ª 2010 The Authors

Bipolar Disorders 2010: 12: 459–472 Journal compilation ª 2010 John Wiley & Sons A/S
BIPOLAR DISORDERS

Review Article

Circadian rhythms and sleep in bipolar

disorder
Murray G, Harvey A. Circadian rhythms and sleep in bipolar disorder. Greg Murraya and Allison Harveyb
Bipolar Disord 2010: 12: 459–472. ª 2010 The Authors. a
Faculty of Life and Social Sciences, Swinburne
Journal compilation ª 2010 John Wiley & Sons A ⁄ S. University of Technology, Hawthorn, Victoria,
Australia, bDepartment of Psychology,
Objective: Biological rhythm pathways are highlighted in a number of University of California, Berkeley, CA, USA
etiological models of bipolar disorder, and the management of circadian
instability appears in consensus treatment guidelines. There are,
however, significant conceptual and empirical limitations on our
understanding of a hypothesised link between circadian, sleep, and
emotion regulation processes in bipolar disorder. The aim of this article
is to articulate the limits of scientific knowledge in relation to this
hypothesis.

Methods: A critical evaluation of various literatures was undertaken.

The basic science of circadian and sleep processes, their involvement in doi: 10.1111/j.1399-5618.2010.00843.x
normal emotion regulation, and the types of evidence suggesting Key words: bipolar disorder – circadian – emotion
circadian ⁄ sleep involvement in bipolar disorder are reviewed. regulation – sleep

Results: Multiple lines of evidence suggest that circadian and sleep- Received 23 December 2009, revised and
wake processes are causally involved in bipolar disorder. These processes accepted for publication 25 May 2010
demonstrably interact with other neurobiological pathways known to be
important in bipolar disorder, but are unique in that they are open to Corresponding author:
behavioural manipulation. Greg Murray, Associate Professor
Faculty of Life and Social Sciences
Conclusion: Further research into biological rhythm pathways to Swinburne University of Technology
bipolar disorder is warranted. Person-environment feedback loops are Hawthorn, Victoria 3122, Australia
fundamental to circadian adaptation, and models of circadian Fax: + 61-3-9819-0574
pathogenesis (and treatment) should recognize this complexity. E-mail: gwm@swin.edu.au

