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Sleep and circadian rhythm disruption in neuropsychiatric illnessAarti Jagannath1,2, Stuart N Peirson1 and Russell G Foster1
Available online at www.sciencedirect.com
Sleep and circadian rhythm disruption (SCRD) is a common
feature in many neuropsychiatric diseases including
schizophrenia, bipolar disorder and depression. Although the
precise mechanisms remain unclear, recent evidence suggests
that this comorbidity is not simply a product of medication or an
absence of social routine, but instead reflects commonly
affected underlying pathways and mechanisms. For example,
several genes intimately involved in the generation and
regulation of circadian rhythms and sleep have been linked to
psychiatric illness. Further, several genes linked to mental
illness have recently been shown to also play a role in normal
sleep and circadian behaviour. Here we describe some of the
emerging common mechanisms that link circadian rhythms,
sleep and SCRD in severe mental illnesses. A deeper
understanding of these links will provide not only a greater
understanding of disease mechanisms, but also holds the
promise of novel avenues for therapeutic intervention.
Addresses1 Department of Clinical Neurosciences (Nuffield Laboratory of
Ophthalmology), University of Oxford, Level 5-6 West Wing, John
Radcliffe Hospital, Headley Way, Oxford OX3 9DU, United Kingdom2 F.Hoffmann-La Roche AG, Pharma Research & Early Development,
DTA Neuroscience pRED Grenzacherstrasse 124, Basel CH4070,
Switzerland
Corresponding authors: Peirson, Stuart N ([email protected])
and Foster, Russell G ([email protected])
Current Opinion in Neurobiology 2013, 23:xx–yy
This review comes from a themed issue on Circadian Rhythm and
Sleep
Edited by Clifford Saper and Amita Sehgal
S0959-4388/$ – see front matter, Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.conb.2013.03.008
IntroductionSleep disruption is a notable and long-recognized feature
of mental illness. The majority of patients with schizo-
phrenia, bipolar disorder and major depressive disorder
report sleep disturbances, although the mechanistic
relationship between these neuropsychiatric illnesses
and sleep remains unclear [1�]. Sleep/wake cycles are
partially regulated by the circadian clock and recent
studies have implicated circadian disruption, both at
the level of clock genes themselves and clock outputs,
in the aetiology of these disorders. Here we consider the
major developments in the last few years linking the
circadian clock and sleep with neuropsychiatric disease.
Please cite this article in press as: Jagannath A, et al.: Sleep and circadian rhythm disruption in neu
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Circadian rhythms and sleep: from basicmechanisms to healthThe Earth’s 24 hour cycle of light and darkness results in
a predictably changing environment, providing a key
selective advantage to organisms that are able to anticip-
ate and exploit these rhythmic changes. Consequently,
most aspects of physiology and behaviour display 24 hour
variations, driven by an endogenous circadian clock (from
the Latin circa — approximately and diem — day). In
mammals, the mechanism providing this rhythm is a
molecular transcriptional-translational feedback loop
(TTFL), consisting of the transcription factors CLOCK
and BMAL1 which drive the expression of clock genes
including Period and Cryptochrome that in turn feed-back
to regulate their own expression (Figure 1a) [2]. This
TTFL also regulates the expression of clock-controlled
genes in a rhythmic manner, resulting in the oscillation of
tissue-specific metabolic and physiological functions.
This molecular oscillator mechanism is found in most
cells throughout the body. As a result, the circadian
system comprises a network of synchronized cell
autonomous 24 hour oscillators that fine-tune physiology
and behaviour to the varied demands of the environmen-
tal day [3]. This synchronization is achieved via a master
circadian pacemaker, which in mammals, is located in the
suprachiasmatic nuclei (SCN) in the ventral hypothala-
mus [4]. The SCN clock is in-turn entrained by the
environmental light/dark cycle, detected by retinal
photoreceptors (rods, cones and melanopsin-containing
photosensitive ganglion cells) and relayed via the retino-
hypothalamic tract [5]. Ill-defined neural and hormonal
signals from the SCN, and feedbacks from peripheral
outputs, result in an entrained and synchronized temporal
network (Figure 1b,c). If the signals necessary for entrain-
ment of central and peripheral oscillators are uncoupled,
clocks in different tissues can become desynchronized,
resulting in a state of internal desynchrony as experienced
in jet lag [6].
