The Genetics of Valproic Acid Resistance

Bipolar or manic depression is a major health problem world-wide causing a substantial reduction in quality of life, with current treatments still giving a poor prognosis for recovery. Biological predisposition is a major factor in the occurrence of this disorder, yet no genes have been identified as giving rise to this disorder. Previous work in Dictyostelium, however, has defined genes involved in the response to lithium - a commonly used bipolar treatment, providing insight into how specific enzymes found to be elevated in bipolar patients may function in this disorder.

We are now using a pharmacogenetics approach to define mechanisms of valproic acid (VPA) action, a drug increasingly being used in the treatment of bipolar depression. This drug was originally identified as an anti-epileptic treatment and is also teratogenic. The mechanism of its function in these processes remains unknown, although it has been associated with inositol depletion in regard to bipolar depression efficacy and inhibition of histone deacetylase (HSDA) in regard to its teratogenicity.

We have isolated a range of Dictyostelium mutants resistant to VPA during growth, and are characterizing the genes giving rise to these mutants. The identification of these genes and the biochemical mechanism of action of VPA will define novel genes involved in manic depression, epilepsy and in VPA teratogenicity and will help identify its cellular mechanism of action.