Review
1.
Introduction
2.
The circadian clock and its
regulators in humans
3.
Evidence for circadian
dysregulation in BD
4.
Lessons from existing circadian
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rhythm-related treatments
5.
Conclusion
6.
Expert opinion
Sleep- and circadian
rhythm--associated pathways
as therapeutic targets
in bipolar disorder
Frank Bellivier†, Pierre-Alexis Geoffroy, Bruno Etain & Jan Scott
†
Groupe Hospitalier Saint-Louis-Lariboisie`re-Fernand Widal, Department of Psychiatry, Paris
Cedex, France
Introduction: Disruptions in sleep and circadian rhythms are observed in
individuals with bipolar disorders (BD), both during acute mood episodes
and remission. Such abnormalities may relate to dysfunction of the molecular
circadian clock and could offer a target for new drugs.
Areas covered: This review focuses on clinical, actigraphic, biochemical and
genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the
susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to
act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic
response to lithium. Interventions such as sleep deprivation, light therapy
and psychological therapies may also target sleep and circadian disruptions
in BDs efficiently for treatment and prevention of bipolar depression.
Expert opinion: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of
the molecular clock in order to identify critical targets within the circadian
pathway. The investigation of such targets using human cellular models or
animal models combined with ‘omics’ approaches are crucial steps for new
drug development.
Keywords: bipolar disorders, circadian rhythm, sleep, therapeutic response
Expert Opin. Ther. Targets [Early Online]
1.
Introduction
The recognition of abnormal sleep and circadian rhythms as core symptoms of
bipolar disorder (BD) led to the development of important research efforts to
characterize these features [1]. It has also stimulated the development of new pharmacological and nonpharmacological treatments. Abnormal sleep and circadian
rhythms are found in individuals at high risk of developing BD and are observed in
euthymic, prodromal and syndromal periods [2]. The role of sleep disturbances as
disease course modifiers is also well established, mainly due to their association
with treatment-refractory or prolonged mood phases and as predictors of early
relapse [3-5].
Taken together, these data suggest that the exploration of sleep and circadian
rhythms, and their modification by psychological and pharmacological interventions alongside the study of putative associated biomarkers in the blood or in the
brain could facilitate the development of novel therapeutic targets.
In this review, we summarize data obtained from remitted bipolar cases (i.e., in
euthymic periods). We first review the molecular functioning of the circadian clock.
Then we present data demonstrating disruptions of sleep and circadian rhythms in
10.1517/14728222.2015.1018822 © 2015 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631
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1
F. Bellivier et al.
Article highlights.
.
.
.
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.
Disruptions in sleep and circadian rhythms are part of
the pathophysiology of bipolar disorders.
Preliminary studies suggested that genetic variants in
circadian genes were associated with bipolar disorders
but also with lithium response.
Cellular and animal models have also been used with
some promising results to identify circadian pathways as
potential targets for mood stabilizers, mainly lithium.
There is an urgent need to combine clinical, biochemical
and global ‘omics’ approaches to disentangle the
potential circadian targets for existing drugs but also to
validate models to be used in the screening of new
compounds.
Targeting sleep and circadian rhythms related pathways
may be an important avenue for developing new
mood-stabilizing agents.
This box summarizes key points contained in the article.
BD at phenotypic, biochemical (melatonin and cortisol) and
genetic levels. Lastly, new avenues for the development of
new drugs targets are presented.
The circadian clock and its regulators in
humans
2.
A circadian rhythm is any biological process that displays an
endogenous, entrainable oscillation of about 24 h. A circadian
clock drives these rhythms, which have been widely observed
in plants, animals, fungi and cyanobacteria. Biological
temporal rhythms include daily, tidal, weekly, seasonal and
annual rhythms. Although circadian rhythms are endogenous
(biologically determined; ‘built-in’; self-sustained), they are
adjusted to the local environment by external cues called zeitgebers, commonly the most important of which is daylight [6].
Circadian rhythmicity is present in the sleeping and feeding
patterns, core body temperature, brain wave activity, hormone production, cell regeneration and several biological
activities [7]. The main brain structures controlling circadian
rhythms are the suprachiasmatic nuclei (SCN) located in the
hypothalamus and the pineal gland.
The molecular circadian clock
The SCN, located in the anterior hypothalamus, host ‘the
master circadian pacemaker.’ The pacemaker comprises a
complex network of transcriptional--translational feedback
loops that result in the rhythmic expression of clock genes
(with a periodicity of just over 24 h) [7]. The main players in
these feedback loops are circadian locomotor output cycles
kaput (CLOCK), BMAL1, period homolog (PER), CRY,
REV-ERBa (or nuclear receptor subfamily1, groupe D, member1 [orphan nuclear receptor REV-ERBa] [NR1D1]), timeless homolog (TIMELESS) and retinoid-related orphan
receptor A (RORA) proteins (Figure 1). Another regulatory
loop involves TIMELESS, PER, CLOCK and BMAL1 [8].
2.1
2
Glycogen synthase kinase 3b (GSK3b) (a well-known site of
action of lithium) is involved in the regulation of the circadian
clock as it phosphorylates CRY, BMAL1, PER2, CLOCK,
TIMELESS and REV-ERB [9-11]. The molecular structure of
the circadian clock is highly conserved throughout the evolution of species, suggesting that circadian rhythms are mainly
biologically determined (genetic aspects are discussed further
in a later section) [12]. In humans, it is well established that circadian rhythms are also influenced by environmental factors
such as light, external temperature, social activities, seasonal
variations and psychological factors. The day--night cycle is
the main environmental driver that synchronizes the circadian
‘clock’ with environmental time signals [7]. This synchronization process involves retinal ganglion and retinohypothalamic
tracts that converge to the SCN.
