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: 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
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ABSTRACT: Circadian rhythms in the sleep/wake cycle, along with a range of physiological measures, are severely disrupted in individuals with major depressive disorder (MDD). Moreover, several central circadian genes have been implicated as potential genetic factors underlying the illness through candidate gene studies and some genome wide association studies. However, investigations into the molecular underpinnings of circadian disturbances in the human brain have been quite challenging. In their recent publication, Li and colleagues have used a novel approach to determine the rhythmic patterns of circadian gene expression in several regions of the human brain, and how these patterns are disrupted in MDD. Their findings demonstrate that in healthy subjects, several brain regions outside the suprachiasmatic nucleus (the master clock) exhibit diurnal gene expression patterns that are disrupted in the brains of MDD subjects. These findings will provide the foundation for future studies of gene-specific drug targets, and biomarkers for the disease.BioEssays 09/2013; · 5.42 Impact Factor
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ABSTRACT: Introduction Findings from actigraphic studies suggesting that sleep and circadian rhythms are disrupted in bipolar disorder (BD) patients have been undermined by methodological heterogeneity and the failure to adequately address potential confounders. Method Twenty-six euthymic BD cases and 29 healthy controls (HC), recruited from University Paris-Est and matched for age and gender, were compared on subjective (Pittsburgh Sleep Questionnaire Inventory; PQSI) and objective (mean scores and variability in actigraphy) measures of sleep as recorded by over 21 consecutive days. Results Multivariate generalized linear modelling (GLM) revealed significant differences between BD cases and HC for five PSQI items (total score and four subscales), four actigraphy variables (mean scores) and five actigraphy variability measures. Backward stepwise linear regression (BSLR) indicated that a combination of four variables (mean sleep duration, mean sleep latency, variability of the fragmentation index over 21 days, and mean score on PSQI daytime dysfunction sub-scale) correctly classified 89% of study participants as cases or controls (Chi-square=39.81; df=6; p=0.001). Limitations The sample size (although larger than most actigraphy studies) and incomplete matching of cases and controls may have influenced our findings. It was not possible to control for potential effects of psychotropic medication or differences in employment status between groups. Conclusions When potential confounders of sleep and circadian profiles are adequately taken into account (particularly age, gender, daytime sleepiness, mood symptoms, body mass index, and risk of sleep apnoea), a selected subset of quantitative (mean scores) and qualitative (variability) features differentiated euthymic BD cases from HC.Journal of Affective Disorders 04/2014; 158:1–7. · 3.30 Impact Factor