Genetics of circadian rhythms and mood spectrum disorders.
ABSTRACT 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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ABSTRACT: Genetic studies have revealed several clock gene variations/mutations involved in the manifestation of sleep disorders or interindividual differences in sleep-wake patterns, but only part of the genetic risk can be explained by the gene variations/mutations identified to date. Recent progress in research into circadian rhythm generation has provided efficient tools for eliciting the molecular basis of clock-relevant sleep disorders, complementing traditional genetic analysis. While the human master clock resides in the suprachiasmatic nucleus of the hypothalamus (central clock), peripheral tissue cells also generate self-sustained circadian oscillations of clock gene expression (peripheral clock), enabling estimation of individual human clock properties through a single collection of skin fibroblasts or venous blood cells. Some of the established cell lines exhibit autonomous circadian oscillations of clock gene expression, and introduction of clock gene variations into these cell lines by gene targeting makes it possible to investigate changes in the circadian phenotype induced by these variations/mutations without the need for generating transgenic animals. Estimation of human clock properties using peripheral tissue cells, in addition to genetic analysis, will facilitate comprehensive explication of the genetic risk of a variety of disorders relevant to biological clock disturbances, including sleep disorders, mood disorders, and metabolic diseases.MGG Molecular & General Genetics 04/2013; · 2.58 Impact Factor
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ABSTRACT: Circadian rhythm disturbances have been associated with bipolar disorder (BD) during both the mood episodes and the periods of remission. Circadian phase preferences for the evening have been reported for remitted patients, whereas the amplitude and stability of their rhythms have never been assessed using questionnaires. The primary aim of our study was the validation of a French version of the Circadian Type Inventory (CTI), whereas its secondary aim was the comparison between remitted patients with BD and healthy controls for rhythm stability and amplitude and for phase preference. For this purpose, we used the CTI and the Composite Scale of Morningness (CSM) that assesses phase preference (''morning'' or ''evening'' type). First, we report here on the validation of the French version of the 11-item Circadian Type Inventory in a sample of 140 remitted patients with BD and 156 healthy controls. Principal components analysis revealed a two-factor structure (FR: flexibility/rigidity scale corresponding to rhythm stability; LV: languid/vigorous scale corresponding to rhythm amplitude) explaining 52% of the variance in the control group and 47% in the bipolar group. Cronbach's alpha was 0.75 for FR and 0.73 for LV. The test-retest reliability was 0.74 for FR and 0.86 for LV (3 wks) and 0.62 for FR and 0.72 for LV (6 mos). LV and FR scores correlated with the Composite Scale of Morningness score (p50.00001 and p ¼ 0.0002, respectively). Second, as compared with controls, patients with BD were more languid (p50.00001) and showed an evening preference (p ¼ 0.0003), but they did not differ from the controls with regard to flexibility/rigidity. The French version of the CTI appeared to have satisfactory psy-chometrics characteristics. Bipolar patients exhibited not only abnormalities in phase preference but also in amplitude as measured by languidity. Since circadian rhythm dysfunction has been shown to predict poor functioning and mood relapses in interepisodic patients with BD, this tool would appear to be a promising, easy-to-use, measure of the amplitude and flexibility of circadian rhythms that could enrich the arsenal of assessments used in clinical settings.Chronobiology International 07/2013; · 4.35 Impact Factor
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ABSTRACT: Kleine-Levin syndrome (KLS) is a rare sleep disorder (1-2 reported cases per one million individuals) primarily affecting young subjects. Episodes are characterized by hypersomnia, cognitive impairment, feelings of derealization, and, less frequently, hyperphagia (66%), hypersexuality [53% (principally men)], and depressed mood [53% (predominantly women)]. KLS cases are frequently misdiagnosed and pose therapeutic challenges (i.e., amantadine and mood stabilizers are only marginally effective). The cause of KLS is unknown, but an association between KLS and mood disorders has been suggested by some clinical analogies. We report the case of a 44-year-old Caucasian woman with bipolar I disorder referred by her psychiatrist to our psychiatric center for recurrent and resistant major depression according to DSM-IV-TR criteria. Following examination, we confirmed the diagnoses of bipolar I disorder and KLS. The patient experienced about 15 evenly distributed KLS episodes, each lasting about one week, which occurred during the six years following her first manifestation at age 18 years. An electroencephalogram was performed during a KLS episode and showed high-amplitude theta waves in the left and right temporal lobes, with predominance in the left hemisphere. The pronounced bipolar disorder symptomatology, starting at 15 years of age with major depression and a suicide attempt, had impeded the identification of KLS, which was not diagnosed until the age of 42. Bipolar disorder may obscure KLS, with each condition adversely affecting the course of the other, and consequently, the co-occurrence of KLS and bipolar disorder may be underestimated. KLS and bipolar disorder may share common vulnerability factors, such as immune-inflammatory and circadian disturbances, and there may be a genetic predisposition for both. Additionally, mood stabilizers may be effective for KLS and bipolar disorder.Bipolar Disorders 09/2013; · 4.62 Impact Factor