3. Circadian rhythms and bipolar disorder Westrich & Sprouse�����781
adrenocortical (HPA) axis: the SCN-timed release of
ACTH controls the peak (early morning) and nadir
(midnight) of cortisol secretions in diurnal species. In
addition to the HPA axis, the SCN controls the release of
melatonin from the pineal gland, and also controls the
sleep-wake cycle, feeding behavior, body temperature,
locomotor activity and the immune system response.
The disruption of normal circadian rhythms in these
systems can result in disease, including depression
(hypercortisolemia) [7], bipolar disorder (abnormal
sleep-wake cycle related to cycling of mood) [8] and severe
dementia (increased nocturnal activity) [9].
The biological clock in desynchrony
An organism can entrain to LD cycles of slightly differing
lengths from the 24-h day (eg, typically from 23 to 26 h),
but this relationship is weakened when internal circadian
rhythms are compacted or stretched to 22- or 28-h
days. Under these conditions, internal circadian rhythms
resort to their endogenous period length and animals
'free-run' independently of the influence of light, the
most powerful zeitgeber (an exogenous cue functioning
as a synchronizer). This outcome is referred to as
'forced desynchrony', defined as a dissociation of circadian
behaviors from the external solar clock, in some cases
resulting in multiple dissociated internal rhythms [10].
For example, the rhythms of locomotor activity, core
body temperature, sleep stages and melatonin secretion
are internally desynchronized in rats exposed to 22-h LD
cycles, but the impact of the shortened day is not equal
for every function [11]. In particular, melatonin release
schedules become the product of two distinct oscillator
mechanisms, one driven by the LD cycle, the other by
internal timekeeping.
One explanation for the observed desynchrony in rats
exposed to shortened days could reflect the disparate
components of the circadian rhythm that are under the
control of different subregions of the SCN. The RHT
projects primarily to the ventrolateral aspect of the SCN
(vlSCN); therefore, systems receiving input from the
efferent projections of this subregion entrain to the
LD cycle. The vlSCN projects to the dorsomedial division
(dmSCN). Abrupt changes in the LD cycle may induce
dissociations in rhythmic clock gene expression between
the vlSCN and dmSCN [11]. For example, under forced
desynchrony conditions, rapid eye movement sleep (REMS)
– directly controlled via dmSCN – free-runs with the
endogenous circadian period, while slow-wave sleep (SWS)
is synchronized with the sleep episode via direct input
from vlSCN [12]. Investigators have considered
whether these delicately balanced connections might be
dysregulated in patients with psychiatric disorders,
thereby resulting in rhythms that are desynchronized
with the 24-h day. Further research is required, but
an understanding of the mechanisms underlying the
effects of lithium may provide some insight. A commonly
prescribed mood stabilizer, lithium delays circadian
rhythms as a consequence of its ability to prolong
period length. This impact is observed in some rhythmic
functions in rats (eg, wheel running, body temperature,
corticosteroid levels and REM sleep), but has not been
observed in others (eg, pineal serotonin, melatonin and liver
glycogen) [13].
Circadian rhythm dysregulation in bipolar
disorder
Human perceptions of mood occur in a cyclical pattern;
misalignments between internal and external rhythms
may result in mood alterations, such as major depressive
disorder (MDD), depressive states linked to seasonality
or seasonal affective disorder (SAD), and mood swings
that occur on a cyclical basis or with bipolar disorder.
In neurodegenerative states, the loss of SCN function
can manifest as agitation or aggression in patients with
severe dementia – the 'sundowning' effect observed in
Alzheimer's disease. In this review, discussions focus on
bipolar disorder, as multiple lines of evidence suggest
a link for the condition with rhythmic disturbances
(for other circadian rhythm-based disease states, see
references [14-17]).
