The mechanisms of action of lithium in bipolar disorder

Abstract Lithium has mood stabilization, neuroprotective, and antisuicidal effects. However, the mechanism of lithium remains unclear. The genetic basis for lithium treatment response in bipolar disorder is likely through upregulating and/or downregulating specific genes in neurons and other cells. The regulation of gene expression is believed through intracellular pathways in which calcium level and glycogen synthase kinase-3 are key elements. Modulation of enzymes and proteins of lithium can affect neuronal shapes and dendritic spines, release of neurotransmitters, production of cytokines, regulation of circadian rhythm, and reduction of oxidative burden. These functions are essential for cell survival, neuroplasticity, and prevention of cell death. However, most of these benefits more likely occur in lithium responders. Changes in brain volumes and neuronal connectivity and functional differences between lithium-treated and nonlithium-treated patients and between lithium responders and lithium nonresponders support the neurotrophic and neuroprotective effects of lithium.