Genetics of circadian rhythms and mood spectrum disorders

Inserm, U955, Créteil 94000, France.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology (Impact Factor: 4.37). 08/2011; 21 Suppl 4(Suppl 4):S676-82. DOI: 10.1016/j.euroneuro.2011.07.007
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Mood spectrum disorders (bipolar disorder, recurrent depressive disorder and seasonal affective disorder) are accompanied by circadian deregulations, which can occur during acute mood episodes as well as during euthymic periods, and are particularly common among bipolar patients in remission. This suggests that altered circadian rhythms may be biological markers of these disorders. Rhythm dysfunctions have been observed in mood disorder patients by using actigraphic measures and by assessing social metric rhythms, diurnal preferences and melatonin secretion. Since many of these markers are heritable and therefore driven by clock genes, these genes may represent susceptibility factors for mood spectrum disorders. Indeed, several genetic association studies have suggested that certain circadian gene variants play a role in susceptibility to these disorders. Such connections to circadian genes such as CLOCK, ARNTL1, NPAS2, PER3 and NR1D1 have been repeatedly demonstrated for bipolar disorders, and to a lesser extent for recurrent depressive disorders and seasonal affective disorders. The study of circadian phenotypes and circadian genes in mood spectrum disorders represents a major field of research that may yet reveal the pathophysiological determinants of these disorders.

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Available from: Bruno Etain, Sep 11, 2015
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    • "Ces récurrences suivent fréquemment une cyclicité saisonnière, puisque 25 % des sujets avec TB présentent des épisodes dépressifs de caractéristique saisonnière et une cyclicité des épisodes maniaques est retrouvé chez 15 % d'entre eux [7]. En plus de cette cyclicité des épisodes, des anomalies des rythmes circadiens, dont certaines ont pu être associées à des vulnérabilités génétiques, apparaissent chez les patients avec TB lors de toutes les phases de la maladie [8] [9]. Plusieurs études ont, de plus, évoqué la présence d'anomalies saisonnières de ces rythmes comportementaux et physiologiques dans le TB [10]. "
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    ABSTRACT: Introduction: Bipolar disorders (BD) are frequent mood disorders associated with a poor prognosis mainly due to a high relapse rate. Depressive relapses may follow a seasonal cyclicality, and bright-light therapy (BLT) has been established as the treatment of choice for seasonal affective disorder (SAD). The use of BLT for seasonal unipolar depression is well known, but the scientific literature is much poorer on the management of seasonal depressive episodes in BD. In addition, some specificities related to BD must be taken into account. Methods: We conducted a comprehensive review using Medline and Google Scholar databases up to August 2014 using the following keywords combination: "bipolar disorder" and "light therapy" or "phototherapy". Papers were included in the review if (a) they were published in an English or French-language peer-reviewed journal; (b) the study enrolled patients with BD and SAD; and (c) the diagnosis was made according to the DSM or ICD criteria. Results: BLT was considered among the first-line treatments for SAD with a size effect similar to antidepressants. Most of the studies did not distinguish between patients with unipolar and bipolar disorders. However, it has been demonstrated that the most significant risk of BLT in patients with BD is the mood shift. Thus, the most important therapeutic adaptation corresponds to the use of an effective mood stabilizer, as with any antidepressant. Another therapeutic adaptation in first intention is that the times of exposure to light should be shifted from morning to midday. This review also includes therapeutic guidelines regarding the management of BLT in seasonal bipolar depressive episodes. Discussion: There are very few specific data on seasonal bipolar depressive episodes. This literature review has highlighted that BLT should be handled as a regular antidepressant treatment in patients suffering from seasonal bipolar depressive episodes.
    L Encéphale 10/2015; DOI:10.1016/j.encep.2015.09.003 · 0.70 Impact Factor
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    • "In another GWA study in the US, nominally significant associations were detected for PER2 and PER3 to schizophrenia (Mansour et al., 2009). Circadian gene polymorphisms have been investigated also in relation to major depression (Etain et al., 2011; Johansson et al., 2003; Partonen, 2012), which * Shared senior authorship. "
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    ABSTRACT: Circadian rhythm disturbances overlap between psychotic disorders, e.g. schizophrenia, and major depression. We hypothesized that circadian gene variants previously associated with unipolar depression would be overrepresented also in patients with psychotic disorder. Six genetic polymorphisms in ARNTL, PER2 and CRY2 were genotyped in 566 schizophrenia spectrum disorder patients and 926 controls. The rs2290036-C variant of ARNTL was over-represented in psychosis patients, and the variants rs934945-G and rs10462023-G of PER2 were associated with a more severe psychotic disorder. The directions of these genetic associations were in line with those previously identified for depression.
    Chronobiology International 03/2015; 32(4):1-6. DOI:10.3109/07420528.2015.1012588 · 3.34 Impact Factor
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    • "Because developmental MeHg-induced changes in brain functioning may affect multiple behavioral domains, we used different behavioral tasks to investigate the long-term effect of perinatal MeHg-exposure on memory, anxiety-and depressionlike parameters. In addition, since mood spectrum disorders in humans are linked to impaired circadian mechanisms (Etain et al., 2011), where Bdnf signaling plays an important role (Liang et al., 2000), we aimed at analyzing diurnal physiological parameters and behavior of the MeHg-exposed and TK+ mice using metabolic cages. We were interested to correlate behavioral data with the levels of Bdnf and TrkB transcripts in the prefrontal cortex and the hippocampus, the brain regions critical for learning/memory processes and development of mood disorders. "
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    ABSTRACT: Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze test and depression-like behavior in the forced swim test in only wild-type mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze and open field tests was ameliorated by TK+ background only in the open field test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure.
    Frontiers in Behavioral Neuroscience 09/2014; 8:315. DOI:10.3389/fnbeh.2014.00315 · 3.27 Impact Factor
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