The sleep/wake cycle is perhaps the most familiar circa-
dian cycle. However, in addition to the circadian clock,
sleep is also regulated by homeostatic processes. Sleep
homeostasis can be defined as the sleep/wake-dependent
aspect of sleep regulation, such that an increase in sleep
propensity occurs when sleep is absent/curtailed, whilst
sleep propensity is reduced in response to excess sleep
[7]. The precise mechanisms involved remain unclear.
However, adenosine has emerged as a clear candidate,
levels of which rise in the basal forebrain during wakeful-
ness and fall during sleep [8�]. In addition, light levels,
social cues, stress hormones and melatonin all play key
modulatory roles in sleep. Sleep itself arises from the
ropsychiatric illness, Curr Opin Neurobiol (2013), http://dx.doi.org/10.1016/j.conb.2013.03.008
Current Opinion in Neurobiology 2013, 23:1–7
2 Circadian Rhythm and Sleep
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Figure 1
04.00
Melatonin
Stress Hormones
CBT
Z
ZZ
Z
Z
Z
Z
ZZZ
ZZ
Z
Z
Alertness
Nucleus
Per, Cry
PER
(a) (b) (c)
PER
CRY
CRY
CLO
CK
BM
AL1
Current Opinion in Neurobiology
Generation of circadian rhythms and their role in the regulation of physiology. (a) The molecular clock comprises a transcriptional-translational
feedback loop of the transcription factors CLOCK and BMAL1 which drive the expression of Per and Cry, in addition to a host of genes regulating
physiology and metabolism. PER and CRY in turn repress CLOCK:BMAL, thereby autoregulating their own expression. The period of this loop is
around 24 hours. (b) In humans, the master clock is housed in the SCN, and this clock communicates and entrains the peripheral clocks of the body,
resulting in coordinated rhythmic physiological outputs. (c) Examples of such outputs include (from upper to lower) the regulation of melatonin
secretion by the pineal, the level of stress hormones, the regulation of core body temperature (CBT) and alertness levels.
interaction between multiple brain nuclei and neuro-
transmitter systems that collectively either promote sleep
or wakefulness, (see [9,10] for details). The resulting
coordinated neuronal activity gives rise to changes in
activity patterns, body posture and responsiveness to
stimuli, all of which characterize the sleep/wake states
[11].
In addition to the sleep/wake cycle, many of our meta-
bolic and physiological functions, including the regula-
tion of body temperature and blood pressure display
marked circadian rhythms [12]. Both are closely linked
with sleep, and for a long time, were thought to be a part
of the sleep response. However, lesion studies on rats
demonstrated that body temperature and sleep are
regulated separately by the circadian system [13]. Given
the pivotal role of the circadian clock, one would predict
that disruptions either of the clock itself or of the down-
stream components of the circadian timing system can
cause pathological changes in metabolism and physi-
ology. The reasons for this are two-fold: firstly, changes
in circadian timing cause desynchrony amongst the
multiple oscillators within the circadian network and
the environment; secondly, CLOCK and BMAL1 are
transcription factors that directly control the expression
of many genes that regulate metabolism and other aspects
of physiology. Indeed, mice with mutations in the
Please cite this article in press as: Jagannath A, et al.: Sleep and circadian rhythm disruption in neu
Current Opinion in Neurobiology 2013, 23:1–7
circadian clock genes Clock and Bmal1 are obese, hyper-
glyceamic and hypoinsulineamic [14,15]. Rev-erbA and
Rev-erbB are clock genes that function in concert with
Clock, and double knock-out mice show severe disruption
of lipid metabolism [16]. Further, several studies have
shown interesting links between the circadian clock and
drug/alcohol abuse (see [17] for details).
