3111T/C CLOCK GENE POLYMORPHISM IS NOT ASSOCIATED WITH SLEEP DISTURBANCES IN UNTREATED DEPRESSED PATIENTS

Sleep patterns, frequently altered in depression, have been hypothesized to be under genetic control. The circadian locomotor output cycles kaput (CLOCK) T3111C variant has been studied in association with sleep disturbances in depressed patients. The aim of this study was to investigate possible effects of T3111C CLOCK on insomnia, daytime sleepiness, sleep quality, and depression severity in a sample of 100 major depressive disorder patients. Inclusion criteria were: major depressive disorder, drug-free for any antidepressant and/or benzodiazepines for at least four weeks previously to the study, and a minimum score of >17 on the Hamilton Rating Scale for Depression. The Morningness–Eveningness Questionnaire, Epworth Sleepiness Scale, Athens Insomnia Scale, and Pittsburgh Sleep Quality Index were applied. No significant difference was found concerning genotype or allele groups and Hamilton Rating Scale for Depression items or clusters. No difference was found between genotypes and comorbidity, chronotype distribution, Epworth Sleepiness Scale, Athens Insomnia Scale, or Pittsburgh Sleep Quality Index total scores. Overall, the present findings did not support the hypothesis of an effect of the T3111C CLOCK variant on sleep disturbances in major depressive disorder. Further analysis of clock machinery will clarify the contribution of clock genes to the maintenance of mental health. (Author correspondence: alessandro.serretti@unibo.it)     

The CLOCK Gene and Mood Disorders: A Case-Control Study and Meta-analysis

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n?=?867) and MDD (n?=?139) compared to controls (n?=?889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p_BP?=?.605 and global p_MDD?=?.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders. (Author correspondence: tarok@fujita-hu.ac.jp)     

The CLOCK gene and mood disorders: a case-control study and meta-analysis

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n=867) and MDD (n=139) compared to controls (n=889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p(BP)=.605 and global p(MDD)=.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders.     

Association of CLOCK,ARNTL, and NPAS2 gene polymorphisms and seasonal variations in mood and behavior

Seasonal affective disorder (SAD) is a condition of seasonal mood changes characterized by recurrent depression in autumn or winter that spontaneously remits in spring or summer. Evidence has suggested that circadian gene variants contribute to the pathogenesis of SAD. In this study, we investigated polymorphisms in the CLOCK, ARNTL, and NPAS2 genes in relation to seasonal variation in 507 healthy young adults. Seasonal variations were assessed with the Seasonality Pattern Assessment Questionnaire. The prevalence of SAD was 12.0% (winter-type 9.3%, summer-type 2.8%). No significant difference was found between the groups in the genotype distribution of ARNTL rs2278749 and NPAS2 rs2305160. The T allele of CLOCK rs1801260 was significantly more frequent in seasonals (SAD?+?subsyndromal SAD) compared with non-seasonals (p?=?0.020, odds ratio?=?1.89, 95% confidence interval?=?1.09–3.27). Global seasonality score was significantly different among genotypes of CLOCK rs1801260, but not among genotypes of ARNTL rs2278749 and NPAS2 rs2305160. However, statistical difference was observed in the body weight and appetite subscales among genotypes of ARNTL rs2278749 and in the body weight subscale among genotypes of NPAS2 rs2305160. There was synergistic interaction between CLOCK rs1801260 and ARNTL rs2278749 on seasonality. To our knowledge, this study is the first to reveal an association between the CLOCK gene and seasonal variations in mood and behavior in the Korean population. Although we cannot confirm previous findings of an association between SAD and the ARNTL and NPAS2 genes, these genes may influence seasonal variations through metabolic factors such as body weight and appetite. The interaction of the CLOCK and ARNTL genes contributes to susceptibility for SAD.     

