Bipolar Disorder, Circadian Rhythm and Clock Genes

Abstract

Sleep disturbance and abnormal circadian rhythm might be closely related to bipolar disorder. Several studies involving disturbed sleep/wake cycle, changes in rhythms such as melatonin and cortisol, clock genes, and circadian preference have shown the relationship between bipolar disorder and circadian rhythm. The results differed across different studies. In some studies, a delay in the circadian rhythm was observed in the depressive episode and advanced circadian rhythm was observed during the manic episode. In other studies, a delay in circadian rhythm was observed independent of mood episodes. Accordingly, circadian rhythm disorder was proposed as a trait marker for bipolar disorder. The altered circadian rhythm may represent a pathological mechanism that contributes to the mood episodes. However, a prospective cohort study is needed for further clarification.

BIPOLAR DISORDER AND SLEEP

Bipolar disorder is a chronic mental disorder characterized by a clinical course involving recurrent mood episodes such as mania, hypomania, and depression [1-3]. The clinical diagnosis and treatment of bipolar disorder is most often based on sleep disorders accompanied by mood episodes. Therefore, studies have actively investigated sleep disorders associated with bipolar disorder.

Previous studies have shown that the sleep disturbance observed in bipolar disorder differs according to the accompanying mood episode. In general, decreased sleep demand is frequently observed in manic episodes [4], and insomnia and hypersomnia are frequently detected in depressive episodes [5]. Changes in sleep structure occur in addition to quantitative changes in sleep observed during the clinical course. Several polysomnography studies have confirmed a decrease in rapid eye movement (REM) sleep during the duration of manic episodes [6-8]. However, the results of polysomnography conducted during the period of depressive episode were not observed consistently [9,10]. Because of this marked change in sleep during mood episodes, the Diagnostic and Statistical Manual of Mental Disorders 5th edition, text revision (DSM-5-TR) diagnostic criteria for manic episodes and depressive episodes include changes in sleep quality and quantity [11].

However, recent studies have shown that the subjective quality of sleep is reduced and is often accompanied by sleep disturbances in the euthymic state of bipolar disorder [12-14]. Several studies of patients with bipolar disorder have confirmed that not only insomnia, but also changes in the sleep-wake cycle, such as delayed sleep phase, are often observed during remission [15-17]. In a study using actigraphy, the sleep time of patients with bipolar disorder in the euthymic state was increased, the sleep latency was delayed, and wakefulness after sleep onset (WASO) was not constant [12,18,19]. For this reason, DSM-5-TR describes the occurrence of sleep disorders in euthymic state as well as depressive episodes and manic episodes [11].

The frequent occurrence of sleep disturbances during the euthymic state of bipolar disorder suggests a closely relationship with the pathophysiology of bipolar disorder [12]. Disturbances in the sleep-wake cycle are known to play a role in the development of several psychiatric disorders, including mood disorders [19,20]. This is because sleep plays an important role in emotional regulation [21,22]. Previous studies showing changes in sleep before the onset of bipolar disorder or lack of sleep triggering manic episodes support this finding [23,24]. For this reason, in addition to known risk factors for developing bipolar disorder, such as a family history or sub-threshold symptoms, studies also suggested sleep disturbance as one of the high-risk symptoms [25,26]. However, the evidence indicating sleep disturbances before the onset of bipolar disorder was mostly dependent on retrospective studies.

Despite the evidence linking bipolar disorder to sleep changes, it was not clear whether this phenomenon was a pre-existing temperamental feature, a symptom of mood episodes, or a concomitant disease. However, further studies are needed for effective diagnosis and treatment strategies for patients with bipolar disorder. Therefore, in this review, the recent knowledge of the biological mechanisms of sleep disorders, which are closely related to the pathophysiology of bipolar disorder, will be reviewed, and the current clinical status and future prospects will be examined.

