Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders

Abstract

Breno Satler Diniz,1 Rodrigo Machado-Vieira,2,3 Orestes Vicente Forlenza2 1Department of Mental Health, National Institute of Science and Technology – Molecular Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil; 2Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil; 3Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, USA Abstract: In the last two decades, a growing body of evidence has shown that lithium has several neuroprotective effects. Several neurobiological mechanisms have been proposed to underlie these clinical effects. Evidence from preclinical studies suggests that neuroprotection induced by lithium is mainly related to its potent inhibition of the enzyme glycogen synthase kinase-3ß (GSK-3ß) and its downstream effects, ie, reduction of both tau protein phosphorylation and amyloid-ß42 production. Additional neuroprotective effects include increased neurotrophic support, reduced proinflammatory status, and decreased oxidative stress. More recently, neuroimaging studies in humans have demonstrated that chronic use is associated with cortical thickening, higher volume of the hippocampus and amygdala, and neuronal viability in bipolar patients on lithium treatment. In line with this evidence, observational and case registry studies have shown that chronic lithium intake is associated with a reduced risk of Alzheimer's disease in subjects with bipolar disorder. Evidence from recent clinical trials in patients with mild cognitive impairment suggests that chronic lithium treatment at subtherapeutic doses can reduce cerebral spinal fluid phosphorylated tau protein. Overall, convergent lines of evidence point to the potential of lithium as an agent with disease modifying properties in Alzheimer’s disease. However, additional long-term studies are necessary to confirm its efficacy and safety for these patients, particularly as chronic intake is necessary to achieve the best therapeutic results. Keywords: lithium, Alzheimer’s disease, prevention, GSK-3ß, neuroprotection