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New clue to bipolar disorder

Researchers identify a gene in the continuing effort to demystify manic depression.

June 16, 2003|Benedict Carey | Times Staff Writer

In the past year, researchers have begun to map out a genetic basis for one of psychiatry's most baffling conditions -- bipolar disorder, a lifelong mental disease in which people zigzag from exuberant emotional highs to paralyzing periods of despair.

The latest findings come from UC San Diego, where doctors plan to report today that they have identified a gene that's linked to the disorder in up to 10% of sufferers.

The discoveries represent a significant advance in doctors' understanding of what causes the mood swings and pave the way for the development of a genetic test that could help diagnose and treat the condition.

"We're getting very close to having a test that could at least help us tell whether a person with a family history is at a higher or lower risk" of developing the disease, said Dr. John Kelsoe, a psychiatrist at UC San Diego and the study's lead author. The paper appears in the June 16 issue of Molecular Psychiatry, a medical journal.

Bipolar disorder, or manic depression, afflicts 5 million to 10 million Americans. The illness often begins in late adolescence and many patients report that they suffered symptoms for years without getting a proper diagnosis. Although any genetic screening test would raise many questions about patient privacy, many people with the disorder would welcome it, said Sue Bergeson, vice president of the Depression and Bipolar Support Alliance, a patient advocacy organization. "Anything that helps speed up diagnosis and improve treatment is wonderful news," she said.

Psychiatrists have long known that bipolar disorder runs in families: People who have a brother, sister or parent with the illness are about seven times more likely to develop it than those who don't have such a family history. But there are multiple genes involved, researchers say, and only now are scientists beginning to narrow down the search. Dr. Pamela Sklar, a research psychiatrist at Harvard University, said that no one has done studies large enough to discern which genes increase people's risk of developing the disease or to explain how they do so. For now, she said, the new research provides "some very good leads to follow to establish genetic susceptibility."

Two of the genes that doctors have identified appear to act as biological thermostats, helping the body dampen bursts of brain chemicals during stress or excitement. One of them, brain-derived neurotrophic factor helps short-circuit the effect of stress hormones when it's time to relax, studies suggest.

In the San Diego study, Kelsoe led a team of investigators who studied genetic data in 428 families with a history of bipolar disorder. Looking for any genes that were especially active in the family members who had the disorder, they focused on one called GRK3. GRK3 acts to keep nerve cells from being overwhelmed by stimulating brain messengers, such as dopamine, by reducing their sensitivity to the chemicals. A mutation in the gene might leave a person hypersensitive to dopamine, producing precisely the sort of extended highs that manic depressives experience. Kelsoe calculated that mutations in this gene turned up in 3% to 10% of those with bipolar disorder -- a significant link.

"If you have a mutation and the gene can't turn on, then you might have a baseline supersensitivity to this stimulation," Kelsoe said. Day to day, as neural messengers flood the system due to some excitement, the brain would be unable to quickly blunt the sensation. The result: a manic episode, which is then followed inevitably by a crash, he said. "Instead of maintaining balance in the system, you're going way up and way down."

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