critical role in the emotion dysregulation at the

Introduction and overview
Circadian rhythm hypotheses have been prominent
in the explanation of bipolar disorder (BD) for
more than 20 years (1, 2). Changes in sleep are part
of diagnostic criteria (3), and stabilising daily
rhythms is recognised as therapeutic in consensus
treatment guidelines (4, 5). Biological rhythmicity
is also a priority for patients, who report significant
concern about their sleep (6) and readily appreciate
the importance of rhythm stability (7).1 In short,
there is consensus that biological rhythms play a
1 and sleep moderation of emotion is reviewed,
The term biological rhythms is used to encompass both
circadian and sleep-wake processes.
Neither GM nor AH has any commercial associations that
might pose a conflict of interest in connection with this
manuscript.
heart of BD. Biological rhythm approaches are
compatible with other neurobiological explana-
tions of BD, and this article includes numerous
examples of overlap between circadian ⁄ sleep path-
ways and other targets of investigation.
The aim of this review article is to encourage
further research into these important pathways by
tracing the limits of scientific knowledge about
biological rhythms in BD. We first outline the
basics of circadian rhythms and sleep, highlighting
the challenge of empirically separating these two
factors. In the next section, literature on circadian
largely focusing on nonclinical populations. Evi-
dence for an association between biological
rhythms and BD is detailed next, and causal
inferences considered. The penultimate section
critically considers potential mechanisms of
459
Murray and Harvey
biological rhythm action in BD, particularly the
impact of clock genes and the putative role of rapid
eye movement (REM) sleep in emotion regulation.
Finally, we review clinical implications of the
fact that biological rhythmicity is modified by
behaviour.
Circadian rhythms and sleep
Circadian system
The endogenous circadian time-keeping system,
strongly conserved across species, is adapted to
optimise engagement with the earthÕs cyclic envi-
ronment by predicting critical environmental
change (8). In mammals, the circadian pacemaker
responsible for the temporal internal organisation
and generation of endogenous rhythms of approx-
imately 24 hours is located in the hypothalamic
suprachiasmatic nucleus (SCN) (9). At the molec-
ular level, intrinsically rhythmic cells of the SCN
generate self-sustained rhythmicity via an autoreg-
ulatory transcription-translation feedback loop
involving the genes: circadian locomotor output
cycles kaput (Clock), Bmal1 (also known as Arntl),
period homologue 1 (Per1), Per2, Cryptochrome 1
(Cry1), and Cry2 (10). The SCN output rhythm
arises from nonlinear dynamic interaction between
the cells in the SCN (11, 12).
The endogenous period generated in the SCN is
close to but generally not equal to 24 hours. The
process by which the pacemaker is both set to a
24-hour period and kept in appropriate phase with
seasonally shifting astronomical day length is
called entrainment. An important property of the
circadian system, therefore, is its fundamentally
open nature, and this open nature includes feed-
back to the pacemaker from clock-controlled
activity of the organism (13, 14). Entrainment
occurs via zeitgebers (environmental events that
can affect phase and period of the clock), the most
prominent of which is the daily alternation of light
SCN
Light
pacemaker
Fig. 1. Schematic representation of the circadian system. SCN = suprachiasmatic nucleus.
460
and dark due to the planetÕs rotation (15). To a
lesser degree, the SCN is also responsive to
nonphotic cues, including arousal ⁄ locomotor activ-
ity, social cues, feeding, sleep deprivation, and
temperature (16).
As shown in Figure 1, the circadian system is a
network including multiple feedback loops (14).
The peripheral clocks (extra-SCN oscillators in
many organs and tissues) that the SCN orches-
trates impact on the central clock. For example,
redox potentials within cells are affected by circa-
dian modulation of the mitochondrial oxidative
phosphorylation pathway, but redox potential in
turn affects the concentrations of oscillator com-
ponents (including Clock, Mop3 and NPAS2) and
thereby the rate of reactions in the SCN (17, 18).
The output rhythms themselves also affect the
clock. For example, one of the major functional
targets of SCN output is the pineal gland and its
release of melatonin. There is a processing loop
from the SCN to the pineal gland and back,
supporting a process whereby when melatonin is
synthesized (during the subjective night), it is
detected by receptors in the SCN (MT1 and
MT2), which moderate clock resetting at dusk
and dawn (19). The SCN also appears to modify its
own inputs (e.g., 20, 21). For example, lesion
studies in rats suggest that retinal circadian
rhythms in Per2 messenger RNA are dependent
on SCN functioning (22).
Functionally, the most important clock feedback
is behaviour itself. Behaviour influences the circa-
dian clock directly (arousal is a zeitgeber) (16), but
also indirectly via gating of light exposure. This is
demonstrated clinically in the use of light treatment
for seasonal affective disorder (23, 24) and the use
of social rhythm stabilization to moderate relapse
risk in BD (25, 26; see below). Given circadian
involvement in the sleep-wake cycle, evidence for
the effectiveness of cognitive-behavioural interven-
tions for insomnia also speaks to this important
feedback loop (27).
Output
Peripheral rhythms in
physiology
oscillators
and
behaviour