SLEEP AND CIRCADIAN RHYTHM

As the Earth in which we live rotates every 24 hours and the day and night are changing, the creatures living on it exhibit a certain rhythm. This phenomenon that shows a certain periodicity in activities of life such as reproduction and metabolism is called biological rhythm. When the duration of this rhythm is approximately 24 hours, it is called circadian (circa diem, meaning about a day in Latin), infradian (infra diem) when the duration is longer than 24 hours, and ultradian (ultra diem) for shorter duration [27]. Thus, the circadian rhythm refers to a biological rhythm that changes every 24 hours, which also affects sleep. The factors that control sleep are largely divided into sleep/wake homeostasis and circadian rhythm, and are controlled by the interaction between the two factors [28]. The circadian rhythm represents a time control device that plays a role in regulating the physiological actions such as sleep-wake cycle, body temperature, hormone secretion, and rhythms related to daily life such as mood and behavior [29].

A person’s circadian rhythm per se is slightly different from 24 hours, but if the endogenous rhythm is not adjusted to the environment, the cycle will not coincide with 24 hours. Therefore, in order to adjust the internal time to 24 hours, our body must capture an environmental signal called zeitgeber (an exogenous time signal). The external cues include several indicators such as temperature, meals, and day and night cycles. The internal rhythm is adjusted to these external signals and further to the 24-hour cycle. Among these external signals, the diurnal and nocturnal changes in light stimuli have the greatest influence on the circadian rhythm [27,30]. Therefore, the circadian rhythm may be advanced or delayed depending on the time of exposure to light [31].

In most mammals, including humans, the central clock that regulates the circadian rhythm is located in the suprachiasmatic nucleus (SCN) in the anterior part of the hypothalamus [32]. When light strikes the retina, the central biological clock located in the SCN processes and transfers the information to various parts of the brain such as the hypothalamus, thalamus, and amygdala, thereby regulating the circadian rhythm. This circadian information is transmitted through hormones and metabolites, and also via direct neural connections including the autonomic nervous system and neuroendocrine system [31,33]. However, such a circadian clock maintains a unique circadian rhythm as the gene is expressed in most tissues and body organs as well as SCN, which acts as a central clock [34,35]. The circadian rhythm can be regulated by light because virtually all cells in the body act as autonomous circadian oscillators, and the biological clock in these peripheral tissues is known as the peripheral clock [33,36]. Thus, SCN serves as a master pacemaker that adjusts the circadian rhythm of the peripheral clock in response to the external environment.

Melatonin produced in the pineal gland is one of the circadian information delivery systems regulated by SCN. Melatonin is released into the cerebrospinal fluid, circulates, and acts in various tissues. The production of melatonin is suppressed by light, resulting in circadian fluctuations. The amount gradually increases during the night, reaches its peak in the middle of the night, followed by a decline [37]. One of the most important roles of melatonin is to transmit time information to various parts of the body, and thereby regulate physiological functions such as sleep, diet, weight, and reproduction [27].

Another circadian pathway is mediated by cortisol, a steroid hormone synthesized and secreted by adrenal cortex along the hypothalamus-pituitary-adrenal axis (HPA axis). Cortisol levels generally peak during waking and decrease during the night. SCN acts on the HPA axis to regulate the circadian rhythm of cortisol production [38]. Cortisol affects the peripheral clock of almost all tissues and organs, regulating the circadian phase in stressful situations [39]. Cortisol does not reach the SCN, regardless of changes in the rest of the body. Therefore, the SCN can maintain its own circadian rhythm and once the stress is resolved, the peripheral clock is resynchronized [38]. In addition, changes in temperature and intake of food are known to play a role in controlling the peripheral clock [33].

Social cues such as bedtime, mealtime, work time and exercise also play an important role in the regulation of the sleep wake cycle [40]. In order to ensure adequate sleep to meet the demands of daily life such as school or commute time, the sleep time created by the endogenous circadian rhythm must be appropriately adjusted to the external signal. Failure to do this can lead to severe daytime sleepiness or circadian rhythm disturbances with chronic insomnia.

