Bipolar disorder (BD) is a common mental illness that affects 1‐2% of the world's population, including >100,000 veterans, causing severe mood symptoms, volumetric of loss of brain gray matter, and elevated rates of suicide. Among its symptoms, BD is associated with disrupted daily 24 hr rhythms (circadian rhythms) in sleep and activity. However, due to similarities and overlap with other psychiatric syndromes, it is commonly misdiagnosed and treatment delays are frequent. Lithium is an excellent treatment for BD, but 30‐50% of lithium treated patients fail to respond fully to treatment and/or suffer side‐effects. These factors cause needless delays from unsuccessful treatment, increasing cost, disability, and extending the window or risk for suicide. Because of these challenges, new techniques to diagnose BD, and more rapidly identify lithium responders would be of tremendous clinical utility. While the suprachiasmatic nucleus of the hypothalamus is the “master clock” for circadian rhythms, the genes that control circadian rhythms (“clock genes”) are functional in peripheral tissues and can be studied in cultured skin cells (fibroblasts) from patients. Lithium has effects on circadian rhythms in fibroblasts, altering the expression of clock genes, increasing rhythm amplitude (intensity) and lengthening period (the duration between cycles). Using bioluminescent reporter genes (Per2::luc), one can accurately study the circadian clock in tissues from BD patients and controls. Using this approach, we have identified clock gene abnormalities in BD, and circadian rhythm differences in period that distinguish lithium responsive and non‐ responsive BD patients. In other studies, we have identified neurotrophins as pharmacogenetic indicators of therapeutic response to lithium in BD patients. Interestingly, neurotrophins are expressed rhythmically under the control of the circadian clock. In this proposal, we aim to extend upon this work and synthesize these observations to 1) Establish a cellular model of lithium responsive BD based on cell death and protection by lithium 2) Determine the effect of circadian rhythm amplitude on regulating the vulnerability of neurons to oxidative/excitotoxic cell death and 3) Determine the relationship between circadian period and lithium responsiveness, focusing on neuroprotection by lithium. The methodological approach is molecular and cell based, using genetic (siRNA knockdown) and pharmacological means to manipulate circadian amplitude, period and overall rhythmicity in human fibroblasts, stem‐ cell derived induced neurons, and immortalized mouse hippocampal neurons. Following these manipulations, differences in circadian rhythm parameters (amplitude/period) and cell death will be measured in the absence and presence of lithium. It is expected that cells from lithium‐responsive patients will be more able to benefit from the protective effects of lithium in cell death assays. Furthermore, short‐...