Sleep
Phylogenetically, sleep is a more recent and less
ubiquitous adaptation than circadian rhythmicity
(28). The specific adaptive function of sleep is
unknown, but sleep is widely believed to perform a
restorative function associated with the strength-
ening of immune function, somatic growth, and an
anabolic metabolic state (29). Evidence is also
accumulating for sleepÕs role in particular types of
cognition (30, 31), memory consolidation, and
brain plasticity (32–35).
Based on characteristic physiological patterns,
normal sleep can be divided into two distinct
states: REM and non-REM (NREM). During
REM (or paradoxical) sleep, the brain is highly
activated, the muscles of the body are paralyzed,
and dreaming occurs. In NREM, growth hormone
is preferentially secreted and protein synthesis is
increased, leading to the view that NREM may be
critical for energy conservation and restoration.
Characteristic electroencephalograph (EEG) pat-
terns support NREM sleep being further catego-
rized into substages: 1 (drowsiness, transition to
sleep, lowest arousal thresholds), 2 (light sleep),
and 3 and 4 (deep sleep, highest arousal thresh-
olds). Together, stages 3 and 4 are often called
delta or slow wave sleep (SWS) (36).
On a typical night, sleep of a young adult begins in
stage 1 NREM and progresses through deeper
NREM stages. The first episode of REM sleep
occurs approximately 80–100 min after sleep onset.
Thereafter, NREM sleep and REM sleep cycle with
a period of approximately 90 min. NREM stages 3
and 4 concentrate in the early cycles and REM sleep
episodes lengthen across the night. Therefore, in a
normal night of sleep, SWS predominates in the
early part of the sleep phase, while REM is more
prevalent later in the night. Indeed, we are most
likely to wake through the gate of REM sleep.
The relationship between circadian and sleep processes
The sleep-wake cycle is regulated by two proc-
esses, one of which is the clock-like circadian
system described above (typically called Process
C). The second factor is sleepÕs (hourglass-like)
homeostatic self-modulation [Process S (37)]. Proc-
ess S is accumulated during wakefulness, dissipates
during sleep, and regulates duration and structure
of sleep on the basis of the history of sleep and
wakefulness. The bidirectional interaction between
Processes C and S predicts the propensity, timing,
and internal structure of sleep (38–40).
For what follows, it is important to note that
protocols for investigating the interaction between
Circadian rhythms and sleep in BD
Processes C and S are unsuitable for people
diagnosed with BD. Under normal conditions,
Process C and Process S operate in synchrony (41),
and in the field we can only observe the sleep-wake
cycle, which is a complex endpoint of volition,
SCN output, and the sleep homeostat (Fig. 2).
Most of what we know about separate circadian
and sleep processes, therefore, comes from labora-
tory studies. In the forced desynchrony (FD)
protocol, a non-24-hour sleep-wake schedule (typ-
ically 28 hours) is enforced. Under these condi-
tions, the circadian oscillator continues to cycle at
approximately 24 hours and desynchronises from
the sleep-wake cycle which adopts the enforced
28-hour period, thereby enabling separate estimate
of circadian and sleep-homeostatic components
(42). The sleep disruption and isolation of the
multiday FD protocol make it unsuitable for
individuals vulnerable to emotion dysregulation,
and therefore fundamental questions about Process
C and S involvement in BD cannot be directly
tested.
The neurobiology of the C · S interaction is not
fully understood. Arousal is mediated by neurons
of the ascending reticular activating system which
project to the thalamus and basal forebrain (43,
44). Research by Saper and others (45–47) suggests
that the mechanism by which arousal is curtailed to
produce sleep involves the ventrolateral preoptic
nucleus (VLPO), a group of neurons in the
hypothalamus which, via release of galanin and
GABA, inhibits activity of the locus coeruleus,
raphe nucleus, and the tuberomammillary nucleus.
Mutual inhibition between arousal circuits and the
VLPO ensures extended periods of wake undis-
turbed by sleep and vice versa. Stability in sleep or
wake, and rapid switching between the two states,
is achieved by a putative bistable switch (45). This
Social time
and volition
Sleep-wake cycle
SCN Sleep
pacemaker homeostat
Fig. 2. Interaction between circadian and sleep homeostatic
mechanisms in modulating the 24-hour rhythm of activity.
SCN = suprachiasmatic nucleus.
461
Murray and Harvey
switch is modulated by a circadian alerting signal
