Social Jetlag and Related Risks for Human Health: A Timely Review.

The term social jetlag is used to describe the discrepancy between biological time, determined by our internal body clock, and social times, mainly dictated by social obligations such as school or work. In industrialized countries, two-thirds of the studying/working population experiences social jetlag, often for several years. Described for the first time in 2006, a considerable effort has been put into understanding the effects of social jetlag on human physiopathology, yet our understanding of this phenomenon is still very limited. Due to its high prevalence, social jetlag is becoming a primary concern for public health. This review summarizes current knowledge regarding social jetlag, social jetlag associated behavior (e.g., unhealthy eating patterns) and related risks for human health.

Sleep and Metabolic Syndrome.

Metabolic syndrome (MetS) refers to the clustering of risk factors for cardiovascular disease and diabetes, including central adiposity, hypertension, dyslipidemia, and hyperglycemia. During the past 20 years, there have been parallel and epidemic increases in MetS and impaired sleep. This article describes evidence on the association between MetS and short sleep duration, circadian misalignment, insomnia, and sleep apnea. Potential mechanisms where impaired sleep desynchronizes and worsens metabolic control and interventions to improve sleep and potentially improve MetS are presented.

Predictors of Suicidal Ideation and Preparatory Behaviors in Individuals With Bipolar Disorder: The Contribution of Chronobiological Dysrhythmicity and Its Association With Hopelessness.

OBJECTIVE: To examine the role of chronobiological dysrhythmicity in suicidal ideation and behaviors and its relation with hopelessness. METHODS: One hundred twenty-seven patients (77 females, mean age of 47.4 ± 12.5 years) with a major depressive episode and bipolar disorder (BD) type I or II (according to Structured Clinical Interview for DSM-5 assessment) were recruited in 2019 and assessed for depressive and manic symptoms (Beck Depression Inventory-II, Young Mania Rating Scale) and with the Biological Rhythms Interview of Assessment in Neuropsychiatry, Beck Hopelessness Scale, and Scale for Suicide Ideation. Univariate regression and mediation analyses were performed. RESULTS: Forty-one patients (32.3%) showed clinically significant suicidal ideation and were more frequently affected by BD type I (P = .029) with mixed features (P = .022). Compared to nonsuicidal individuals, they had significantly more depressive symptoms (P = .019), higher emotional component of hopelessness (P = .037), and higher dysrhythmicity of sleep (P = .009), activities (P = .048), and social life (P = .019). Passive and active suicidal ideation and suicidal plans were best predicted by dysrhythmicity of sleep and social life. Dysrhythmicity of sleep and social life mediated the direct effect of depressive symptoms on passive and active suicidal ideation and also of active ideation on suicidal plans. The emotional component of hopelessness was related to dysrhythmicity of social life and mediated its effect on suicidal plans (P = .010). CONCLUSIONS: Chronobiological alterations directly contributed to passive and active suicidal ideation and to suicidal preparation, with a key role of dysrhythmicity of sleep, activities, and social life. Chronobiological alterations also impacted the emotional component of hopelessness, hence indirectly contributing to suicidal ideations and plans. These findings call for the systematic screening of these dysrhythmicity dimensions when considering suicidal risk in individuals with BD.

Association between circadian rhythm disruption and polycystic ovary syndrome.

OBJECTIVE: To explore the association of circadian rhythm disruption with polycystic ovary syndrome (PCOS) and the potential underlying mechanism in ovarian granulosa cells (GCs). DESIGN: Multicenter questionnaire-based survey, in vivo and ex vivo studies. SETTING: Twelve hospitals in China, animal research center, and research laboratory of a women's hospital. PATIENTS/ANIMALS: A total of 436 PCOS case subjects and 715 control subjects were recruited for the survey. In vivo and ex vivo studies were conducted in PCOS-model rats and on ovarian GCs collected from women with PCOS and control subjects. INTERVENTION(S): The PCOS rat model was established with the use of testosterone propionate. MAIN OUTCOME MEASURE(S): Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), RNA sequencing, rhythmicity analysis, functional enrichment analysis. RESULT(S): There was a significant correlation between night shift work and PCOS. PCOS-model rats presented distinct differences in the circadian variation of corticotropin-releasing hormone, adrenocorticotropic hormone, prolactin, and a 4-h phase delay in thyrotropic hormone levels. The motif enrichment analysis of ATAC-seq revealed the absence of clock-related transcription factors in specific peaks of PCOS group, and RNA sequencing ex vivo at various time points over 24 hours demonstrated the differential rhythmic expression patterns of women with PCOS. Kyoto Encyclopedia of Genes and Genomes analysis further highlighted metabolic dysfunction, including both carbohydrate and amino acid metabolism and the tricarboxylic acid cycle. CONCLUSION(S): There is a significant association of night shift work with PCOS, and genome-wide chronodisruption exists in ovarian GCs.

