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Commentary
January 1999

Glycine AgonistsWhat Can They Teach Us About Schizophrenia?

Arch Gen Psychiatry. 1999;56(1):13-17. doi:10.1001/archpsyc.56.1.13

IN THIS issue of the ARCHIVES, Goff et al1 and Heresco-Levy et al2 report results of clinical trials in which patients with schizophrenia were treated with D-cycloserine, a partial agonist at the glycine site on theN-methyl-D-aspartate (NMDA) subtype of glutamate (Glu) receptor, or glycine, a full agonist at the same site. As indicated by both groups, the rationale for these studies is based on the NMDA receptor hypofunction (NRHypo) hypothesis of schizophrenia. A major underpinning of this hypothesis is the observation that hypofunction of NMDA receptors induced by various NMDA antagonist drugs precipitates a transient psychotic state in healthy subjects.310 Phencyclidine (PCP) and ketamine, the most extensively studied of these agents, when administered to healthy subjects, more faithfully mimic a broad range of schizophrenia-type symptoms than other psychotomimetics, including lysergic acid diethylamide (LSD) and amphetamines.3,6,8,10 It is believed that patients with schizophrenia are unusually sensitive to pharmacological blockade of NMDA receptors, in that administration of PCP to stabilized patients with chronic schizophrenia can trigger a recrudescence of acute psychotic symptoms lasting for up to several months.11,12 In contrast, LSD causes only a brief hallucinogenic state that does not last longer in schizophrenic patients than in healthy subjects.3 Also relevant is the observation that a high percentage of adults display psychotic symptoms (called "emergence" reactions) upon awakening from ketamine anesthesia, whereas pediatric patients at any age prior to adolescence show little or no susceptibility to this NRHypo-associated phenomenon.1317 Thus, humans become susceptible to the mechanism by which NRHypo induces psychotic reactions at the same age that psychotic symptom formation begins to occur in schizophrenia. These several parallels between the drug-induced NRHypo state and schizophrenia have fueled speculation that an NRHypo mechanism may contribute to the pathophysiological mechanisms of schizophrenia. Accordingly, researchers are beginning to look for evidence that the NMDA receptor system may be dysfunctional in schizophrenia.

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