Lithium response in bipolar disorders and core clock genes expression.

Objectives: We examine if the lithium response is associated with changes in core clock genes expressions. Methods: The effect of a therapeutic concentration of lithium (1mM) on the expression levels of 17 circadian genes, was examined in lymphoblastoid cell lines (LCLs) derived from two well-characterized groups of BD patients, defined as lithium non-responders (NR, n = 20) or excellent responders (ER, n = 16). Quantitative real-time PCR (qRT-PCR) were conducted at 2, 4 and 8 days (d2, d4, d8) with and without lithium exposure. Results: At d2, in ER only, <i>BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40, and CSNK1D</i> were upregulated, whereas <i>NR1D1</i> was downregulated. At d4, in ER only, <i>CRY1</i> was downregulated. At d8, in NR only, <i>GSK3β</i> was upregulated and <i>DBP, TIMELESS</i> and <i>CRY1</i> were downregulated. Significant Group×Lithium interactions existed for <i>NR1D1</i> at d2 (p = 0.02), and <i>CRY1</i> at d4 (p = 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time×Group interaction) for <i>PER3, NR1D1, DBP, RORA, CSNK1D, and TIMELESS</i>; and a significant Time×Lithium interaction for <i>NR1D1</i>. Co-expression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium. Conclusions: In LCLs, lithium influences circadian genes expressions with differences in amplitude and kinetics according to the patient’s lithium response status.