Lithium response in bipolar disorders and core clock genes expression

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