View Full Version : Lithium & Gene Expression

04-08-05, 09:44 AM
from Kimberly Bailey Read

The Research Continues
Since the early 1800s, Lithium has been a first-line medication in the treatment of bipolar disorder (manic depression). Its effectiveness in reducing mania and stabilizing mood is well studied and documented. However, the pharmacology - the characteristics of a drug that make it medically effective – of Lithium is not fully understood ... yet. Researchers continue to seek the mechanism by which lithium reduces emotional instability.

In the quest to gain knowledge about Lithium and, by extension, bipolar disorder, a research team "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" (Hardman, 2005).

To understand the research findings of this study, it is important to know that genes are much more than what we were taught in the simple lectures we probably all remember from high school science.

It is true that the genes we inherit from our parents determine almost everything about us – hair color, nose shape, height, intelligence, sex, etc. However, we are much more complicated then this simplistic presentation allows. I am sure you would prefer not to have a crash course in genetic biology, so suffice it to say that one important aspect of genetics is that many genes in our makeup can "change expression." They can be <i>activated or deactivated.</i> They can begin producing or change production of chemicals in the body.
Inositol monophosphate is a chemical in the brain that works as a switch - turning the activity of certain genes on and off. In some cases the presence of inositol causes a gene to activate, and in other cases it causes a gene to shut down. Specifically, inositol seems to be the switch for genes that produce a hormone called PACAP (which for the scientists among you is the neuropeptide hormone pituitary adenylate cyclase activating polypeptide). A shortage of PACAP in mice brains has been linked to hyperactivity and defects in circadian (day-night) behavior, which are both also characteristic of humans with bipolar disorder.

Lithium is known to inhibit production of inositol. Therefore, these researchers “hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium’s therapeutic efficacy in bipolar disorder” (Brandish, et al, 2005).

What does this mean? PACAP is important in regulating certain aspects of our behavior which may be associated with bipolar disorder. The production of PACAP in the brain is turned on by the absence of inositol. Lithium decreases the amount of inositol that is produced in the brain, thus allowing for more PACAP.

This possible insight into Lithium's mechanism in stabilizing mood holds incredible potential for improved treatment. As previously noted, the effectiveness of Lithium for the majority of those with this disorder is well-established. However, the side effects are quite numerable and, for some, intolerable. Additionally, there are those for whom Lithium is an inadequate treatment. Through the findings of this study and others to follow, perhaps it will not be too much longer before specific gene-targeted medications are available.