The fluctuations of metabotropic glutamate receptor subtype 5 (mGluR5) in the amygdala in fear conditioning model of male Wistar rats following sleep deprivation, reverse circadian and napping.

Sleep is involved in metabolic system, mental health and cognitive functions. Evidence shows that sleep deprivation (SD) negatively affects mental health and impairs cognitive functions, including learning and memory. Furthermore, the metabotropic glutamate receptor subtype 5 (mGluR5) is a metabolic biomarker, which is affected by various conditions, including stress, sleep deprivation, and cognitive and psychiatric disorders. In this research, we investigated the effect of SD and reverse circadian (RC), and two models of napping (continuous and non-continuous) combined with SD or RC on fear-conditioning memory, anxiety-like behavior and mGluR5 fluctuations in the amygdala. 64 male Wistar rats were used in this study. The water box apparatus was used to induce SD/RC for 48 h, and fear-conditioning memory apparatus was used to assess fear memory. The results showed, fear-conditioning memory was impaired following SD and RC, especially in contextual stage. However, anxiety-like behavior was increased. Furthermore, mGluR5 was increased in the left amygdala more than the right amygdala. Additionally, continuous napping significantly improved fear-conditioning memory, especially freezing behavior. In conclusion, following SD and RC, fear-conditioning memory in contextual stage is more vulnerable than in auditory stage. Furthermore, increase in anxiety-like behavior is related to increase in the activity of left amygdala and mGluR5 receptors.

How do stress, sleep quality, and chronotype associate with clinically significant depressive symptoms? A study of young male military recruits in compulsory service

Objective: Although studies have shown an association between poor sleep and chronotype with psychiatric problems in young adults, few have focused on identifying multiple concomitant risk factors. Methods: We assessed depressive symptoms (Beck Depression Inventory [BDI]), circadian typology (Morningness-Eveningness Questionnaire [MEQ]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), perceived stress (Perceived Stress Scale [PSS]), social rhythm (Social Rhythm Metrics [SRM]), and salivary cortisol (morning, evening and night, n=37) in 236 men (all 18 years old). Separate analyses were conducted to understand how each PSQI domain was associated with depressive symptoms. Results: Depressive symptoms were more prevalent in individuals with higher perceived stress (prevalence ratio [PR] = 6.429, p < 0.001), evening types (PR = 2.58, p < 0.001) and poor sleepers (PR = 1.808, p = 0.046). Multivariate modeling showed that these three variables were independently associated with depressive symptoms (all p < 0.05). The PSQI items subjective sleep quality and sleep disturbances were significantly more prevalent in individuals with depressive symptoms (PR = 2.210, p = 0.009 and PR = 2.198, p = 0.008). Lower levels of morning cortisol were significantly associated with higher depressive scores (r = -0.335; p = 0.043). Conclusion: It is important to evaluate multiple factors related to sleep and chronotype in youth depression studies, since this can provide important tools for comprehending and managing mental health problems.

How do stress, sleep quality, and chronotype associate with clinically significant depressive symptoms? A study of young male military recruits in compulsory service.