Depression Scores Associate With Chronotype and Social Jetlag in a Rural Population

In public health, mood disorders are among the most important mental impairments. Patients with depressive episodes exhibit daily mood variations, abnormal patterns in sleep-wake behavior, and in the daily rhythms of several endocrine-metabolic parameters. Although the relationship between the sleep/circadian processes and mood disorders is poorly understood, clock-related therapies, such as light therapy, sleep deprivation, and rigid sleep schedules, have been shown to be effective treatments. Several studies investigated the relationship between circadian phenotype (chronotype) and depression. These focused mainly on urban populations and assessed diurnal preferences (Morningness-Eveningness score) rather than the actual timing of sleep and activity. Here, we used the Beck Depression Inventory (BDI) in an essentially rural population (N?=?4051), and investigated its relation to circadian phenotype (chronotype and social jetlag), assessed with the Munich Chronotype Questionnaire (MCTQ). In our study design, we (i) normalized both chronotype and BDI scores for age and sex (MSF_sas and BDI_as, respectively); (ii) calculated individual social jetlag (misalignment of the biological and social time); and (iii) investigated the relationship between circadian phenotypes and BDI scores in a population homogeneous in respect to culture, socioeconomic factors, and daily light exposure. A 15.65% (N?=?634) of the participants showed mild to severe depressive BDI scores. Late chronotypes had a higher BDI_as than intermediate and early types, which was independent of whether or not the participants were smokers. Both chronotype and BDI_as correlated positively with social jetlag. BDI_as was significantly higher in subjects with >2?h of social jetlag than in the rest of the population—again independent of smoking status. We also compared chronotype and social jetlag distributions between BDI categories (no symptoms, minimal symptoms, and mild to severe symptoms of depression) separately for men and women and for four age groups; specifically in the age group 31–40 yrs, subjects with mild to severe BDI scores were significantly later chronotypes and suffered from higher social jetlag. Our results indicate that misalignment of circadian and social time may be a risk factor for developing depression, especially in 31- to 40-yr-olds. These relationships should be further investigated in longitudinal studies to reveal if reduction of social jetlag should be part of prevention strategies. (Author correspondence: karla.allebrandt@med.uni-muenchen.de)     

Clock genes associate with white matter integrity in depressed bipolar patients

Human genetic studies have implicated specific genes that constitute the molecular clock in the manifestation of bipolar disorder (BD). Among the clock genes involved in the control system of circadian rhythms, CLOCK 3111 T/C and Period3 (PER3) influence core psychopathological features of mood disorders, such as patterns of sleep, rest, and activity, diurnal preference, cognitive performances after sleep loss, age at the onset of the illness, and response to antidepressant treatment. Furthermore, several studies pointed out that bipolar symptomatology is associated with dysfunctions in white matter (WM) integrity, suggesting these structural alterations as a possible biomarker of the disorder. We hypothesise that CLOCK and PER3 polymorphisms could be potential factors affecting WM microstructure integrity in bipolar patients. The relationship between these clock genes and DTI measures of WM integrity in a sample of 140 (53 M; 87 F) patients affected by BD type I was studied. Tract-based spatial statistics analyses on DTI measures of WM integrity were performed for each clock gene polymorphism, between the genetic groups. We accounted for the effect of nuisance covariates known to influence WM microstructure: age, sex, lithium treatment, age at the onset of the illness, and the number of illness episodes. We found that compared to T homozygotes, CLOCK C carriers showed a widespread increase of the mean diffusivity in several WM tracts. Compared with PER3^5/5 homozygotes, PER3^4/4 homozygotes showed significantly increased radial diffusivity and reduced fractional anisotropy in several brain WM tracts. No significant difference was observed between heterozygotes and the other subgroups. Altogether, this pattern of results suggests WM disruption in CLOCK C carrier and in PER3⁴ homozygotes. Sleep promotes myelination and oligodendrocyte precursor cell proliferation and associates with higher expression of genes coding for phospholipid synthesis and myelination in oligodendrocytes. These clock genes play a pivotal role in maintaining circadian rhythms and the sleep-wake cycle. Thus, it may be suggested that CLOCK rs1801260*C and PER3^4/4 influence myelination processes by regulating sleep quality and quantity.     