CIRCADIAN RHYTHM AND CIRCADIAN PREFERENCE (TYPE)

Circadian Preference

Each individual shows a different circadian preference in daily life. Accordingly, the circadian type is classified into morning and evening types [41]. In general, individuals belonging to the morning type prefer to perform intellectual and physical activities in the morning, and the type that prefers activities in the late afternoon or evening is classified as the evening type [42]. These individual preferences for circadian patterns are closely related to circadian rhythm, and are known to change with age as well as genetic and environmental factors [43].

Evening Type and Mental Illness

Depending on the circadian preference, there are differences in individual mental health and lifestyle. Studies suggest that the morning type is generally healthier in terms of lifestyle and overall life satisfaction than the evening type [42,44]. In addition, even though the biological clock is set relatively late, the evening type wakes up early due to social obligations such as attending school and going to work. As a result, the evening type gets insufficient sleep relative to the desire to sleep, and thus the quality of sleep is lower than that of the morning type, leading to increased cases of daytime drowsiness [45,46].

Studies investigating circadian preferences and psychiatric disorders confirmed that the evening type is associated with depression and seasonal affective disorder [47,48]. Relatively consistent results were also found in adolescent studies. Evening type was associated with depression and suicidal thoughts as well as a higher risk of behavioral problems and habitual substance use [49]. In another study, it was confirmed that the evening type of circadian cycle and the problems of mood regulation were independently related, regardless of sleep-related indicators such as sleep quality and quantity, and bedtime [50].

Bipolar Disorder and Circadian Preference

Several studies analyzing circadian preferences of patients with bipolar disorder confirmed that patients with bipolar disorder prefer the evening type [51-54]. In a longitudinal follow-up study of patients with bipolar disorder, the evening type was associated with sleep disturbance regardless of mood episodes. Based on these results, the evening type was suggested as a trait marker for bipolar disorder [55]. Thus, sleep disturbances or circadian rhythm disorders are commonly observed in bipolar disorder, especially in individuals with the evening type.

BIPOLAR ILLNESS AND CIRCADIAN RHYTHM DISORDER

Effect of Circadian Rhythm Disorder in Bipolar Disorder

Patients with bipolar disorder often manifest disturbances in circadian rhythm, such as an advanced sleep phase, during the manic episode [56]. In another study, based on the findings of high prevalence of sleep disturbance in patients in the remission phase, it was estimated that the functional deterioration between episodes was mostly attributed to circadian rhythm disturbances [57]. The fact that disturbances in circadian rhythm persist even during remission suggests that circadian rhythm disorders are closely related to the pathophysiology of bipolar disorder.

Endocrine disturbances associated with melatonin and cortisol, which are generally encountered in circadian rhythm disorders, were also frequently observed in patients with bipolar disorder [58,59]. Neurotransmitters such as dopamine, serotonin, and noradrenaline, which are related to the mechanism of bipolar disorder, are also closely related to melatonin synthesis. In a systematic review of patients with bipolar disorder, abnormalities in circadian rhythm, including an imbalance in secretion of melatonin and cortisol, were identified regardless of mood episodes [52]. In recent studies, the increase in serum cortisol and inflammatory activity observed in circadian rhythm disorders has been linked to the increased risk of bipolar disorder [60,61].

Further evidence suggests that circadian rhythm disorders may increase the risk of developing bipolar disorder. Several studies focused on the effect of irregular social rhythm on mood episodes in high-risk groups of bipolar disorder, and irregular social zeitgeber was associated with the first mood episode [62,63]. Other studies investigated the effects of circadian rhythm disorders in patients with bipolar disorder in remission. A 2-year longitudinal study found that irregular sleep duration observed in patients with remission may serve as a risk indicator for recurrent depressive episodes [64]. Sleep disturbance increases the risk of developing bipolar disorder suggesting that circadian rhythm disorder should be the focus of clinical attention for diagnosing and treating bipolar disorder.