The SCN oscillation controls the rhythmic expression of
clock-controlled genes, which are widely distributed among
all peripheral tissues such as liver, endocrine tissues, heart,
skeletal muscles, and so on [13,14]. The rhythmic expression
of these genes controls rhythmic functions including the
sleep--wake cycle, feeding behavior, core body temperature,
release of hormones, and metabolic regulation [7,15].
Variations in the gene sequence or in the expression profile
of the circadian genes observed in bipolar individuals are
further described in the ‘genetic’ section of this review (see
Section 3.3).
The melatoninergic system
The pineal gland is another important element of the circadian system and is the brain structure where melatonin is synthesized. The dark--light cycle regulates melatonin secretion
via the SCN. Melatonin secretion is high during the periods
of darkness, whereas light inhibits its secretion [16,17]. Seasons
of the year also regulate melatonin secretion due to changes in
the number of daylight hours. Melatonin is a useful marker of
circadian regulation and activity and it can be assayed in
blood, saliva and urine. The most valid circadian melatonin
phase marker is the dim light melatonin onset (DLMO)
[18,19]. Blood melatonin concentration increases before
bedtime, remains high during nocturnal sleep and decreases
rapidly after light exposure (in particular, sunlight and blue
wavelength). Body temperature and cortisol concentrations
follow inverse circadian variations [20].
2.2
Circadian systems and neurotransmitters that
regulate mood
2.3
Circadian rhythms influence serotonergic [21-23], dopaminergic [24-27] and noradrenergic [28,29] neurotransmissions.
Serotonin (5HT) signaling via efferent pathways from
median raphe nuclei to SCN increases the regularity of circadian rhythms [30-32]. These serotonergic projections represent
the anatomical interface between circadian functions and
mood regulation [33]. 5HT regulates the SCN activity by
photic [34-36] and nonphotic factors [32,37]. Moreover,
Expert Opin. Ther. Targets (2015) 19(6)
Sleep- and circadian rhythm--associated pathways as therapeutic targets in bipolar disorder
Nucleus
RORs
Ccg
RRE
Per1/Per2
RRE
Cry1/Cry2
RRE
REV-ERBa
REV-ERBs
RRE
Bmal1
Bmal1
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RRE
CLOCK
RRE
RORa
REV-ERBs
CRYs
PERs
CK1ε/δ
RORs
Cytoplasm
Figure 1. Molecular circadian clock. Black arrow: relocation, Green arrow: stimulation, Red arrow: inhibition.
bmal1: Brain and muscle ARNT like 1 orphan nuclear receptor REV-ERBa; Ccg: Clock-controlled gene; CLOCK: Circadian locomotor output cycles kaput;
CRY: Cryptochrome; PER: Period homolog; ROR: Retinoid-related orphan receptor.
serotonergic activity is influenced by light exposure and time
of year [38]. Interestingly, in Drosophila, serotonergic signaling increases the phosphorylation of SHAGGY (homolog of
human GSK3b) and light-induced degradation of TIMELESS [39]. In the pineal gland, melatonin is synthesized from
5HT and the SCN modulates the catabolism of 5HT into
melatonin [40].
In the retina, dopamine (DA) plays an important role in the
adaptation to light [41]. Moreover, in the tegmental ventral area
and substantia nigra, DA signaling is a key component of the
sleep/wake cycle and rapid eye movement (REM) sleep [42,43].
In the SCN, the activity of the CLOCK--BMAL1 complex is
regulated by dopaminergic D2 receptors [44]. Finally, noradrenalin regulates the melatonin synthesis in the pineal gland [45].
In summary, disruption of circadian rhythms and abnormal emotional regulation are core features of BD that may
result from complex interactions between serotonergic and
dopaminergic systems and the circadian clock [46].
3.
Evidence for circadian dysregulation in BD
Phenotypic characteristics
Individuals with BD demonstrate abnormal chronobiological
rhythms that affect mainly sleep homeostasis and circadian
3.1
rhythms. Disrupted circadian rhythms are observed in individuals who later develop BD, even before disease onset, and
in BD cases during acute episodes and during inter-episode
periods [47] (see the following sections and Table 1).
Chronotypes
The term chronotype refers to the attributes of individuals
that reflect the time of the day that their physical functions
(hormone level, body temperature, cognitive faculties, eating
and sleeping) are active, change or reach a certain level. However, this term is often used in research to describe a person’s
preference for daytime versus nighttime activities. The
€
Horne--Ostberg
morningness--eveningness questionnaire [48],
the Composite Scale of Morningness [49] and the Munich
ChronoType Questionnaire [50] are the most frequently used
tools to categorize individuals as ‘morning types’ or ‘evening
types.’ Studies using such measures demonstrate that, in the
general population, diurnal preference (i.e., morningness-eveningness) is a heritable trait [51-55] and is strongly associated
with other endogenous phase markers, such as circadian shifts
in body temperature [56,57], salivary melatonin secretion [58]
and the cortisol awakening response [59]. In a given subject,
morningness--eveningness preference is relatively stable over
3.1.1
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Table 1. Circadian phenotypes as potential trait markers of bipolar disorders.
Circadian parameter
Association with
bipolar disorders
Presence
during remission
Heritability
Over-represented
among high-risk subjects
for bipolar disorders
Lifestyle irregularity
Evening type
Higher sleep--wake cycle variability
Higher cortisol secretion
Supersensitivity of nocturnal plasma
melatonin in response to light
Lower overnight serum melatonin
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
?
Yes
Yes
Yes (awaking)
Yes
Yes
?
Yes
Yes (afternoon)
Yes
Yes
Yes
Yes
?
time, as confirmed in studies of various populations with
different cultural habits [60,61].
