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Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures
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Lithium response in bipolar disorders and core clock genes expression.

Pierre A Geoffroy1,2,3,4, Emmanuel Curis1,5,6,7, Cindie Courtin1,5

  • 1a Inserm U1144 , Paris , France.

The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry
|January 19, 2017
PubMed
Summary

Lithium treatment alters circadian gene expression in bipolar disorder patients, with distinct patterns observed in excellent responders versus non-responders. These findings highlight the link between lithium

Keywords:
Bipolar disordercircadian genescircadian rhythmsclock geneslithium carbonate

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Area of Science:

  • Chronobiology
  • Neuropharmacology
  • Genetics

Background:

  • Bipolar disorder (BD) treatment often involves lithium, but its precise molecular mechanisms remain incompletely understood.
  • Circadian rhythm disturbances are implicated in the pathophysiology of BD.
  • Individual responses to lithium vary significantly, suggesting underlying biological differences.

Purpose of the Study:

  • To investigate the association between lithium response and the expression of core clock genes in patients with bipolar disorder.
  • To determine if lithium differentially affects circadian gene expression in lithium-non-responders (NR) and excellent responders (ER).

Main Methods:

  • Lymphoblastoid cell lines (LCLs) from BD patients (NR, n=20; ER, n=16) were treated with therapeutic lithium (1 mM).
  • Quantitative real-time PCR (qRT-PCR) was used to measure the expression levels of 17 circadian genes at 2, 4, and 8 days post-treatment.
  • Statistical analyses included examining Group × Lithium interactions and longitudinal temporal changes.

Main Results:

  • Lithium significantly altered circadian gene expression in excellent responders (ER) at day 2, with upregulation of genes like BHLHE41, RORA, and PER1, and downregulation of NR1D1.
  • Differential effects were observed over time, with significant Group × Lithium interactions for NR1D1 and CRY1.
  • Longitudinal analyses revealed distinct temporal expression patterns for several circadian genes (PER3, NR1D1, DBP, RORA, CSNK1D, TIMELESS) between NR and ER groups.

Conclusions:

  • Lithium influences the expression of circadian genes in LCLs derived from bipolar disorder patients.
  • The amplitude and kinetics of these gene expression changes differ based on the patient's lithium response status.
  • These findings suggest that circadian gene modulation by lithium may underlie differential treatment responses in bipolar disorder.