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. This article presents the evolution of the views on these mechanisms, and both the old and new findings are discussed. Among the old mechanisms, lithium's effect on the purinergic system; electrolyte metabolism; membrane transport; and second messenger systems, namely, cyclic nucleotide and phosphatidylinositol (PI), glycogen synthase kinase-3beta (GSK-3β), brain-derived neurotrophic factor, and neurotransmitters, are discussed. The new data were obtained from in vitro studies, molecular biology, and genetic research. They showed the effects of lithium on the immune system, biological rhythms, telomere functions, and mitochondria. In this article, each lithium mechanism is considered in the light of its association with the pathogenesis of bipolar disorder or/and as a marker of the lithium response. Although not exhaustive, this review elucidates the multiple potential mechanisms of lithium action. It was also observed that many seemingly "old" mechanisms have experienced a resurgence in research conducted during the 21st century. Additionally, many studies converged on the previously postulated mechanisms of lithium inhibiting GSK-3β and PI.