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Lithium has been used for the treatment of mood disorders for over 60 years, yet the exact mechanisms by which it exerts its therapeutic effects remain unclear. Two enzymatic chains or pathways emerge as targets for lithium: inositol monophosphatase within the phosphatidylinositol signalling pathway and the protein kinase glycogen synthase kinase 3. Lithium inhibits these enzymes through displacing the normal cofactor magnesium, a vital regulator of numerous signalling pathways. Here we provide an overview of evidence, supporting a role for the inhibition of glycogen synthase kinase 3 and inositol monophosphatase in the pharmacodynamic actions of lithium. We also explore how inhibition of these enzymes by lithium can lead to downstream effects of clinical relevance, both for mood disorders and neurodegenerative diseases. Establishing a better understanding of lithium’s mechanisms of action may allow the development of more effective and more tolerable pharmacological agents for the treatment of a range of mental illnesses, and provide clearer insight into the pathophysiology of such disorders.

Lithium: the pharmacodynamic actions of the amazing ion