Chronotypes and affective disorders: A clock for mood?

Abstract

Affective disorders are often accompanied by circadian rhythm disruption and the major symptoms of mental illness occur in a rhythmic manner. Chronotype, also known as circadian preference for rest or activity, is believed to exert a substantial influence on mental health. Here, we review the connection between chronotypes and affective disorders, and discuss the potential underlying mechanisms between these two phenomena.

Keywords

chronotype affective disorder circadian clock clock gene

1 Introduction

The circadian rhythm is a universal feature of living organisms and influences nearly every biological process [1, 2]. The circadian rhythm is controlled by the endogenous circadian clock and entrained by the external environment. Although human beings work and rest with a period of ˜ 24 h, the timing of activity and rest varies among the population [3]. Some individuals tend to get up early and go to bed early while others prefer sleeping late and waking up late. This circadian preference can be defined as the chronotype of an individual.

Individual chronotypes are regarded as rather stable traits with a normal distribution of morningness vs. eveningness in the general population. About 40% of the adult population belong to the morning-type or evening-type categories, while approximately 60% of the population has no preference [4]. Chronotype is influenced by many factors, including age, gender, heredity, social constraints, and environmental factors [5 –7]. The most commonly used measures to assess chronotypes are subjective self-reports such as the Morningness-Eveningness Questionnaire (MEQ) and Munich ChronoType Questionnaire (MCTQ) [8, 9]. MEQ assesses the “feeling best” rhythm and the preferred time of individuals in various situations. MCTQ reflects the mid-sleep point on free days, which is calculated as the midpoint between sleep start time and end time on free days and strongly correlates with MEQ scores [10]. In addition, the chronotype of an individual can be measured objectively by recording one’s daily activity with devices such as acti-watches or by assessing the timing of dim light melatonin onset (DLMO) [11]. Subjective approaches are easier to manipulate in larger samples while objective methods are believed to be more accurate. Some studies have compared these two types of methods and found them to be significantly correlated, albeit with some minor differences [12, 13]. In recent years, with the advancement of high-throughput RNA profiling techniques, it was shown that a significant portion of the genome exhibits rhythmic expression, which is driven by the circadian clock [14]. Therefore, rhythmic transcriptomes in human periphery blood cells can also be used as an indicator of circadian phase, which is another objective method to assess chronotype. Algorithms such as TimeSignature and BodyTime have been developed to estimate the human circadian phase based on gene expression in blood monocytes [15, 16]. Partial least squares regression has been applied to analyze the transcriptomic profiles of human blood cells to predict melatonin rhythm phase [17].

Chronotype influences many aspects of health given the extensive effects of circadian rhythm on behavior and physiology [5]. Circadian rhythm disruption has been widely observed among patients with affective illnesses. Abnormalities in core body temperature rhythm and melatonin secretion were reported in patients with bipolar disorder (BD) [18]. The daily rhythm of hundreds of genes in the human brain that are involved in essential physiological events, including the sleep/wake cycle and metabolism, were found to be profoundly dysregulated in major depressive disorder (MDD) [19]. Circadian disruption is reliably associated with various adverse mental health conditions and well-being in large populations [20]. In recent years, a growing number of studies indicate a link between affective disorders and chronotype, which we will discuss in detail in this review.

2 Chronotype and major depressive disorder

MDD, which is also known as unipolar depressive disorder, is defined as one or more major depressive episodes and the lifetime absence of mania and hypomania [21]. A great number of studies support the conclusion that eveningness is associated with depressive disorder and the severity of depressive symptoms in patients with depressive disorder. Depressed patients showed more evening preference than controls [22]. Adults with current MDD had an increased chance of having a later chronotype in a Netherlands cohort study which included 676 currently depressed patients, 831 remitted patients, and 437 healthy controls [23]. Young patients (age 12–30) with depression also exhibited greater evening preference and a larger proportion of them are “extreme evening” chronotypes [24]. The chronotype of hospitalized patients with depressive syndromes were also investigated. Eveningness was directly associated with elevated depression severity in depressed inpatients [25, 26]. Consistently, depressive symptoms were significantly more serious in evening-type individuals than morning-type individuals during admission. Moreover, eveningness was related to greater subjective cognitive impairment in 804 individuals with self-reported symptoms of unipolar depression [27]. Cognitive symptoms were also significantly more obvious in eveningtypes vs. morning-types for inpatients [28]. In addition, studies have evaluated the relationship between suicidality and chronotype in patients with MDD. Compared to morning-type participants, evening-type participants exhibited a higher tendency toward suicidality [29, 30].

Moreover, eveningness was demonstrated to be associated with a higher incidence of depressive states and increased depressive symptom severity in the general population. In a large general adult population consisting of 10,503 Finnish participants, eveningness was significantly associated with a greater likelihood of being diagnosed with depressive disorder, antidepressant medication, and the severity of depressive symptoms [31]. In another study, eveningness was associated with an increased likelihood of depression among 100,402 individuals within the UK Biobank cohort [32]. In many studies from different countries conducted on both students and adults, individuals with the evening chronotype reported increased depression [33 –37]. Evening-type individuals with a phase delay of molecular oscillations estimated by the temporal profile of clock gene mRNA expression in hair follicles were 20 times more likely to be depressed than control individuals in a study including 528 undergraduate students in the US [38]. Among 1,068 medical students in Mexico City, depressive symptom severity was higher in non-morning chronotypes and the evening chronotype was associated with depression [39]. In addition, the evening chronotype was associated with elevated symptoms of depression in adolescents in a cross-sectional study and a longitudinal study encompassing a 48-month assessment [40, 41]. Given these data, it can be concluded that evening-types are more likely to report depressive symptoms and depressive disorder in both adults and adolescents from many different countries.

Delayed sleep phase syndrome (DSPS) is characterized by a habitually delayed sleep–wake schedule as compared to a conventional or socially acceptable one. In a study including 90 DSPS patients, 64% were in a moderate or severe depressive state, indicating that there is a high prevalence of depressive symptoms among evening-type patients [42]. There were no significant differences in the occurrence of depressive disorders between the individuals with DSPS and those with merely an evening preference, suggesting that mood is primarily influenced by having an evening chronotype, rather than a sleep complaint [43].