OBJECTIVE: Although studies have shown an association between poor sleep and chronotype with psychiatric problems in young adults, few have focused on identifying multiple concomitant risk factors. METHODS: We assessed depressive symptoms (Beck Depression Inventory [BDI]), circadian typology (Morningness-Eveningness Questionnaire [MEQ]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), perceived stress (Perceived Stress Scale [PSS]), social rhythm (Social Rhythm Metrics [SRM]), and salivary cortisol (morning, evening and night, n=37) in 236 men (all 18 years old). Separate analyses were conducted to understand how each PSQI domain was associated with depressive symptoms. RESULTS: Depressive symptoms were more prevalent in individuals with higher perceived stress (prevalence ratio [PR] = 6.429, p < 0.001), evening types (PR = 2.58, p < 0.001) and poor sleepers (PR = 1.808, p = 0.046). Multivariate modeling showed that these three variables were independently associated with depressive symptoms (all p < 0.05). The PSQI items subjective sleep quality and sleep disturbances were significantly more prevalent in individuals with depressive symptoms (PR = 2.210, p = 0.009 and PR = 2.198, p = 0.008). Lower levels of morning cortisol were significantly associated with higher depressive scores (r = -0.335; p = 0.043). CONCLUSION: It is important to evaluate multiple factors related to sleep and chronotype in youth depression studies, since this can provide important tools for comprehending and managing mental health problems.

Effects of circadian rhythm disorder on the hippocampus of SHR and WKY rats.

The present study investigated the effects of circadian rhythm disorder (CRD) on the hippocampus of SHR and WKY rats. Male SHR rats (n = 27) and WKY rats (n = 27) were randomly divided into six groups: SHR and WKY normal (N)CR, SHR and WKY CRD 16/8 (CRD16/8), and SHR and WKY CRD 12/12 (CRD12/12). Activity patterns were adjusted using different photoperiods over 90 days and any changes were recorded. Rats were tested in the Morris water maze and in a novel object recognition experiment; serologic analysis, magnetic resonance imaging (diffusion tensor imaging + arterial spin labeling), hippocampal Nissl staining, Fluoro-Jade B staining, and immunohistochemistry were also performed. The results showed that both types of inverted photoperiod reduced CR amplitude and prolonged the circadian period. CRD and hypertension reduced memory performance and novel object recognition and preference. The decreases in memory and preference indices were greater in rats in the CRD12/12 group compared to the CRD16/8 group. CRD and hypertension decreased fractional anisotropy values, the number of neurons and astrocytes in the hippocampus, and the expression of brain-derived neurotrophic factor and synapsin 1; it also enhanced the degeneration of neurons and microglia and reduced blood flow in the hippocampus, and increased nuclear factor κB, caspase, neuron-specific enolase, and interleukin-6 levels. These findings reveal a biological basis for the link between CRD and cognitive decline, which has implications for CRD caused by shift work and other factors.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update.

This British Association for Psychopharmacology guideline replaces the original version published in 2010, and contains updated information and recommendations. A consensus meeting was held in London in October 2017 attended by recognised experts and advocates in the field. They were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aiming to reach consensus where the evidence and/or clinical experience was considered adequate, or otherwise to flag the area as a direction for future research. A draft of the proceedings was circulated to all speakers for comments, which were incorporated into the final statement.

Circadian Rhythms in Obsessive-Compulsive Disorder: Recent Findings and Recommendations for Future Research.

PURPOSE OF REVIEW: Circadian rhythms are a topic of growing interest in mental health, particularly in obsessive-compulsive disorder. However, the consistency of this link has not been carefully examined. Thus, the present review integrates findings from the past 5 years in order to determine the strength of such a relationship and identify areas for clarification and extension. RECENT FINDINGS: Findings revealed inconsistent evidence for a link between circadian rhythms and OCD. Chronotype is unrelated to OCD symptoms in adolescents but predicts OCD symptoms in adults. Results on delayed sleep timing are equivocal. Circadian rhythm disorders predict OCD treatment outcome. Preliminary evidence implicates decreased light exposure and diurnal symptom variability in OCD. The relationship between circadian rhythms and OCD may vary by age, diagnostic status, and assessment method. Recent findings are limited by an overreliance on convenience samples and singular self-report methods. Recommendations for future research on the role of circadian rhythms in OCD are discussed.

Eveningness is associated with greater subjective cognitive impairment in individuals with self-reported symptoms of unipolar depression.

