Sleep and circadian rhythm disruption in neuropsychiatric illness

CONEUR-1210; NO. OF PAGES 7

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

www.sciencedirect.com

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


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http://www.sciencedirect.com/science/journal/09594388

2 Circadian Rhythm and Sleep


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



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




SCRD in psychiatric illness Jagannath, Peirson and Foster 3


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


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.


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






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]).



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






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



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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Mouse developed as a model of mania showing a clock defect.

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Development of potent drugs to target circadian clock, showing an effectat the level of the SCN by altering SCN clock gene expression patterns.


















































































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Sleep and circadian rhythm disruption in neuropsychiatric illness