Lithium response in bipolar disorders and core clock genes expression

<p><b>Objectives:</b> We examine whether the lithium response is associated with changes in the expression of core clock genes.</p> <p><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.</p> <p><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.</p> <p><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.</p

Lithium effects on serine-threonine kinases activity: High throughput kinomic profiling of lymphoblastoid cell lines from excellent-responders and non-responders bipolar patients

<p><b>Objectives:</b> Lithium is the leading mood stabiliser for maintenance treatment in bipolar disorder (BD). However, response to lithium is heterogeneous with more than 60% of patients experiencing partial or no response. <i>In vitro</i> and <i>in vivo</i> molecular studies have reported the implication of kinases in the pathophysiology of BD.</p> <p><b>Methods:</b> Since kinases are putative targets for lithium therapeutic action, we conducted the first pilot study using kinase array technology to evaluate the global serine/threonine kinases (STK) profiles in cell lines from BD I subtype patients classified as lithium excellent-responders (ER) and non-responder (NR) to lithium treatment.</p> <p><b>Results:</b> We found significant differences in the basal STK profiles between ER and NR to lithium. We also tested lithium influence on the global STK profile and found no significant difference between ER vs NR cell lines.</p> <p><b>Conclusions:</b> The results obtained in this exploratory study suggest that multiplex kinase activity profiling could provide a complementary approach in the study of biomarkers of therapeutic response in BD.</p