BACKGROUND: Eveningness is associated with depression diagnosis and increased depressive symptom severity. Time-of-day preference has been linked with differences in cognitive function in the general population, with cognitive difficulties being a major factor in psychosocial impairment in depression. We therefore investigated the impact of time-of-day preference and self-reported depressed state on subjective cognitive function. METHODS: Participants over the age of 18 with a self-reported history of depression completed an online questionnaire. They provided demographic and mental health information, and completed self-report scales assessing depression symptoms, time-of-day preference, and cognition. Participants were classified as "currently" or "previously depressed" based on self-reported symptoms, and as having a morning, neither, or evening time-of-day preference. RESULTS: A total of 804 participants reporting a history of unipolar depression were included. Currently-depressed participants reported more cognitive difficulties in all areas measured. Evening types reported more complex attentional and retrospective memory difficulties than neither types, and reported more executive and prospective memory difficulties than both neither and morning types. There was an additive effect of mood state and time-of-day preference, with self-reported depressed evening types reporting the most cognitive problems. LIMITATIONS: Depression history, time-of-day preference, and cognitive function were assessed using unsupervised self-report measures. Time-of-day preference does not necessarily reflect the physiological circadian system. CONCLUSIONS: Both depressed state and evening preference were individually associated with subjective cognitive complaints in people with a self-reported history of unipolar depression. The additive effect of poor mood and eveningness is important given the high prevalence of eveningness in depression. Assessment of time-of-day preference could help to identify those susceptible to cognitive symptoms, and inform treatment.

Internalizing symptoms and chronotype in youth: A longitudinal assessment of anxiety, depression and tripartite model.

Biological rhythm theories highlight the reciprocal relations between dysregulated circadian patterns and internalizing psychopathology. Chronotype characterizes individuals' diurnal preference, as some exhibit more morningness or eveningness. Previous research suggests that eveningness prospectively predicts depression in adolescence. Anxiety often co-occurs with depression, but little is known about longitudinal, reciprocal associations between chronotype and anxiety, and whether this relationship remains after controlling for depression. We assessed different forms of anxiety (social, panic, separation), positive/negative affect, anxious arousal (from tripartite theory), and depression, in relation to chronotype to better understand the specificity and directionality of associations between chronotype and internalizing problems in adolescence. Community youth participated in three assessment time points: T1, T2 (18-months post-T1), and T3 (30-months post-T1) as part of a larger longitudinal study. Youth completed self-report measures of anxiety, depression, positive and negative affect, and chronotype. Regression analyses showed that eveningness: (1) concurrently associated with decreased separation anxiety, elevated symptoms of depression and low levels of positive affect, (2) was prospectively predicted by elevated depression, (3) did not predict later symptoms of anxiety. The reciprocal, prospective relationship between chronotype and internalizing psychopathology is specific to depression during adolescence.

Developmental pathways towards mood disorders in adult life: Is there a role for sleep disturbances?

INTRODUCTION: Mood disorders are among the most prevalent and serious mental disorders and rank high among to the leading global burdens of disease. The developmental psychopathology framework can offer a life course perspective on them thus providing a basis for early prevention and intervention. Sleep disturbances, are considered risk factors for mood disorders across childhood, adolescence and adulthood. Assuming that sleep disturbances may play a pivotal role in the pathogenesis of mood disorders from a life course point of view, we reviewed the data on developmental pathways towards mood disorders in adult life in relation to sleep disturbances. METHOD: From February 2017, a systematic search was conducted in PubMed, PsycINFO and Embase electronic databases for literature on developmental pathways to mood disorders in adult life in relation to sleep disturbances and to 1) pre-natal stress, 2) early brain developmental processes, and 3) temperaments, character and attachment style. RESULTS: Eleven, 54 and 15 articles were respectively selected. CONCLUSIONS: Experimental and clinical studies revealed that exposure to prenatal/early life stress results in sleep disturbances such as poor sleep and altered circadian regulation phases and may predict or even precipitate mood disorders in adulthood. Chronic sleep disruption may interfere with neuronal plasticity, connectivity and the developing brain thus contributing to the development of mood disorders. In addition sleep and circadian dysregulations have been shown to be related to those temperaments, character and attachment styles which are considered precursors of mood disorders. Sleep and circadian behaviours may serve as early targets regarding mood disorders.