Bipolar disorder is a chronically relapsing condition that is
characterized by a spontaneous cycling of mood between
depression and mania [18]. Such mood swings can be
rapid, or there can be extended periods of euthymia
(ie, neutral mood) between episodes. The modulation of
various circadian signaling pathways has been described,
but little is known regarding the mechanisms that underlie
the manic and depressive states and the factors that
initiate the switch between states. Abnormalities observed
in patients with bipolar disorder include a shortening
of the normal 24-h period length of endogenous rhythms
and/or a blunting of the rhythms (loss of amplitude).
Several non-invasive approaches are available to monitor
such changes (eg, rest:activity rhythms measured
by actigraphy, melatonin cycling and self-assessment
questionnaires). In practice, these biomarkers reveal that
phase advances occur in patients with bipolar disorder,
resulting from the period shortening that generally
precedes the switch to a hypomanic state (occurring
prior to the manifestation of full mania). For example,
shifts in the temporal distribution of REM sleep and the
circadian rhythm of body temperature have been
observed in patients with bipolar disorder during manic-
depressive cycles. The peak or acrophase of REM sleep
and body temperature occurs progressively earlier during
the hypomanic period and progressively later during
depressive episodes [18].
A consideration of a causal link between altered internal
phase relationships and bipolar disorder has not been
evaluated extensively. One framework, established in the
late 1970s, depicts a 'cyclic beat' that occurs when the
phase of the shortened internal rhythms periodically
coincides with that of the prevailing day. The frequency of
this 'beat' reflects the disparity in period length between
the internal and external rhythms; in some patients
with bipolar disorder, the rate of this beat predicts the
frequency of mood swings [1,19]. Data from animal models
4. 782 Current Opinion in Investigational Drugs 2010 Vol 11 No 7
are limited but supportive of this correlation. Rats placed
in a 28-h forced desynchrony paradigm exhibited a
range of rest-activity patterns. In some animals, bouts of
hyperlocomotor activity (ie, a manic-like state) occurred
with a frequency that was predicted using the cyclic beat
phenomenon [20]. Additional studies are required to
confirm this relationship, but the notion that rhythmic
disparities control mood in bipolar disorder should
encourage further research. Potential areas of study
include assessing whether patients with bipolar disorder
experience symptom improvement in a time-shortened
day that is designed to match their period length and,
conversely, whether healthy individuals experience mood
swings in the presence of long-day forced desynchrony
schedules.
Such questions may be addressed initially in animal models,
such as Clock mutants and D-box binding protein (Dbp)
knockouts (Table 1). Clock mutants have a free-running
period of 25 to 27 h and have completely arrhythmic
activities after several weeks in constant darkness [21],
while Dbp mutants have a short period length of
approximately 20 to 22 h [22,23]. Both animal models
display mania-like behavior, but only the Dbp model
possesses a depressive phenotype (hypolocomotor
behavior) [22-24]. Although Dbp is not essential
for the generation of circadian rhythms, the gene
controls downstream clock-controlled gene expression
(Figure 1), regulating clock outputs such as circadian sleep
consolidation and the time course of slow-wave sleep δ
power [23]. Interestingly, the typically depressive
phenotype of these animals switched to the manic state
following exposure to a stressor (ie, chronic isolation plus
acute exposure to forced swim, tail suspension or tail
flick tests); reversal to the basal phenotype was achieved
with the mood stabilizer valproate [25]. Despite such
face validity, no single animal model captures all aspects
of bipolar disorder (Table 1); instead, multiple approaches
are needed.
Beyond information gained from the use of biomarkers
related to clinical state, gene expression studies have
revealed rare abnormalities that suggest that a poorly
functioning body clock results in a poorly functioning
host. For example, a SNP of T → C in the 3' flanking region
of the human Clock gene has been associated with a
diurnal preference for 'eveningness' (ie, greater alertness
and function in evening hours) in patients with bipolar
disorder who carry at least one copy of the 3111
C allele. More importantly, this substitution appears to
predict the number of manic and depressive episodes
accurately [26]. Other circadian genetic links to bipolar
disorder have also been reported, including genes
encoding vasoactive intestinal peptide (VIP), RORβ,
glycogen synthase kinase 3β (GSK3β), PER, casein
kinase I (CKI) and Rev-Erbα [27-33], cumulatively
suggesting that circadian effects may be causal factors
in bipolar disorder.
