The Mechanisms of Lithium Action: The Old and New Findings

Despite lithium's presence in modern psychiatry for three quarters of a century, the mechanisms of its therapeutic action have not been fully elucidated. In the article, the evolution of the views on these mechanisms is presented, and both the old and new findings are discussed. Among the old mechanisms, lithium effect on the purinergic system, electrolyte metabolism and membrane transport, second messenger systems: cyclic nucleotide and phosphatidylinositol (PI), glycogen synthase kinase-3beta (GSK-3β), brain-derived neurotrophic factor, and neurotransmitters, are discussed. The new data have been obtained from in vitro studies, molecular biology and genetic researches. They also showed the effect of lithium on the immune system, biological rhythms, and telomere functions. In the article, each lithium mechanism is considered in the light of its association with the pathogenesis of bipolar disorder or/and as a marker of lithium response. This review, although not complete, shows that the possible mechanisms of lithium action are multifold. It turned out that many apparent “old” mechanisms had their revival in research performed in the 21st century. Additionally, many studies eventually converged on the mechanisms postulated in the 1980s/1990s of inhibitiing GSK-3β and PI by lithium.