Circadian disruption can also profoundly impact sleep.
Sleep disruption is associated with a wide range of
emotional, cognitive and somatic disorders. There are
strong links between sleep disruption and cognitive func-
tion, specifically in memory consolidation where learning
improves significantly after a night of sleep, and this
performance gain can be lost with disruption of just
REM sleep [18,19]. Disrupted sleep impairs immune
system function [20], with the activity of natural killer
cells in humans reducing by as much as 28% after one
night of sleep deprivation [21]. For a detailed review of
the health consequences of sleep disruption see [11].
Sleep and circadian rhythm disruption (SCRD)SCRD is a common feature of neuropsychiatric disease.
This observation is not new. Indeed, in 1883 Emil Krae-
pelin described the association between abnormal sleep
patterns and mental health [22], and the clear links
between sleep and bipolar disorder were described over
ropsychiatric illness, Curr Opin Neurobiol (2013), http://dx.doi.org/10.1016/j.conb.2013.03.008
www.sciencedirect.com
SCRD in psychiatric illness Jagannath, Peirson and Foster 3
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30 years ago [23]. Up to 80% of patients with depression or
severe mental illness such as schizophrenia report sleep
abnormalities [1]. Although SCRD is amongst the diag-
nostic criteria for psychiatric disorders, the aetiology of
SCRD is poorly understood and its treatment neglected.
Part of the issue is that sleep disruption shows a spectrum
of severity, ranging from little to severe within the same
diagnostic category of illness [24]. In addition, sleep
disruption has been largely attributed to the effect of
medication and the disrupted lifestyle that result from
mental illness [25]. However, recent advances in our
understanding of the mechanisms underlying sleep and
circadian rhythms are helping to provide direct links
between SCRD and neuropsychiatric disease, especially
in schizophrenia, bipolar disorder and major depression
(Figure 2).
Bipolar disorderBipolar disorder is a mood disorder where patients experi-
ence cycles of mood elevation and intense activity
(mania) followed by depression. The artist Van Gogh,
who has been suggested to have suffered from bipolar
disorder [26], worked prolifically during manic episodes,
followed by periods of exhaustion and depression. Inter-
estingly, reports indicate he also suffered from insomnia
and Van Gogh said he spent as much as three weeks at a
time without sleep [27].
The links between disrupted sleep and bipolar disorder
are now well documented; a decreased need for sleep
Please cite this article in press as: Jagannath A, et al.: Sleep and circadian rhythm disruption in neu
Figure 2
Current Opinion in Neurobiology
Sleep Disruption Psychiatric Illness
Common mechanism - disrupted circadian
clock
Stress Axis Social Isolation
Medication
Cognitive/Health Problems Stress Axis
Developmental
Links between SCRD and psychiatric disorders. Rather than a linear
relationship whereby psychiatric illness results in SCRD as a result of
stress axis, social isolation and/or medication, recent evidence suggests
a more cyclic relationship, psychiatric illness and SCRD reinforce one
another and share common and overlapping mechanisms. Defects in
neurotransmission/neurodevelopment, and cognitive/health problems
can impinge on both the sleep/circadian and psychiatric axis, while
stress, social isolation and medication resulting from psychiatric illness
can contribute to sleep/circadian disruption.
