Bipolar mood disorder, often called manic depression, is a long-term psychiatric illness that causes dramatic changes in energy, behaviour and mood. The underlying cause, or causes, of this disorder are unknown and there is no cure for this illness. In most cases, the disease is treated with mood-stabilising medications. Of these, lithium is the most common and possibly the best; however, despite over 50 years of clinical use, its therapeutic mechanisms remain unknown.
At the cellular level, lithium causes depletion of myo-inositol. One prevalent hypothesis is that this reduces inositol (1,4,5)-trisphosphate [IP3, also known as Ins(1,4,5)P3], an important intracellular signalling molecule. So far, extensive investigation has failed to establish whether inhibition of IP3 signalling is the therapeutic mechanism for lithium or whether changes in IP3 are associated with the disorder.
This study provides the first demonstration that lithium has a major effect on phosphatidylinositol (3,4,5)-trisphosphate [PIP3, also known as PtdIns(3,4,5)P3], an alternative inositol-based signalling molecule. Lithium suppresses PIP3 signalling in both the social amoeba Dictyostelium and cultured human neutrophil cells. It does this by suppressing synthesis of the phosphoinositide precursors of PIP3. Increased expression of the enzyme inositol monophosphatase (IMPase) reverses the effects of lithium, suggesting that lithium acts through inositol depletion. Interestingly, in the absence of lithium, elevated IMPase leads to elevated PIP3 signalling.
These findings have important implications in lithium therapy and neurochemistry. PIP3 is a major signalling molecule in neurons, and suppression of PIP3 signalling may have significant neuromodulatory effects in bipolar mood disorder patients. There is a strong familial predisposition for bipolar mood disorder suggesting a genetic component. These findings support further investigation of genes associated with PIP3 signalling, such as the IMPase gene IMPA2. The ability of lithium to target PIP3 might also lead to new therapeutic uses for lithium. Aberrant PIP3 signalling is linked to a range of neurological diseases, including macrocephaly, epilepsy and autism. Beyond the nervous system, regulators of PIP3 signalling are frequently mutated in tumours and inheritable diseases. Furthermore, the mood stabilisers valproic acid and carbamazepine also deplete inositol and may be used to suppress PIP3 signalling. Unlike lithium, these drugs can be chemically modified, presenting a route to new generations of PIP3 inhibitors.
