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Lithium Blocks Enzyme To Help Cells’ Clocks Keep On Tickin’

Science Update

NIMH-funded researchers have discovered how lithium likely fixes body clocks gone awry, stabilizing sleep-wake cycles and other daily rhythms disturbed along with mood in bipolar disorder. By blocking an enzyme, lithium, a natural salt, stabilizes a receptor that serves as a pivotal link in the clocks' intricate workings, report Peter Klein, M.D., and colleagues at the University of Pennsylvania in the February 17, 2006 issue of Science.


A master clock in the brain, reset by light, enforces a daily rhythm within every cell that mirrors the organism's activity cycles, such as sleep, body temperature and metabolism. For this intracellular clock to work properly, clock genes must turn on and off in synchronized, rhythmic feedback loops — a process likely upset in bipolar disorder.

In cultured cells, Klein and colleagues showed that lithium triggers a critical step in synchronizing the rhythmic expression of the clock genes. Lithium turned off the enzyme GSK-3ß, causing the receptor Rev-erbα to degrade, leading to the rhythmic turning-on of the protein Bmal1, which starts the clock cycle. The results reveal a pathway by which lithium may act to restore daily rhythms in bipolar disorder.

A version of the GSK-3ß gene has been linked to a milder, more easily treatable form of bipolar disorder. Valproic acid, another mood stabilizer used to treat bipolar disorder, has also been found to modulate daily rhythms. The researchers suggest that "targeting Rev-erbα degradation may have potential in the treatment of bipolar and circadian disorders."

Yin l, Wang J, Klein PS, Lazar MA, Nuclear receptor rev-erbα is a critical lithium-sensitive component of the circadian clock.  Science, Vol. 311. no. 5763, pp. 1002 - 1005.