www.sciencedirect.com
while maintaining energy levels is the most common
symptom of mania [28]. However, bipolar disorder is a
complex disease and this is reflected in its pathophy-
siology, which remains poorly understood after decades
of research. What we do know comes from studies on
the therapeutic targets of lithium, a standard treatment
for bipolar disorder. At this level, several links with the
circadian clock emerge. One of the targets of lithium is
glycogen synthase kinase B (GSK3B), and lithium, via
GSK3B regulates the clock gene Rev-erba, which in turn
regulates levels of Bmal1 [29�]. As a drug target for
bipolar disorder, GSK3B remains very attractive, and a
screen to identify modulators of the circadian clock led
to the identification of a small molecular inhibitor of
GSK3B, which acted to shorten circadian period [30�].However, Meng et al., showed recently that chronic
lithium treatment lengthens circadian period by
increasing Per2 transcription [31�], indicating there
may be more to lithium’s therapeutic effect than its
action on GSK3B. For example, lithium acts upon
several other targets including Inositol Monophospha-
tase (IMPase) and Protein Kinase C Epsilon (PKCe)
[32]. Whether these additional targets act on the circa-
dian system remains to be determined.
Two recent clock gene mutants have provided unex-
pected models of mania. Clock mutant mice show a
striking mania phenotype with hyperactivity, decreased
sleep, lowered depression-like behaviour, lower anxiety
and an increased value for rewards. Interestingly many of
these behaviours were normalised upon chronic treat-
ment with lithium [33��]. This raises interesting ques-
tions about the mechanism of action, given that lithium is
unlikely to be modulating Clock itself, and therefore mood
stabilization may not be directly linked to Clock. Mukher-
jee et al. showed this phenotype can be replicated with
RNAi-mediated knockdown of Clock in the ventral teg-
mental area (VTA) alone. The VTA contains the dopa-
minergic cell bodies of the mesocorticolimbic dopamine
system which have been implicated in the drug and
natural reward circuitry of the brain and the suggestion
is that CLOCK might be a transcriptional regulator of a
VTA-specific cassette of genes, disruption of which
results in a mania phenotype [34�]. The authors also
showed changes in a number of targets including ion
channels and genes involved in dopamine synthesis fol-
lowing knockdown of Clock. Furthermore, the Afterhours(Afh) mutant, which carries a mutation in Fbxl3, a reg-
ulator of CRY degradation [35], shows reduced anxiety
and depression-like behaviours consistent with mania
[36]. In addition to these clock mutants, Kirshenbaum
et al. showed that Myshkin (Mykl) mutant mice with a
mutation in the Na+,K+-ATPase Atp1a3, also provide an
animal model of mania. Again, these animals show both
sleep and circadian rhythm abnormalities [37�]. Remark-
ably, all three models show a lengthened circadian period
(27, 25 and 27 hours respectively for the Clock, Mykl and
ropsychiatric illness, Curr Opin Neurobiol (2013), http://dx.doi.org/10.1016/j.conb.2013.03.008
Current Opinion in Neurobiology 2013, 23:1–7
4 Circadian Rhythm and Sleep
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Afh mutants). It remains to be determined whether cir-
cadian rhythms in a subset of bipolar patients show a
similar period lengthening.
SchizophreniaRecent studies have provided strong evidence for
SCRD in schizophrenia, where abnormal phasing and
instability of circadian rhythms, sleep disturbances and
fragmented rest-activity patterns have been clearly
described [38��,39,40]. For example, Wulff et al.[38��] compared rest-activity patterns in a cohort of
patients with schizophrenia with matched healthy
unemployed controls and showed significant sleep/cir-
cadian disruption in all 20 patients studied. Of these,
half showed severe circadian misalignment in sleep–wake and melatonin cycles, demonstrating that abnor-
mal entrainment of the circadian system is prevalent in
schizophrenia.
As the pathogenesis of schizophrenia remains poorly
understood, there are several hypotheses on the
mechanistic causes of the disease, of which those focus-
ing upon abnormal neurotransmission [41] and neuro-
development [42] are perhaps the most plausible.