The 3111T/C Polymorphism Interacts With Stressful Life Events to Influence Patterns of Sleep in Females

Genetic variations in clock-relevant genes have been investigated in relation to sleep abnormalities, both in healthy populations and in mood-disorder patients with inconsistent results. Environmental influences may moderate associations between genes and phenotype. The authors examined the CLOCK 3111T/C polymorphism and several variants within the PER3 gene and their possible interaction with stressful life events in a group of female volunteers (n?=?415). Gene-environment (G?×?E) interactions and gene main effects were investigated on depressive symptoms using the Beck Depression Inventory and on change of sleep patterns (Item 16). Results showed a G?×?E interaction on alteration of sleeping pattern: the 3111C homozygous genotype reported greater disruption in sleep pattern after the experience of stressful life events. Within the PER3 gene, one G?×?E interaction was observed with rs228642 on sleep change. These findings show that the 3111T/C polymorphism is not associated with depressive symptoms, but only with symptoms of sleep change in the case of prior stressful life experiences. The combination of a sensitive genotype (3111C/C) and environmental stress increases vulnerability to circadian rhythm disruption in females. (Author correspondence: laura.mandelli@unibo.it)     

Variants of the CLOCK gene affect the risk of idiopathic male infertility in the Han-Chinese population

Recent experimental animal studies suggested that the circadian locomotor output cycles kaput protein gene (CLOCK) has been reported to play a critical role in sperm function and male fertility. The aim of this study was to determine whether variants of the CLOCK gene are involved in idiopathic male infertility. The study included 478 idiopathic infertile men and 194 fertile controls who completed physical examinations. Each subject donated 5?ml of peripheral blood and a sample of semen in the ejaculate. An aliquot of each blood sample was used to separate the serum for the measurement of testosterone as well as follicular stimulating hormone (FSH) using the standard radioimmunoassay. The rest of the blood samples was used to extract the DNA for the assay of three tagging single-nucleotide polymorphisms of CLOCK gene, viz., rs1801260, rs3817444 and rs3749474, using the real-time fluorescence quantitative PCR. The ejaculate of each subject was used for semen analysis by computer-assisted semen analysis system. The results indicated: (a) the variant rs1801260 associated with normal semen parameters was linked to a significant increase in the risk of idiopathic infertility, (b) the variant rs3817444 associated with both normal and abnormal semen parameters also indicated an increased risk of idiopathic infertility, and (c) the variants rs3749474 associated with both normal and abnormal semen parameters, on the other hand, conferred no significant risk for male infertility. Furthermore, elevated serum testosterone and FSH levels were correlated with the three variants of CLOCK gene in idiopathic infertility. The findings demonstrate that the human subjects with variants of the CLOCK gene are associated with idiopathic male infertility and therefore may be applied as a risk factor of male infertility.     

PROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-α MEDIATES HIGH-FAT,DIET-ENHANCED DAILY OSCILLATION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 ACTIVITY IN MICE

Acute thrombotic events frequently occur in the early morning among hyperlipidemic patients. The activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of the fibrinolytic system, oscillates daily, and this is considered one mechanism that underlies the morning onset of acute thrombotic events in hyperlipidemia. Although several studies have reported the expression of the PAI-1 gene is under the control of the circadian clock system, the molecular mechanism of the circadian transactivation of PAI-1 gene under hyperlipidemic conditions remains to be elucidated. Here, the authors investigated whether hyperlipidemia induced by a high-fat diet (HFD) enhances the daily oscillation of plasma PAI-1 activity in mice. The mRNA levels of the PAI-1 gene were increased and rhythmically fluctuated with high-oscillation amplitude in the livers of wild-type mice fed with the HFD. Circadian expression of proxisome proliferator-activated receptor-α (PPARα) mRNA was also augmented as well as that of PAI-1. Chromatin immunoprecipitaion showed the HFD-induced hyperlipidemia significantly increased the binding of PPARα to the PAI-1 promoter. Luciferase reporter analysis using primary hepatocytes revealed CLOCK/BMAL1-mediated PAI-1 promoter activity was synergistically enhanced by cotransfection with PPARα/retinoid X receptor-α (RXRα), and this synergistic transactivation was repressed by negative limbs of the circadian clock, PERIOD2 and CRYPTOCHROME1. As expected, HFD-induced PAI-1 mRNA expression was significantly attenuated in PPARα-null mice. These results suggest a molecular link between the circadian clock and lipid metabolism system in the regulation of PAI-1 gene expression, and provide an aid for understanding why hyperlipidemia increases the risk of acute thrombotic events in the morning. (Author correspondence: ssoeda@fukuoka-u.ac.jp)     