An interesting area of research is whether bipolar
disorder in all patients results from circadian rhythm
abnormalities. Such uniformity would be unlikely, given
the heterogeneous nature of psychiatric disorders. The
available data are both intriguing and puzzling. For
example, one study suggested a differential association
of clock genes in mood disorders, with Cry1 and neuronal
PAS domain-containing protein-2 (NPAS2; a paralog of
Clock) possessing a closer link to unipolar depression,
and VIP and Clock yielding more bipolar disorder-specific
effects [34]. Other studies, however, failed to detect
Genetic manipulation Phenotype/similarities to bipolar disorder Missing components/disadvantages of model References
Dbp knockout Period length < 24 h
Decreased locomotor activity and sleep EEG
abnormalities
Switch to hyperactivity following exposure to stress
Pharmacological and/or light treatments to
alter the phenotype unavailable
[22,23,25]
Clock mutants Increased overall locomotor activity
Hyperactivity in a novel environment
Reduced anxiety
Increased preference for cocaine
(mania-like behavior)
Period length > 24 h
No evidence of depressive-like behavior
[21,24]
Vipr2 knockout Period length < 24 h
Increased wheel-running in DD compared with LD
Arrhythmicity in absence of environmental cues
(in a subset of animals)
Limited assessment of mood- and stress-related
behaviors available
[65]
VPAC2
R transgenics
(overexpression)
Period length < 24 h
Resynchronization more quickly than in wild type
to phase advance
Unknown receptor compensation because of
overexpression
[66]
Cry1 knockout Period length < 24 h
Poorly synchronized circadian rhythmicity
Limited assessment of mood- and stress-related
behaviors available
[67]
Clock Circadian locomotor output cycles kaput gene, Cry1 cryptochrome 1 gene, Dbp D-box binding protein gene, DD dark:dark, LD light:dark,
Vipr2 vasoactive intestinal peptide receptor 2 gene, VPAC2
R vasoactive intestinal peptide receptor 2 protein gene
Table 1. Selected animal models of bipolar disorder.
7. Circadian rhythms and bipolar disorder Westrich & Sprouse�����785
with 5-HT2C
blockade [60,62,63]. Such a possibility
seems unlikely, however, given the weak affinity of the
compound for this serotonin receptor subtype (pKi
= 6.39)
[63]. Studies examining non-synthetic melatonin in MDD
have yielded mixed results. In the most comprehensive
assessment of non-seasonal depression, published in
2010, a trend toward improvement was noted, although
statistical significance was lacking as a result of the
small sample size (n = 31) [64]. Thus, further research is
required to gain a fuller understanding of the roles of
agomelatine and melatonin on circadian rhythm-related
disorders.
Conclusion
The mechanistic link connecting circadian rhythm
dysfunction to psychiatric disorders is supported by
several sources of evidence, although a causal link
remains elusive. Those correlations that are known to
exist – between the clinical phenotype and the circadian
state, and between animal models of rhythm function and
animal models of disease – still await the development of
successful investigational drugs that can serve as proof of
mechanism. Many areas of research are possible beyond
bipolar disorder. Studies might focus on MDD, SAD and
sundowning to assess the application of investigational
drugs in the circadian field. Beyond agomelatine and
melatonin, the search for second-generation chronobiotics
(eg, CKIδ inhibitors or lithium-like GSK3β modulators)
should also continue, given that preclinical and clinical
research has highlighted the potential benefits of such
drugs to maintaining a properly functioning circadian
rhythm in humans.
