Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is a well-documented circadian modulator. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium’s effect on the clock is fundamental to its mood-stabilizing effects.
We analysed the circadian rhythms of bipolar patient-derived fibroblasts and their responses to lithium and three small molecule modulators that phenocopies lithiums circadian response. Here we show, relative to controls patients exhibited a wider distribution of circadian period, and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed attenuated circadian responses to lithium as well as to other chronomodulators that mimics lithium. We further observed that the typical lithium-induced behavioural changes in mice were phenocopied by three chronomodulatory drugs and that a dysfunctional clock ablates this response.
Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. This advances our understanding of the role of circadian rhythms in BD and supports the wealth of evidence demonstrating a close relationship between circadian rhythms and the pathophysiology of BD. Our findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.