The lithium salts used in the United States are the carbonate(tetrahydrate) and the citrate. Lithium chloride is not usedbecause of its hygroscopic nature and because it is more irritatingthan the carbonate or citrate to the GI tract. The active species in these salts is the lithium ion. Theclassic explanation for its antimanic activity is that it resemblesthe sodium ion (as well as potassium, magnesium, andcalcium ions) and can occupy the sodium pump. Unlike thesodium ion, it cannot maintain membrane potentials.Accordingly, it might prevent excessive release of NTs(e.g., DA) that characterize the manic state. Many of theactions of lithium ion have been reviewed.Despite considerableinvestigation, the mode of action of lithium remainsunclear. The major possibility is that lithium reduces signaltransduction through the phosphatidylinositol signalingpathway by uncompetitive inhibition of inositol phosphatase.As a result, the pool of inositol available for the resynthesis of phosphatidylinositol-4,5-bisphosphate (PIP2)is depleted, the cellular levels of PIP2 is decreased, thereby,enzymatic formation of the second messengers is reduced.
Clinical Use
The indications for lithium salts are acute mania (oftenwith a potent neuroleptic agent for immediate control, becauselithium is slow to take effect) and as a prophylactic toprevent occurrence of the mania of bipolar manic–depressiveillness. Lithium salts are also used in severe recurrentunipolar depression. One effect of the drug that might bepertinent is an increase in the synthesis of presynaptic serotonin.Some have speculated that simply evening out transmission,preventing downward mood swing, for example,could be a basis for antidepressant action. Because of its water solubility, the lithium ion is extensivelydistributed in body water. It tends to become involvedin the many physiological processes involving sodium,potassium, calcium, and magnesium ions, hence, many sideeffects and potential drug interactions exist. The margin ofsafety is low; therefore, lithium should be used only when plasma levels can be monitored routinely. In the desireddose range, side effects can be adequately controlled. Because of the toxicity of lithium, there is substantial interestin design of safer compounds. As more is learnedabout lithium’s specific actions, the likelihood of successfuldesign of compounds designed to act on specific targets isincreased. Actually, carbamazepine and valproic acid,which target sodium channels, are proving to be effective.These two drugs are discussed in the anticonvulsant section.