Analysis of genetic association and epistasis interactions between circadian clock genes and symptom dimensions of bipolar affective disorder

Bipolar affective disorder (BD) is a severe psychiatric disorder characterized by periodic changes in mood from depression to mania. Disruptions of biological rhythms increase risk of mood disorders. Because clinical representation of disease is heterogeneous, homogenous sets of patients are suggested to use in the association analyses. In our study, we aimed to apply previously computed structure of bipolar disorder symptom dimension for analyses of genetic association. We based quantitative trait on: main depression, sleep disturbances, appetite disturbances, excitement and psychotic dimensions consisted of OPCRIT checklist items. We genotyped 42 polymorphisms from circadian clock genes: PER3, ARNTL, CLOCK and TIMELSSS from 511 patients BD (n?=?292 women and n?=?219 men). As quantitative trait we used clinical dimensions, described above. Genetic associations between alleles and quantitative trait were performed using applied regression models applied in PLINK. In addition, we used the Kruskal–Wallis test to look for associations between genotypes and quantitative trait. During second stage of our analyses, we used multidimensional scaling (multifactor dimensionality reduction) for quantitative trait to compute pairwise epistatic interactions between circadian gene variants. We found association between ARNTL variant rs11022778 main depression (p?=?0.00047) and appetite disturbances (p?=?0.004). In epistatic interaction analyses, we observed two locus interactions between sleep disturbances (p?=?0.007; rs11824092 of ARNTL and rs11932595 of CLOCK) as well as interactions of subdimension in main depression and ARNTL variants (p?=?0.0011; rs3789327, rs10766075) and appetite disturbances in depression and ARNTL polymorphism (p?=?7?×?10^?4; rs11022778, rs156243).     

CRY2 Genetic Variants Associate with Dysthymia

People with mood disorders often have disruptions in their circadian rhythms. Recent molecular genetics has linked circadian clock genes to mood disorders. Our objective was to study two core circadian clock genes, CRY1 and CRY2 as well as TTC1 that interacts with CRY2, in relation to depressive and anxiety disorders. Of these three genes, 48 single-nucleotide polymorphisms (SNPs) whose selection was based on the linkage disequilibrium and potential functionality were genotyped in 5910 individuals from a nationwide population-based sample. The diagnoses of major depressive disorder, dysthymia and anxiety disorders were assessed with a structured interview (M-CIDI). In addition, the participants filled in self-report questionnaires on depressive and anxiety symptoms. Logistic and linear regression models were used to analyze the associations of the SNPs with the phenotypes. Four CRY2 genetic variants (rs10838524, rs7121611, rs7945565, rs1401419) associated significantly with dysthymia (false discovery rate q<0.05). This finding together with earlier CRY2 associations with winter depression and with bipolar type 1 disorder supports the view that CRY2 gene has a role in mood disorders.     

PHOTOPERIOD AT BIRTH DOES NOT MODULATE THE DIURNAL PREFERENCE IN ASIAN POPULATION

Two research groups reported that diurnal preference in Canadian and South European populations was modulated by the season of birth. The aim of the present study was to examine this association in the Japanese population. In this study, 1156 college students were administered the Morningness-Eveningness Questionnaire and asked the date and place of birth. Our results demonstrated that neither photoperiod nor season of birth modulated diurnal preference in the Japanese population. Two biological differences are reported to exist between Caucasians and Asians: polymorphisms of circadian clock genes and difference in ocular photosensitivity. These ethnic differences might characterize the circadian photosensitivity in infancy. (Author correspondence: takao@keyaki.cc.u-tokai.ac.jp).     