deriving from the SCN, and, on the other side of
the switch, the homeostatic sleep drive. The neural
mechanisms of the sleep homeostat are unknown,
but there is growing evidence that the wake-linked
accumulation of the endogenous neuromodulator
adenosine may be involved (48, 49).
Sleep, circadian function, and affect
As in the study of other psychiatric disorders, it is
not uncommon to conceptualize BD as the extreme
clinical manifestation of a neurobehavioral trait
that is distributed throughout the population. Spe-
cifically, BD can be characterised as a pathologically
elevated propensity to emotional dysregulation (50–
52). Before reviewing the known associations
between biological rhythms and BD, it is therefore
useful to review findings linking biological rhythms
to emotion regulation in normal populations.
Circadian interactions with emotion
The circadian system modulates current mood
state, particularly positive affect (53–56), and
challenges to the circadian system, such as shift
work and jet lag, have negative consequences for
mood (57–59). Under naturalistic conditions, emo-
tional state also moderates circadian function via
its influence on social rhythms, light exposure,
arousal, and sleep (16, 60). Bidirectional influence
can also be traced at the neurobiologic level:
afferents from the SCN project via the paraven-
tricular thalamic nucleus to the mesolimbic dopa-
minergic reward system (61), while emotion circuits
impact circadian (and homeostatic) aspects of sleep
regulation (62, 63).
Sleep disturbance and emotion regulation
Behavioural data support the popular assumption
that sleep disturbance strongly increases negative
mood, irritability, and affective volatility (e.g., 64–
69). Sleep loss has been shown not only to increase
negative emotional response to goal-thwarting
events, but also to decrease positive emotional
responses to goal-enhancing events (70). High
levels of emotional arousal can, in turn, disturb
sleep, raising the possibility of a vicious cycle
between sleep disturbance and emotion dysregula-
tion (71). At the neural-systems level, sleep
deprivation has been linked to decreased medial-
prefrontal cortical activity and increased amygdala
activation, a distribution of activation consistent
with impaired top-down regulation of emotional
responses (72).
462
Particular importance of REM sleep in emotion regulation
The sleep state most strongly regulated by the
SCN, REM sleep, may be particularly important in
emotional processing and emotion regulation. Key
findings include correlations between presleep
mood and REM parameters, prospective associa-
tions between dream content and psychological
outcomes, and REM-facilitated recall of emotional
information (73, 74). There is also converging
evidence concerning the role of REM in emotional
processing (75–79).
The neurobiology of dreaming is an area of
growing interdisciplinary interest. Stickgold and
colleagues (33, 80) proposed that dreaming is the
conscious awareness of critical ÔofflineÕ cortical
generation functions occurring during sleep. In
this model, dreaming is distinguished by the
activation of neural networks supporting weak
cortical associations in the absence of dorsolateral
prefrontal cortex or hippocampal feedback, but in
the presence of active error detection circuits (in
the anterior cingulate cortex) and affective evalu-
ation of errors by the amygdala and orbitofrontal
cortex (81, 82). Potential implications of REM
neurobiology for emotion regulation in BD are
considered below in the subsection ÔSleep-specific
mechanismsÕ.
Neurotransmitters and the sleep · circadian · emotion
interaction
At least two neurotransmitter circuits are critical
in the link between biological rhythms and
emotion. First, dopaminergic pathways, especially
cells of the ventral tegmental area (VTA) and
zona compacta of the substantia nigra (SNc), are
strongly implicated in reward motivation and
positive affects (83–85). Dopamine has been
called a key substance in the regulation of
sleep-wake (86), and dopaminergic neurons of
the VTA and SNc are again implicated (87),
particularly in REM sleep (88). Dopaminergic
pathways also have multiple interactions with the
SCN (e.g., 55, 61, 89, 90). Second, serotonergic
pathways have pronounced (albeit complex)
relationships with anxiety and stress responses
(91). Serotonergic pathways are critical in circa-
dian function (92) [and vice versa (93)], sleep per
se (46, 94), and the interaction between stress and
sleep (67, 95–98).
From normal populations to patients with BD
The above review presents strong behavioural
evidence for the notion that emotion and emotion