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![REVIEW
Current Opinion in Investigational Drugs 2010 11(7):779-787
© Thomson Reuters (Scientific) Ltd ISSN 2040-3429
Introduction
The regulation of mood follows a circadian pattern – an
oscillation of physiological and behavioral events over
a period of approximately 24 h; disturbances in these
endogenous rhythms can contribute to psychiatric
disorders. Mood alterations occur when the internal rhythms
become desynchronized with external environmental cues,
such as daylight. Such a causal link has been postulated
for more than 30 years [1]. Historically, evidence of the
connection has relied on the successful management of
symptoms by use of pharmacological and light therapies
that have an impact on circadian rhythms. The changes
achieved in the amplitude or phase (ie, timing of peaks
and troughs) of various circadian output parameters by
such therapies suggest that chronobiological disturbances
are involved in both the cause and treatment of mood
alterations. This review encompasses aspects of animal
and clinical studies of circadian behavior, as well as
molecular findings, that provide evidence for the
involvement of circadian abnormalities in psychiatric
disorders, particularly in bipolar disorder. Therapeutic
approaches that can resynchronize internal timekeeping
to match the solar day highlight what might be gained
by circadian rhythm-centric modalities of treatment. In
particular, pharmacological approaches that may be used
to achieve such resynchronization are discussed.
The mammalian molecular clock and its
physiological role
Endogenous clocks drive numerous physiological and
behavioral functions to oscillate with a circadian rhythm.
Such a system allows organisms that experience daily
light:dark (L:D) cycles to adapt their internal functions
continuously to the prevailing environment. Consequently,
one of the primary functions of the circadian clock is to
maintain both plants and animals in synchrony with their
surroundings, to cause a temporary suspension of the
natural homeostatic drive to adjust to the time of day
and, as a result, to ensure the health of the organism. In
mammals, the principal circadian pacemaker is located
in the suprachiasmatic nucleus (SCN) of the anterior
hypothalamus. Although the SCN has an endogenous
rhythm that is slightly shorter or longer than 24 h
(depending on inter-species as well as intra-species
differences), it is synchronized precisely to this time period
by dominant light cues. Phase regulation depends on input
to the SCN from the retina through the retinohypothalmic
tract (RHT), which enables the transmission of light and
therefore ensures the entrainment of daily rhythms to
24-h cycles [2,3]. 'Peripheral clocks' with tissue-specific
functions are located throughout the body and are under
the control of the master clock in the SCN, but may not
necessarily have the same phase [4,5]. Together, the
central and peripheral clocks comprise the circadian system.
When the clocks are in synchrony, normal functioning
prevails; when not in proper synchrony, problems may
ensue, such as the malaise and fatigue associated with
jet lag.
At the molecular level, the rhythms of both central
and peripheral clocks are controlled by a primary
transcriptional-translational negative feedback network
comprised of clock genes, including circadian locomotor
Circadian rhythm dysregulation in bipolar disorder
Ligia Westrich* & Jeffrey Sprouse
Address
Lundbeck Research USA Inc, Neuroscience, 215 College Road,
Paramus, NJ 07652, USA
Email: lwes@lundbeck.com
*To whom correspondence should be addressed
When circadian rhythms – the daily oscillations of various physiological and behavioral events that are controlled by a central timekeeping
mechanism – become desynchronized with the prevailing light:dark cycle, a maladaptative response can result. Animal data based
primarily on genetic manipulations and clinical data from biomarker and gene expression studies support the notion that circadian
abnormalities underlie certain psychiatric disorders. In particular, bipolar disorder has an interesting link to rhythm-related disease
biology; other mood disturbances, such as major depressive disorder, seasonal affective disorder and the agitation and aggression
accompanying severe dementia (sundowning), are also linked to changes in circadian rhythm function. Possibilities for pharmacological
intervention derive most readily from the molecular oscillator, the cellular machinery that drives daily rhythms.