Clinical Implications of Circadian Rhythm Disorder

Predictors of the onset of bipolar disorder

Based on the phenomenon in which circadian rhythm disorders are prominent in bipolar disorder, studies investigated the implications of circadian rhythm disorders as a trait marker of bipolar disorder. In one study, circadian rhythm disorders were proposed as predictors of the onset of bipolar disorders and recurrent mood episodes [65]. In a recent study of adolescents and adults, a 10-year prospective study confirmed that decreased sleep quality significantly increased the risk of developing bipolar disorder. In particular, difficulty in falling asleep and early awakening have been suggested as variables predicting the onset of bipolar disorder [13]. In other studies, circadian rhythm disorder predicted the recurrence of patients in remission [66,67]. In a cohort study of children, inadequate sleep and frequent nighttime awakening may be prognostic indicators of the onset of bipolar disorder [68]. Another study suggested decreased sleep quality as a predictor of bipolar disorder. Among individual sleep scales, difficulty in falling asleep and early morning awakening were associated with the onset of bipolar disorder [13].

Treatment of bipolar illness via normalization of circadian rhythm

The association between circadian rhythm disorder and bipolar disorder has been utilized as a treatment strategy for recovery of patients with bipolar disorder. In addition to pharmacological treatments such as lithium and melatonin, interventions such as light therapy, dark therapy, sleep deprivation, and social rhythm therapy are under investigation to normalize the circadian rhythm [69]. Studies showing that lithium, one of the treatment options for bipolar disorder, normalizes circadian rhythm in bipolar disorder [70,71]. Melatonin, which plays an important role in regulating and normalizing the circadian rhythm, is effective not only for sleep disorders but also for mood symptoms in bipolar disorder [72]. Ramelteon, an M1/M2 melatonin receptor agonist, has a significant effect in preventing recurrence of bipolar disorder [73]. Additive therapy using agomelatine, another M1/M2 melatonin receptor agonist, affects mood symptoms by advancing the circadian rhythm [74]. Light therapy, which is mainly used as an adjunct to drug therapy, was found to be effective in improving depressive symptoms without increasing the risk of manic switch in bipolar disorder [75]. Dark treatment, which regulates the circadian rhythm by staying in a dark room at night, has been shown to be effective in a study of patients with manic episodes [76]. In a recent study, the effect of wearing blue light-blocking glasses at night by manic patients was also confirmed as an additive therapy [77,78]. Social zeitgeber theory has been used to explain the role of life events in depressive episodes. According to this theory, life stress can interfere with an individual’s social life, and further interfere with biological circadian rhythms, leading to mood episodes [79]. Social rhythm therapy and interpersonal therapy have been found to be effective in improving mood symptoms of bipolar disorder and preventing recurrence [80].

Genetic Tendency of Sleep and Circadian Rhythms in Bipolar Disorder

Several studies of individuals with a family history of bipolar disorder have shown frequent sleep changes than the general population [68,81-83]. Compared with general population, sleep disturbances were observed more frequently among parents of patients with bipolar disorder [68,81] and poor sleep quality was more common [83]. Two prospective cohort studies showed decreased sleep in subjects with a family history of bipolar disorder [72,84]. However, a study of children of patients with bipolar disorder showed inconsistent results of changes in sleep [85,86]. This is thought to be due to the small sample size. The fact that sleep disorders are more prominently observed in subjects with a family history of bipolar disorder suggests the role of a sleep-related genetic factor.

CIRCADIAN RHYTHM AND CLOCK GENES

The study of genes involved in circadian rhythm started with a study involving Drosophila genes in the 1970s. At the time, the researchers speculated that an unknown gene mutation disrupted the circadian rhythm of fruit flies, and designated this gene as the Period gene [87]. In the 1980s, researchers successfully isolated the Period gene and identified the PER protein encoded by this gene. PER protein accumulates at night, decomposes during the day, changes every 24 hours, and is synchronized with the circadian rhythm [88]. In the 1990s, the second clock gene, the Timeless gene, was discovered, and the mechanism underlying the regulation of the circadian rhythm via interaction with the Period gene was explained [89]. Based on these studies, researchers were awarded the Nobel Prize in Physiology or Medicine in 2017.

