Potential New Target Found for Developing Medications to Treat Bipolar Disorder

Medications that target the protein BAG1, which regulates a process that can trigger symptoms in people who have bipolar disorder, may offer a new way of treating the disease, according to NIMH scientists. Their study was published online June 18, 2008, in the Proceedings of the National Academy of Sciences.

People with bipolar disorder, also called manic depressive illness, experience unusually intense emotional states that occur in distinct periods called mood episodes. An overly joyful or overexcited state is called a manic episode, and an extremely sad or hopeless state is called a depressive episode.

Among other functions, the protein BAG1 regulates the activity of glucocorticoid receptors (GRs). Receptors, proteins on the surface of or inside cells, are where brain chemicals exert their effects. Glucocorticoids are hormones that activate GRs and can trigger both manic and depressive episodes in susceptible individuals.

In the study, Husseini K. Manji, M.D., director of the NIMH Mood and Anxiety Disorders Program, and colleagues compared mice genetically engineered to over-produce BAG1 with mice that produced only half the normal levels of the protein, as well as normal mice that served as the control group.

In stressful test conditions, mice that produced higher levels of BAG1 showed less anxiety than control group mice. Over-producing mice also showed rapid spontaneous recovery from depression-like behaviors. Mice that produce half the normal amount of protein showed somewhat delayed spontaneous recovery.

In another test, mania-like symptoms were chemically induced in the mice, causing them to move around more than normal. Mice with higher levels of BAG1 recovered faster from the mania-like symptoms, returning to normal rates of movement about four hours earlier than control group mice.

The main treatments for bipolar disorder, the medications lithium and valproate, are both known to enhance the action of BAG1. To date, however, no studies have conclusively shown that BAG1 is linked with mood disorders in humans. BAG1 is also important for regulating neuronal survival.

The current findings suggest that medications that directly affect BAG1 may be a potential new strategy for developing more targeted treatments to improve recovery from both depressive and manic episodes in bipolar disorder, as well as managing stress-related reactions in general.

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