Improving On Lithium In Depression

Lithium salts have been used for decades in the management of patients with manic depression, but they have severe toxicity problems and because their mechanism of action has been obscure it has been impossible to design rationally safer and more potent mimics. Now researchers at Merck Sharpe & Dohme's research facilities in the UK believe they have identified a crucial enzyme involved in the process which could lead to a new generation of effective drugs for bipolar disorder.

Reporting their findings in the Proceedings of the National Academy of Sciences, the MSD researchers believe they have uncovered convincing evidence to support a theory put forward in the mid-1980s that lithium acts by a mechanism known as the inositol depletion hypothesis. Inositol phosphates are found in cell membranes throughout the body and are thought to play a central role as secondary messengers within cells.

The inositol depletion hypothesis states that after inositol phosphates (IP3, IMP etc) have been used to trigger secondary events in the cell, they are recycled by the action of an enzyme, inositol monophosphatase, to form inositol. If this process occurs too rapidly, eg in certain central neurons of manic depressives, the cells become overactive and mood swings result. Lithium is thought to inhibit this enzyme, preventing excessive recycling and bringing calcium levels back under control.