

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