Decoding Schizophrenia - Understanding Schizophrenia

Written by Daniel C. Javitt and Joseph T. Coyle

One example of the research implicating NMDA receptors in schizophrenia relates to the way the brain normally processes information. Beyond strengthening connections between neurons, NMDA receptors amplify neural signals, much as transistors in old-style radios boosted weak radio signals into strong sounds. By selectively amplifying key neural signals, these receptors help the brain respond to some messages and ignore others, thereby facilitating mental focus and attention. Ordinarily, people respond more intensely to sounds presented infrequently than to those presented frequently and to sounds heard while listening than to sounds they make themselves while speaking. But people with schizophrenia do not respond this way, which implies that their brain circuits reliant on NMDA receptors are out of kilter.

If reduced NMDA receptor activity prompts schizophrenia's symptoms, what then causes this reduction? The answer remains unclear. Some reports show that people with schizophrenia have fewer NMDA receptors, although the genes that give rise to the receptors appear unaffected. If NMDA receptors are intact and present in proper amounts, perhaps the problem lies with a flaw in glutamate release or with a buildup of compounds that disrupt NMDA activity.

Some evidence supports each of these ideas. For instance, postmortem studies of schizophrenic patients reveal not only lower levels of glutamate but also higher levels of two compounds (NAAG and kynurenic acid) that impair the activity of NMDA receptors. Moreover, blood levels of the amino acid homocysteine are elevated; homocysteine, like kynurenic acid, blocks NMDA receptors in the brain. Overall, schizophrenia's pattern of onset and symptoms suggests that chemicals disrupting NMDA receptors may accumulate in sufferers' brains, although the research verdict is not yet in. Entirely different mechanisms may end up explaining why NMDA receptor transmission becomes attenuated.

New Schizophrenia Treatment Possibilities

Regardless of what causes NMDA signaling to go awry in schizophrenia, the new understanding--and preliminary studies in patients--offers hope that drug therapy can correct the problem. Support for this idea comes from studies showing that clozapine (Clozaril) , one of the most effective medications for schizophrenia identified to date, can reverse the behavioral effects of PCP in animals, something that older antipsychotics cannot do. Further, short-term trials with agents known to stimulate NMDA receptors have produced encouraging results. Beyond adding support to the glutamate hypothesis, these results have enabled long-term clinical trials to begin. If proved effective in large-scale tests, agents that activate NMDA receptors will become the first entirely new class of medicines developed specifically to target the negative and cognitive symptoms of schizophrenia.

The two of us have conducted some of those studies. When we and our colleagues administered the amino acids glycine and D-serine to patients with their standard medications, the subjects showed a 30 to 40 percent decline in cognitive and negative symptoms and some improvement in positive symptoms. Delivery of a medication, D-cycloserine, that is primarily used for treating tuberculosis but happens to cross-react with the NMDA receptor, produced similar results. Based on such findings, the National Institute of Mental Health has organized multicenter clinical trials at four hospitals to determine the effectiveness of D-cycloserine and glycine as therapies for schizophrenia; results should be available this year. Trials of D-serine, which is not yet approved for use in the U.S., are ongoing elsewhere with encouraging preliminary results as well. These agents have also been helpful when taken with the newest generation of atypical antipsychotics, which raises the hope that therapy can be developed to control all three major classes of symptoms at once.

None of the agents tested to date may have the properties needed for commercialization; for instance, the doses required may be too high. We and others are therefore exploring alternative avenues. Molecules that slow glycine's removal from brain synapses--known as glycine transport inhibitors--might enable glycine to stick around longer than usual, thereby increasing stimulation of NMDA receptors. Agents that directly activate "AMPA-type" glutamate receptors, which work in concert with NMDA receptors, are also under active investigation. And agents that prevent the breakdown of glycine or D-serine in the brain have been proposed.

Many Avenues of Attack

Scientists interested in easing schizophrenia are also looking beyond signaling systems in the brain to other factors that might contribute to, or protect against, the disorder. For example, investigators have applied so-called gene chips to study brain tissue from people who have died, simultaneously comparing the activity of tens of thousands of genes in individuals with and without schizophrenia. So far they have determined that many genes important to signal transmission across synapses are less active in those with schizophrenia--but exactly what this information says about how the disorder develops or how to treat it is unclear.

Genetic studies in schizophrenia have nonetheless yielded intriguing findings recently. The contribution of heredity to schizophrenia has long been controversial. If the illness were dictated solely by genetic inheritance, the identical twin of a schizophrenic person would always be schizophrenic as well, because the two have the same genetic makeup. In reality, however, when one twin has schizophrenia, the identical twin has about a 50 percent chance of also being afflicted. Moreover, only about 10 percent of first-degree family members (parents, children or siblings) share the illness even though they have on average 50 percent of genes in common with the affected individual. This disparity suggests that genetic inheritance can strongly predispose people to schizophrenia but that environmental factors can nudge susceptible individuals into illness or perhaps shield them from it. Prenatal infections, malnutrition, birth complications and brain injuries are all among the influences suspected of promoting the disorder in genetically predisposed individuals.

Over the past few years, several genes have been identified that appear to increase susceptibility to schizophrenia. Interestingly, one of these genes codes for an enzyme (catechol-O-methyltransferase) involved in the metabolism of dopamine, particularly in the prefrontal cortex. Genes coding for proteins called dysbindin and neuregulin seem to affect the number of NMDA receptors in brain. The gene for an enzyme involved in the breakdown of D-serine (D-amino acid oxidase) may exist in multiple forms, with the most active form producing an approximately fivefold increase in risk for schizophrenia. Other genes may give rise to traits associated with schizophrenia but not the disease itself. Because each gene involved in schizophrenia produces only a small increase in risk, genetic studies must include large numbers of subjects to detect an effect and often generate conflicting results. On the other hand, the existence of multiple genes predisposing for schizophrenia may help explain the variability of symptoms across individuals, with some people perhaps showing the greatest effect in dopamine pathways and others evincing significant involvement of other neurotransmitter pathways.

Finally, scientists are looking for clues by imaging living brains and by comparing brains of people who have died. In general, individuals with schizophrenia have smaller brains than unaffected individuals of similar age and sex. Whereas the deficits were once thought to be restricted to areas such as the brain's frontal lobe, more recent studies have revealed similar abnormalities in many brain regions: those with schizophrenia have abnormal levels of brain response while performing tasks that activate not only the frontal lobes but also other areas of the brain, such as those that control auditory and visual processing. Perhaps the most important finding to come out of recent research is that no one area of the brain is "responsible" for schizophrenia. Just as normal behavior requires the concerted action of the entire brain, the disruption of function in schizophrenia must be seen as a breakdown in the sometimes subtle interactions both within and between different brain regions.

Because schizophrenia's symptoms vary so greatly, many investigators believe that multiple factors probably cause the syndrome. What physicians diagnose as schizophrenia today may prove to be a cluster of different illnesses, with similar and overlapping symptoms. Nevertheless, as researchers more accurately discern the syndrome's neurological bases, they should become increasingly skilled at developing treatments that adjust brain signaling in the specific ways needed by each individual. 

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