Decoding Schizophrenia

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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

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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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DANIEL C. JAVITT and JOSEPH T. COYLE have studied schizophrenia for many years. Javitt is director of the Program in Cognitive Neuroscience and Schizophrenia at the Nathan Kline Institute for Psychiatric Research in Orangeburg, N.Y., and professor of psychiatry at the New York University School of Medicine. His paper demonstrating that the glutamate-blocking drug PCP reproduces the symptoms of schizophrenia was the second-most cited schizophrenia publication of the 1990s. Coyle is Eben S. Draper Professor of Psychiatry and Neuroscience at Harvard Medical School and also editor in chief of the Archives of General Psychiatry. Both authors have won numerous awards for their research. Javitt and Coyle hold independent patents for use of NMDA modulators in the treatment of schizophrenia, and Javitt has significant financial interests in Medifoods and Glytech, companies attempting to develop glycine and D-serine as treatments for schizophrenia.

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