0066-4219/96/0401-047$08.00 47 Annu. Rev. Med. 1996. 47:47–56 Copyright © 1996 by Annual Reviews Inc. All rights reserved HOW DOES LITHIUM WORK ON MANIC DEPRESSION? Clinical and Psychological Correlates of the Inositol Theory R. H. Belmaker, M.D., Yuly Bersudsky, M.D., Galila Agam, M.D., Joseph Levine, M.D., and Ora Kofman, M.D. Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel KEY WORDS: lithium, inositol, manic depression ABSTRACT How lithium works in manic-depressive illness is unknown. Recently, however, a powerful hypothesis has been gaining momentum. Distinguished by its test- ability and clinical implications, the inositol depletion hypothesis of lithium action is relevant to treatment of lithium side effects, to the development of new compounds with the clinical profile of lithium, and to new experimental treat- ment of depression. LITHIUM Lithium (Li) is a simple monovalent cation, which as a salt is used in the treatment of mania, in the augmentation treatment of depression, and in the prophylaxis of manic-depressive illness. As these are common disorders asso- ciated with almost normal life spans, large numbers of patients are being maintained on Li salt treatment. Lithium’s numerous clinical side effects, its interactions with antihypertensives and with general anesthesia, and its poten- tial for neurotoxicity, however, make it a concern. Li has numerous biological effects. It markedly increases choline levels in red blood cells, probably by inhibiting transport. However, the effect in red