Research explains lithium’s dual anti-manic/ anti-depressive effect

Researchers at the UW 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 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 that lithium causes glutamate to accumulate in synapses of mice and monkey brain slices, but exactly how it worked remained unclear until now.

In the current study, functioning slices of mice brain were examined following exposure to lithium, while control slices were not exposed to the drug. The researchers observed that lithium raised the glutamate level by slowing its reuptake. The higher the lithium dose, the greater the inhibition, they found.

To study the chronic effect of the lithium, the UW team administered it to live mice for two weeks. To their surprise, they saw that glutamate reuptake increased. This “up-regulation” resulted in less neurotransmitter in the synapse, which would produce an anti-manic effect.

“We were especially interested to find that the reuptake mechanism in the 18 lithium-treated mice was stabilized in a very narrow range, compared to the 18 controls,” he said.

Hokin speculates a compensatory mechanism in the reuptake system strives over time to reset raised glutamate levels down into a fixed range. When the levels are too low, as postulated in depression, lithium brings them up into the stable region.

The research findings support clinical observations, he noted.

“It takes a few weeks before lithium begins to relieve depression and mania in bipolar patients,” he said. “It’s now apparent an adaptive reuptake mechanism that brings glutamate within a ‘normal’ range works over time to curb both the highs and lows.”

What’s more, he added, lithium doesn’t change the moods of people who aren’t bipolar, suggesting that their glutamate levels may be positioned consistently within the set zone, and therefore would not be affected by the drug.