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Neuropsychopharmacology. 2019 Feb;44(3):620-628. doi: 10.1038/s41386-018-0273-8. Epub 2018 Nov 16.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Author information

1
Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 3350 La Jolla Village Dr. MC 116A, San Diego, CA, 92161, USA. mmccarthy@ucsd.edu.
2
Psychiatry Service, VA San Diego Healthcare, San Diego, CA, 92161, USA. mmccarthy@ucsd.edu.
3
Psychiatry Service, VA San Diego Healthcare, San Diego, CA, 92161, USA.
4
Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 3350 La Jolla Village Dr. MC 116A, San Diego, CA, 92161, USA.
5
Department of Clinical Medicine, Section for Psychiatry, University of Bergen, Bergen, Norway.
6
Department of Psychiatry, Dalhousie University, Halifax, Canada.
7
Department of Psychiatry, University of Chicago, Chicago, USA.
8
Department of Psychiatry, Indiana University, Bloomington, USA.
9
Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway.
10
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, 19104, USA.
11
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
12
Departments of Neuroscience and Psychiatry, Icahn School of Medicine at Mt Sinai, New York, USA.
13
Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA.
14
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, USA.
15
Department of Psychiatry, University of Iowa, Iowa City, USA.
16
Department of Psychiatry, The Mayo Clinic, Rochester, USA.
17
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, USA.
18
Department of Psychiatry, Johns Hopkins University, Baltimore, USA.
19
Norment and KG Jebsen Centre for Neuropsychiatry, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
20
Division of Psychiatry, St. Olav University Hospital of Trondheim and Department of Mental Health Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
21
Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.

Abstract

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

PMID:
30487653
PMCID:
PMC6333516
[Available on 2020-02-01]
DOI:
10.1038/s41386-018-0273-8
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