Keywords Biological clock, bipolar disorder, circadian rhythm, desynchronization, entrainment, kinase, light:dark cycle, oscillator,
period length](https://image.slidesharecdn.com/15759854-b097-41cc-8bd6-04e0be462cb5-150317155217-conversion-gate01/85/westrich-sprouse-2010-coid-circadian-rhythm-dysregulation-in-bipolar-disorder-1-320.jpg)
![780 Current Opinion in Investigational Drugs 2010 Vol 11 No 7
output cycles kaput (Clock), brain and muscle arnt-like-1
(Bmal1), period 1/2 (Per1/2), cryptochrome 1/2 (Cry1/2),
and their protein products, all of which vary in quantity
over a 24-h cycle [6] (Figure 1). The BMAL1-CLOCK
transcription factor complex activates the transcription
of Per and Cry during daylight periods. In the cytoplasm,
the PER and CRY proteins heterodimerize and translocate
to the nucleus to block their own transcription, by
interfering with the BMAL1-CLOCK complex. Concurrently,
PER and CRY undergo post-translational modification,
specifically phosphorylation, in a precise, rhythmic and light
phase-specific manner. The phosphorylated PER-CRY
complex degrades during the phase of darkness, thus
attenuating its inhibition of the BMAL1-CLOCK complex
and allowing activation of Per and Cry transcription to
resume. This process underscores the significance of
post-translational modifications in determining and
controlling endogenous cyclical rhythms. As part of a
second regulatory loop, the BMAL1-CLOCK transcription
activator complex also controls the transcription of
Rev-Erbα, which subsequently represses the transcription
of Bmal1 by competing for the retinoic acid-related
orphan receptor β (RORβ) in the Bmal1 promoter region
[6]. The timing of a complete cycle is close to the
prevailing light:dark cycle; synchronization occurs when
light cues align the rhythms.
Endogenous clocks have the ability to respond to various
salient changes in the environment – primarily light, food
and temperature – allowing mammals to anticipate and
coordinate their physiological needs with the available
resources and demands of the environment. The most
thoroughly characterized response to external cues is
the circadian rhythm of the hypothalamic-pituitary-
Figure 1. The mammalian circadian clock: A series of transcriptional-translational feedback loops.
The core clock genes circadian locomotor output cycles kaput (Clock) and brain and muscle arnt-like-1 (Bmal1) are transcribed and form
heterodimers in the cytoplasm, and then re-enter the nucleus to activate the transcription of period (Per) and cryptochrome (Cry) genes. PER
and CRY protein products form heterodimers in the cytoplasm that, upon phosphorylation, re-enter the nucleus and repress further
BMAL1-CLOCK activation of transcription, thus completing one cycle of the oscillator (dotted arrows). Phosphorylation also primes the
PER-CRY hetereodimer for degradation, allowing a new cycle of transcription to occur. A secondary autoregulatory loop results from the
activation of Rev-Erbα transcription by the BMAL1-CLOCK complex. Phosphorylated Rev-Erbα then re-enters the nucleus to repress Bmal1
transcription by competing with RAR-related orphan receptor β (RORβ). Mouse albumin D element-binding protein (DBP) is located
downstream of the molecular oscillator, and controls the expression of other clock-controlled genes. Two key kinases in these loops are
casein kinase I δ (CKIδ) for the phosphorylation of the PER-CRY complex and glycogen synthase kinase 3β (GSK3β) for the phosphorylation
of Rev-Erbα. Degradation of these proteins is accomplished via the β−TrCP and FBXL3 ubiquitin ligase complexes.
(Adapted with permission from Lundbeck Research USA Inc. © 2010 Lundbeck Research USA Inc)
BMAL1
CLOCK
Nucleus
Cytoplasm
—
BMAL1
CLOCK
BMAL1
CLOCK P
BMAL1
CLOCK
Rev-Erbα
Bmal1, Clock
PER
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REV-ERBα
PER
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RORB
FBXL3
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