New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview

For the past 60 years, lithium has been the drug of choice for the maintenance treatment of bipolar disorder due to its potent ability to prevent both manic and depressive episodes. However, although lithium has been associated with many effects within different cellular pathways and biological systems, its specific mechanism of action in stabilizing mood remains largely elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms through which lithium exerts its effects. These insights are derived from investigations utilizing cellular and animal models of neuropsychiatric and neurodegenerative disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Additionally, novel animal and human models have enhanced our comprehension of how lithium-induced alterations at the homeostatic synaptic plasticity level might contribute to its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with micro-RNA expression. This perspective offers an intriguing potential to bridge the gap between the molecular actions of mood stabilizers and their clinical effectiveness.. Finally, we explore the repurposing potential of lithium beyond bipolar disorder. A deeper understanding of the therapeutic mechanisms of lithium provides the opportunity to develop predictive models of response to lithium treatment and identify new biological targets. Significance Statement Lithium has been the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. In this review, we provide the most recent evidence on lithium9s various mechanisms of action. Recent research has further strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the homeostatic synaptic plasticity level, and regulation of micro-RNA expression as key mechanisms providing an intriguing perspective that may help fill the mechanism underlying its clinical efficacy.