MORNINGNESS-EVENINGNESS,SEX, AND THE ALTERNATIVE FIVE FACTOR MODEL OF PERSONALITY

Recent research on personality and circadian typology indicates that evening-type subjects are more extraverted, impulsive, and novelty-seeking, while morning ones tend to be more introverted, conscientious, agreeable, and emotionally stable. The purpose of this study was to examine the differences between circadian typologies on the Zuckerman's Alternative Five Factor Model of personality (AFFM), which has a strong biological basis, controlling for sex and age. A sample of 533 university students (168 men) participated in the study. Results showed that morning-type subjects had significant higher scores than evening-type and neither-type subjects in Activity, and in its subscales General Activity and Work Activity. A significant interaction between circadian typology and sex was found for Neuroticism-Anxiety: morning-type men showed higher scores than evening-type and neither-type, who had the lowest scores. Women presented the opposite pattern: neither-type obtained the highest scores, while morning-type showed the lowest. This is the first time the AFFM has been used in the context of circadian rhythms research. The results suggest that activity is the only trait related to extraversion associated with morningness, while Neuroticism-Anxiety was modulated by sex. These results might help highlight previous results on the association between morningness-eveningness and other models of personality assessment, and they offer new data that calls for further research. (Author correspondence: anna.muro@uab.cat)     

Seasonal Effect on Infants' Sleep Regulation: A Preliminary Study in a Mediterranean Climate

Infants' sleep-wake rhythms are influenced by multiple factors, including developmental and contextual aspects, as well as circadian cycles. Empirical studies that address the seasonal impact on infants' sleep are scarce. The present study examined aspects of sleep schedule and quality, comparing summer and winter months in a Mediterranean climate. This report is based on a convenience sample of 34 healthy 7-mo-olds, an age in which sleep is well consolidated and regulated compared with the first few months of life. Sleep was measured with actigraphy, in the home context. It was found that compared with winter, in the summer months, sleep onset occurred at a later hour, and more motor activity during sleep was detected. Although the overall sleep quality, as defined by sleep efficiency score, was similar in the two seasons, in the summer, more active sleep was observed. The authors discuss the finding in terms of circadian rhythms, developmental characteristics, as well as possible environmental factors and family routines, and call for more studies, in different climates and geographical zones, and in different developmental periods. (Author correspondence: cohen.dini@gmail.com or anats@edu.haifa.ac.il)     

Young Women With Major Depression Live on Higher Homeostatic Sleep Pressure Than Healthy Controls

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75–25?Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement. (Author correspondence: Christian.cajochen@upkbs.ch)     

CIRCADIAN MODULATION OF CRUSTACEAN HYPERGLYCEMIC HORMONE IN CRAYFISH EYESTALK AND RETINA

Previous studies suggested the retina could be a putative locus of daily crustacean hyperglycemic hormone (CHH) secretion, as it possesses its own metabolic machinery and is independent of the well-known CHH eyestalk locus responsible for the circadian secretion of this peptide. However, it has been proposed that hemolymph glucose and lactate concentrations play a dual role in the regulation of CHH in crayfish. To elucidate the temporal relationship between these two different CHH production loci and to examine their relationship with glucose regulation, we investigated the expression of CHH daily and circadian rhythms in the eyestalk and retina of crayfish using biochemical methods and time series analysis. We wanted to determine whether (1) putative retina and eyestalk CHH rhythmic expressions are correlated and if the oscillations of the two metabolic products of lactate and glucose in the blood due to CHH action on the target tissue correlate, and (2) retina CHH (RCHH) and the possible retinal substrate glycogen and its product glucose are temporally correlated. We found a negative correlation between daily and circadian changes of relative CHH abundance in the retina and eyestalk. This correlation and the cross-correlation values found between eyestalk CHH and hemolymph and glucose confirm that CHH produced by the X-organ sinus gland complex is under the previously proposed dual feedback control system over the 24?h time period. However, the presence of both glycogen and glucose in the retina, the cross-correlation values found between these parameters and hemolymph lactate and glucose, as well as RCHH and hemolymph and retina metabolic markers suggest RCHH is not under the same temporal metabolic control as eyestalk CHH. Nonetheless, their expression may be linked to common rhythms-generating processes. (Author correspondence: mlfm@hp.fciencias.unam.mx; mfajul@gmail.com)     