3 Chronotype and seasonal affective disorder

Mood is easily affected by seasonal light changes [44, 45]. Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes generally occurring in autumn/winter and remitting in spring/summer [46]. As light treatment is the most-preferred therapy for SAD and light resets the phase of circadian rhythm, differences in chronotypes have long been considered as a possible cause of SAD [47]. Individuals with syndromal or subsyndromal SAD are more likely to be evening type while evening-type individuals are more susceptible to SAD than morning-type individuals. In a population sample of 4,905 Finnish adults, participants with symptoms of SAD had significantly increased odds of having evening chronotypes [48]. In 3,435 Russian adolescents aged 10–20 years old, there were significant differences in chronotype between individuals with or without SAD. Later sleeping and waking times were observed in both males and females with SAD [49]. A group of 327 adult participants with DSPS were 3.3 times more likely to report SAD when compared with 331 controls [50]. During polar nights, Chinese expeditioners at Zhongshan Station experienced delayed circadian rhythm and sleep phase, exhibiting altered chronotype as well as an increased incidence of sub-syndromal SAD [51]. In a study testing the effects of high-density negative air ions in treating SAD, subjects with a morning chronotype responded better than those with an evening chronotype [52].

Despite these findings, some studies report a lack of significant links between chronotype and SAD. Morning-evening preference was not found to be associated with SAD for 101 young participants in Poland between 20 and 30 years of age [53]. In another investigation, the success of light therapy was not dependent on the chronotype of 132 SAD patients tested, suggesting that the anti-depressive effect of morning light cannot be explained by a phase shift of the biological clock [54]. However, these studies used relatively small samples and need to be further validated.

The seasonality of mood can be defined as the annual mood variation of an individual. It is associated with chronotypes in both the general population and patients with affective disorders. Evening-type participants received higher mood seasonality scores than intermediate and morningtypes in a study investigating the relationship between circadian preference and mood seasonality in 1,539 adolescents [55]. In another study, 1,715 university students with enhanced seasonality of mood were more likely to be evening-types [56]. A positive association was also found between worse mood and phase delay in winter across 3 years among a random community sample with 244 adults in Melbourne [57]. Similarly, a study of 469 young Finnish adults found that diurnal preference toward eveningness was more likely to be associated with seasonal variations in mood and behavior, compared to those with diurnal preference toward morningness [58]. On the other hand, morningness was associated with lower seasonality of mood in 489 old Order Amish individuals [59]. It has also been demonstrated that a higher level of depression significantly correlated with larger seasonal changes and seasonality was more prevalent in the bipolar group and was associated with evening preference [60, 61].

4 Chronotype and bipolar disorder

BD is a severe mental illness which is characterized by alternating manic or hypomanic and major depressive episodes, separated by euthymic periods when symptoms are reduced or absent. BD patients display mood states ranging from extreme mania to severe depression and show both of these opposite symptoms simultaneously during mixed states [62]. In a large number of studies evaluating chronotypes in both adult and adolescent BD patients, BD was usually associated with evening preference [13, 63]. BD patients showed delayed chronotype (daytime midpoint) and greater midpoint variability than healthy controls [64]. One study assessed the chronotype of children and adolescents with BD, and no difference was found when comparing BD children (age 7–17) and controls. However, BD adolescents (age 13 and older) displayed significantly greater eveningness compared to their peers [65]. In the general population, late chronotype is also associated with bipolarity (bipolar tendency). In a group of 302 individuals, evening-types displayed significant bipolarity or mood fluctuations [66]. Another study based on 1,449 web questionnaires also supported the conclusion that eveningness is associated with bipolarity [67].

Moreover, evening preference is associated with different stages of BD. In a sample of 752 French euthymic BD patients, the number of participants having an evening chronotype was double of that with morning chronotype [68]. Brazilian and French outpatients with BD were significantly more likely to show an evening preference than control subjects when in remission [69, 70]. However, chronotype did not significantly differ between 119 remitted BD patients and 136 control individuals in a study conducted in the US. In this study, healthy controls were significantly younger than BD patients and circadian differences were probably was masked by the influence of age [71]. In Asian countries, eveningness chronotype has been reported to be associated with frequent recurrences of episodes associated with BD [72].

Evening chronotype is associated with increased mood symptoms in BD patients, including depression and mania. In an Arctic population including BD patients and their healthy relatives, lifetime manic behavior was increased among subjects with “the night owl” chronotype [73]. BD patients with elevated depressive mood scores were more likely to be evening-types [74]. In addition, patients with rapid cycling BD were more phase-delayed than control subjects [75]. Lithium is an effective mood stabilizer for alleviating mood symptoms in BD, but some patients are unresponsive to it. Compared to lithium non-responders, lithium-responsive BD patients showed morningness preference [76]. Additionally, BD patients treated with lithium exhibited an increased morning preference [77]. Independent of mood state and treatment, evening preference has a stable association with BD, implying that an evening chronotype may be a trait marker for BD [78].

The chronotype difference between BD subtypes have been investigated as well. Bipolar I disorder (BD-I) involves periods of severe mood episodes from mania to depression while bipolar II disorder (BD-II) involves milder episodes of hypomania that alternate with periods of severe depression [62]. Korean patients with BD-I showed a significantly greater preference for evening than control individuals [79]. Among BD-I patients, younger participants and those with rapid changes in mood were significantly more likely to exhibit evening preference [80]. Evening preference was also more prevalent in BD-II patients in Korea [61]. Moreover, 43 Korean patients with BD-II showed more eveningness than 106 patients with BD-I [81]. However, this has been controversial as another study failed to detect significant differences in morningness-eveningness scores between 134 BD-I cases and 56 BD-II cases in the US [74]. The subjects in these two studies were from different countries and the sample size for BD-II was relatively small, thus the results need further validation.

5 Chronotype and anxiety disorder

Individuals with anxiety disorders are excessively fearful, anxious, or avoidant of perceived threats in the environment, such as social situations or unfamiliar locations, or internal causes. The fear or anxiety is marked, persistent, and impairing [82]. Eveningness was found to be associated with anxiety disorders in a number of studies. Patients with anxiety disorders were more likely to be evening-types based on a study consisting of 1,468 inpatients [83]. According to the data from a large cohort in the Netherlands consisting of 1,944 participants, late types were more likely to be anxious and the severity of anxiety tended to be increased in the late group [23]. There was a significant association between chronotype and anxiety, and eveningness significantly predicted increased anxiety [84]. Female nurses with eveningness-oriented preference appeared to be more prone to demonstrating anxiety than those with morningness [85]. Among 641 healthy Korean individuals, evening-type subjects were more likely to possess anxious temperaments, which might contribute to their vulnerability for affective disorders [86].