Genetic studies have implicated a number of proteins
involved in glutamatergic synaptic transmission and
therefore schizophrenia has often been considered a
disease of the synapse [41,43]. Studies on two mouse
mutants of synaptic proteins, vasoactive intestinal poly-
peptide (VIP) receptor 2 (Vipr2) and the exocytotic
synaptic protein SNAP25, show strong links with the
circadian system. Vipr2, the receptor for VIP in the
SCN, plays an important role in synchronizing neuronal
oscillations [44] and Vipr2 knockout mice show a range
of circadian abnormalities, including disrupted rest/
activity patterns, reduced clock gene expression and
attenuated SCN electrical activity [45]. A role for Vipr2in schizophrenia was recently emphasized by a large-
scale genome-wide association study which identified a
rare copy number variant, involving a microduplication
of Vipr2, which confers a significant risk of schizo-
phrenia [46��]. The Blind-drunk (Bdr) mouse, which
has been proposed as a model for schizophrenia carries
a mutation in Snap25, a gene encoding an exocytotic
synaptic protein [47��,48]. These mice display phase
advanced and fragmented circadian rhythms in loco-
motor activity, however clock gene expression within
the SCN itself is not perturbed. Conversely, the
rhythms of SCN output parameters, such as of arginine
vasopressin (Avp) and plasma corticosterone are both
phase-advanced, indicating that disrupted synaptic con-
nectivity can alter output signals, and give rise to
SCRD [47��]. Furthermore, additional evidence for
mechanistic links between these disorders comes from
studies describing SCRD in animal models involving
genes that have been associated with schizophrenia,
including Nrg1, Tcf4, Pde4d and Cckar (see [49]).
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DepressionPerhaps the clearest links between SCRD and psychiatric
disease are in major depressive disorder, where up to 90%
of all patients report sleep disruption [1�]. Since other
reviews have considered this topic in some detail (see
[1�,50]), this review will focus only upon recent develop-
ments pertinent to the involvement of the circadian/sleep
systems. The link between the circadian system and
depression has been evident since the 1960s and 70s, when
it was discovered that depressive patients lose 24 hour
rhythmicity in cortisol secretion [51]. Patients with depres-
sion are resistant to suppression of cortisol secretion after
dexamethasone administration [52] so much so that a
dexamethasome suppression test has been used as a bio-
logical marker for depression. The hypothesis that
impaired central stress hormone regulation can cause or
modulate the course of development of depression has
gained traction [53] and the strong circadian component to
corticosteroid regulation should prompt further research
into the role of circadian rhythm disruption in depression.
Further, many antidepressants such as imipramine, clomi-
pramine and mirtazipine are also sedative with strong
hypnotic activity and are also used as sleep inducing agents
[1�]. Indeed the management of sleep in depression has
shown therapeutic benefit [54–56] and this points to strong
mechanistic links between sleep and depression (see [1] for
detailed discussion on this point).
Seasonal affective disorder (SAD) is a sub-type of depres-
sion where individuals experience depressive symptoms
and show hypersomnia only in the winter months. Whilst
polymorphisms in the clock genes Npas2 and Per2 have
been associated with SAD [57], recent work has impli-
cated polymorphisms in Opn4 (melanopsin, [58,59�]),which result in individuals varying their sleep onset
and chronotype as a function of day length. OPN4 is
the photopigment of the photosensitive retinal ganglion
cells (pRGCs), which directly signal light information to
the SCN as well as the ventrolateral preoptic nuclei
(VLPO) [60]. Given the success of bright-light therapy
with SAD and unipolar depression [61], this link to OPN4
and day length provides suggestive evidence that some
forms of depression might be linked directly to the photic
pathways that regulate sleep and circadian rhythms. A
further link between the SCRD and depression comes
from a recent study showing that aberrant light exposure
produces depression-like symptoms and impaired learn-
ing in wild-type mice, which could be corrected by
administration of antidepressants. However, mood and
learning were not affected in mice lacking pRGCs,
demonstrating the ability of light to regulate mood
directly [62�].
