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NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development
Open accessAbstract
There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.
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“As a pharmacological model of schizophrenia, ketamine allows for controlled and transient NMDAR manipulation in healthy volunteers (Krystal et al. 2003).”
From Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model (2014) · cites this paper as Krystal et al. 2003
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Metadata
- Authors
- Krystal, J. H., D'Souza, D. C., Mathalon, D., Perry, E., Belger, A., & Hoffman, R.
- Affiliations
- VA Connecticut Healthcare System (US)
- Yale University (US)
- Yale New Haven Hospital (US)
- Corresponding author
- Krystal, John H.
- Venue
- Psychopharmacology
- Published
- 2003-09-01
- Volume
- 169
- Issue
- 3-4
- Pages
- 215-233
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W2020140782
- Cited by
- 530
- References
- 307
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 11 · 2023: 16 · 2022: 11 · 2021: 15 · 2020: 20 · 2019: 19 · 2018: 24 · 2017: 27 · 2016: 28 · 2015: 28 · 2014: 20 · 2013: 33 · 2012: 40
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institutes of Health (5k02aa000261-04)
- National Institute on Alcohol Abuse and Alcoholism (K02 AA 00261-01)
- National Institute of Mental Health (5P50 MH44866-12, P50MH044866)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- schizophrenia, NMDA receptor antagonists, ketamine, glutamatergic function, cortical connectivity, disinhibition, schizophrenia pharmacotherapy, cognitive impairment, translational neuroscience, antipsychotic drug development
- MeSH terms
- Animals, Cerebral Cortex, Cognition, Humans, Ketamine, Models, Neurological, Neural Pathways, Schizophrenia, Antipsychotic Agents, Receptors, N-Methyl-D-Aspartate, Excitatory Amino Acid Antagonists, Glutamic Acid
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