Mood stabilizers: protecting the mood…protecting the brain

The mechanism underlying the therapeutic action of mood stabilizers in bipolar disorder is not completely understood. The discovery that anticonvulsant agents, such as valproate (VPA), were effective in the treatment of bipolar disorder suggested a common biochemical mechanism(s) with lithium. Recent research has focused on how VPA and lithium change the activities of cellular signal transduction systems, especially the cyclic AMP and phosphoinositide second messenger pathways. Despite being structurally dissimilar, VPA produces effects on the protein kinase C (PKC) signalling pathway that are similar to lithium, although the VPA effects appear to be largely independent of myo-inositol. Furthermore, the therapeutic benefit of either drug require a prolonged administration suggesting alterations at the genomic level. Studies have revealed that both VPA and lithium altered the expression of several early inducible genes belonging to the AP-1 family of transcription factors; this family is responsible for controlling the expression of a number of genes including cytoprotective proteins such as the anti-apoptotic protein, bcl-2. Evidence shows that chronic administration of VPA or lithium can stimulate bcl-2 expression as well as inhibit GSK-3β activity, which renders a cell less susceptible to apoptosis. Thus, the mood stabilizers may act to restore the balance among aberrant signalling pathways in specific areas of the brain and prevent degeneration.