regulation are associated with circadian function
and sleep. Neuroanatomical pathways subserving
these associations have been outlined, and the
interacting role of two critical neurotransmitters
(dopamine and serotonin) has been described. It
seems reasonable to propose that the same rela-
tionships hold in patients with BD, and indeed to
hypothesize that the symptoms of mood episodes
in BD may be attributable, at least in part, to the
pathways described here. It is particularly note-
worthy that an independent literature argues for
dopaminergic and serotonergic circuits as critical
pathways in BD (e.g., 99–102).
Until recently, there was little integration
between research into biological rhythm and
neurotransmitter approaches to psychopathology.
Early steps in this direction are captured in the
hypothetical model of Figure 3 [adapted from
Harvey et al. (102)], in which emotion regulation
and sleep disturbance are proposed as the overt
manifestation of interactions between dopaminer-
gic, serotonergic, and circadian ⁄ sleep biology.
It is worth noting three caveats on generalizing
from nonclinical to BD populations. First, the
multiplicity of BDÕs clinical manifestations is a
challenge to generalization. For example, the
sleep disturbance common in mania (decreased
need for sleep) contrasts with that in bipolar
depression (insomnia and hypersomnia) (103).
Second, much of what we know about sleep and
emotion regulation is based on sleep-deprivation
studies, while hypersomnia is a common symptom
of bipolar depression. Finally, some provocative
disjunctions need to be recognized: (i) in nonclin-
ical samples, sleep restriction may decrease
reward sensitivity (70), while mania appears to
involve positive feedback between sleep loss and
reward seeking (104); and (ii) in nonclinical
samples, REM sleep appears to support emotion
regulation (72, 105), while in mood disorder
samples, increased density and decreased latency
of REM are associated with pathology (106; see
below).
Neurobiology
DA function
Genetic Sleep/circadian
processes biology
5-HT function
Fig. 3. Emotion regulation and sleep disturbance as a final common pathway from neurobiological abnormality to bipolar disorder
[adapted with permission from Harvey et al. (102)]. DA = dopamine.
Circadian rhythms and sleep in BD
Sleep, circadian function, and mood symptoms in BD
A number of specific links have been demon-
strated between BD and circadian and ⁄ or sleep
function. Our aim here is to consider critically the
nature and implications of these known associa-
tions, and it is useful to group findings as shown in
Table 1.
The findings summarised in Table 1 indicate that
most phases of BD (depressed, manic, episode
prodrome, and interepisode periods) are cross-
sectionally associated with sleep and ⁄ or circadian
rhythm abnormalities. Clinical research shows that
disturbed sleep affects quality of life in BD (107,
108), and, as reviewed above, sleep disturbance is
detrimental to emotion regulation. Evidence that
BD is associated with sleep disturbance therefore
suggests that outcomes in BD can be improved by
addressing sleep difficulties across phases of the
disorder. Such interventions are briefly introduced
below in the section ÔPsychosocial interventions
targeting biological rhythms in BDÕ.
Beyond the immediate clinical implications of
poor sleep, a range of evidence also suggests that
biological rhythm disturbance is etiologically
involved in BD. Not only is there prospective data
linking sleep to mood in BD, but sleep changes
reliably precede episodes (especially mania) and
correlate with symptom load. Most strikingly,
manipulation of sleep (sleep deprivation) improves
bipolar depression and can induce hypoma-
nia ⁄ mania in some patients. This conclusion aligns
with current clinical practice, in which sleep
monitoring is a central relapse prevention strategy
(109).
The literature cited in Table 1 also provides
support for circadian dysfunction as a causal path-
way to BD. First, relapse can be precipitated by
zeitgeber challenge (particularly light manipula-
tion), and effective treatments for acute episodes
moderate circadian parameters. Second, a range of
data suggests that Ôcircadian instabilityÕ may act as
a traitlike vulnerability or diathesis to BD. For
Phenomenology Diagnosis
Sleep
disturbance
Bipolar
disorder
Emotion
dysregulation
463
Murray and Harvey

