Abstract
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 well documented to induce period lengthening and amplitude enhancement of the circadian clock. 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 analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), 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 muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient’s circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.
Highlights
IntroductionBipolar disorder (BD) is a chronic illness characterized by recurrent episodes of abnormal mood
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKNuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, South Parks Road, Oxford OX1 3RE, UKAddenbrookes Hospital, Cambridge University Hospitals NHSBipolar disorder (BD) is a chronic illness characterized by recurrent episodes of abnormal mood
We show that drugs that phenocopy lithium’s circadian response in patient fibroblasts elicit behavioral alterations akin to those for lithium in mice, and that a Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder dysfunctional clock grossly alters murine lithium-induced behavioral responses, suggesting an intricate link between the circadian clock and lithium therapy
Summary
Bipolar disorder (BD) is a chronic illness characterized by recurrent episodes of abnormal mood. It affects 1–3% of the population worldwide and is one of the major causes of chronic disability [1, 2]. The first-line treatment is lithium, Foundation Trust, Cambridge CB2 0QH, UK 4 Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford OX3 7JX, UK 5 Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford OX3 7JX, UK 6 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK 7 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK functioning as a potent mood stabilizer in most patients [3,4,5]. One leading hypothesis is that lithium modulates circadian gene expression, and the stabilization of sleep and circadian rhythms might offer novel treatment paradigms
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