Is competition between Li+ and Mg2+ the underlying theme in the proposed mechanisms for the pharmacological action of lithium salts in bipolar disorder?

Lithium salts have been in use for the treatment of bipolar disorder for more than 50 years, but their pharmacological mode of action remains a matter of conjecture. Li(+) and Mg(2+) share many physicochemical properties. Not surprisingly, many reported cellular targets for Li(+) action involve Mg(2+)-activated enzymes, which are inhibited by Li(+). In this Account, we describe results from our and other laboratories that suggest that a competition mechanism between Li(+) and Mg(2+) ions for Mg(2+)-binding sites in cellular components is the underlying theme in putative mechanisms of Li(+) action.