In the late 1990s, studies analyzing the clock genes in mammals greatly increased our understanding of circadian rhythms at the cellular level [90]. Mammalian circadian rhythms are created via a transcription/translation feedback loop [91]. Genes involved in the core clock circuit include Clock, Bmal1, Cryptochrome, and Period genes. The Clock and Bmal1 genes are the highest-level transcription factors, which regulate the remaining genes (Period, Cryptochrome). First, the transcriptional activator of the Clock and Bmal1 genes binds to the E-box sequence located at the promoter of the Cry and Per genes, thereby promoting gene expression. Subsequently, when CRY and PER proteins accumulate in the cytoplasm, the accumulated proteins move to the cell nucleus as dimers, resulting in a negative feedback that inhibits the transcription of genes regulated by CLOCK–BMAL1. When the level of CRY and PER proteins decreases, the transcriptional regulation by CLOCK-BMAL1 is reactivated, resulting in periodic gene expression regulation [92]. This central clock circuit is stabilized by a secondary Ror/Rev-Erb loop that activates (RORα) or inhibits (REV-ERBα) and regulates Bmal1 and Cry1 transcription (Fig. 1) [93].

Fig. 1.

Brief mechanism of the clock genes.

BIPOLAR DISORDER AND CLOCK GENES

Alongside studies analyzing the role of clock genes in circadian rhythm, other studies also investigated the clock genes in patients with bipolar disorder [94]. A recent study, on lymphoblastoid cell lines of bipolar disorder patients, shows that lithium influences the expression of clock genes [95].

Several studies analyzed the CLOCK 3111C/T single nucleotide polymorphism. In some studies, the evening circadian type was prominent when one or more CLOCK 3111C alleles were present in patients with bipolar disorder, and the sleep phase was delayed, resulting in delayed bedtime and inadequate total sleep time [96,97]. The recurrence of bipolar disorder was doubled in the homozygote of the 3111C allele [97]. In animal studies, mice with mutations in the Clock gene showed behavior similar to manic episodes such as hyperactivity and decreased sleep demand, and continued administration of lithium reduced many of these behaviors [98]. However, other studies failed to corroborate the significant association between the CLOCK gene and bipolar disorder [99].

Mutations in the BMAL1 gene have also been associated with bipolar disorder in several studies [100,101]. The BMAL1 gene is known to be associated with sleep disorders such as weakened sleep-wake cycles, fragmented sleep, increased total sleep time and increased slow-wave sleep [102]. In another study, the BMAL1 gene was associated with the prophylactic effect of lithium in patients with bipolar disorder [103]. In addition, a recent study found a significant difference in methylation of the BMAL1 gene between bipolar disorder patients and controls, suggesting that epigenetic regulation of BMAL1 gene may be related to circadian rhythm changes in bipolar disorder patients [104].

Among the Period genes, the gene that was found to be most associated with bipolar disorder was the PER3 gene [105]. Mutations in this gene were related to the onset of bipolar disorder, response to treatment, circadian fluctuations in mood, and temperament [103,106]. In a recent study, the PER2 gene was also associated with the therapeutic effect of lithium [107]. The period gene is also associated with the circadian type, and the PER1 and PER3 polymorphisms are associated with the evening type [108,109]. A PER gene mutation suggested altered sleep wake cycle and advanced the sleep phase [108,110].

Among the Cryptochrome genes, CRY2 is known to be strongly related to bipolar disorder [105]. The CRY2 gene was specifically related to rapid cycling [111]. Recent studies have shown that mutations in CRY1 (rs8192440) were associated with an effective response to lithium treatment [112]. Cryptochrome genes are involved in the regulation of sleep homeostasis. CRY1 is associated with the advance of sleep phase, and CRY2 is associated with the delay of sleep phase [113].