Future perspectivesIt is becoming increasingly clear that there are common
and overlapping pathways that link SCRD and neurop-
sychiatric illness (Figure 2). As neuropsychiatric disorders
ropsychiatric illness, Curr Opin Neurobiol (2013), http://dx.doi.org/10.1016/j.conb.2013.03.008
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SCRD in psychiatric illness Jagannath, Peirson and Foster 5
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involve defects in neurotransmission, and the regulation of
sleep is dependent on a broad range of neurotransmitter
systems, the involvement of common neurotransmitters
probably accounts for the primary comorbidity of these
disorders [1�]. However, although linked by overlapping
neural pathways, the SCRD and psychiatric phenotype will
be modulated by the cognitive, health, stress and devel-
opmental pathologies that arise from SCRD and the paral-
lel impact of the social isolation, medication and abnormal
stress responses that are associated with psychiatric illness.
Such destabilizing insults on normal physiology may give
rise to impaired CNS function arising from internal desyn-
chronisation of oscillators in different brain regions [63�].Abnormal stress responses have also been linked to SCRD,
as patients with schizophrenia are reported to show elev-
ated cortisol levels [64]. In addition, the role of sleep in
synaptic homeostasis may also be central to understanding
the relationship between healthy and abnormal cognitive
function [65]. Clearly, these mechanisms are not mutually
exclusive, and mechanistic explanations will be greatly
aided by gaining a more complete picture of the SCRD
and cognitive phenotypes of individuals with different
neuropsychiatric illnesses.
Whilst SCRD alone is unlikely to cause psychiatric illness
(see [63�]), in individuals with a high risk of mental illness
due to genetic and/or environmental factors, SCRD may
trigger or exacerbate symptoms. For example, disrupted
sleep and frequent travel across time zones can precipi-
tate manic episodes in predisposed subjects [66,67�]. If
SCRD does indeed precede the development of psychia-
tric symptoms, then SCRD may provide a valuable diag-
nostic marker for early intervention. By extension, the
stabilization of sleep and circadian rhythms in individuals
with psychiatric disorders would be predicted to have a
positive effect on the psychiatric symptoms. Indeed,
recent pilot data provide compelling evidence that that
the treatment of insomnia by using cognitive behavioural
therapy (CBT) improves persistent persecutory delusions
in patients with schizophrenia [68].
If such pilot data can be confirmed, then the stabilization
of sleep/circadian rhythms might provide a new and
powerful therapeutic target for the treatment of these
disorders by combining CBT and agents that regulate
sleep and circadian rhythms. In terms of drug targets,
there has been recent success in the development of small
molecule modulators of clock function using in vitro cell-
based screens. The targets of these drugs include Casein
Kinase 1-epsilon, GSK3B and PER1/2. Two recent stu-
dies have shown positive effects of such drugs in treating
metabolic disorders related to the clock. A small molecule
activator of CRYPTOCHROME was used to lengthen
circadian period with the effect of inhibiting glucagon-
induced gluconeogenesis in primary hepatocytes [69]. In
addition, synthetic REV-ERB agonists developed by Solt
et al. have been shown to treat obesity, dyslipidaemia and
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hyperglycaemia in diet-induced obese mice [70�]. More-
over, these drugs acutely altered circadian behaviour and
clock gene expression in the hypothalamus of treated
mice [70�]. Such molecules that act on the circadian
and sleep pathways may provide future alternative
approaches for the treatment of neuropsychiatric disease.
ConclusionsRecent research, from both human subjects and animal
models has provided strong links between disrupted
clock function, sleep regulation and neuropsychiatric
disease. Whilst we clearly need a better understanding
of the complex mechanisms underlying these associ-
ations, the stabilization of sleep and circadian rhythms
may provide a novel future approach for the treatment of
these devastating illnesses.
AcknowledgementsThis work was funded by a Wellcome Trust Strategic Award to RGF andSNP. AJ is funded by a Roche Postdoctoral Fellowship. The authors wouldalso like to thank our colleagues in the Oxford Sleep and CircadianNeuroscience Institute (SCNi) for many stimulating discussions which havegreatly contributed to the ideas contained herein. Finally, we would like tothank the Editors for their valuable feedback.
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