Several studies of individuals with BD demonstrate a
significantly higher prevalence of ‘evening chronotypes’ than
reported in healthy controls [62-66] or cases of recurrent major
depressive disorder [67]. In individuals with BD, eveningness is
also associated with earlier age of onset, a rapid-cycling course,
and other factors such as a reduction in the peak of the melatonin secretion at night [64]. Furthermore, population-based
studies demonstrate that eveningness is more common in
cyclothymic individuals (especially those with at least one
prior episode of depression), and some, but not all, studies
of temperaments that are putatively linked to risk of BD
(such as hyperthymia) show a higher prevalence of this chronotype in the at-risk populations [68]. In summary, although
possible confounders were not always taken into account in
these studies, this heritable trait (vesperal preference) commonly co-occurs with BD and may be associated with some
risk syndromes, early illness onset and course characteristics.
Sleep--wake cycles
Polysomnography (PSG) and actigraphy are the main tools
used to assess sleep--wake cycles and studies suggest that BD
cases differ in several important aspects from healthy
controls [69]. For example, higher-density REM sleep during
the first REM period, more frequent nocturnal arousals and
higher sensitivity to the cholinergic receptor agonist were
observed on PSG recordings of remitted bipolar cases compared with healthy controls [70,71]. Several actimetry studies
show that euthymic BD cases have a greater variability in their
sleep/wake patterns and poorer sleep quality than individuals
with insomnia or controls [72-80]. Interestingly, a recent
meta-analysis of actigraphy studies in remitted BD cases confirmed significant differences on several sleep parameters
compared to healthy controls: longer sleep latency, longer
sleep duration, more wake after sleep onset and poorer sleep
efficiency [81]. Furthermore, small-scale studies of actigraphy
and DLMO identify that delayed sleep phase -- the most
common circadian disorder, especially in adolescents -- is
3.1.2
4
even more prevalent in young people with emerging mood
disorders compared to their peers, being twice as common in
unipolar depression compared to healthy controls (14 vs 7%)
and four times more common in young adults with recent
onset BD [82]. Other small-scale studies of individuals at
high risk for BD suggest that they exhibit greater variability
in sleep duration, fragmentation and efficiency, as well as
shorter sleep duration, later and more variable bedtimes, and
lower relative amplitude of activity patterns than control subjects [80,83]. Twin- and family-based studies show that sleep
length is heritable and the genetic contribution to the variance
was 33% for sleep quality and to sleep disturbance was 40%
for sleep pattern [84,85].
Although actigraphy studies have mainly focused on sleep
profiling, in recent years, there has been an increasing interest
in using the data to assess daytime activity. Such studies reveal
that the daily activity of euthymic BD cases is significantly
lower than other mental health service users or control participants [86]. In addition, investigations of lifestyle regularity
indicate that diurnal preference and regularity of sleep and
social rhythms are highly interconnected [87,88]. While BD
cases may demonstrate disrupted social rhythms as a consequence of the illness, it has also been demonstrated that individuals at risk of BD or with subsyndromal presentations
exhibit less regularity of lifestyle than healthy controls even
before the disorder is fully manifested [89-91]. The most prominent abnormalities are lower regularity of daily activities and
more variation in sleep duration [72,92]. In euthymic BD, activity level predicts the onset of major depressive, hypomanic and
manic episodes during the following 3 years [92]. These findings are also consistent with the idea that individuals with
BD or BD spectrum are more sensitive to environmental clues
that precipitate or contribute to mood, sleep and activity disruptions, which are the commonest prodromal symptoms of
further episodes [93]. Finally, several studies investigated differences between bipolar I and II and failed to show any difference [62,65,67]. Studies using actigraphy have included only
type I (or very limited number of bipolar type II) [81].
Expert Opin. Ther. Targets (2015) 19(6)
Sleep- and circadian rhythm--associated pathways as therapeutic targets in bipolar disorder
Table 2. Association studies between circadian genes and bipolar disorders.
Gene
Online Mendelian inheritance in man (OMIM) nomenclature
Ref.
CLOCK
NPAS2
ARNTL1 (or BMAL1)
Circadian locomotor output cycles kaput
Neuronal PAS domain protein 2
Aryl hydrocarbon receptor nuclear translocator-like 1
(or brain and muscle ARNT like 1)
Periodhomolog 1
Periodhomolog 2
Periodhomolog 3
Cryptochrome 1
Cryptochrome 2
Timeless homolog
Nuclear receptor subfamily 1, group D, member 1
(or orphan nuclear receptor REV-ERBa)
Retinoid-related orphan receptor A
Retinoid-related orphan receptor B
Casein kinase 1 d
Casein kinase 1 e
Glycogen synthase kinase 3 b
Basic helix-loop-helix domain containing, class B, 2
Acetyl serotonin methyl transferase
Aryl alkylamine N-acetyl transferase
[131,133-136]
[135]
[117]
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PER1
PER2
PER3
CRY1
CRY2
TIMELESS
NR1D1 (or REV-ERBa)
RORA
RORB
CSNK1d
CSNK1e
GSK3b
BHLHB2
ASMT
AANAT
Biochemical phenotypes
The secretion of cortisol and melatonin shows a circadian
pattern. Biochemical studies have investigated their secretion
in plasma, serum or saliva.
3.2
Hypothalamic--pituitary--adrenal axis: cortisol
In healthy individuals, cortisol secretion has a morning peak
with a 24-h cycle. In a given individual (from the general
population), the cortisol awakening response is highly regular
across extended periods [94]. The 24-h cortisol secretion is
significantly higher in patients with BD than in controls,
irrespective of the phase of BD (manic, depressive or euthymic) [95]. This is consistent with the observation of glucocorticoid receptor mRNA in the hippocampi and amygdala nuclei
in patients with BD by comparison with healthy controls [96].
