Researchers Gain Insights Into Drugs Used for Manic-Depression

Many people who suffer from bipolar disorder, or manic-depression, seem to respond best to a two-drug combination treatment. Researchers at the University of Wisconsin Medical School now believe they understand why.

In the current Proceedings of the National Academy of Sciences, the scientists show that both drugs stimulate release of a chemical that triggers brain cell activity responsible for helping control the wild mood swings of bipolar disorder. Used together, the drugs may achieve a desired outcome without causing dangerous side effects.

Some three million Americans suffer from bipolar disorder, consisting of major bouts of depression followed by episodes of mania that may lead to disastrous decisions and actions. As many as one in five manic-depressives commits suicide.

Until recently, lithium was the best medication available for the disease, but because of undesirable side effects many people discontinue its use. In the past few years, an anticonvulsant drug prescribed for epilepsy, called valproate, was also found to be effective. Clinicians discovered that best results often occurred by using a combination of both drugs, especially in patients who have a form of the disease that recurs frequently.

“Lithium can be very effective but it can cause gastrointestinal and kidney problems, weight gain and grogginess, making many people want to stop using it. At higher levels the drug can be highly toxic,” said UW Medical School professor of pharmacology Lowell Hokin. “Valproate does not produce the same toxicity.”

Hokin and his team have studied lithium for years in an effort to understand how it could control depression and mania at the same time.

Their earlier research revealed that lithium increases release of the neurotransmitter glutamate, in turn activating a receptor, NMDA, through which calcium must travel to enter a brain cell. Activation of the NMDA receptor also elevates levels of IP3, which is associated with calcium, the substance that controls many physiological processes.

“Lithium probably normalizes mood swings by helping shift the level of calcium more toward normal when levels are either abnormally high during mania or low during depression,” he said. “This seems to occur by the simultaneous elevation of IP3 and the down-regulation of the IP3 receptor.”

In the current research, the UW scientists showed that, like lithium, valproate also stimulates glutamate release and IP3 accumulation in the brains of mice. They also saw that each drug triggers glutamate release by different mechanisms, producing an additive, enhanced effect.

“This additive effect may explain the clinical observation that in some patients the use of the two drugs together can produce the best results,” he said.

Contact: Dian Land, 608-263-9893, dianland@macc.wisc.edu