Recent studies have focused on the enzyme glycogen synthase kinase 3 beta (GSK3b), with inconsistent conclusions. The enzyme GSK3b plays an important regulatory role in the transcription of clock genes in SCN. Some studies demonstrated a relationship between the age of onset of bipolar disorder and this enzyme in SCN [114,115], whereas other studies reported no significant association [116]. Other studies suggested that the activity of GSK3b was related to the therapeutic inhibitory effect of lithium [100,117]. However, other studies found no link between gene polymorphism and the response to lithium treatment (Table 1) [118,119].

Table 1.

Relationship between bipolar disorder and clock genes (overview of the reviewed sources)

Authors	Samples	Genes	Summary points
Benedetti et al., 2003 [97]	Bipolar I disorder	CLOCK	Homozygotes for C variant of CLOCK show a higher recurrence rate
Roybal et al., 2007 [98]	Mice	CLOCK	Mice carrying a mutation in CLOCK show a mania-like behavior and increased dopaminergic activity in the ventral tegmental area
Kishi et al., 2009 [99]	Schizophrenia Bipolar disorder Major depressive disorder	CLOCK	SNPs in CLOCK show no significant association with bipolar disorder and major depressive disorder
Soria et al., 2010 [101]	Major depressive disorder Bipolar disorder	CLOCK	SNPs in CLOCK were associated with bipolar disorder
Rybakowski et al., 2014 [103]	Bipolar disorder	BMAL1	SNPs of BMAL1 were associated with the lithium prophylactic response
Bengesser et al., 2018 [104]	Bipolar disorder	BMAL1	Methylation of BMAL1 was significantly different in bipolar disorder group
Rybakowski et al., 2014 [106]	Bipolar disorder	BMAL1 PER	Hyperthymic temperament was associated with SNPs of BMAL1 Depressive temperament was associated with a SNP of PER3
McCarthy et al., 2013 [107]	Bipolar disorder (skin fibroblast)	PER	Li specifically affects the expression rhythm of PER3 in skin fibroblasts
Sjöholm et al., 2010 [111]	Bipolar disorder	CRY	CRY2 was associated with rapid cycling
McCarthy et al., 2011 [112]	Bipolar disorder	CRY	CRY1 variant was associated with good treatment response

CONCLUSIONS

Sleep disturbances and abnormal circadian rhythms were found to be closely related to bipolar disorder. Several studies investigating disturbances of sleep/wake cycle, changes in melatonin and cortisol levels, expression of clock genes, and circadian preferences have confirmed the relationship between bipolar disorder and circadian rhythm. An evening circadian preference was commonly observed in bipolar disorder, which was also confirmed via changes in hormones related to circadian rhythm such as melatonin and cortisol. The changes in circadian rhythm varied across different studies. In some studies, a delay in the circadian rhythm was observed in the depressive episode and advanced circadian rhythm was detected in the manic episode. In other studies, a delay in circadian rhythm was observed independent of mood episodes, and accordingly, the circadian rhythm disorder was proposed as a trait marker for bipolar disorder. Several studies have shown that treatments focused on sleep disorders and circadian rhythm disorders are effective in treating the mood symptoms of bipolar disorder and reducing recurrence. Genetic studies have reported changes in circadian rhythms observed in bipolar disorder, circadian preference, and clock gene mutations related to responses to drugs such as lithium. However, the results showed inconsistent results.

The relationship between abnormal circadian rhythm and the pathophysiology and clinical course of bipolar disorder remains unclear. Prior studies of bipolar disorder found changes in circadian rhythm regardless of mood episodes, and mutations in genes associated with circadian rhythms have been identified. These studies suggest that the changes in circadian rhythm represent pathological mechanisms contributing to the generation of mood episodes. Thus, the genetic vulnerability of the circadian rhythm affects the sleep/wake cycle and the secretion of hormones, resulting in sleep disorders in patients with bipolar disorder and mood episodes. However, a prospective cohort study is needed to elucidate the mechanisms involved.