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Circadian Rhythm Linked to Bipolar Disorder

Research with mice offers first insight into possible connection

TUESDAY, March 20, 2007 (HealthDay News) -- A gene involved in regulating circadian rhythms -- daily rhythms, including the wake/sleep cycle -- may also play a central role in the manic phase of bipolar disorder.

Mice with a particular mutation in the CLOCK gene, which is central in regulating circadian rhythms, displayed behavior very similar to manic behavior in humans. Given lithium, a drug used to treat bipolar disorder, the mice returned to many of their normal behaviors.

The findings could serve as a launching point for further research into bipolar disorder, whose mechanisms continue to elude scientists.

"It gives us a really nice model of mania to be able to study how mania develops and how the treatments for mania work, because a lot of the actions of mood stabilizers have been a mystery," said Colleen McClung, study senior author and assistant professor of psychiatry at the University of Texas Southwestern Medical Center at Dallas. "Bipolar has been difficult to study."

David J. Earnest, a professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine, added: "It really does provide something beyond an associative or correlative observation that circadian rhythms are disturbed when patients are experiencing bipolar disorder. In this animal model, this mutation in the CLOCK gene produces behavioral patterns which are very similar to bipolar disorder."

Scientists have long suspected that circadian rhythms might be involved in psychiatric disorders, particularly bipolar disorder.

Bipolar disorder is characterized by alternating swings of very high and very low -- or depressed -- moods, along with changes in energy and the ability to function. About 5.7 million American adults, or about 2.6 percent of the population 18 and older, may have bipolar disorder, according to the U.S. National Institute of Mental Health.

Almost all people suffering from this disorder also have irregularities in circadian functions including sleep/wake, hormonal, appetite and body temperature. Major disruptions in the sleep/wake cycle can trigger a bipolar episode. And many of the treatments for bipolar disorder, such as lithium, can shift circadian rhythms.

There has been some indication that the CLOCK gene, one of the most important genes involved in circadian rhythm, might also be implicated in the disorder. But the evidence hasn't been definitive.

"I think the connection has always been there, but most of the studies were correlative," Earnest said. "We really couldn't say that there was a definitive connection between circadian rhythm disturbances. It was just an association."

For the new study, which appears in this week's Proceedings of the National Academy of Sciences, McClung and her colleagues tested mice that had a mutation in the CLOCK gene to see if there were similarities to humans with bipolar disorder.

Indeed, the mice exhibited hyperactivity, more risk taking, a preference for "reward" substances such as cocaine and sugar, and less depression.

And when the mice were given lithium, their behavior stabilized.

"Taken together, this whole profile of behaviors is very similar to bipolar patients when they're in a manic stage," McClung said. "This is really important, because there hasn't been a good or complete model of human mania. This is the most complete model ever described."

The researchers went one step further to try to determine what part of the brain was involved. When they put a functional clock gene back into the dopamine cells of the mice (dopamine is involved in reward and mood regulation), they found this also corrected some of the manic behaviors.

"This is exciting, because it pinpoints the area of the brain where CLOCK is functioning," McClung said. "We really didn't know what CLOCK was doing there. It looks like CLOCK is regulating dopamine activities, and that could be what's causing these types of behaviors."

But Earnest also issued some caveats.

"The overall behavior of the mice looks very similar to what you see in patients with bipolar disorder," he said. "But how do we fully equate what we see in their activity to a clinical situation with regard to bipolar depression? We can argue one way or the other that this is fully indicative of an animal model for bipolar depression."

More information

To learn more about bipolar disorder, visit the U.S. National Institute of Mental Health.

SOURCES: Colleen McClung, Ph.D., assistant professor of psychiatry, University of Texas Southwestern Medical Center at Dallas; David J. Earnest, Ph.D., professor of neuroscience and experimental therapeutics, Texas A&M Health Science Center College of Medicine, College Station; March 19-23, 2007, Proceedings of the National Academy of Sciences
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