Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.

Autor: Sanghani HR; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK., Jagannath A; Nuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, South Parks Road, Oxford, OX1 3RE, UK. aarti.jagannath@ndcn.ox.ac.uk., Humberstone T; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK., Ebrahimjee F; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK., Thomas JM; Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QH, UK., Churchill GC; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK., Cipriani A; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK.; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, OX3 7JX, UK., Attenburrow MJ; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK.; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, OX3 7JX, UK., Perestenko OV; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Cowley SA; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Cader MZ; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK., Peirson SN; Nuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, South Parks Road, Oxford, OX1 3RE, UK., Harrison PJ; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK.; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, OX3 7JX, UK., Foster RG; Nuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, South Parks Road, Oxford, OX1 3RE, UK., Goodwin GM; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK., Vasudevan SR; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. Sridhar.vasudevan@pharm.ox.ac.uk.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2021 Sep; Vol. 26 (9), pp. 5252-5265. Date of Electronic Publication: 2020 May 13.
DOI: 10.1038/s41380-020-0769-6
Abstrakt: 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.
(© 2020. The Author(s).)
Databáze: MEDLINE
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