For over fifty years, the mood stabilizer lithium has proven its efficacy in preventing recurrence of mania andsuicide in bipolar patients more than any other drug. However, only a sub-population of patients benefit fromlithium treatment, full benefits may not be apparent for several months, and lithium has adverse, sometimestoxic, side effects. Therefore, a simple, rapid and reliable assay to predict which patients will show atherapeutic response to lithium, which can be applied prior to treatment, is needed. In this proposal, theeffects of lithium on mood stabilization and circadian rhythm expression in peripheral cells (fibroblasts) willbe correlated in lithium-responsive and lithium-insensitive bipolar disorder patients, to determine whethercircadian rhythm expression in human peripheral cells can be used to predict clinical lithium sensitivity inbipolar disorder patients. There is compelling evidence for a circadian component in the pathogenesis of atleast some forms of bipolar disorder, e.g., lithium affects circadian rhythm expression, and scheduled sleepwakecycles and prolonged darkness stabilize mood swings. In addition, the feasibility of using peripheralcells to determine circadian rhythm expression in humans has been reported in a recent study. Having foundthat several physiological factors in blood cells are affected in bipolar disorder patients, it is probable thatperipheral cells and circadian output can be used for a diagnostic assay for lithium responsiveness.A goal of our present proposal is to establish an assay system by which circadian rhythms can be monitoredusing human fibroblasts with a circadian reporter and real time bioluminescence monitoring, and to test thehypothesis that clinical response to lithium can be predicted using human peripheral cells. Therefore, specificaims will be: (1) To establish and optimize a screening method by which circadian rhythms can be monitoredin human peripheral cells, and (2) to test the hypothesis that lithium differentially affects circadian Bmallbioluminescencerhythms in fibroblasts of lithium-responsive and lithium-insensitive patients.By testing the effects of lithium on circadian rhythm expression in human peripheral cells, we expect toestablish an assay to pre-screen patients for lithium responsiveness prior to drug treatment, and, in futurestudies, to dissect the mechanisms responsible for bipolar disorder, particularly from the viewpoint of lithiumsensitivity and circadian rhythm generation. The model and assay system should also be useful in medium tohigh throughput screening for new drugs to treat both lithium-responsive and -resistant patients with bipolardisorder.
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