Letters to the Editor
May 2002

Is NMDA Receptor Hypofunction in Schizophrenia Associated With a Primary Hyperglutamatergic State?

Author Affiliations

Copyright 2002 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2002

Arch Gen Psychiatry. 2002;59(5):466-467. doi:

It has been known that the blockade of the N-methyl-D-aspartate receptor (NMDAR) induces a psychotomimetic state resembling schizophrenia. This clinical observation has led to developing the NMDAR hypofunction theory of schizophrenia, which states that the hypoglutamatergic state at postsynaptic NMDARs is involved in the pathophysiology of schizophrenia.1 In a recent article, Anand et al2 reported that lamotrigine, an agent inhibiting presynaptic glutamate release, attenuated the neuropsychiatric effects of ketamine, a noncompetitive NMDAR antagonist. In an attempt to explain the mechanism of action of lamotrigine, the authors hypothesized that ketamine may increase presynaptic glutamatergic release, producing a hyperglutamatergic state that enhances postsynaptic non–NMDAR-mediated glutamate transmission, and lamotrigine may attenuate the drug-induced effects by decreasing presynaptic glutamate release. Lamotrigine has been clinically tested to damp glutamate transmission in strokes, seizures, and cases of Alzheimer disease in which excessive glutamatergic transmission may be involved as a major pathophysiological mechanism.35 However, in schizophrenia, NMDAR-mediated hypoglutamatergic transmission may be involved.1,6 This is consistent with the findings that agents enhancing glutamate transmission at NMDARs can reverse psychomotor disturbances induced by NMDAR antagonists, including ketamine, MK-801, and phencyclidine (PCP) in animals,7 and show antipsychotic effects in patients with schizophrenia.8

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