Neurobiology of Lithium: An Update

Lithium remains a first-line approach for the treatment of acute mania and the prophylactic managementof manic-depressive illness, yet the underlying neurobiological mechanisms remain as yet undefined.In this paper we critically examine the accumulated preclinical and clinical evidence for the actionof lithium in the brain and suggest areas that may be most productive for future investigation, i.e., membranetransport systems, neurotransmitter receptor regulation, second messenger generating systems,protein kinase C (PKC) regulation, and gene expression. In their experimental design, preclinical investigationshave often jeopardized the physiologic relevance of their studies by a relative lack of attention toissues such as therapeutic concentrations, acute versus chronic exposure, and a lack of adequate cationand/or psychotropic controls. Future studies should account for the established prophylactic efficacy oflithium, the higher risk for relapse into mania after abrupt discontinuation, the ability of lithium to stabilizerecurrent depression associated with unipolar disorder, and the efficacy of lithium in the treatment ofrefractory major depressive disorder in the presence of an antidepressant. Studies of the action of lithiumin receptor mediated phosphoinositide signaling in the brain over the past several years have opened upheuristic lines of investigation that stem from lithium’s uncompetitive inhibition of the enzyme inositolmonophosphatase. Subsequent studies involving regulation of inositol transport, PKC isozymes and activity,and the expression of the major PKC substrate MARCKS (myristoylated alanine-rich C-kinasesubstrate) have offered potential avenues for understanding the complexity of the action of long-termlithium in the brain. These studies will offer us a better understanding of the neuroanatomical sites ofaction of lithium and together with ongoing clinical investigations using brain imaging in patients withmanic-depressive illness a more complete understanding of the pathophysiology of this disease.