Consistently, evening-types also reported more symptoms of anxiety in young individuals. Eveningness was associated with elevated anxiety in adolescents and incoming college students [40, 87, 88]. Among college students, the eveningtype group also displayed a larger proportion of anxiety and suffered from increased anxiety symptoms than the other two chronotypes [34, 89, 90]. In a study including 1,406 adolescents, anxiety was associated with eveningness during weekdays but not on the weekend, and a greater proportion of evening-types were found in the high-anxiety group [91]. However, no significant connection was found between circadian phase preference and anxiety in a US sample of 838 undergraduate college students [92]. A lower prevalence rate of psychiatric disorders in this population may account for this discrepancy.

6 Clock gene variants underlying chronotype and affective disorders

These associations between chronotype and various affective disorders imply that there is a role for altered circadian clock in the pathological processes of affective disorders. Therefore, many studies have searched for the potential contribution of clock genes in mood regulation, and a number of genetic variants associated with both chronotypes and affective disorders have been identified (Table 1).

Table 1

Clock gene variants associated with both chronotype and affective disorders.

Gene	Variant	Allele	Class	Type	Amino acid	Chronotype	Affective disorder	Reference
PER3	rs150812083	C/G	SNP	Coding	P/A	FASP	SAD	[98]
PER3	rs139315125	A/G	SNP	coding	H/R	FASP	SAD	[98]
PER3	rs57875989	4/5VNTR	Indel	coding	ALSTGSPPMK-NPSHPTAS	evening preference	less anxiety, less depression, earlier age of onset of BD-I	[99 –107]
PER3	rs228697	C/G	SNP	coding	P/A	evening preference	anxiety	[105, 106]
CLOCK	rs1801260	T/C	SNP	3’ untranslated region	N/A	evening preference, especially in BD patients	higher recurrence rate of BD, more severe BD symptoms	[112, 113, 119 –121]

SNP, single nucleotide polymorphism; FASP, familial advanced sleep phase; SAD, seasonal affective disorder; BD, bipolar disorder; BD-I, bipolar I disorder.

The human PERIOD3 (PER3) gene is believed to serve as a link between circadian rhythm and mood regulation. PER3 shares several highly conserved domains with PER1 and PER2, acting as their dimerizing partner [93, 94]. Unlike its paralog Per1 and Per2, Per3 was shown to be non-essential for the endogenous circadian clock in mice [95]. Multiple studies demonstrated that PER3 is involved in sleep regulation and may influence circadian preference [96, 97]. Familial advanced sleep phase (FASP) is a human behavioral phenotype defined by early sleep time and early morning awakening. Thus, individuals with FASP are extreme morning-types. Three FASP subjects have been found to carry two rare variants in the PER3 gene (PER3-P415A/H417R). These individuals also displayed elevated Beck Depression Inventory scores, Global Seasonality Scores, and Problem Severity Scores, which are strongly suggestive of SAD. At the molecular level, these variants lead to decreased PER3 protein levels and destabilized PER1 and PER2 proteins, which may contribute to alterations in the clock phase [98]. Transgenic mice carrying human PER3-P415A/H417R displayed about 4 h of phase delay under extreme short photoperiod (4 hours light: 20 hours dark, 4L20D), but not under normal lighting conditions (12 hours light: 12 hours dark, 12L12D). In addition, increased despair-like behaviors were observed in hPER3- P415A/H417R transgenic mice on both tail suspension test and forced swim test under 4L20D (unpublished result). PER3-P415A/H417R are the only verified clock gene variants which regulate the phase of circadian rhythm (chronotype) and mood. In most cases, eveningness, not morningness, is associated with SAD, but PER3-P415A/H417R individuals displayed advanced sleep phase whereas hPER3-P415A/H417R transgenic mice exhibited delayed phase. Further mechanistic characterizations will be required to explain the discrepancy between human and mouse phenotypes, as well as how advanced sleep phase is linked to SAD in individuals carrying PER3- P415A/H417R alleles.

The most-studied variant of PER3 is a length polymorphism (rs57875989) located on exon 18. These coding-region variable number tandem repeats (VNTRs) encode an 18-amino-acid tandem motif which is repeated 4 (PER3⁴) or 5 (PER3⁵) times [99]. Four-repeat allele has been linked to DSPS and extreme evening preference [100] and this correlation has been replicated in several studies [101 –103]. However, this association between PER3 polymorphism and diurnal preference appeared to attenuate with age and was significant only in the youngest group (18–29 years old) [104]. In a group of 380 undergraduate and graduate students, the frequency of the 4-repeat allele was higher in evening-types and lower in morning-types, whereas PER3 ^4/4 and PER3 ^5/5 genotypes are less frequent in morning-types and in evening-types, respectively [105]. PER3 VNTR has also been reported to be associated with affective disorders. Individuals carrying a PER3⁴ allele displayed more anxiety [105]. In addition, PER3^4/4 was significantly associated with depression and evening preference in another study consisting of 546 undergraduate subjects [106]. In a sample of 99 patients affected by BD-I, PER3 VNTR influenced the patients’ age at onset of illness: earlier age of onset in PER3 ^5/5 individuals and later age in PER3 ^4/4 [107]. As PER3 VNTR motif contains clusters of potential phosphorylation sites for the key clock kinase casein kinase 1, this polymorphism could influence the stability and nuclear localization of PER3. It was predicted that decreased or increased phosphorylation levels associated with PER3 ^4/4 and PER3 ^5/5 lead to a lengthened or shortened period length, respectively [105]. This altered period length can result in altered phase under light-dark conditions, which manifests as morning/evening chronotypes in the human population.

A single nucleotide polymorphism (SNP) of PER3, rs228697, was significantly associated with evening preference and anxiety in a population of 380 undergraduate and graduate students [105]. At this site, mutation from C to G leads to a proline-to-alanine substitution at amino acid 864 of the protein and may change the tertiary structure of PER3 [105]. The frequency of the G allele and the distribution of GG homozygous alleles were higher in evening-types. Individuals homozygous for GG were more likely to be the evening type and were more likely to be anxious. In another study including 546 undergraduates, GG homozygous individuals also reported significantly higher anxiety and evening preference [106].

