One drug used to treat bipolar disorder is lithium, an inhibitor of GSK-3 proteins controversially linked to congenital heart defects. However, new data indicate that mice lacking GSK-3-beta die before birth, mostly at the late stage of embryonic development because of numerous defects in the heart. It is therefore suggested that it might be wise to exercise caution when considering whether to treat women of childbearing age with newer, more powerful GSK-3 inhibitors.
Individuals with bipolar disorder are usually treated with 'mood stabilizing' drugs, one of which is lithium — an inhibitor of GSK-3 proteins.
As new drugs that are more powerful inhibitors of GSK-3 are under development despite controversial studies suggesting a link between lithium therapy and congenital heart defects, Thomas Force and colleagues, at Thomas Jefferson University, Philadelphia, set out to determine whether GSK-3 proteins are important for heart development in mice.
In the study, mice lacking GSK-3-alpha were born with a normal heart; however, mice lacking GSK-3-beta died before birth. Some of the embryos died of severe liver degeneration approximately half way through gestation, but most died at the late stages of development.
These embryos exhibited numerous defects in the heart, including thickening of the heart muscle due to increased proliferation of the heart muscle cells. The authors therefore suggest that although controversy remains as to whether lithium is teratogenic, it would be wise to exercise caution when considering whether to treat women of childbearing age with the new generation of GSK-3 inhibitors.
- Deletion of GSK-3-beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. Journal of Clinical Investigation, (in press)
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