Daytime midpoint as a digital biomarker for chronotype in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is associated with later sleep and daily activity (evening rather than morning chronotype). Objective chronotype identification (e.g., based on actigraphs/smartphones) has potential utility, but to date, chronotype has mostly been assessed by questionnaires. Given the ubiquity of accelerometer-based devices (e.g. actigraphs/smartphones) worn/used during daytime and tendency to recharge rather than wear at night, we assessed chronotype using daytime (rather than sleep) interval midpoints. METHODS: Sixty-one participants with BD type I (BD-I) or II (BD-II) and 61 healthy controls completed 25-50 days of continuous actigraphy. The Composite Scale of Morningness (CSM) was completed by a subset of this group. Daytime activity midpoint was calculated for each daytime interval, excluding naps. Evening chronotype was defined as having a daytime interval midpoint at or after 16:15:00 (4:15:00 PM). RESULTS: BD versus controls had delayed daytime midpoint (mean ±â€¯standard deviation) (16:49:07 ±â€¯01:26:19 versus 16:12:51 ±â€¯01:02:14, p < 0.01), and greater midpoint variability (73.3 ±â€¯33.9 min versus 58.1 ±â€¯18.3 min, p < 0.01). Stratifying by gender and age, females and adolescents with BD had delayed and more variable daytime midpoints versus controls. Adults with BD had greater midpoint variability than controls. Within-person mean and standard deviations of daytime midpoints were highly correlated with sleep midpoints (r = 0.99, p < 0.01 and r = 0.86, p < 0.01, respectively). Daytime midpoint mean was also significantly correlated with the CSM (r = -0.56, p < 0.01). LIMITATIONS: Small sample size; analyses not fully accounting for daytime napping. CONCLUSIONS: Wrist actigraphy for determination of daytime midpoints is a potential tool to identify objective chronotype. Exploration of the use of consumer devices (wearables/smartphones) is needed.

Depressive symptoms and actigraphy-measured circadian disruption predict head and neck cancer survival.

OBJECTIVE: Depressive symptoms have demonstrated prognostic significance among head and neck cancer patients. Depression is associated with circadian disruption, which is prognostic in multiple other cancer types. We hypothesized that depressive symptoms would be associated with circadian disruption in head and neck cancer, that each would be related to poorer 2-year overall survival, and that relationships would be mediated by tumor response to treatment. METHODS: Patients (N = 55) reported on cognitive/affective and somatic depressive symptoms (PHQ-9) and wore an actigraph for 6 days to continuously record rest and activity cycles prior to chemoradiation. Records review documented treatment response and 2-year survival. Spearman correlations tested depressive symptoms and circadian disruption relationships. Cox proportional hazard models tested the predictive capability of depressive symptoms and circadian disruption, separately, on survival. RESULTS: Depressive symptoms were significantly associated with circadian disruption, and both were significantly associated with shorter survival (somatic: hazard ratio [HR] = 1.325, 95% confidence interval [CI] = 1.089-1.611, P = .005; rest/activity rhythm: HR = 0.073, 95% CI = 0.009-0.563, P = .012; nighttime restfulness: HR = 0.910, 95% CI = 0.848-0.977, P = .009). Tumor response to treatment appeared to partly mediate the nighttime restfulness-survival relationship. CONCLUSIONS: This study replicates and extends prior work with new evidence linking a subjective measure of depression and an objective measure of circadian disruption-2 known prognostic indicators-to shortened overall survival among head and neck cancer patients. Continued examination should elucidate mechanisms by which depressive symptomatology and circadian disruption translate to head and neck cancer progression and mortality.

Sex Differences in Photic Entrainment and Sensitivity to Ethanol-Induced Chronodisruption in Adult Mice After Adolescent Intermittent Ethanol Exposure.