The human circadian locomotor output cycles kaput gene (CLOCK) is a central component of the circadian clock. CLOCK protein consists of 846 amino acids, acting both as a transcription factor as well as perhaps an acetyltransferase [108, 109]. rs1801260 (3111T/C) is the most-studied SNP of the human CLOCK gene. It is located at position 3111 in the 3’ untranslated region, a region important for mRNA stability. Clock knockout mouse embryonic fibroblasts transfected with human CLOCK-3111C showed increased levels of CLOCK and Per2 mRNA levels [110]. In luciferase reporter assays conducted on human cells, the luciferase gene was expressed significantly higher when it was fused to the 3’-UTR region of CLOCK carrying the 3111C SNP, strongly suggesting that 3111C increases the level of CLOCK mRNA [111]. Rs1801260 was reported to be associated with a delay in preferred timing of activity and sleep. Subjects carrying the C allele exhibited a significant evening preference in more than 400 American and Japanese participants [112, 113]. However, this variant is neither associated with evening preference nor DSPS in the UK and Brazilian population, as well as in 415 unrelated women in northeastern Greece [114 –116]. The C allele was associated with late chronotype and severe depression in patients with affective disorders, although case-control investigations were not able to identify an association between CLOCK rs1801260 and mood disorders [117, 118]. Compared to T/T homozygotes, carriers of the C allele displayed a delayed sleep onset in 39 bipolar depressed inpatients [119]. This polymorphism may exert an influence on BD recurrence, as the recurrence rate in homozygotes for the C allele was nearly double than homozygotes for the T allele and heterozygotes in 101 BD-I patients [120]. In 87 depressed patients with BD-I, rs1801260*C carriers showed higher rates of suicidal ideation and increased depression severity than patients with T/T homozygotes [121].

Despite the discrepancies found in human genetics data, Clock^Δ19 mutant mice were able to recapitulate the manic symptoms of BD patients. Clock^Δ19 mutation results in an A to T nucleotide transversion at a splice donor site, causing a skipping of exon 19 and subsequently deletion of 51 amino acids in the CLOCK protein [109]. Clock^Δ19/Δ19 mice displayed a lengthened circadian period and an overall behavioral profile that was strikingly similar to bipolar patients in the manic state. Clock^Δ19/Δ19 mice showed a greater preference for a range of rewarding stimuli, including rewarding electrical stimulation and sucrose. Accordingly, these Clock mutant mice were extremely hyperactive and exhibited increased exploration on the open field test and increased swimming in the forced swim test, suggesting reductions in both anxiety and depression-like behaviors. Lithium, a commonly prescribed mood stabilizer for treating mania, was able to reverse manic-like behavior of the Clock mutant mice [122, 123]. Reduced anxietyand depression-related behaviors of Clock^Δ19/Δ19 mice were only observed during the daytime, revealing a profound manic-like phenotype emerging during the day followed by a period of euthymia at night. This rapid mood-cycling coincided with abnormal daytime spikes in dopaminergic activity, tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine synthesis) levels, and dopamine synthesis in the ventral tegmental area (VTA) of Clock^Δ19/Δ19 mice. Daytime inhibition of TH by Alpha-methyl-DL-p-tyrosine methyl ester (AMPT) reversed manic-like behaviors in Clock^Δ19/Δ19 mice. At the molecular level, CLOCK acted as a negative regulator of TH transcription in the VTA. In short, Clock^Δ19 mutation enhanced dopamine synthesis, leading to manic-like behavioral states during daytime [123, 124]. Overall, these results imply that CLOCK may indeed regulate both chronotypes and mood states in humans.

7 Discussion and conclusion

In summary, it appears that under the majority of the circumstances, the evening chronotype is associated with affective disorders, increased severity of symptoms, such as worse depressive or anxious mood, higher seasonality scores, increased bipolarity, and higher suicidality or suicidal ideation.

Social schedules, such as school and work, exert profound influences on chronotypes. In most cases, school and work starts relatively early in the morning. Evening chronotypes tend to go to bed late but have to get up at a relatively early time on school/work days, thus accumulating sleep debts which lead to increased sleep on free days. Therefore, late chronotypes display a larger difference in sleep timing between work and free days. The discrepancy in sleep/wake times between work and free days reflects differences between actual sleep/wake times and endogenous circadian phase, which is described as social jetlag [125]. Social jetlag leads to sleep disturbances, such as poor sleep quality and daytime sleepiness, which may be critical risk factors for various affective disorders. Eveningness may result in suffering from more social jetlag and accompanying sleep disturbances. However, a study found that there was no difference in social jetlag between patients with MDD and healthy controls [126]. Chronotype was reported to significantly correlate with specific subtypes of anxiety disorders, but did not predict these anxiety subtypes after controlling for insomnia [37]. In a survey including 1,403 students (undergraduates and graduates), insomnia, nightmares, and circadian phase delay were associated with increased depression, anxiety, and other symptoms [127]. There were statistically significant associations between insomnia and depression, whereas weak associations were detected between chronotype and depression [127]. These findings imply that the sleep disturbances in evening-types may be a major contributor to the development of anxiety and depression.

However, sleep problems are not the sole contributing factor, as some studies reported that eveningness is associated with depression, independent of sleep [30, 36, 128]. Eveningness was found to be associated with an increased risk of remission to depression or depression severity even after adjusting for insomnia severity in MDD and BD patients, supporting the significant and independent role of circadian factor in contributing to depressive symptoms [25, 30]. In a study including 1,814 participants, evening preference was associated with an increased incidence of depressive states, even after adjusting for differences in sleep parameters [36]. Another study also supported that evening chronotype per se was an independent risk factor for higher negative emotionality, regardless of the effects of time spent in bed and sleep complaints [128].

Chronotypes may regulate mood by adjusting phase relationship between sleep and other physiological rhythms. Individuals with evening preference displayed phase delays in core body temperatures and melatonin rhythms when compared with morning-types [129, 130]. It has been reported that the interval between circadian phase of melatonin or core temperature rhythms and usual wake time was longer in morningtypes. Thus, while evening-types wake up at a later clock hour than morning-types, morningtypes actually wake up at a later circadian phase [131]. In addition, the variance of circadian phase was greater among subjects with delayed sleep types [132]. For evening-types, the relative delay of melatonin or core body temperature rhythms against sleep phase leads to internal desynchronization and thus may increase the risk for affective disorders. Indeed, some circadian interventions have been reported to be effective for reducing depressive symptoms, such as light therapy and chronotherapy [133, 134].

