Beyond Lithium For Bipolar Disorder

While lithium treatment has proven to be a godsend for many of the two million Americans with bipolar disorder, it is not without its downside. People on the drug may develop hypothyroidism, tremors, cognitive impairment, and excessive thirst and urination and gain weight.

However, better treatments for bipolar disorder depend on a better understanding of the still-mysterious mechanism by which lithium damps the highs and lows of the disorder. Now, researchers led by Philip Brandish of Merck & Co., Inc., and Edward Scolnick of the Broad Institute (formerly of Merck and Co., Inc.) have identified genes whose activity appears to be switched on by lithium, suggesting more direct targets for drugs to treat the disorder.

Lithium is known to inhibit the production of an important cellular switch, called inositol monophosphate, so the researchers set out to find genes that were activated by this inhibition. They treated slices of rat brain with lithium chloride as well as a chemical that depletes inositol. The also treated other slices with the two chemicals, but added inositol.

The researchers used DNA microarrays--so-called "gene chips"--to detect genes that were unequivocally activated when inositol was depleted in the brain slices.

They discovered several genes that they concluded "suggest new directions toward the treatment of bipolar disorder."

The behavior of one such activated gene, called GPR88, has been found to be associated with a rat model of mania, they said. This gene codes for a protein that is an "orphan receptor"--that is, its cellular function in sensing external chemical signals is unknown.

The researchers also found that the gene called AD-CYAP1 was upregulated in the treated brain slices. This gene codes for a signaling molecule called PACAP in the brain and is known to be close to a chromosomal region that genetic studies have shown to be associated with a higher risk of bipolar disorder.

PACAP protein is found throughout the central nervous system, said the researchers. They cited studies demonstrating that mice in which the gene is knocked out show hyperactivity and defects in their circadian (day-night) behavior--both also characteristic of humans with bipolar disorder. Also, in animals, lithium has been shown to affect such circadian behavior. The protein also has been found to affect the activity of a key neurotransmitter, dopamine, in the brain, said the researchers. What's more, they found two other genes--PAM and GCH--that are involved in producing PACAP to be upregulated in the treated brain tissue.

Brandish and his colleagues said that such findings "suggest a coordinated upregulation of genes leading to increased dopamine signaling. In the light of the recent clinical data and human genetic linkage, it is tempting to speculate that PACAP night be a therapeutic effector of lithium in bipolar disorder."

They concluded that "the data presented here warrant further investigation of PACAP signaling in the brain and of the orphan receptor GPR88 as potential new targets in bipolar disorder."

Philip E. Brandish, Ming Su, Daniel J. Holder, Paul Hodor, John Szumiloski, Robert R. Kleinhanz, Jaime E. Forbes, Mollie E. McWhorter, Sven J. Duenwald, Mark L. Parrish, Sang Na, Yuan Liu, Robert L. Phillips, John J. Renger, Sethu Sankaranarayanan, Adam J. Simon, and Edward M. Scolnick: "Regulation of Gene Expression by Lithium and Depletion of Inositol in Slices of Adult Rat Cortex"

* * *

The researchers include Philip E. Brandish, Ming Su, Daniel J. Holder, Paul Hodor, John Szumiloski, Sang Na, Yuan Liu, Robert L. Phillips, John J. Renger, Sethu Sankaranarayanan, and Adam J. Simon of Merck & Co., Inc.; Robert R. Kleinhanz, Jaime E. Forbes, Mollie E. McWhorter, Sven J. Duenwald, and Mark L. Parrish of Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co. Inc.; and Edward M. Scolnick of The Broad Institute (formerly of Merck and Co., Inc.). Conflict of Interest Statement: The authors are employees of Merck & Co., Inc. and potentially own stock and/or hold stock options in the company.

Publishing in Neuron, Volume 45, Number 6, March 24, 2005, pages 861-872. http:/?/?www.neuron.org

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