GENE-GENE INTERACTION BETWEEN SEROTONIN TRANSPORTER (SLC6A4) AND CLOCK MODULATES THE RISK OF METABOLIC SYNDROME IN ROTATING SHIFTWORKERS

Serotonergic neurotransmission and the master circadian CLOCK gene are physiological modulators of the circadian system. In addition, both are involved in the physiopathology of metabolic syndrome (MS). The authors sought to examine the potential effect of the gene-gene interaction between the functional 44-bp insertion/deletion polymorphism in the promoter region (serotonin-transporter-linked promoter region polymorphism or 5-HTTLPR) of the serotonin transporter gene (SLC6A4) and common variants of the gene CLOCK on the genetic risk underlying MS of shift-workers. To test this hypothesis, 856 men were studied; 518 dayworkers were compared with 338 rotating shiftworkers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health-related behaviors, and biochemical determinations were obtained from every participant. 5-HTTLPR genotypes were determined using polymerase chain reaction followed by gel electrophoresis. Six tag single-nucleotide polymorphisms (SNPs) in the CLOCK gene with a minor allele frequency >10 % (rs1554483 C/G, rs11932595 A/G, rs4580704 C/G, rs6843722 A/C, rs6850524 C/G, and rs4864548 A/G), encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r²?>?.8), were genotyped. A significant interaction between the 5-HTTLPR variant and the haplotype rs1554483–rs4864548 of the CLOCK gene was detected for diastolic (p?=?.0058) and systolic blood pressure (p?=?.0014), arterial hypertension (p?=?.033), plasma triglycerides levels (p?=?.033), and number of MS components (p?=?.01). In all these cases, the higher values were observed in rotating shiftworkers homozygous for the SLC6A4 S allele and carrying the haplotype composed by the CLOCK rs1554483 G and rs4864548 A variants. In conclusion, these data suggest a potential interaction (epistatic effect) of serotonin transporter and CLOCK gene variation on the genetic susceptibility to develop MS by rotating shiftworkers. (Author correspondence: cpirola@ciudad.com.ar or pirola.carlos@lanari.fmed.uba.ar)     

EVENING PREFERENCE IS RELATED TO THE INCIDENCE OF DEPRESSIVE STATES INDEPENDENT OF SLEEP-WAKE CONDITIONS

Although evening preference has recently been identified as a risk factor for depression, it has not been substantiated whether evening preference is a direct risk factor for depressive states, or if it is associated secondarily through other factors, such as delayed sleep timing and shortened sleep duration. The objective of this study is to investigate associations in Japanese adult subjects between evening preference and incidence of depressive states, adjusting for various sleep parameters related to depressive states. The Morningness-Eveningness Questionnaire (MEQ), the Pittsburgh Sleep Quality Index (PSQI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were administered to 1170 individuals (493 males/677 females; mean and range 38.5 and 20–59 yrs) to assess their diurnal preferences, sleeping states, and presence of depression symptoms. Subjects were classified into five chronotypes based on MEQ scores. Evening preference was associated with delayed sleep timing, shortened sleep duration, deteriorated subjective sleep quality, and worsened daytime sleepiness. Logistic regression analysis demonstrated that the extreme evening type (odds ratio [OR]?=?1.926, p?=?.018) was associated with increased incidence of depressive states and that the extreme morning type (OR?=?0.342, p?=?.038) was associated with the decreased incidence of depressive states, independent of sleep parameters, such as nocturnal awakening (OR?=?1.844, p?<?.001), subjective sleep quality (OR?=?2.471, p?<?.001), and daytime sleepiness (OR?=?1.895, p?=?.001). However, no significant associations were observed between the incidence of depressive states and sleep duration, sleep timing, and sleep debt (levels of insufficient sleep). Although the findings of this study do not demonstrate a causative relationship between evening preference and depression, they do suggest the presence of functional associations between mood adjustment and biological clock systems that regulate diurnal preference. They also suggest that evening preference might increase susceptibility to the induction of mood disorders. (Author correspondence: mishima@ncnp.go.jp)     