In addition, eveningness is linked to mood dysregulation. Cognitive reactivity is the extent to which negative thoughts become activated when mood is low, and it is a vulnerability marker of affective disorders. Cognitive reactivity may mediate the effects of chronotype on depression status, even when controlling for insomnia [135]. In addition, eveningness has been reported to be associated with impaired emotional regulation (i.e. reduced cognitive reappraisal and increased expression suppression) after controlling for factors, including sleep quality. This may confer a risk for future depression [136].

Both chronotypes and affective disorders are affected by multiple genetic and environmental factors. Some clock gene polymorphisms have been reported to be associated with chronotype and affective disorders, providing some insights regarding how chronotypes may affect mood, but the underlying mechanisms need further characterization. In recent years, neurobiological research has revealed key circuits regulating mood, providing new directions to investigate for circadian rhythm and mood regulation. In the future, a combination of approaches at molecular, cellular, circuit, and system levels shall facilitate further elucidation of the mechanisms underlying the connections between chronotype and affective disorders.

Footnotes

Conflict of interests

All contributing authors have no conflict of interests related to this paper.

Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (No. 31930021, No. 31671360) to Luoying Zhang, and China Postdoctoral Science Foundation (No. 2018M632826) to Qiang Gao.

References

Takahashi

Hong

, et al. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008, 9(10): 764–775.

Zhang

. Circadian control of global transcription. Biomed Res Int. 2015, 2015: 187809.

Roenneberg

Kuehnle

Juda

, et al. Epidemiology of the human circadian clock. Sleep Med Rev. 2007, 11(6): 429–438.

Adan

Archer

Hidalgo

, et al. Circadian typology: a comprehensive review. Chronobiol Int. 2012, 29(9): 1153–1175.

Roenneberg

Merrow

. The circadian clock and human health. Curr Biol. 2016, 26(10): R432–R443.

Zhang

. The molecular genetics of human sleep. Eur J Neurosci. 2018, in press, DOI 10.1111/ejn.14132.

Roenneberg

Kantermann

Juda

, et al. Light and the human circadian clock. In Circadian Clocks. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013.

Horne

Ostberg

. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol. 1976, 4(2): 97–110.

Roenneberg

Wirz-Justice

Merrow

. Life between clocks: daily temporal patterns of human chronotypes. J Biol Rhythms. 2003, 18(1): 80–90.

10.

Zavada

Gordijn

Beersma

, et al. Comparison of the Munich chronotype questionnaire with the horne-ostberg’s morningness-eveningness score. Chronobiol Int. 2005, 22(2): 267–278.

11.

Lewy

Cutler

Sack

. The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms. 1999, 14(3): 227–236.

12.

Kantermann

Sung

Burgess

. Comparing the morningness-eveningness questionnaire and Munich ChronoType questionnaire to the dim light melatonin onset. J Biol Rhythms. 2015, 30(5): 449–453.

13.

Gershon

Kaufmann

Depp

, et al. Subjective versus objective evening chronotypes in bipolar disorder. J Affect Disord. 2018, 225: 342–349.

14.

Archer

Laing

Möller-Levet

, et al. Mistimed sleep disrupts circadian regulation of the human transcriptome. Proc Natl Acad Sci USA. 2014, 111(6): E682–E691.

15.

Wittenbrink

Ananthasubramaniam

Münch

, et al. High-accuracy determination of internal circadian time from a single blood sample. J Clin Invest. 2018, 128(9): 3826–3839.

16.

Braun

Kath

Iwanaszko

, et al. Universal method for robust detection of circadian state from gene expression. Proc Natl Acad Sci USA. 2018, 115(39): E9247–E9256.

17.

Laing

Möller-Levet

Poh

, et al. Blood transcriptome based biomarkers for human circadian phase. Elife. 2017, 6: e20214.

18.

Soreca

. Circadian rhythms and sleep in bipolar disorder: implications for pathophysiology and treatment. Curr Opin Psychiatry. 2014, 27(6): 467–471.

19.

Bunney

Meng

, et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci USA. 2013, 110(24): 9950–9955.

20.

Lyall

Wyse

Graham

, et al. Association of disrupted circadian rhythmicity with mood disorders, subjective wellbeing, and cognitive function: a cross-sectional study of 91 105 participants from the UK Biobank. Lancet Psychiatry. 2018, 5(6): 507–514.

21.

Uher

Payne

Pavlova

, et al. Major depressive disorder in DSM-5: implications for clinical practice and research of changes from DSM-IV. Depress Anxiety. 2014, 31(6): 459–471.

22.

Drennan

Klauber

Kripke

, et al. The effects of depression and age on the Horne-Ostberg morningness-eveningness score. J Affect Disord. 1991, 23(2): 93–98.

23.

Antypa

Vogelzangs

Meesters

, et al. Chronotype associations with depression and anxiety disorders in a large cohort study. Depress Anxiety. 2016, 33(1): 75–83.

24.

Fares

Hermens

Naismith

, et al. Clinical correlates of chronotypes in young persons with mental disorders. Chronobiol Int. 2015, 32(9): 1183– 1191.

25.

Müller

Kundermann

Cabanel

. Eveningness and poor sleep quality independently contribute to self-reported depression severity in psychiatric inpatients with affective disorder. Nord J Psychiatry. 2016, 70(5): 329–334.

26.

Müller

Cabanel

Olschinski

, et al. Chronotypes in patients with nonseasonal depressive disorder: Distribution, stability and association with clinical variables. Chronobiol Int. 2015, 32(10): 1343– 1351.

27.

Coleman

Cain

. Eveningness is associated with greater subjective cognitive impairment in individuals with self-reported symptoms of unipolar depression. J Affect Disord. 2019, 256: 404–415.

28.

Müller

Olschinski

Kundermann

, et al. Patterns of self-reported depressive symptoms in relation to morningness-eveningness in inpatients with a depressive disorder. Psychiatry Res. 2016, 239: 163–168.

29.

Bahk

Han

Lee

. Biological rhythm differences and suicidal ideation in patients with major depressive disorder. J Affect Disord. 2014, 168: 294–297.

30.

Chan

Lam

, et al. Eveningness and insomnia: independent risk factors of nonremission in major depressive disorder. Sleep. 2014, 37(5): 911– 917.

31.

