Neurobiology of lithium: an update.

Lithium remains a first-line approach for the treatment of acute mania and the prophylactic management of 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 action of lithium in the brain and suggest areas that may be most productive for future investigation, i.e., membrane transport systems, neurotransmitter receptor regulation, second messenger generating systems, protein kinase C (PKC) regulation, and gene expression. In their experimental design, preclinical investigations have often jeopardized the physiologic relevance of their studies by a relative lack of attention to issues such as therapeutic concentrations, acute versus chronic exposure, and a lack of adequate cation and/or psychotropic controls. Future studies should account for the established prophylactic efficacy of lithium, the higher risk for relapse into mania after abrupt discontinuation, the ability of lithium to stabilize recurrent depression associated with unipolar disorder, and the efficacy of lithium in the treatment of refractory major depressive disorder in the presence of an antidepressant. Studies of the action of lithium in receptor mediated phosphoinositide signaling in the brain over the past several years have opened up heuristic lines of investigation that stem from lithium's uncompetitive inhibition of the enzyme inositol monophosphatase. Subsequent studies involving regulation of inositol transport, PKC isozymes and activity, and the expression of the major PKC substrate MARCKS (myristoylated alanine-rich C-kinase substrate) have offered potential avenues for understanding the complexity of the action of long-term lithium in the brain. These studies will offer us a better understanding of the neuroanatomical sites of action of lithium and together with ongoing clinical investigations using brain imaging in patients with manic-depressive illness a more complete understanding of the pathophysiology of this disease.