Cortisol secretion, in particular cortisol awakening response, is
a heritable trait and the heritability of cortisol secretion has
been estimated to be 62% [97-99]. However, investigations of
cortisol secretion in high-risk individuals have produced conflicting results [100-102]. In addition, increased cortisol secretion
is not very specific to BD (also encountered in unipolar
depression, psychotic disorders as well as eating disorders), as
confirmed in a recent meta-analysis [103].
3.2.1
Pineal function: melatonin
Hypersensitivity to light has been proposed as a trait marker
of mood disorders including seasonal affective disorders and
BD [104,105], although some publications do not support this
conclusion [106,107]. However, studies focusing on nocturnal
melatonin secretion report lower levels of secretion in BD
cases compared with controls [108,109] and indicate the
3.2.2
[135]
[135,188]
[117,131,135]
[147]
[134,135,137]
[132,134,135,148,197]
[132,146-148,197]
[127,128,137]
[127,128]
[135]
[118,134,135]
[144,145,148]
[140]
[138,139]
[138]
existence of abnormal amplitude and periodicity of melatonin
secretion [47]. Some researchers suggest that findings of
reduced nocturnal melatonin levels in BD that occurred
independent of current mood state suggest that this may be
a trait rather than a state marker of BD [109]. In contrast, daytime melatonin levels appear to be elevated in manic patients
compared to controls [110]. Recently, Robillard et al. used
saliva samples and demonstrated that compared to unipolar
patients, bipolar patients had later DLMO and smaller
melatonin AUC than the unipolar group [111].
Interestingly, monozygotic and dizygotic twin studies show
a genetic component to nocturnal melatonin secretion and
sensitivity to light [112]. Furthermore, supersensitivity in the
melatonin response to light exposure has been shown in individuals at high risk of BD [113]. However, no differences in
total pineal volume have been observed between BD cases
and healthy controls [114].
Genetic studies
Circadian genes may increase vulnerability to several psychiatric disorders [115]. In particular, genomic and post-genomic
studies may help to identify pathways implicated in vulnerability to BD as well as in treatment response. Some circadian
genes as well as genes encoding proteins involved in related
pathways are strong candidate genes in BD. In this section,
we review genetic and pharmacogenetic studies that have
investigated some circadian genes.
3.3
Genetic association studies and candidate gene
approach
3.3.1
Findings regarding circadian gene polymorphisms and vulnerability to BD are summarized in Table 2. The most replicated
Expert Opin. Ther. Targets (2015) 19(6)
5
F. Bellivier et al.
findings involve the CLOCK, NPAS2, aryl hydrocarbon receptor nuclear translocator-like 1 (or brain and muscle ARNT
like 1) (ARNTL1), NR1D1, PER3, related orphan receptor B
(RORB) and CSNKe genes. Although GSK3b is often
regarded as a strong candidate gene, no association with
GSK3b gene polymorphism has been reported [116-118]. However, the frequency of a copy number variant in the GSK3b
locus has been shown to be higher in BD cases compared
with controls [119].
Human cell cultures
Cell cultures derived from human skin biopsies, blood samples [120] or hair follicle cells [121] have been used in laboratory
experiments. Cultures of human fibroblasts have been used to
examine circadian functions, including the amplitude- and
phase-resetting responses, and these have been found to be
correlated with the chronotype of the individual from whom
the cells were derived [122]. Using a transcriptomic approach,
Yang et al. demonstrated that the amplitude of rhythmic
expression of BMAL1, REV-ERBa and D site of albumin promoter (DBP) was lower in fibroblasts derived from BD cases
than controls [123]. In this study, the overall mRNA expression
levels for DEC2 and DBP were reduced in biological material
drawn from BD cases. Posttranslational modifications were
also observed with reduced level of GSK3b phosphorylation
in BD individuals.
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3.3.2
Animal studies
The role of circadian genes in modulating behavior has also
been highlighted in genetically manipulated animals. In
mice, the deletion of exon 19 in the CLOCK gene is associated
with manic-like hyperactivity, craving for rewarding stimuli
(similar to BD cases in a manic state), less depression-like
behavior, lower anxiety levels and abnormal sleep/wake
cycles [124]. The manic-like behavior of the Clock mutant
mice can be reversed by lithium treatment or the restoration
of a functional CLOCK gene in the ventral tegmental
area [125]. Other examples of mouse models involving circadian genes include transgenic mice overexpressing GSK3b,
which show a manic-like phenotype [126].
In summary, the results of studies using different experimental design, in different species, can be difficult to interpret.
Convergent functional genomic approaches are particularly
useful to integrate data from classical genetic studies, gene
expression studies in human cell cultures or in animals and
postmortem human brain studies. Studies applying convergent functional genomics suggest that ARNTL1, GSK3b,
RORA and RORB are the top candidate circadian genes for
BD [127,128].
3.3.3
Disrupted circadian rhythms in BD and circadian
genes
3.3.4
PER3, REV-ERBa and GSK3b genes have been associated
with an early age of BD onset [129-133]. This is consistent
with the observation that early age at onset is associated with
6
more severe circadian disruptions (eveningness and sleep quality). Other circadian genes are associated with rapid cycling of
BD and/or with a high recurrence of illness: CRY2, CLOCK,
ARNTL2, TIMELESS and CSNK1e [134,135]. These findings
suggest that variations in some circadian genes may explain
the high sensitivity to rhythm changes observed in BD, and
may be associated with disease onset or relapses.
Two studies have examined the relationship between circadian gene variants and chronotypes in patients with BD: in a
Korean sample, the CLOCK gene 3111T/C variant was associated with an extreme evening chronotype [135,136], and a
nonsynonymous coding single-nucleotide polymorphism
(SNP) in PER3 and two intronic SNPs in CSNK1e were
associated with eveningness [118].