BACKGROUND: Evidence supports a role for the circadian system in alcohol use disorders, but the impact of adolescent alcohol exposure on circadian timing later in life is unknown. Acute ethanol (EtOH) attenuates circadian photic phase-resetting in adult, but not adolescent, rodents. However, nearly all studies have focused on males and it is unknown whether this adolescent-typical insensitivity to EtOH persists into adulthood after adolescent drinking. METHODS: Circadian activity was monitored in C57BL/6J mice receiving adolescent intermittent EtOH (AIE) exposure (15% EtOH and water every other day throughout adolescence) or water alone followed by 24 days wherein EtOH was not available (washout). Mice then received a challenge dose of EtOH (1.5 g/kg, intraperitoneal) or saline 15 minutes prior to a 30-minute phase-delaying light pulse and then were released into constant darkness (DD). To control for possible phase-shifting by EtOH challenge alone, a separate group of mice underwent AIE exposure (or water-only) and washout and then received an EtOH or saline injection, but did not receive a light pulse prior to DD. RESULTS: Striking sex differences in nearly all measures of circadian photic entrainment were observed during adolescence but AIE effects were subtle and few. Only EtOH-naïve adult male mice showed attenuated photic phase-shifts with EtOH challenge, while all other groups showed normal phase-resetting responses to light. AIE-exposed females showed a persistent delay in activity offset. CONCLUSIONS: Adult male AIE-exposed mice retained adolescent-like insensitivity to EtOH-induced suppression of photic phase-resetting, suggesting AIE-induced "lock-in" of an adolescent behavioral phenotype. Adult AIE-exposed females showed delayed initiation of the rest phase. Our results also indicate that intermittent EtOH drinking has subtle effects on circadian activity in mice during adolescence that differ from previously reported effects on adult males. The observed sex differences in circadian activity, EtOH consumption and preference, and responses to EtOH challenge merit future mechanistic study.

[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

The role of eveningness in obsessive-compulsive symptoms: Cross-sectional and prospective approaches.

BACKGROUND: Eveningness may be defined as the tendency to be most active and alert during the evening. Previous research has linked eveningness with maladaptive psychological outcomes, and recent evidence has highlighted circadian dysregulation as a novel factor in psychopathology, including obsessive-compulsive disorder (OCD). However, limited research has examined the unique relationship between eveningness and OC symptoms. Two studies were conducted to thoroughly examine the links between eveningness and OC symptoms, while also considering the role of depression symptoms and sleep-related factors. METHODS: Using a cross-sectional approach, Study 1 examined the association between eveningness and OC symptoms when controlling for depression symptoms. Study 2 then employed a prospective approach to examine the extent to which the relationship between eveningness and change in OC symptoms over 4 months is mediated by change in sleep disturbance and total sleep time when controlling for depression symptoms. RESULTS: Results indicated that depression better accounts for the cross-sectional association between eveningness and OC symptoms. However, eveningness was found to be a more robust prospective predictor of change in OC symptoms in Study 2. Furthermore, sleep disturbance, but not total sleep time, partially mediated the relationship between eveningness and OC symptoms. LIMITATIONS: Single-method self-report approach, unselected sample, and lack of experimental manipulation. CONCLUSIONS: These findings suggest that eveningness may contribute to the development of OC symptoms over time, in part due to its effect on sleep disturbance. Future research examining the role of circadian dysregulation in OCD may uncover novel physiological mechanisms.

Genetic polymorphisms associated with circadian rhythm dysregulation provide new perspectives on bipolar disorder.

OBJECTIVES: The objective of this study was to present a broad view of how genetic polymorphisms in genes that control the rhythmicity and function of circadian rhythm may influence the etiology, pathophysiology and treatment of bipolar disorder (BD). METHODS: A bibliographic search was performed to identify and select papers reporting studies on variations in circadian genes and BD. A search of Medline, Google Scholar, Scopus, and Web of Science was carried out to review the literature. RESULTS: Several studies provide evidence of contributions of variations in circadian genes to disease etiology, pathophysiological variations and lithium drug response. Dysfunction of the sleep-wake cycle, an important brain function regulator, is indicated as the primary means by which circadian gene variations act in mood disorders. CONCLUSIONS: Investigations of the effects of circadian genes have suggested that the chronotype offers hope for guiding and improving management of patients with BD. However, BD is a disease of a complex nature and presents multiple endophenotypes determined by different associations between genetics and the environment. Thus, new genomic studies to delimit variations that may help improve the clinical condition of these patients are extremely important.