Lithium Begins to Reveal Its Secrets

The mechanism of action of the antimania drug lithium has been the subject of research for nearly 30 years. However, after 51 years on the market, lithium—considered by many bipolar disorder experts to be the most efficacious drug available to treat the disorder—is still not well understood. A new report from National Institutes of Health (NIH) investigators, however, may shed light on a mechanism of action shared not only by lithium, but other antimania medications as well.

Stanley Rapoport, M.D., chief of the Brain Physiology and Metabolism Section of the National Institute on Aging, reported in the July Archives of General Psychiatry that lithium selectively interacts with the “arachidonic acid (AA) cascade,” reducing the amount of AA recycled in brain cells. The report postulated that the AA cellular signaling cascade—a long series of chemical reactions within the cell that results in the production of various proteins, enzymes, and other cellular signaling molecules—is “functionally hyperactive in mania.” Drugs that target components of the cascade, Rapoport concluded, might be candidate treatments for mania.

A report detailing the same effects on the AA cascade by the anticonvulsant drug valproic acid, now commonly used as an antimania medication, is pending publication in Biological Psychiatry.

Finding a common mechanism of action between medications that are quite different structurally and chemically is a significant step in the search for a pathological basis for bipolar disorder. Once researchers know how the drugs work, they can work backward to discover the biological root of the disorder.

Focusing on the interactions of lithium with cellular cascades is old news. Over the last 20 to 25 years, Rapoport told Psychiatric News, research has focused on a cascade referred to as the phospholipase C pathway, a series of chemical steps resulting in the production of the brain chemical inositol, among other substances. Out of this research came the “inositol depletion theory.” This holds that the symptoms of bipolar disorder are related to changes in the production and metabolism of inositol, resulting in an overall shortage of the chemical.

According to some researchers, an enzyme in the pathway that converts precursors into inositol is somehow inhibited by lithium. Additional data have been reported that indicate lithium may interfere with a second major cellular signaling cascade, involving the conversion of adenylate cyclase into adenosine tri-phosphate (ATP), the basic chemical fuel that drives all cellular processes.

“Now, I’m not saying they’re wrong,” Rapoport said, “because we really don’t know all the actions of lithium; what I am saying is that those pathways have largely been investigated. But what has been ignored is phospholipase-A2 (PLA2) [the group of enzymes that start the cascade involving AA], the third of the three major cellular signaling cascades.”

One reason for not looking at the AA cascade was that, until recently, it was very difficult to measure AA production and recycling in living animals, although it could be done in cell culture. Rapoport and his colleagues at NIH developed a method using a radio-isotope tracer to image AA production and turnover in living animals. The new method allows researchers to quantify just how much AA is being used and recycled by brain cells.

Using the imaging method, Rapoport found that lithium fed to rats for six weeks at doses geared to achieve therapeutic blood levels reduced the AA turnover in rat brains by 75 percent. The report also details that the reduction in AA turnover was highly specific—other parts of the PLA2 cascade were not affected. When the same procedure and imaging techniques were repeated with long-term administration of valproic acid, AA turnover was again specifically reduced.

Intriguingly, when Rapoport looked further, he found that lithium was selectively reducing the gene expression and enzyme activity of a single specific enzyme within the PLA2 group of related enzymes. That specific enzyme turned out to be cyclooxygenase 2 (COX-2), a major component of the pathway that produces inflammation in tissues. (COX-2 inhibitor drugs like Vioxx and Celebrex are effective anti-inflammatory medications.) Although Rapoport and his colleagues are still studying the effect of valproic acid on the AA cascade, it appears as though it achieves the same reduction in AA availability, but through a different enzyme target.

“Our hypothesis,” Rapoport said, “is that it is the PLA2-initiated release of arachidonic acid and its secondary conversion by cyclooxygenases to prostaglandins that is the target for lithium and possibly for valproic acid and other anticonvulsants used in bipolar disorder.”

Rapoport’s lab is now looking at the AA cascade and other known antimania medications, such as carbamazepine.

“The interesting side product of this research,” Rapoport concluded, “is that now we have a testable hypothesis: Do COX-2 inhibitors help in bipolar disorder?” If his hypothesis is correct, the answer should be yes. Rapoport assured Psychiatric News that he’s working on it.

The article “Do Lithium and Anticonvulsants Target the Brain Arachidonic Acid Cascade in Bipolar Disorder?” is posted on the Web at http://archpsyc.ama-assn.org/issues/current/rfull/ynv10318.html. ▪

Arch Gen Psychiatry 2002 59 592