Merikanto

Kronholm

Peltonen

, et al. Circadian preference links to depression in general adult population. J Affect Disord. 2015, 188: 143–148.

32.

Lane

Vlasac

Anderson

, et al. Genomewide association analysis identifies novel loci for chronotype in 100, 420 individuals from the UK Biobank. Nat Commun. 2016, 7: 10889.

33.

Merikanto

Lahti

Kronholm

, et al. Evening types are prone to depression. Chronobiol Int. 2013, 30(5): 719–725.

34.

Prat

Adan . Relationships among circadian typology, psychological symptoms, and sensation seeking. Chronobiol Int. 2013, 30(7): 942–949.

35.

Chiu

Yang

Kuo

. Chronotype preference matters for depression in youth. Chronobiol Int. 2017, 34(7): 933–941.

36.

Kitamura

Hida

Watanabe

, et al. Evening preference is related to the incidence of depressive states independent of sleep-wake conditions. Chronobiol Int. 2010, 27(9/10): 1797–1812.

37.

Alvaro

Roberts

Harris

. The independent relationships between insomnia, depression, subtypes of anxiety, and chronotype during adolescence. Sleep Med. 2014, 15(8): 934–941.

38.

Nguyen

Murray

Anderson

, et al. In vivo molecular chronotyping, circadian misalignment, and high rates of depression in young adults. J Affect Disord. 2019, 250: 425–431.

39.

Romo-Nava

Tafoya

Gutiérrez-Soriano

, et al. The association between chronotype and perceived academic stress to depression in medical students. Chronobiol Int. 2016, 33(10): 1359–1368.

40.

Pabst

Negriff

Dorn

, et al. Depression and anxiety in adolescent females: the impact of sleep preference and body mass index. J Adolesc Health. 2009, 44(6): 554–560.

41.

Haraden

Mullin

Hankin

. Internalizing symptoms and chronotype in youth: a longitudinal assessment of anxiety, depression and tripartite model. Psychiatry Res. 2019, 272: 797–805.

42.

Abe

Inoue

Komada

, et al. Relation between morningness-eveningness score and depressive symptoms among patients with delayed sleep phase syndrome. Sleep Med. 2011, 12(7): 680–684.

43.

Reid

Jaksa

Eisengart

, et al. Systematic evaluation of Axis-I DSM diagnoses in delayed sleep phase disorder and evening-type circadian preference. Sleep Med. 2012, 13(9): 1171–1177.

44.

Kripke

Elliott

Welsh

, et al. Photoperiodic and circadian bifurcation theories of depression and Mania . F1000Res. 2015, 4: 107.

45.

Einat

Kronfeld-Schor

Eilam

. Sand rats see the light: short photoperiod induces a depression-like response in a diurnal rodent. Behav Brain Res. 2006, 173(1): 153–157.

46.

Rosenthal

Sack

Gillin

, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry. 1984, 41(1): 72–80.

47.

Meesters

Gordijn

. Seasonal affective disorder, winter type: current insights and treatment options. Psychol Res Behav Manag. 2016, 9: 317–327.

48.

Sandman

Merikanto

Määttänen

, et al. Winter is coming: nightmares and sleep problems during seasonal affective disorder. J Sleep Res. 2016, 25(5): 612–619.

49.

Borisenkov

Petrova

Timonin

, et al. Sleep characteristics, chronotype and winter depression in 10-20-year-olds in northern European Russia. J Sleep Res. 2015, 24(3): 288–295.

50.

Lee

Rex

Nievergelt

, et al. Delayed sleep phase syndrome is related to seasonal affective disorder. J Affect Disord. 2011, 133(3): 573–579.

51.

Chen

Xiong

, et al. Circadian rhythm and sleep during prolonged Antarctic residence at Chinese Zhongshan station. Wilderness Environ Med. 2016, 27(4): 458–467.

52.

Bowers

Flory

Ametepe

, et al. Controlled trial evaluation of exposure duration to negative air ions for the treatment of seasonal affective disorder. Psychiatry Res. 2018, 259: 7–14.

53.

Oginska

Oginska-Bruchal

. Chronotype and personality factors of predisposition to seasonal affective disorder. Chronobiol Int. 2014, 31(4): 523–531.

54.

Knapen

Gordijn

Meesters

. The relation between chronotype and treatment outcome with light therapy on a fixed time schedule. J Affect Disord. 2016, 202: 87–90.

55.

Tonetti

Fabbri

Martoni

, et al. Circadian type and mood seasonality in adolescents. Psychiatry Clin Neurosci. 2012, 66(2): 157–159.

56.

Natale

Adan Scapellato

. Are seasonality of mood and eveningness closely associated? Psychiatry Res. 2005, 136(1): 51–60.

57.

Murray

Allen

Trinder

. Seasonality and circadian phase delay: prospective evidence that winter lowering of mood is associated with a shift towards Eveningness. J Affect Disord. 2003, 76(1/2/3): 15–22.

58.

Merikanto

Suvisaari

Lahti

, et al. Eveningness relates to burnout and seasonal sleep and mood problems among young adults. Nord J Psychiatry. 2016, 70(1): 72–80.

59.

Zhang

Evans

Raheja

, et al. Chronotype and seasonality: morningness is associated with lower seasonal mood and behavior changes in the Old Order Amish. J Affect Disord. 2015, 174: 209–214.

60.

Oyane

Bjelland

Pallesen

, et al. Seasonality is associated with anxiety and depression: the Hordaland health study. J Affect Disord. 2008, 105(1/2/3): 147–155.

61.

Baek

Kim

, et al. Lifetime characteristics of evening-preference and irregular bed-rise time are associated with lifetime seasonal variation of mood and behavior: comparison between individuals with bipolar disorder and healthy controls. Behav Sleep Med. 2016, 14(2): 155–168.

62.

Tondo

Vázquez

Baldessarini

. Depression and Mania in bipolar disorder. Curr Neuropharmacol. 2017, 15(3): 353–358.

63.

Melo

MCA

Abreu

RLC

Linhares Neto

, et al. Chronotype and circadian rhythm in bipolar disorder: a systematic review. Sleep Med Rev. 2017, 34: 46–58.

64.

Kaufmann

Gershon

Depp

, et al. Daytime midpoint as a digital biomarker for chronotype in bipolar disorder. J Affect Disord. 2018, 241: 586–591.

65.

