Lithium, circadian rhythm, and bipolar disorder

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For over fifty years, the mood stabilizer lithium has proven its efficacy in preventing recurrence of mania and suicide in bipolar patients more than any other drug. However, only a sub-population of patients benefit from lithium treatment, full benefits may not be apparent for several months, and lithium has adverse, sometimes toxic, side effects. Therefore, a simple, rapid and reliable assay to predict which patients will show a therapeutic response to lithium, which can be applied prior to treatment, is needed. In this proposal, the effects of lithium on mood stabilization and circadian rhythm expression in peripheral cells (fibroblasts) will be correlated in lithium-responsive and lithium-insensitive bipolar disorder patients, to determine whether circadian rhythm expression in human peripheral cells can be used to predict clinical lithium sensitivity in bipolar disorder patients. There is compelling evidence for a circadian component in the pathogenesis of at least some forms of bipolar disorder, e.g., lithium affects circadian rhythm expression, and scheduled sleepwake cycles and prolonged darkness stabilize mood swings. In addition, the feasibility of using peripheral cells to determine circadian rhythm expression in humans has been reported in a recent study. Having found that several physiological factors in blood cells are affected in bipolar disorder patients, it is probable that peripheral 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 monitored using human fibroblasts with a circadian reporter and real time bioluminescence monitoring, and to test the hypothesis that clinical response to lithium can be predicted using human peripheral cells. Therefore, specific aims will be: (1) To establish and optimize a screening method by which circadian rhythms can be monitored in human peripheral cells, and (2) to test the hypothesis that lithium differentially affects circadian Bmallbioluminescence rhythms 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 to establish an assay to pre-screen patients for lithium responsiveness prior to drug treatment, and, in future studies, to dissect the mechanisms responsible for bipolar disorder, particularly from the viewpoint of lithium sensitivity and circadian rhythm generation. The model and assay system should also be useful in medium to high throughput screening for new drugs to treat both lithium-responsive and -resistant patients with bipolar disorder.