Table 1. Associations between bipolar disorder (BD) and biological rhythm function

Neurobiology shared between BD and biological rhythms

• Circadian and sleep function are subserved by the same brain regions (153) and neurotransmitters (e.g., 99, 100) are implicated in
mood disorder.
• Polymorphisms in circadian genes have been associated with symptoms of BD in preclinical and human studies (129, 147, 162, 181).

Biological rhythms as diatheses to BD

• Sleep disturbance and instability of 24-hour rhythms continue when BD patients are not acutely ill (6, 182–185).
• Dysregulation of 24-hour activity rhythms has been reported in a familial high-risk sample (186) and in individuals at risk of
hypomania (187).
• Neuroticism, the primary (albeit nonspecific) temperamental predisposition to BD, may be associated with circadian instability (119).
• Biological sensitivity to light, as measured in nighttime suppression of the pineal hormone melatonin, has been proposed as a trait
marker of vulnerability to BD (188).
• Delayed circadian phase of melatonin secretion has been reported in euthymic BD patients (189), and BD patients self-report as more
evening type (190).

Cross-sectional associations
• Some clinical features of BD are timed phenomena: diurnal variation in mood and early-morning wakening in depression, as well as
seasonal and other cyclic variation in symptoms, are suggestive of circadian involvement (142).
• Circadian rhythms (including activity, body temperature, melatonin, cortisol and thyrotropin) are altered in episodes of BD
(see 111, 191 for a review).
• Mania is strongly associated with decreased need for sleep, and insomnia and hypersomnia are both reliably found in bipolar
depression (see 103 for a review).
• Within BD, short sleep duration is associated with more severe symptomatology, while both short and long sleep duration are
associated with poorer function and quality of life (192).
• Episodes of BD have been associated with sleep polysomnographic changes (e.g., 193–195). The most consistent finding is
abnormalities of rapid eye movement (REM) sleep in both mania and bipolar depression [typically shorter latency and increased
density (see 103)].

Predictive relationships
• Episodes of BD can be precipitated by zeitgeber challenges, including seasonal change and time-zone travel (see 196 for a review).
• Sleep disturbance is the most common prodrome of mania and a significant prodromal symptom of bipolar depression (197). Altered
sleep often precedes deterioration in clinical state and worsens further during an episode (197–199).
• Prospective evidence of a complex association between sleep length and mood change in BD has been found in a number of studies
(198, 200–203).

Experimental and treatment effects

• Deliberate sleep deprivation is a same-day powerful treatment for bipolar (and unipolar) depression (203, 204). Maintenance of the
therapeutic effect beyond the next sleep phase is a target of current research (171).
• In a recent study, combined sleep deprivation, sleep phase advance and timed light was an effective adjunctive intervention for
bipolar depression (205).
• Bright light can induce symptoms of mania (171) and has significant effects on bipolar depression (206).
• Experimentally induced sleep deprivation induces hypomania or mania in a proportion of patients (199, 203).
• Bright light can induce symptoms of mania, and Ôdark therapyÕ has been found to stabilize patients with rapid-cycling BD (171, 207).
• Effective treatments for BD (lithium, antidepressants, anxioloytics, electroconvulsive therapy) affect circadian function (208–210).
• Lithium and selective serotonin reuptake inhibitors impact genes involved in circadian function (92, 132, 211, 212).
• Future course in BD is predicted by sleep disruption and REM density (106).
• Effective psychosocial treatments for BD decrease REM density (213, 214).
• Improved social rhythmicity decreases relapse in BD (26).

