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Commentary |

Glycine Agonists:  What Can They Teach Us About Schizophrenia?

Nuri B. Farber, MD; John W. Newcomer, MD; John W. Olney, MD
Arch Gen Psychiatry. 1999;56(1):13-17. doi:10.1001/archpsyc.56.1.13.
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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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A, Under normal conditions, theN-methyl-D-aspartate (NMDA) synapse is flooded with glycine. Glial glycine transporters (GlyT1) probably maintain the amount of glycine at a level that ensures near maximal occupation of the glycine recognition site on the NMDA receptor. When glutamate (Glu) is released by the presynaptic terminal, it transverses the synaptic cleft and binds to the Glu binding site on the NMDA receptor. Only when both the glycine and Glu binding sites are occupied does the receptor become activated and open its ion channel. The frequency and duration of channel opening depends primarily on the frequency of Glu release and efficiency of uptake mechanisms in both the presynaptic axon and glia that rapidly remove Glu from the synaptic cleft. Treating a schizophrenic patient with glycine would be expected to have a profoundly beneficial effect if the concentration of glycine in the cleft region is well below saturation levels, but would have only a mild effect or no effect if the concentration is close to or at saturation levels. B, In addition to the Glu and glycine binding sites, the NMDA receptor has multiple other binding sites through which its channel function can be modulated. Binding at the polyamine site facilitates Glu-activated opening of the cation channel. In contrast, binding of zinc, magnesium, or phencyclidine (PCP) ligands to their respective sites inhibits NMDA receptor function. C, Multiple agents can modulate the NMDA receptor via these different binding sites. The NMDA receptor is so named because NMDA preferentially binds to this particular Glu binding site. CPP, CPPene, and CGS19755 also preferentially bind to the NMDA/Glu binding site. Since they inhibit Glu's binding, they are termed "competitive antagonists." D-cycloserine binds to the anatomically distinct glycine site where it functions as a partial agonist. Ketamine, PCP, and MK-801 all bind to the "PCP binding site," which is inside the ion channel. Once bound, they block the flow of ions through the channel and thus inhibit the functioning of the receptor. Because they interact at a site distinct from the Glu binding site, they do not compete with Glu for binding and are termed "noncompetitive antagonists."

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