The World Journal of Biological Psychiatry
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Lithium response in bipolar disorders and core clock genes expression Pierre A. Geoffroy, Emmanuel Curis, Cindie Courtin, Jeverson Moreira, Thomas Morvillers, Bruno Etain, Jean-Louis Laplanche, Frank Bellivier & Cynthia Marie-Claire To cite this article: Pierre A. Geoffroy, Emmanuel Curis, Cindie Courtin, Jeverson Moreira, Thomas Morvillers, Bruno Etain, Jean-Louis Laplanche, Frank Bellivier & Cynthia Marie-Claire (2017): Lithium response in bipolar disorders and core clock genes expression, The World Journal of Biological Psychiatry, DOI: 10.1080/15622975.2017.1282174 To link to this article: http://dx.doi.org/10.1080/15622975.2017.1282174
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Date: 01 March 2017, At: 09:48
THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, 2017 http://dx.doi.org/10.1080/15622975.2017.1282174
ORIGINAL INVESTIGATION
Lithium response in bipolar disorders and core clock genes expression Pierre A. Geoffroya,b,c,d, Emmanuel Curisa,e,f,g, Cindie Courtina,e, Jeverson Moreiraa,e, Thomas Morvillersa, Bruno Etaina,b,c,d, Jean-Louis Laplanchea,b,e, Frank Belliviera,b,c,d and Cynthia Marie-Clairea,b,e a Inserm U1144, Paris, France; bUniversite Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, France; cAP-HP, GH SaintLouis–Lariboisiere–F. Widal, P^ole de Psychiatrie et de Medecine Addictologique, Paris, France; dFondation FondaMental, Creteil, France; eUniversite Paris Descartes, UMR-S 1144, Paris, France; fLaboratoire de biomathematiques, Faculte de pharmacie de Paris Universite Paris Descartes, Paris, France; gDepartement de biostatistiques et d'informatique medicales, H^ opital Saint-Louis, APHP, Paris, France
ABSTRACT
ARTICLE HISTORY
Objectives: We examine whether the lithium response is associated with changes in the expression of core clock genes. Methods: 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, n ¼ 20) or excellent responders (ER, n ¼ 16). Quantitative real-time PCR (qRT-PCR) was conducted at 2, 4 and 8 days (d2, d4 and d8) with and without lithium exposure. Results: At d2, in ER only, BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40 and CSNK1D were upregulated, whereas NR1D1 was downregulated. At d4, in ER only, CRY1 was downregulated. At d8, in NR only, GSK3b was upregulated and DBP, TIMELESS and CRY1 were downregulated. Significant Group Lithium interactions existed for NR1D1 at d2 (P ¼ 0.02), and CRY1 at d4 (P ¼ 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time Group interaction) for PER3, NR1D1, DBP, RORA, CSNK1D and TIMELESS; and a significant Time Lithium interaction for NR1D1. Coexpression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium. Conclusions: In LCLs, lithium influences expression of circadian genes with differences in amplitude and kinetics according to the patient’s lithium response status.
Received 25 September 2016 Revised 27 November 2016 Accepted 2 January 2017
Introduction Bipolar disorders (BD) are severe and chronic brain disorders affecting 1–4% of the population worldwide (Merikangas et al. 2007). They are ranked as one of the most burdensome of diseases with a peak age of onset in adolescence and early adulthood (Collins et al. 2011; Geoffroy et al. 2013; Whiteford et al. 2013). BD are defined by mood episodes recurrences (depressive and manic), as well as being associated with major disruptions in circadian rhythms during all phases of the disorder, including abnormal sleep/wake cycles, as well as alterations in biochemical, appetite, seasonal and social rhythms (McClung 2007; Harvey 2008; Geoffroy et al. 2014b; Gonzalez 2014; Milhiet et al. 2014). BD are complex disorders with a heritability of about 60–85% (McGuffin et al. 2003; Lichtenstein et al. 2009). Numerous associations between circadian gene polymorphisms and BD have been identified
KEYWORDS
Bipolar disorder; clock genes; circadian genes; circadian rhythms; lithium carbonate
(Mansour et al. 2005; Nievergelt et al. 2006; Shi et al. 2008; Mansour et al. 2009; Etain et al. 2011; Geoffroy et al. 2015). Furthermore, some of these circadian genes, such as CLOCK, GSK3b, ASMT, RORA and TIMELESS, have been linked to clinical circadian disturbances that are associated with BD (Benedetti et al. 2003; Benedetti et al. 2004; Benedetti et al. 2007; Etain et al. 2014; Geoffroy et al. 2014c). Naturalistic studies have shown that about 40% of BD patients treated with lithium (Li) show no improvement, with about 30% having a partial response and only 30% present showing complete remission (Baldessarini & Tondo 2000; Garnham et al. 2007). Given this variability of response to Li prophylaxis, several studies attempted to identify clinical and biological factors associated with good Li response, although this has produced conflicting results with no transfer to routine clinical practice (Kleindienst
