PtdIns(3,4,5)P(3) and inositol depletion as a cellular target of mood stabilizers.

Lithium (Li+) is the mood stabilizer most frequently used in the treatment of bipolar mood disorder; however, its therapeutic mechanism is unknown. In the 1980s, Berridge and colleagues proposed that Li+ treatment acts via inhibition of IMPase (inositol monophosphatase) to deplete the cellular concentration of myoinositol. Inositol depletion is also seen with the alternative mood stabilizers VPA (valproic acid) and CBZ (carbamazepine), suggesting a common therapeutic action. All three drugs cause changes in neuronal cell morphology and cell chemotaxis; however, it is unclear how reduced cellular inositol modulates these changes in cell behaviour. it is often assumed that reduced inositol suppresses Ins(1,4,5)P-3, a major intracellular signal molecule, but there are other important phosphoinostide-based signal molecules in the cell. in the present paper, we discuss evidence that Li+ has a substantial effect on PtdIns(3,4,5)P-3, an important signal molecule within the nervous system. As seen for Ins(1,4,5)P-3 signalling, suppression of PtdIns(3,4,5)P-3 signalling also occurs via an inositol-depletion mechanism. This has implications for the cellular mechanisms controlling phosphoinositide signalling, and offers insight into the genetics underlying risk of bipolar mood disorder.