Kim

Weissman

Puzia

, et al. Circadian phase preference in pediatric bipolar disorder. J Clin Med. 2014, 3(1): 255–266.

66.

Jeong Jeong

Moon

Min Park

, et al. The relationship between chronotype and mood fluctuation in the general population. Psychiatry Res. 2015, 229(3): 867–871.

67.

Chrobak

Tereszko

Dembinska-Krajewska

, et al. The role of affective temperaments assessed by the Temperament Evaluation of Memphis, Pisa and San Diego-Autoquestionnaire (TEMPS-A) in the relationship between morningness-eveningness and bipolarity. J Affect Disord. 2018, 232: 83–88.

68.

Godin

Henry

Leboyer

, et al. Sleep quality, chronotype and metabolic syndrome components in bipolar disorders during the remission period: Results from the FACE-BD cohort. Chronobiol Int. 2017, 34(8): 1114–1124.

69.

Giglio

Magalhães

Andersen

, et al. Circadian preference in bipolar disorder. Schlaf Atmung. 2010, 14(2): 153–155.

70.

Boudebesse

Lajnef

Geoffroy

, et al. Chronotypes of bipolar patients in remission: validation of the French version of the circadian type inventory in the FACE-BD sample. Chronobiol Int. 2013, 30(8): 1042–1049.

71.

Saunders

Novick

Fernandez-Mendoza

, et al. Sleep quality during Euthymia in bipolar disorder: the role of clinical features, personality traits, and stressful life events. Int J Bipolar Disord. 2013, 1: 16.

72.

Subramanian

Sarkar

Kattimani

. Bipolar disorder in Asia: Illness course and contributing factors. Asian J Psychiatr. 2017, 29: 16–29.

73.

Pirkola

Eriksen

Partonen

, et al. Seasonal variation in affective and other clinical symptoms among high-risk families for bipolar disorders in an Arctic population. Int J Circumpolar Health. 2015, 74: 29671.

74.

Wood

Birmaher

Axelson

, et al. Replicable differences in preferred circadian phase between bipolar disorder patients and control individuals. Psychiatry Res. 2009, 166(2/3): 201–209.

75.

Ashman

Monk

Kupfer

, et al. Relationship between social rhythms and mood in patients with rapid cycling bipolar disorder. Psychiatry Res. 1999, 86(1): 1–8.

76.

McCarthy

Wei

Nievergelt

, et al. Chronotype and cellular circadian rhythms predict the clinical response to Lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacology. 2019, 44(3): 620–628.

77.

Kanagarajan

Gou

Antinora

, et al. Morningness-Eveningness questionnaire in bipolar disorder. Psychiatry Res. 2018, 262: 102–107.

78.

Seleem

Merranko

Goldstein

, et al. The longitudinal course of sleep timing and circadian preferences in adults with bipolar disorder. Bipolar Disord. 2015, 17(4): 392–402.

79.

Ahn

Chang

Joo

, et al. Chronotype distribution in bipolar I disorder and schizophrenia in a Korean sample. Bipolar Disord. 2008, 10(2): 271–275.

80.

Mansour

Wood

Chowdari

, et al. Circadian phase variation in bipolar I disorder. Chronobiol Int. 2005, 22(3): 571–584.

81.

Chung

Lee

Kim

, et al. Circadian rhythm characteristics in mood disorders: comparison among bipolar I disorder, bipolar II disorder and recurrent major depressive disorder. Clin Psychopharmacol Neurosci. 2012, 10(2): 110–116.

82.

Craske

Stein

. Anxiety. Lancet. 2017, 388(10063): 3048–3059.

83.

Lemoine

Zawieja

Ohayon

. Associations between morningness/eveningness and psychopathology: an epidemiological survey in three in-patient psychiatric clinics. J Psychiatr Res. 2013, 47(8): 1095–1098.

84.

Cox

Olatunji

. Differential associations between chronotype, anxiety, and negative affect: a structural equation modeling approach. J Affect Disord. 2019, 257: 321–330.

85.

López-Soto

Fabbian

Cappadona

, et al. Chronotype, nursing activity, and gender: a systematic review. J Adv Nurs. 2019, 75(4): 734–748.

86.

Park

Kim

, et al. Relationships between chronotypes and affective temperaments in healthy young adults. J Affect Disord. 2015, 175: 256–259.

87.

Lin

Gau

. Association between morningnesseveningness and the severity of compulsive Internet use: the moderating role of gender and parenting style. Sleep Med. 2013, 14(12): 1398–1404.

88.

Hsu

Gau

Shang

, et al. Associations between chronotypes, psychopathology, and personality among incoming college students. Chronobiol Int. 2012, 29(4): 491–501.

89.

Vardar

Molla

, et al. Psychological symptoms and sleep quality in young subjects with different circadian preferences. Biol Rhythm Res. 2008, 39(6): 493–500.

90.

Nagane

Suge Watanabe

. Relationship between psychosomatic complaints and circadian rhythm irregularity assessed by salivary levels of melatonin and growth hormone. J Circadian Rhythms. 2011, 9: 9.

91.

Díaz-Morales

. Anxiety during adolescence: considering morningness–eveningness as a risk factor. Sleep Biol Rhythms. 2016, 14(2): 141–147.

92.

Taylor

Clay

Bramoweth

, et al. Circadian phase preference in college students: relationships with psychological functioning and academics. Chronobiol Int. 2011, 28(6): 541–547.

93.

Zylka

Shearman

Weaver

, et al. Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron. 1998, 20(6): 1103–1110.

94.

Yagita

Yamaguchi

Tamanini

, et al. Dimerization and nuclear entry of mPER proteins in mammalian cells. Genes Dev. 2000, 14(11): 1353–1363.

95.

Shearman

Jin

Lee

, et al. Targeted disruption of the mPer3 gene: subtle effects on circadian clock function. Mol Cell Biol. 2000, 20(17): 6269–6275.

96.

Hasan

van der Veen

Winsky-Sommerer

, et al. Altered sleep and behavioral activity phenotypes in PER3-deficient mice. Am J Physiol-Regul Integr Comp Physiol. 2011, 301(6): R1821–R1830.

97.

Archer

Schmidt

Vandewalle

, et al. Phenotyping of PER3 variants reveals widespread effects on circadian preference, sleep regulation, and health. Sleep Med Rev. 2018, 40: 109–126.

98.

Zhang

Hirano

Hsu

, et al. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. Proc Natl Acad Sci USA. 2016, 113(11): E1536–E1544.