Behavioral consequences of at-risk variants have been
studied using phenotypic subjective and objective biomarkers
such as chronotypes, circadian types or sleep--wake patterns.
Using a ‘reverse phenotyping approach’ to look for association
between at-risk polymorphisms and circadian phenotypes, it
has been observed that TIMELESS (rs774045) was associated
with eveningness and languid (i.e., lacking energy in the
morning) circadian type, whereas RORA (rs782931) was associated with rigid (i.e., less flexible) circadian type in euthymic
cases compared to controls [137]. Actigraphy has been used to
explore carriers of the at-risk allele associated with BD of a
common polymorphism (rs4446909) of the promoter of the
acetylserotonin O-methyltransferase gene, encoding one of
the two enzymes involved in melatonin biosynthesis [138].
Interestingly, the GG at-risk genotype was associated with
longer sleep duration, greater activity in active periods of sleep,
and greater interday stability [139]. A further recent study
examining circadian polymorphisms observed that delayed
sleep and eveningness were inversely associated with NFIL3
(rs2482705) and RORC (rs3828057), and that a group of
haplotypes overlapping BHLHE40 was associated with non24-h sleep--wake cycles, with delayed sleep and with BD
(rs34883305, rs34870629, rs74439275 and rs3750275) [140].
These preliminary studies highlight that variants of circadian genes that may increase susceptibility to BD also influence circadian phenotypes, and thus may point to future
treatments after further replication and identification of the
causal polymorphisms.
Pharmacogenetic studies
Most of the pharmacogenetic studies that have tested circadian genes have explored lithium response [141]. Although
the mechanism of action of lithium is unknown, it has been
found that lithium influences the expression of circadian
genes and so it is possible that this pathway is involved in
the therapeutic effects of this mood stabilizer [142].
GSK3a and GSK3b are inhibited by lithium. Lithium acts
on these enzymes either by direct inhibition or indirectly via
other mechanisms such as the formation of a signaling
complex involving b-arrestin 2 and Akt [143]. Genes coding
these enzymes are obvious candidates for modulating lithium
3.4
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Sleep- and circadian rhythm--associated pathways as therapeutic targets in bipolar disorder
therapeutic response. An association of GSK3b (-50 T/C)
polymorphism with the therapeutic response to lithium
among 88 BD-I cases was recently reported: the relapse risk
(measured by the recurrence index) for homozygotes for the
wild variant (C/C) did not change under treatment, whereas
carriers of the mutant T allele showed improvement, suggesting that the GSK3b-50 T/C polymorphism may influence
prophylactic response to lithium in BD [129]. However, this
result has not been replicated in subsequent studies [144,145].
GSK3b also phosphorylates and stabilizes REV-ERBa, one
of the main components of the circadian rhythm system that is
involved in the cyclic regulation of BMAL1. Lithium reduces
REV-ERBa and BMAL1 gene expression, implicating REVERBa as a target of lithium in its mechanism of action [10].
The association between REV-ERBa gene (NR1D1) and
prophylactic response to lithium in BD has been investigated
in three studies. In a sample of 199 Sardinian BD patients
characterized for lithium, no association was found [146]. However, more recently, an association between the rs2314339
variant of the NR1D1 gene and lithium response was
reported. Furthermore, in a sample of 282 Caucasian bipolar
patients characterized for lithium response, an association
between the NR1D1 rs2071427 variant and response to
lithium was found [147]. The same study reported that a variant
in cryptochrome-1 (CRY1; rs8192440) was nominally
associated with the response to lithium. Finally, GSK3b and
NR1D1 genotypes considered together predicted the response
to lithium robustly and additively; the response was proportional to the number of response-associated alleles [148].
Glucocorticoid receptors are likely to regulate circadian
rhythms. A polymorphism of the glucocorticoid receptor
gene (NR3C1) on chromosome 5q31-32 is associated with
lithium responder status [149].
Lessons from existing circadian
rhythm-related treatments
4.
Chronotherapies
Chronotherapeutics are based on controlled exposure to environmental stimuli such as photic, sleep--wake cycle or lifestyle
regulation approaches that are purported to modify biological
rhythms.
Classical chronotherapeutic techniques include light
therapy, sleep phase advance, sleep deprivation therapy
(SDT), dark therapy and extended bed rest. Strong evidence
of efficacy has been demonstrated for SDT and sleep phase
advance disorders [150], with some evidence for light therapy
in patients with BD [151]. Some publications on BD depression indicate that sleep deprivation combined with antidepressants or mood stabilizers may lead to an earlier
response [152-154] and that light therapy may be used in the
treatment of BD depression [155,156]. Other studies suggest
that BD cases who receive medication (mood stabilizer and
antidepressant) in combination with three established
circadian-related treatments (sleep deprivation, bright light,
4.1
sleep phase advance) show an earlier and more sustained
decrease in depression scores than a medication-only
group [157]. There is also some research that indicates that
dark therapy [158,159] or the use of specific lenses that block
blue light [160] can reduce manic symptoms or rapid cycling.
The techniques identified are mainly adopted from sleep
research. However, two other streams of research have
recently been used in BD. First, cognitive behavior therapy
for insomnia (CBT-I) has now been applied to mood disorders [161]. The initial pilot studies of CBT-I for BD demonstrate a good effect in > 60% cases, and suggest that sleep
regulation techniques (especially regularizing bedtimes, etc.)
are the most beneficial. However, it was notable that a small
number of cases (where sleep deprivation was employed)
appeared to be destabilized and demonstrate an increase in
(hypo)manic symptoms [161]. Larger studies are now ongoing,
although there are suggestions that some circadian-based
abnormalities (such as delayed sleep phase) may prove lower
response than other sleep problems in BD [162].
The second source of evidence for psychological interventions modifying sleep in BD comes from studies of the therapies that were developed specifically for individuals with BD.