CONTACT Pierre A. Geoffroy
[email protected] Service de Psychiatrie Adulte (Pr F Bellivier), H^opital Fernand Widal, 200, rue du Faubourg Saint-Denis, 75475 Paris Cedex 10, France Supplemental data for this article can be accessed at http://dx.doi.org/10.1080/15622975.2017.1282174 ß 2017 Informa UK Limited, trading as Taylor & Francis Group
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et al. 2005; Grof et al. 2009; Geoffroy et al. 2014a). Circadian genes are promising candidates for the study of individual responses to Li given that: (1) disrupted circadian rhythms are a core expression of susceptibility to BD (Harvey 2008; Gonzalez 2014; Bellivier et al. 2015), and persistent circadian/sleep abnormalities during euthymia are associated with subsequent recurrent episodes (Jackson et al. 2003; Kaplan et al. 2011; Sylvia et al. 2012), (2) Li affects circadian rhythms in animal models as well as in humans (Subramanian et al. 1998; Abe et al. 2000; Padiath et al. 2004; Yin et al. 2006; Campos-de-Sousa et al. 2010; Li et al. 2012; Geoffroy et al. 2016b), (3) pharmacogenetic studies found Li response to be associated with polymorphisms in some circadian genes, including NR1D1 (encoding Rev-Erba), PPARGC1A (PGC-1a), RORA, GSK3b, CRY1, ARNTL, PER2 and TIMELESS (Campos-de-Sousa et al. 2010; Benedetti et al. 2011; McCarthy et al. 2011; McCarthy et al. 2012; Rybakowski et al. 2014; Geoffroy et al. 2016a) and (4) studies of some circadian genes expressions suggest that Li increases the expression of ARNTL, CRY1, PER1, PER2 and CSNK1D (CK1), and decreases the expression of NR1D1, ARNTL, CRY2 and PER3 (Yin et al. 2006; McQuillin et al. 2007; Osland et al. 2011; Freland & Beaulieu 2012; Li et al. 2012; Kim et al. 2013). All these results support the hypothesis that Li response in BD is associated with changes in expression of core clock genes (Moreira & Geoffroy 2016). Thus, we examined the effects of a therapeutic concentration of Li (1 mM) on the expression levels of circadian genes in an in vitro model of lymphoblastoid cell lines (LCLs) derived from patients with BD benefiting from a thorough clinical evaluation of their Li response.
Material and methods Population This sample comprised 36 French Caucasian individuals who met DSM-IV criteria (American Psychiatric Association 2000) for BD-I or BD-II and were recruited from three university-affiliated psychiatric departments in France (Paris, Bordeaux and Nancy). Patients had to be in symptomatic remission for at least 3 months and with scores lower than 5 on the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale at inclusion. With institutional review board ethics approval, participants who gave written informed consent were assessed by a psychiatrist or psychologist trained in the use of the French version of the Diagnostic Interview for Genetic Studies
to establish a retrospective lifetime diagnosis of BD, treatments and other axis I disorders meeting DSM-IV criteria (Nurnberger et al. 1994).
Evaluation of the response to Li For all patients, the response to Li was rated using the Alda scale (Grof et al. 2002) by two trained psychiatrists (PAG and BE), who participated in a study on the reliability of the scale (Manchia et al. 2013). The Alda scale was specifically developed to allow retrospective evaluation of prophylactic treatment response in naturalistic conditions and consists of two subscales (A and B). The A subscale assesses the changes in frequency and severity of mood symptoms, thereby quantifying the degree of improvement in the course of treatment. The B subscale aims to determine the probability that the observed improvement is indeed a result of the treatment through five questions (the number of episodes before Li treatment, the frequency of episodes before Li, the duration of Li treatment, the compliance during period(s) of stability and the use of additional medication during the period of stability). Finally, the total score (TS) is obtained by subtracting the B score from the A score. In order to construct two well defined groups according to the Li response, and based on previous studies and thresholds, nonresponders (NR) were defined by a TS
