Bipolar disorder or manic depression is a major health problem
world-wide, causing a substantial reduction in quality of life,
with current treatments still giving patients a poor outlook
for recovery. Biological predisposition is a major factor in
the occurrence of this disorder, yet no genes have been identified
that give rise to this condition. Previous work (1) in Dictyostelium
however, has defined genes that are associated with the response
to lithium - a widely used bipolar treatment. This work provided
insight into how specific enzymes found to be elevated in bipolar
patients may function in this disorder (2,3).
We are using a pharmacogenetics approach to define the mechanisms
of action of valproic acid (VPA), a drug increasingly being
used in the treatment of bipolar disorder. This drug was originally
identified as an anti-epileptic treatment and is also teratogenic.
The mechanism of its action in these processes remains unknown,
although it has been associated with inositol depletion in regard
to bipolar disorder efficacy and inhibition of histone deacetylase
(HSDA) with respect to its teratogenicity (see figure 1).
We have isolated a range of Dictyostelium mutants resistant
to VPA during growth and development (see figure 2), and are
characterizing the genes giving rise to these mutants. 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.
