Mood stabilizers: protecting the mood ... protecting the brain

The mechanism underlying the therapeutic action of mood stabilizers in bipolar disorder is not completely understood. Thediscovery that anticonvulsant agents, such as valproate (VPA), were effective in the treatment of bipolar disorder suggested acommon biochemical mechanism(s) with lithium. Recent research has focused on how VPA and lithium change the activities ofcellular signal transduction systems, especially the cyclic AMP and phosphoinositide second messenger pathways. Despitebeing 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 drugrequire a prolonged administration suggesting alterations at the genomic level. Studies have revealed that both VPA and lithiumaltered the expression of several early inducible genes belonging to the AP-1 family of transcription factors; this family isresponsible for controlling the expression of a number of genes including cytoprotective proteins such as the anti-apoptoticprotein, bcl-2. Evidence shows that chronic administration of VPA or lithium can stimulate bcl-2 expression as well as inhibitGSK-3h activity, which renders a cell less susceptible to apoptosis. Thus, the mood stabilizers may act to restore the balanceamong aberrant signalling pathways in specific areas of the brain and prevent degeneration