How Lithium Quells a Manic Riot

Although lithium chloride has been the drug of choice for treating manic depression for nearly a half-century, nobody has known how the drug acts to quell the turbulent mood swings characteristic of the illness. Now a study in tomorrow's issue of the Proceedings of the National Academy of Sciences suggests that the drug protects nerve cells from being stimulated to death. Because overstimulation is a hallmark of other brain diseases, such as Huntington's and Parkinson's, the new results offer hope that lithium might be useful in preventing the early stages of these maladies as well.

Lithium is often referred to as a mood-stabilizing drug for manic depressives because it can prevent or reduce the number of manic attacks--in which patients can become hyperactive and delusional--and improve overall mood. Researchers have developed several theories, but little proof, for what causes manic depression and how lithium helps alleviate it. One theory holds that a manic-depressive person's brain produces too much of the neurotransmitter glutamate, which binds to nerve cell triggers called NMDA receptors. The relentless barrage of glutamate, it's thought, might cause nerve cells to self-destruct in the hippocampus, a brain region that helps control mood. Because some alternative manic-depressive drugs work by blocking the NMDA receptor, De-Maw Chuang and his colleagues at the National Institute of Mental Health in Bethesda, Maryland, set out to test whether lithium counteracts the effects of excess glutamate.

The researchers first added toxic amounts of glutamate to cultures of three types of nerve cells: one found throughout the brain and the other two specific to the cerebral cortex and hippocampus. In all three cultures, half the neurons died within 24 hours, Chuang says. But when the researchers added a dose of lithium roughly equivalent to the concentration used in manic-depressive therapy, less than 10% of neurons died over the same length of time. "To our surprise, this neuroprotective is very robust and very long lasting," he says. As in manic-depressive patients treated with lithium, the protection persisted for 24 hours after treatment was stopped.

"It's a very interesting set of observations," says Steven Paul, vice president of research at Eli Lilly and Co., which is testing new drugs for treatment of manic depression. The study, he predicts, "will reinvigorate efforts to understand how lithium really works." He notes that it's unclear whether Chuang's results can be repeated in live animals. Such experiments are already under way, Chuang says, with "encouraging results" so far. He's looking forward to seeing lithium investigated for potential use in other neural diseases in which NMDA receptors get too much stimulation. "This raises the possibility that lithium could be used for protection in these diseases as well," Chuang says.