Although these interventions derive from several different
models, there are a number of shared elements that are common to all therapies, and all effective therapies incorporate
specific techniques aimed at enhancing social and circadian
rhythm stabilization [163]. The classic example of this
approach comes from interpersonal social rhythm therapy
(IPSRT) developed by E. Frank [164] and recently
reviewed [165]. The main difference between these BD-specific
approaches such as IPSRT and CBT-I is that the former
incorporates a number of interventions related to regulation
of daytime activity, reduction of stressors or overstimulation,
and more overtly try to identify and reduce the intake of
substances (caffeine, nicotine, alcohol, etc.) that disrupt
sleep--wake cycles, as well as regularizing sleep patterns.
However, as yet, there is no direct evidence that such changes
mediate change in mental state; indeed, in several studies, stabilizing social rhythms was not associated with improvement
in BD [163]. In addition, no biomarkers of response to any
type of chronotherapy have been identified so far.
Pharmacological treatments
Lithium and valproate may work in part via a chronobiological mechanism [166]. Lithium has phase-delaying properties
because it lengthens the circadian period in a variety of organisms, including humans [142,167]. The amplitude of PER2
protein cycling in the central and peripheral circadian clockwork is enhanced by lithium [168]. As noted previously,
chronic administration of lithium reverses the manic-like
phenotype of transgenic mice carrying a mutation in the Clock
gene [125]. We also previously described that GSK3b and
NR1D1 genes may modulate response to lithium. Low doses
of lithium carbonate and sodium valproate reduce melatonin
secretion in response to light in healthy volunteers, suggesting
4.2
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F. Bellivier et al.
that lithium also acts on the melatonergic system [169,170].
Valproic acid also increases the amount of melatonin receptors in C6 glioma cells [171] and influences the expression of
several circadian genes in the amygdala [172].
Some pharmacological compounds directly act on the
circadian or melatonergic systems. These include melatonin
and melatonin receptor agonists that have the potential to
synchronize the sleep/wake cycle. The efficacy of these treatments is still to be fully established, but several reports suggest
that adjunctive melatonin can improve sleep quality [173-176].
These case reports describe patients in manic, depressive or
rapid-cycling phases of BD who are given the chronobiotic
medications in combination with other mood stabilizer and
treatment regimens [173-176].
Ramelteon is a melatonin receptor agonist that is used for
insomnia and for people who have difficulty falling asleep.
One study in euthymic patients with BD reported that ramelteon (24 weeks) contributes to relapse prevention by comparison with placebo in association with a mood stabilizer [177].
Agomelatin (a melatonin receptor agonist and a serotonin
5-HT2C receptor antagonist) synchronizes circadian rhythms
involving body temperature, cortisol and other hormones in
animal models and in humans [178]. Three studies have
reported the efficacy of agomelatin as an adjunctive treatment
in bipolar depression [179-181].
5.
Conclusion
Several core features of vulnerability to BD onset or to episode
recurrence in established cases of BD appear to indicate underlying abnormalities of the circadian and melatonergic systems.
As such, the further characterization of circadian-related dysregulations and of therapeutic response to novel interventions
that target the circadian system would appear to be a critical
theme for future BD research. Considerable research has
been dedicated to the characterization of circadian mechanisms implicated in the pathophysiology of BD. The most
promising pathways include i) melatonin synthesis and modulation of melatonin receptors, in particular by monoamine
neurotransmission and pulsatile melatonin release regulations;
ii) the brain circadian clock, in particular ARNTL1, CLOCK,
GSK3b, RORA and RORB genes and their regulation and
iii) factors (peptide, proteins, light, etc.) and mechanisms of
modulation of the circadian clock and monoamine neurotransmission. The exploration of GABAergic, dopaminergic,
serotonergic and glutamatergic neurotransmission is also of
major interest, in particular the multiple links between these
systems and circadian rhythms.
It should be emphasized that factors associated with disease
vulnerability and drug response are not necessarily the same.
In terms of future drug development, the exploration of the
biological pathways involved in successful treatments is of
major interest. Lithium and, to a lesser extent, valproate
have produced interesting data. Biomarkers of response of
8
nonpharmacological treatments represent an important
insufficiently covered area of research.
Based on the exploration of the mechanisms underlying lithium efficacy, GSK3b seems to play a central role. However,
GSK3b is involved in many molecular cascades (MAP-1B,
tau, Heat shock factor protein 1, C-JUN, C-AMP Response
Element-binding protein, Cyclin D, b-catenin, etc.) and it
remains unclear which is involved in lithium prophylactic efficacy and in tolerance. Other pathways of interest include myoinositol pathway, WINT pathway, Trkb/BDNF pathway or
protein kinase C. Close links between circadian rhythms and
GABA-ergic, dopaminergic and glutamatergic neurotransmissions lead also to consider lithium effects on these neurotransmitter systems. Lithium inhibits excitatory neurotransmission
by decreasing presynaptic DA activity and inactivating
postsynaptic G-proteins. It also exerts an inhibitory effect
downstream on the adenyl cyclase system, and, via effects on
cAMP, modulates further neurotransmission. Similarly,
lithium promotes inhibitory neurotransmission through its
modulation of glutamatergic neurotransmission by downregulating the NMDA receptor and inhibiting the myo-inositol
second messenger system, which is responsible for maintaining
signaling efficiency. When activated, the myo-inositol system
leads to phosphorylation of phosphoinositides, which in turn
initiate two second messenger pathways involving diaglycerol
and inositol triphosphate. These components of the phosphorylation cycle are responsible for modulating neurotransmission
and regulating genetic transcription. Chronic modulation of
this cycle through lithium exposure eventually alters gene
transcription, including circadian genes. Lithium additionally
inhibits neurotransmission by facilitating the release of
GABA and upregulating the GABAB receptor.
