Research Explains Lithium's Dual Anti-Manic/Anti-Depressive Effect

MADISON, Wis. -- Researchers at the University of Wisconsin Medical School have solved the puzzle of how one drug -- lithium -- can effectively stabilize both the wild euphoria and the crushing melancholy that are the hallmark of manic depression, or bipolar disorder.

As reported in the current (July 7) Proceedings of the National Academy of Sciences, the researchers found that in mice brains, lithium exerts a push/pull effect on the neurotransmitter glutamate, eventually causing it to level off in a stable zone where it can control both extremes.

"Glutamate is the primary excitatory neurotransmitter, carrying messages instantaneously from one nerve cell to another in 85 percent of the brain," said UW Medical School professor of pharmacology Dr. Lowell Hokin, who directed the research. Other neurotransmitters include serotonin, dopamine, norepinephrine and acetylcholine.

Under normal circumstances, an impulse from a nerve cell releases a flood of message-bearing glutamate aimed at a neighboring neuron across the synapse. A structure on the end of the releasing nerve cell, called a reuptake transporter, then shuts off the signal by reabsorbing the glutamate, pumping it back into the cell for reuse.

If the reuptake mechanism malfunctions, inappropriate concentrations of neurotransmitter remain in the synapse. Hokin postulates abnormally low glutamate levels are involved in depression, while elevated levels are responsible for mania.

Nearly a half century ago, Australian psychiatrist John F. Cade discovered lithium's mood-stabilizing effect. It has long been the drug of choice in treating bipolar disorder, which affects approximately 2.5 million Americans. Despite some side effects, lithium usually successfully dampens the mood swings that in the most severe cases end in suicide, the dire result for one in five untreated or unresponsive bipolar patients.

In an earlier study (reported in PNAS, Aug. 30, 1994), Hokin and his colleague showed th

Contact: Lisa Brunette
University of Wisconsin-Madison

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