99.

Ebisawa

Uchiyama

Kajimura

, et al. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep. 2001, 2(4): 342–346.

100.

Archer

Robilliard

Skene

, et al. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep. 2003, 26(4): 413–415.

101.

Pereira

Tufik

Louzada

, et al.

Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it?

Sleep. 2005, 28(1): 29–32.

102.

Lázár

Slak

, et al. Sleep, diurnal preference, health, and psychological well-being: a prospective single-allelic-variation study. Chronobiol Int. 2012, 29(2): 131–146.

103.

Kunorozva

Stephenson

Rae

, et al. Chronotype and PERIOD3 variable number tandem repeat polymorphism in individual sports Athletes . Chronobiol Int. 2012, 29(8): 1004–1010.

104.

Jones

Ellis

von Schantz

, et al. Age-related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities. J Sleep Res. 2007, 16(1): 12–16.

105.

Liberman

Kwon

, et al. Circadian clock model supports molecular link between PER3 and human anxiety. Sci Rep. 2017, 7(1): 9893.

106.

Liberman

Halitjaha

, et al. Modeling strengthens molecular link between circadian polymorphisms and major mood disorders. J Biol Rhythms. 2018, 33(3): 318–336.

107.

Benedetti

Dallaspezia

Colombo

, et al. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett. 2008, 445(2): 184–187.

108.

Doi

Hirayama

Sassone-Corsi

. Circadian regulator CLOCK is a histone acetyltransferase. Cell. 2006, 125(3): 497–508.

109.

King

Zhao

Sangoram

, et al. Positional cloning of the mouse circadian clock gene. Cell. 1997, 89(4): 641–653.

110.

Ozburn

Purohit

Parekh

, et al. Functional implications of the CLOCK 3111T/C singlenucleotide polymorphism. Front Psychiatry. 2016, 7: 67.

111.

Shi

White

Borsetti

, et al. Molecular analyses of circadian gene variants reveal sexdependent links between depression and clocks. Transl Psychiatry. 2016, 6: e748.

112.

Katzenberg

Young

Finn

, et al. A CLOCK polymorphism associated with human diurnal preference. Sleep. 1998, 21(6): 569–576.

113.

Mishima

Tozawa

Satoh

, et al. The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet. 2005, 133B(1): 101–104.

114.

Robilliard

Archer

Arendt

, et al. The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. J Sleep Res. 2002, 11(4): 305–312.

115.

Pedrazzoli

Louzada

Pereira

, et al. Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population. Chronobiol Int. 2007, 24(1): 1–8.

116.

Antypa

Mandelli

Nearchou

, et al. The 3111T/C polymorphism interacts with stressful life events to influence patterns of sleep in females. Chronobiol Int. 2012, 29(7): 891–897.

117.

Calati

Gaspar-Barba

Yukler

, et al. T3111C clock single nucleotide polymorphism and mood disorders: a meta-analysis. Chronobiol Int. 2010, 27(4): 706–721.

118.

Kishi

Yoshimura

Fukuo

, et al. The CLOCK gene and mood disorders: a case-control study and meta-analysis. Chronobiol Int. 2011, 28(9): 825– 833.

119.

Benedetti

Dallaspezia

Fulgosi

, et al. Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression. Am J Med Genet B Neuropsychiatr Genet. 2007, 144B(5): 631–635.

120.

Benedetti

Serretti

Colombo

, et al. Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. Am J Med Genet B Neuropsychiatr Genet. 2003, 123B(1): 23–26.

121.

Benedetti

Riccaboni

Dallaspezia

, et al. Effects of CLOCK gene variants and early stress on hopelessness and suicide in bipolar depression. Chronobiol Int. 2015, 32(8): 1156–1161.

122.

Roybal

Theobold

, Graham

, et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. 2007, 104(15): 6406–6411.

123.

Coque

Mukherjee

Cao

, et al. Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the ClockΔ19 mouse model of Mania . Neuropsychopharmacology. 2011, 36(7): 1478–1488.

124.

Sidor

Spencer

Dzirasa

, et al. Daytime spikes in dopaminergic activity drive rapid moodcycling in mice. Mol Psychiatry. 2015, 20(11): 1479–1480.

125.

Wittmann

Dinich

Merrow

, et al. Social jetlag: misalignment of biological and social time. Chronobiol Int. 2006, 23(1/2): 497–509.

126.

Knapen

Riemersma-van der Lek

Antypa

, et al. Social jetlag and depression status: Results obtained from the Netherlands Study of Depression and Anxiety. Chronobiol Int. 2018, 35(1): 1–7.

127.

Sheaves

Porcheret

Tsanas

, et al. Insomnia, nightmares, and chronotype as markers of risk for severe mental illness: results from a student population. Sleep. 2016, 39(1): 173–181.

128.

Simor

Zavecz

Pálosi

, et al. The influence of sleep complaints on the association between chronotype and negative emotionality in young adults. Chronobiol Int. 2015, 32(1): 1–10.

129.

Kerkhof

van Dongen

. Morning-type and evening-type individuals differ in the phase position of their endogenous circadian oscillator. Neurosci Lett. 1996, 218(3): 153–156.

130.

Liu

Uchiyama

Shibui

, et al. Diurnal preference, sleep habits, circadian sleep propensity and melatonin rhythm in healthy human subjects. Neurosci Lett. 2000, 280(3): 199–202.

131.

Duffy

Dijk

Hall

, et al. Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people. J Investig Med. 1999, 47(3): 141–150.

132.

Sletten

Vincenzi

Redman

, et al. Timing of sleep and its relationship with the endogenous melatonin rhythm. Front Neurol. 2010, 1: 137.

133.

Pail

Huf

Pjrek

, et al. Bright-light therapy in the treatment of mood disorders. Neuropsychobiology. 2011, 64(3): 152–162.

134.

Sikkens

Riemersma-van der Lek

Meesters

, et al. Combined sleep deprivation and light therapy: Clinical treatment outcomes in patients with complex unipolar and bipolar depression. J Affect Disord. 2019, 246: 727–730.

135.

Antypa

Verkuil

Molendijk

, et al. Associations between chronotypes and psychological vulnerability factors of depression. Chronobiol Int. 2017, 34(8): 1125–1135.

136.

Watts

Norbury

. Reduced effective emotion regulation in night owls. J Biol Rhythms. 2017, 32(4): 369–375.