NEW YORK CITY— What do the areas of the brain affected by schizophrenia have in common? “They are synaptically connected by glutamatergic neurons,” related Joseph T. Coyle, Jr, MD, at the 157th Annual Meeting of the American Psychiatric Association. Therefore, “one would have to agree that glutamate must be involved in some way in the pathophysiology of schizophrenia,” asserted Dr. Coyle, the Eben S. Draper Professor of Psychiatry at Harvard Medical School in Boston.

Dr. Coyle reviewed evidence of glutamate’s role in schizophrenia, particularly the contribution of dysfunctional glutamatergic neurotransmission. He suggested that it might be possible to develop schizophrenia treatments that modify the function of the N-methyl-D-aspartic acid (NMDA) receptor, a glutamate receptor subtype that, when hypofunctional, may account for the deficient glutamatergic neurotransmission associated with schizophrenia. Dr. Coyle noted that at least five major pharmaceutical companies are already developing drugs that improve schizophrenia symptoms by enhancing NMDA receptor function.

THE EVIDENCE

The hypothesis that NMDA receptor hypofunction might be important in schizophrenia was not given much credence until investigators performed experiments in which healthy volunteers received subanesthetic infusions of the dissociative anesthetic ketamine, a known NMDA receptor antagonist. The infusions reproduced the positive and negative symptoms of schizophrenia, including paranoia, thought disorder, loose associations, illusions, emotional withdrawal, and psychomotor retardation.

The volunteers displayed other features of schizophrenia, such as selective neurocognitive impairment, abnormal eye tracking, evoked potential abnormalities, and increased dopamine release in the brain. However, Dr. Coyle pointed out, they scored in the normal range on the Mini- Mental State Examination, as patients with schizophrenia typically do.

Postmortem studies have since found a significant reduction in the activity of glutamate carboxypeptidase (GCP) II, the enzyme that degrades the endogenous NMDA receptor antagonist N-acetyl-alpha L-aspartyl-L-glutamate (NAAG), in the hippocampus, prefrontal cortex, and temporal cortex of patients with schizophrenia compared with controls. “If the enzyme that degrades NAAG is reduced, more of this NMDA receptor antagonist would be available in the brain,” Dr. Coyle reasoned.

Magnetic resonance spectroscopy findings support that hypothesis, showing reduced levels of the byproducts of NAAG metabolism in the brain areas where the decreased GCP II activity occurred. The results of these postmortem studies have been replicated, said Dr. Coyle. Further evidence of NMDA receptor hypofunction in schizophrenia was the discovery of a translocation in the human genome at the location of the GCP II gene. The translocation is associated with an increased schizophrenia risk, and so are four polymorphisms in the enzymes that degrade the NMDA receptor agonist D-serine.

Patients with schizophrenia also appear to carry a mutation in the gene encoding for a protein that regulates the degradation of D-serine, another endogenous agonist at the glycine modulatory site. One of the results of the genetic abnormalities seen in these patients is thought to be a large decline in brain levels of D-serine. Low levels of D-serine are the best evidence to date that brain D-serine levels are reduced in schizophrenia, however, noted Dr. Coyle.

INDIRECT STIMULATION

Assuming that NMDA receptor hypofunction contributes to schizophrenia, enhancing the NMDA receptor function may decrease symptoms. The goal, emphasized Dr. Coyle, should be to stimulate the receptor indirectly at the glycine modulatory site. “You would not want to directly activate it because if you overactivate it you will kill neurons,” he warned.

In animal studies, indirect stimulation of the NMDA receptor reversed the effects of NMDA receptor antagonists and enhanced cognition. This strategy has shown promise in double-blind, placebo-controlled clinical trials, as well. These trials focused primarily on schizophrenia treatment with the full NMDA receptor agonists glycine and D-serine, the partial agonist D-cycloserine, and the glycine transporter-1 agonist N-methylglycine.

Reduced negative symptoms and improved cognition were seen in patients with schizophrenia treated with glycine, Dr. Coyle reported. Three trials of D-cycloserine for schizophrenia found improvement in negative symptoms; one of these trials also showed cognitive improvement. Decreased negative and positive symptoms and improved cognition were observed in trials of D-serine and N-methylglycine for schizophrenia.

The negative symptoms of schizophrenia worsened in a dose-finding study in which D-cycloserine, a partial agonist, was added to clozapine. In other trials, adding the full agonists glycine or D-serine to clozapine had no effect on the negative symptoms of schizophrenia. These clinical findings along with the results from animal studies suggest that clozapine’s unique effects on negative symptoms might be due to its effect on the glycine modulatory site on the NMDA receptor.

ADDRESSING CRITICISM

Critics of schizophrenia treatments that target hypofunctional NMDA receptors have argued that such treatment is unlikely to work, because NMDA receptors are present throughout the brain, not just in the areas affected by schizophrenia. However, the positive effect of agonist therapies in some clinical trials may be attributed to enhanced function of a “discrete subpopulation of NMDA receptors,” suggested Dr. Coyle.

The NMDA receptors on GABAergic interneurons in the frontal and temporal cortexes and in the hippocampus may be that discrete subpopulation, he speculated, because studies have shown a heightened sensitivity of those receptors to endogenous and exogenous NMDA receptor antagonists. Furthermore, postmortem analysis of the brains of patients with schizophrenia showed markedly decreased NMDA receptor co-expression on GABAergic interneurons.

Also, functional studies of the hippocampus in patients with schizophrenia have detected abnormally high levels of neuronal activity. “This level of disinhibition is not sufficient for seizures but certainly is sufficient to impair cognition,” remarked Dr. Coyle, “[and it] supports the notion that the excitatory NMDA receptors on these GABAergic interneurons are impaired.”

RECEPTOR HYPOFUNCTION

Dr. Coyle and colleagues proposed that the NMDA receptors on the GABAergic interneurons of brain areas affected by schizophrenia are hypofunctional. The results are disinhibition that impairs cortical-hippocampal processing and disruption of the excitatory output sufficient to trigger subcortical dopamine release that leads to psychosis.

“Enhancing glycine modulatory site occupancy by agonists is a plausible treatment for schizophrenia, especially the negative and cognitive symptoms,” Dr. Coyle maintained. “This strategy … may be more powerful than just the symptomatic treatment that we have been using. By enhancing NMDA receptor function in conjunction with rehabilitation, we may be able not only to deal with symptoms but perhaps to reverse the cognitive and social deficits that are the most disabling aspects of this disorder.”

—Timothy Begany

Suggested Reading
Coyle JT, Tsai G, Goff D. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci. 2003;1003:318-327.
Coyle JT, Tsai G, Goff DC. Ionotropic glutamate receptors as therapeutic targets in schizophrenia. Curr Drug Targets CNS Neurol Disord. 2002;1:183-189.
Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158:1367-1377.
Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2002;42:165-179.

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