6.
Expert opinion
More than a decade after the development of atypical antipsychotics in BD, virtually no new compounds have emerged in
this field. The drug development pipeline is almost empty
with only three available main classes of mood stabilizers
(lithium, anticonvulsants and atypical antipsychotics). The
development of hypothesis regarding pathways altered in BD
should help renew interest in the pathophysiology of BD
and increase prospects for novel pharmacological approaches
to BD.
Clinical, actigraphic, biochemical, genetic, pharmacogenetic and gene expression studies have consolidated the
hypotheses that major disruptions in sleep and circadian
rhythm regulation pathways occur in BD and this research
has provided new insights into the pathophysiological
processes involved in the evolution and progression of BD,
alongside a better understanding of the putative mechanisms
of action of existing treatments (mainly lithium). While these
pathways offer an opportunity to develop novel approaches,
this review demonstrates that the level of evidence implicating
which genes/proteins might be targeted by drugs remains
Expert Opin. Ther. Targets (2015) 19(6)
Sleep- and circadian rhythm--associated pathways as therapeutic targets in bipolar disorder
relatively low and requires further replication in large-scale
well-conducted studies. The next stage of research will need
to incorporate comprehensive translational approaches to
sleep and circadian rhythm pathways, ranging from animal
to human cellular models to provide reliable models for
high-throughput screening of new drugs. Combinations of
phenotypic approaches, large-scale analyses with time
frequency methods and ‘omics’ (genomics, transcriptomic,
proteomic, methylomic) will also be necessary.
Phenotype studies, large data collection analysis
and biochemical markers
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6.1
Characterization of sleep disturbances and circadian rhythm
disruptions in BD cases is common, and persistence of sleep
abnormalities during remission has been identified as a predictor of relapse [4]. Several studies have addressed this issue
using questionnaires that provide quick and inexpensive
assessments of sleep parameters and circadian rhythms. However, the association between these basic assessments and
endogenous measures of sleep or circadian rhythms requires
clarification [182].
More efforts dedicated to ecological assessments such as
actigraphy are required to gain more detailed insights into
daily sleep and circadian rhythm patterns and how they vary
according to environmental stressors and so on. Almost all
ecological studies (using actigraphy for example) have
included small samples (around 30 per study) and few have
targeted BD as compared with a range of mood disorders.
Although two meta-analyses [81,183] have clearly demonstrated
that sleep quality and sleep/wake regularity parameters are
altered among BD cases in remission, little is known regarding variability of such parameters. It has been hypothesized
that for a given parameter, interday or intraday variations
would be more important than the quantity (mean) of the
parameter [72]. This could be achieved only if studies include
larger samples assessed for long periods of time to capture
this variability. Furthermore, the whole field has used the
case--healthy control design, rather than addressing the more
important and clinically relevant question of whether BD is
associated with circadian abnormalities that are not seen in,
for example, unipolar disorders or psychosis.
Initiatives such as Chronorecord have been developed to
allow extended ecological assessments of cases and to provide
feedback to patients in clinical settings [184,185]. This desktop
computer-based assessment is now being replaced by new
technologies that are able to collect data from sensors in
smartphones, and wearable technologies [186]. Actigraphs can
also be worn for long periods of time to collect multiple
parameters concerning sleep and activity, although this
approach does not allow for subjective self-ratings unless
paired with other technologies of self-observations.
Although offering a robust measure of physiological processes, biochemical measures are of more limited use due to
their invasiveness. Repeated collections of plasma for cortisol
or melatonin (e.g., hourly) over a whole day/night cycle are
not often feasible, as they are too disruptive to the individuals’
lifestyle. Collections of saliva rather than venous samples have
increased the feasibility of such biochemical investigations as
they allow a greater degree of self-management of the process.
Currently, this is an evolving field of research in BD, although
findings on cortisol levels are reported in a recent metaanalysis in BD [103]. The use of measures of core temperature
with ingestible capsules is another way to investigate circadian
rhythms that are close to physiological processes [187], but
there are currently no available studies in BD during remission. All these measures can be used to assess circadian
rhythms but also can provide information about the external
validity of questionnaires and actigraphy that are of easier
use in clinical and research practices in large samples.
Human cells and animal models for screening
of new drugs
6.2
More recently, cellular models that can be used to assess
circadian rhythms have been developed in BD. To date, cultured cells derived from human skin biopsies, blood samples
or hair follicle cells have only been anecdotally used to test
transcriptomic and epigenetic aspects related to circadian
pathways in BD. The development of this research field is a
prerequisite to identify dysfunctional pathways that could be
targeted for drug development. Development of cellular
models is rendered easy by the use of peripheral blood
mononuclear cells or fibroblasts using skin biopsy. Induced
pluripotent stem-cell technology and study of differentiated
neuronal lineages from fibroblasts have not yet been
developed in the study of circadian rhythms in BD but their
use can help high-throughput pharmaceutical drug screening
and the study of expression and transcription profiles. Moreover, the modification of such profiles after incubation of cells
with lithium salts [188] (or other drugs to screen) can help
identify how drugs that are known or under development
can modify these profiles.
Postmortem tissues can also be used for methylomic and
RNA sequencing investigations and have provided promising
results in BD [189]. For example, the study of the brain
transcriptome identified dysregulation in circadian pathways
in BD [190].
A few animal models have been developed for BD, based
on sleep or circadian rhythm pathways such as the ClockD19
mice [191], transgenic mice overexpressing GSK3b, Per2 or
Per1 knock-out (KO) mice [192]. New animal models have
also been developed, which are not based on genetic manipulations, but on environmental paradigms that switch the
light--dark cycle [193]. They can extend the appraisal of broader
modifications of circadian pathways by environmental
challenges instead of focusing on one single gene (mutated
or KO mice). The development of new animal models could
be very useful to development of new drugs and would help
preclinical trials. Most of these animal models have used
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F. Bellivier et al.
only lithium challenges but have not been used for larger
screening of compounds.