example, disruption of activity and sleep cycles are

found outside episodes and in children of BD
patients. Further evidence for a circadian diathesis
comes from a possible link between circadian
function and the general vulnerability trait neurot-
icism, and from preclinical and human studies
suggesting an association between specific clock
genes and BD (see below). This conclusion is also
consistent with existing approaches which empha-
size circadian instability as an element of patho-
genesis and a target for relapse prevention efforts
(e.g., 5, 110–113).
464
Mechanisms underpinning biological rhythm
involvement in BD
The mechanisms by which biological rhythms
affect the development, course, and treatment of
BD are not known. Early hypotheses emphasized
gross abnormalities in circadian function, includ-
ing short intrinsic period of the oscillator (114),
phase advance (115), phase delay (116), and
attenuated circadian amplitude (117–119). The
relation between Processes C and S has also been
implicated (120), and Process S itself has been

hypothesised to underpin the therapeutic effect
of sleep deprivation (121). Coupling to external
zeitgebers is critical in some models (26, 118, 122,
123). Physiological investigations of these broad
hypotheses have been scarce over the past decade
(2), and the methodological issues flagged above
are a barrier to progress. Promising foci of
contemporary research are circadian genes and
the role of REM sleep in emotional processing, as
discussed next.
Circadian genes
As research into broad circadian hypotheses has
waned, the study of the genetics of circadian
function in BD has expanded. Traditional candi-
date gene studies have found trends for an asso-
ciation between BD and the CLOCK gene (124,
125), but findings are inconsistent (126). A single
nucleotide polymorphism in the 3¢ flanking region
of CLOCK has also been associated with clinical
features of BD, namely, patterns of more activity
in the evening, delayed sleep onset and less sleep
(127), higher rates of initial, middle and early
insomnia (128), recurrence of illness episodes (128),
and changes in neural response (129).
Several studies show that the mood stabilizer
lithium affects circadian rhythms through the
glycogen synthase kinase 3 beta gene (GSK-3b),
which is a central regulator of the circadian clock
(130–132). Valproic acid may act via the same
intracellular signalling pathway (133, 134). Inves-
tigations of associations between BD, its clinical
features, and GSK-3b have not been consistent
(e.g., 135–137). Findings for an association with
NR1D1 gene (regulation of which by GSK-3b is
important for clock function) are also mixed (138,
139).
Other circadian genes for which some support
exists include PER3 (140, 141), ARNTL (141, 142)
and TIMELESS (142). In addition, Shi et al. (124)
reported an interaction between CLOCK and two
other genes of interest for their potential circadian
function (BHLHB2, CSNK1E). In one genome-
wide association study, the gene VGCNL1 (the
mouse homolog of which regulates circadian func-
tion) had a significant association with caseness
(143). Larger genome-wide studies have not iden-
tified circadian gene associations (144, 145).
Preclinical studies observing the effect of gene
mutations have been a fruitful source of hypoth-
eses. Mice with a mutation in the CLOCK gene
show robust sensitization to cocaine and increases
in the preference for cocaine (146, 147). These mice
also have increased dopaminergic activity in the
VTA which may be responsible for the increase in
Circadian rhythms and sleep in BD
the reward value of cocaine (146). Notably,
CLOCK mutant mice also show mania-like behav-
iour which is reversed by lithium treatment (147),
and this reversal is mediated by altered regulation
of dopamine release in the VTA (146).
Evidence for a BD-relevant pathway linking
circadian genes to the dopaminergic reward system
is consistent with the strong comorbidity between
BD and substance abuse (148), the association
between manic states and psychostimulant use
(149), and the action of atypical antipsychotic
medications for mania (134). A dopaminergic
reward · clock gene circuit has been reliably dem-
onstrated in nonhuman species (e.g., 150, 151) and
is strongly implicated in human mood regulation
(55, 152–156).
It is important to situate these clock gene
findings within the broader genetics of BD. Like
other psychiatric disorders, BD is probably inher-
ited polygenetically, with numerous genes adding
small effects to overall risk (143). Evidence from