DEPRESSED MOOD IN THE WORKING POPULATION: ASSOCIATIONS WITH WORK SCHEDULES AND WORKING HOURS

The impact of working time arrangements (WTA) on health has been studied extensively. Still, little is known about the interrelation between work schedules, working hours, and depressed mood. For work schedules, the underlying assumptions regarding depressed mood refer to a disturbance of social and biological rhythms, whereas for working hours, the assumptions relate to workload and work capacity. Conversely, depressed mood may urge an employee to adjust his/her work schedule and/or number of working hours/week (h/wk). The aim of this study was to assess the association between work schedule and working hours with depressed mood. Using baseline data from the Maastricht Cohort Study, depressed mood in day work was compared with depressed mood in different shiftwork schedules (n?=?8843). Within day work, several categories of working h/wk were studied in association with depressed mood (n?=?7217). The association between depressed mood and several aspects of overtime was assessed separately. Depressed mood was measured with a dichotomous item: “Did you feel down every day over the last two weeks?” Separate logistic regression analyses were conducted for men and women, with adjustments for potential confounders. The odds ratio (OR) for depressed mood was greater for men involved in shiftwork than for men only involved in day work (three-shift OR?=?2.05 [95% confidence interval, CI 1.52–2.77]; five-shift OR?=?1.34 [95% CI 1.00–1.80]; irregular-shift OR?=?1.79 [95% CI 1.27–2.53]). In female employees, five-shift work was associated with a higher prevalence of depressed mood (OR?=?5.96 [95% CI 2.83–12.56]). Regarding the number of working h/wk, men working <26?h/wk had a higher prevalence of depressed mood than men working 36–40?h/wk (OR?=?2.73 [95% CI 1.35–5.52]). After conducting trend analyses, a significant decreasing trend was found in men, whereas an increasing trend was found in women working a high number of hours. Furthermore, a dose-response relationship was present in men regarding the number of overtime h/wk. This study showed that different work schedules and working hours are associated with depressed mood. Shiftwork was related to a higher prevalence of depressed mood than day work. The association was more pronounced for male employees. Regarding the number of working h/wk, male and female employees showed an opposite trend in depressed mood. Because of the possibility of a healthy worker effect and the possibility of a reciprocal relationship between WTA and depressed mood, the reported relation might be underestimated. This study has illustrated that occupational physicians, who deal with depressed mood among workers, should carefully consider the impact of WTA. (Author coorespondence: Karolien.Driesen@epid.unimaas.nl)     

ASSOCIATIONS BETWEEN CHRONOTYPE,SLEEP QUALITY,SUICIDALITY, AND DEPRESSIVE SYMPTOMS IN PATIENTS WITH MAJOR DEPRESSION AND HEALTHY CONTROLS

Research interest concerning associations between sleep characteristics and suicidality in psychopathology has been growing. However, possible linkages of suicidality to sleep characteristics in terms of sleep quality and chronotypes among depressive patients have not been well documented. In the current study, the authors investigated the possible effects of sleep quality and chronotype on the severity of depressive symptoms and suicide risk in patients with depressive disorder and healthy controls. The study was conducted on 80 patients clinically diagnosed with major depression and 80 healthy subjects who were demographically matched with the patient group. All participants completed a questionnaire package containing self-report measures, including the Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Morningness–Eveningness Questionnaire (MEQ), and Suicide Ideation Scale (SIS), and subjects were interviewed with the suicidality section of the Mini-International Neuropsychiatric Interview (MINI). Results are as follows: (a) logistic regression analyses revealed that poor sleep quality and depression symptom severity significantly predicted onset of major depression; (b) morningness-type circadian rhythm may play as a significant relief factor after onset of major depression; (c) sleep variables of chronotype and sleep quality did not significantly predict suicide ideation after controlling for depressive symptoms in the major depression group; and (d) suicide ideation and poor sleep quality were antecedents of depression symptom severity in patients with major depression, and in healthy controls. Findings are discussed under the theoretical assumptions concerning possible relations between chronotype, sleep quality, depression, and suicidality. (Author correspondence: dryavuzselvi@yahoo.com)