Both cellular models derived from human cells and animal
models can be used for the screening of compounds that are
likely to modify circadian rhythms. For example, preliminary
findings using 200,000 synthetic compounds on fibroblast
cells, suprachiasmatic nucleus and peripheral tissue explants
identified a few compounds that lengthen the period in
both central and peripheral clocks or shorten the period of
peripheral clocks [194], and identified cryptochrome inhibitors [195]. Animal model (CLOCK mutation) has been used
to test molecules that act as inhibitors of GSK-3b and attenuates the locomotor hyperactivity of this model of mania [196].
Such examples remain scarce and should lead to a more
generalized use of both cellular and animal models for the
screening of new drugs.
Large-scale pharmacogenetic studies
To date, pharmacogenetics of lithium response based on
sleep- and circadian-related genes is scarce. Although preliminary results have emerged regarding the implication of circadian genes in the response to lithium, the level of replication is
too weak to underlie a single gene within those associated
(ARNTL, TIMELESS, GSK3b and NR1D1) [132,148,197]. The
hypothesis that lithium could target these proteins and/or
act as a modifier of transcription of these genes shed some
light on potential specific mechanisms that are likely to support its mood stabilizer action and then be targeted by other
compounds. Such pharmacogenetic studies have been limited
by sample sizes, restriction to small sets of circadian genes and
unreplicated results. Large-scale pharmacogenetic studies such
as those planned within ConLiGen (the International
Consortium of Lithium Genetics) will offer new insight of
the genes involved in response to lithium and will determine
whether associated genes belong or are related to sleep and/
or circadian rhythm pathways. The goal of this collaboration
is to facilitate high-quality, well-powered analysis of lithium
treatment response data using data from GWAS. If positive
results in sleep or circadian pathways are generated by this
initiative, this will help focusing more precisely on a restricted
set of genes to be then used in cellular or animal models of
BD for the screening of new compounds.
6.3
Bioinformatics tools
Collecting large sets of data from different sources (clinical,
actigraphy, ‘omics’ approaches) over long or sequential
periods of time (months for actigraphy, incubated cells with
compounds assessed at different times) will obviously generate
an enormous volume of data (‘big data’ challenge). Bioinformatics tools will help to integrate and analyze such data.
One challenge is how to analyze phenotypic measures
recorded several times a day for weeks or months. This is
the case for actigraphy that generates a measure of activity
each minute. The relative disadvantage of such an assessment
of circadian rhythms on long periods of time is the generated
large amount of data (‘big data’) and, next the requirement of
complex mathematical modeling. Mathematical models could
achieve precise analysis of circadian rhythms of sleep or other
phenotypes (such as mood) that address time--frequency
methods such as discrete Fourier transform and continuous
or discrete wavelet transform analysis [198]. These methods
are useful in quantifying circadian (but also infradian and
ultradian) patterns in behavioral records. Combining
improved quality of data collection and mathematical analysis
will lead to a more precise characterization of circadian abnormalities in patients with BD that could be targeted when
studying drugs that are existing or in development.
A second challenge refers to ‘omics’ approaches that are
high-throughput molecular profiling techniques that produce
large data sets. Bioinformatics can help to extract relevant
biological information within specific pathways and study
connections between interconnected pathways. Advanced
computational strategies are developing rapidly to deal with
all these ‘omics’ layers.
More generally, from the pharmaceutical perspective, ‘big
data’ analyses have to face several challenges: i) volume of
data; ii) velocity (analytical speed); iii) variability of data;
and iv) complexity of data [199].
The data summarized in this review may represent a new
treatment paradigm for the development of a next generation
of drugs that target sleep and circadian rhythm pathways that
will be added to the pharmacological arsenal for maintenance
therapy in BD. However, this goal will be reached only if multidisciplinary and integrative approaches combine preclinical,
clinical, actigraphy, biochemistry and so-called ‘omics’ with
appropriate bioinformatics tools. This will lead to the identification of a circadian biosignature of BD used in humans,
cellular and animal models to screen new compounds.
Acknowledgment
We would like to acknowledge APBC Hospital F Widal,
Paris, for their technical support.
6.4
10
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Expert Opin. Ther. Targets (2015) 19(6)
Sleep- and circadian rhythm--associated pathways as therapeutic targets in bipolar disorder
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Affiliation
Frank Bellivier†1,2,3,4, MD PhD,
Pierre-Alexis Geoffroy1,2,3,4, MD,
Bruno Etain4,5,6 MD PhD &
Jan Scott7,8 MBBS PhD
†
Author for correspondence
1
Inserm, U1144, Paris, F-75006, France
2
Universite Paris Diderot, UMR-S 1144, Paris,
F-75013, France
3
AP-HP, GH Saint-Louis - Lariboisière - Fernand
Widal, Pôle Neurosciences, 75475 Paris
Cedex 10, France
Tel: +33 1 40 05 48 69;
Fax: +33 1 40 05 49 33;
E-mail: frank.bellivier@inserm.fr
4
Fondation FondaMental, Creteil, 94000, France
5
INSERM, Unite 955, IMRB, Equipe de
Psychiatrie Genetique, Creteil, F-94000, France
6
AP-HP, Hopitaux Universitaires Henri Mondor,
DHU PePsy, Pôle de Psychiatrie, Creteil,
F-94000, France
7
Newcastle University, Institute of Neuroscience,
Academic Psychiatry, Newcastle, UK
8
Institute of Psychiatry, Centre for Affective
Disorders, London, UK
17