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Preemptive strikes against psychosis
July/August 2006
by Trey Popp '97
Psychiatrists have been treating schizophrenia with drugs for half a century, but so far no medication has proven able to cure the disorder completely. Although hallucinations and paranoia can be suppressed, the cognitive deficits that develop during the first several years of psychosis remain irreversible. That problem led Yale psychiatry professor Thomas McGlashan to test a simple but controversial idea: prescribing anti-psychotic drugs to people who are not yet schizophrenic, but appear to be at risk.
Starting in 1997, McGlashan and his team began enrolling patients, mostly adolescents, who seemed to be inching toward the kind of traumatic psychotic event—a suicide attempt or destructive episode—that ordinarily triggers diagnosis and treatment. At the time, a new generation of drugs was raising hopes that the potent neurological side effects of older medications could be avoided. The pharmaceutical company Eli Lilly financed McGlashan’s study to determine whether its new drug, olanzapine, could delay or prevent the onset of schizophrenia.
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An anti-psychotic was given to adolescents who had pre-psychotic symptoms.
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McGlashan reports in the May issue of the American Journal of Psychiatry that preemptive olazapine has benefits, but not enough to outweigh the risks. His research team used a structured interview to identify patients who had pre-psychotic symptoms, such as disorganized thoughts or hearing imaginary sounds. They divided the subjects into two groups. For a year one group received olanzapine and the other received a placebo. Both were observed for a second year while receiving no medication. Although the olanzapine group “converted” to psychosis at a lower rate, the result wasn’t statistically significant because too many patients dropped out of the study. Furthermore, subjects in the olanzapine group gained an average of 20 pounds—likely elevating their risk for future development of diabetes and heart disease. After the second year ended, subjects from both groups converted to psychosis at comparable rates. So, at best, olanzapine delayed schizophrenia rather than preventing it.
McGlashan says the study shows that anti-psychotic drugs probably should not become the clinical standard for pre-psychotic patients. He points to an earlier study showing that cognitive therapy affords about the same degree of protection in these cases as his olanzapine study found.
Many scientists have criticized McGlashan’s study, questioning the ethics of giving powerful drugs to young people who haven’t gone over the edge. William Cooper of Vanderbilt, however, argues that studies like this are essential. He recently found that prescriptions for giving anti-psychotic medications to children in this country doubled between 1996 and 2001. Not enough is known about the drugs to justify this level of use, he says: “The question of whether it is ethical to do [studies like McGlashan's] is really overshadowed by the question of whether it is reasonable to use the drugs on a wide basis without knowing whether they work and cause significant side effects. We need more information.”
McGlashan himself says that one crucial area where physicians need more information is in recognizing those at risk for schizophrenia. In the same issue of AJP, he and his colleagues published a study on early detection that compared Scandinavian communities with and without early psychosis-detection programs. In the community that used a multimedia public health campaign to raise awareness about early symptoms, patients showed significantly decreased rates of suicidal behavior. In an AJP editorial about this study, Jill M. Harkavy-Friedman wrote that early intervention can help health workers “make headway in reducing suicide risk … and improving the quality of life for individuals with schizophrenia and their families.”
Since one percent of Americans suffer from schizophrenia, this kind of amelioration could have significant benefits. Says McGlashan, “When we think about somebody who has schizophrenia, we’re often thinking about somebody homeless, disheveled, screaming at voices in the park,” but the illness is often very quiet in its earliest stages. “It’s a disorder that almost always comes as a surprise to everyone—parents, school, work, and the patients themselves.”
This is no ordinary monkey
by Bruce Fellman
In 2005, biologists from the Wildife Conservation Society (WCS) identified a long-haired brown monkey in the Tanzanian highlands as a new species, Lophocebus kipunji—the first new species of African monkey discovered since 1984. But Yale primatologist Eric Sargis and his colleagues now say that the kipunji is so unusual that it actually belongs in its own genus.
This genus, Rungwecebus, is the first new monkey genus proposed since 1927. “It was exciting to do this, but a little scary,” says Sargis, an assistant professor of anthropology. His group published its findings in the May 11 online edition of Science.
The WCS scientists had first classified the monkey relying on observation of behavior and photographs. They believed the kipunji belonged to the mangabey genus Lophocebus, a group of forest-dwelling primates common in equatorial Africa.
But early this year, a young kipunji was trapped and killed by a farmer protecting his crops. The specimen was flown to the Field Museum of Natural History in Chicago, where it was examined by Sargis, an expert on primate anatomy, and a multidisciplinary team of biologists.
Molecular genetic evidence suggested that the kipunji was a kind of baboon. But when Sargis examined the animal’s skull, he found structural differences that didn’t fit the mold for either genus.
The scientists also concluded that Rungwecebus kipunji needed a conservation plan—and fast. Habitat destruction in the Tanzanian highlands has made it a highly endangered species: research puts the entire kipunji population at 500 to 1,000. “Now that we’ve discovered it, we have to make sure we don’t lose it,” says Sargis.
A killer in the gut
by Jessica Ruvinsky '95
According to the World Health Organization diarrhea kills at least two million children every year in the developing world. The reason for the deaths is severe fluid loss as infections or toxins disrupt the way the intestines control how much water gets absorbed or secreted from the body.
But this global problem may have a submicroscopic solution, say School of Medicine professors Steven Hebert and John Geibel. The scientists and their colleagues have identified a molecular receptor in mice that helps regulate liquid traffic in the intestine. In the June 7 online early edition of the Proceedings of the National Academy of Sciences, they describe how this receptor works and how it might provide a target for a “unique therapy” that could reduce or stop the intestinal fluid loss.
In general, diarrhea is a self-limiting illness in which offending bacteria and the toxins they create are flushed from the body. The standard treatment is fluid replacement. But organisms like the cholera bacteria in some contaminated drinking water and the E. coli strain in some undercooked hamburgers cause a particularly pernicious type of diarrhea: they produce compounds that activate the “water-out” side of the intestines' chemical-balance equation—and activate it uncontrollably. “The intestines will secrete literally gallons of fluid a day,” says Hebert, who chairs the cellular and molecular physiology department. Fluid replenishment can’t keep up, and the result can be dehydration and chemical imbalance that may be fatal.
But by activating calcium-sensing receptors that line the intestinal tract, the Yale researchers have been able to turn this “profound secretory state” into one of fluid absorption. Geibel is currently collaborating with an as-yet unnamed drug company to develop a drug that might literally turn off a killer.  |