human studies suggests that these genetic effects
are probabilistic, nonspecific, contingent on
gene · gene · environment interactions, and caus-
ally remote from the phenotype (157). Given small
genetic effects on risk, it is not surprising that
failure to replicate associations is common, and
that researchers have sought to refine the pheno-
type under investigation. In particular, endophe-
notypes [quantitative phenotypes intermediate
between the genotype and the disorder (158)], are
a major focus of contemporary study. Disturbance
of circadian function is commonly forwarded as a
candidate endophenotype for BD (e.g., 142, 159–
163).
Sleep-specific mechanisms
The potential importance of REM sleep in normal
emotion regulation was reviewed above. Recently,
this hypothesis has been extended to make predic-
tions about the role of REM in psychiatric
disorders, including BD (105, 164). Walker and
colleagues propose that the neurobiology of REM
sleep is critical in processing episodic emotional
memories, and describe three features of REM
neurobiology that together support this role. First,
emotional experiences of the preceding day are
reactivated by increased arousal in limbic and
paralimbic structures. Second, integration of the
emotional experiences with other aspects of seman-
tic memory are facilitated by dominant theta
oscillations in subcortical and cortical nodes.
Finally, REM occurs in the absence of noradren-
ergic arousal, suggesting a brain state that supports
emotional processing unencumbered by high
465
Murray and Harvey
anxiety. In parallel, the REM state is dominated by
cholinergic neurochemistry, providing an ideal
substrate for neocortical consolidation of memory
information. Taken together, REM sleep seems
adapted to progressively decouple emotions from
the memory of emotional experiences, potentially
improving next-day mood (164).
Under this model, the increased REM density
seen in unipolar and bipolar depression (106) has
two implications. First, it may represent a failed
attempt to depotentiate negative emotional expe-
riences across nights. Second, because emotional
memories are preferentially encoded during REM
sleep (34), increased REM density may patholog-
ically reinforce negative self-narratives, maintain-
ing negative moods postsleep (105). The
translational implications of this Ôsleep to forget,
sleep to rememberÕ model have not been teased out,
and there are some contradictory data (e.g., 165),
but the model raises the exciting possibility that
manipulating sleep architecture may therapeuti-
cally regulate the balance of emotion and memory
of past experiences. Important questions for future
research include comparisons of the REM-emotion
regulation association in healthy controls versus
patients across the phases of BD.
Psychosocial interventions targeting biological
rhythms in BD
Interactions between biology and psychosocial
factors cannot be ignored in a biological rhythm
approach to BD (166). The circadian system is
adapted to be open to external cues, and environ-
mental manipulations (particularly light exposure)
have predictable effects on amplitude and phase of
the endogenous oscillator (167, 168). Under natu-
ralistic conditions, human exposure to zeitgebers is
gated by behaviour, prominently the sleep-wake
cycle (Circadian rhythms and sleep). The sleep-wake
cycle is in turn moderated by volitional and social
factors, and mediated partly through cognitive
mechanisms (Sleep, circadian function, and affect).
Biological rhythms therefore function as an open-
loop system crossing multiple levels of persons and
their environment (21). Psychosocial factors are
integral to a biological rhythm explanation of BD,
a fact which underpins the recent development of
some novel adjunctive psychosocial interventions
for BD.
The social zeitgeber hypothesis proposes that
fundamental circadian instability in BD can be
moderated by increased stabilization of daily
rhythms and zeitgeber exposure [which could
include light itself (112)]. This hypothesis takes
clinical form in social rhythm therapy (169), which
466
is a largely behavioural psychotherapy aimed at
helping patients maintain stability in their social
rhythms and so reduce the risk of relapse. In the
treatment of BD, social rhythm therapy is typically
integrated with principles from interpersonal psy-
chotherapy in a treatment known as interpersonal
and social rhythm therapy (IPSRT) (169). IPSRT
has proven effective in two large studies (26, 170).
Interest in biological rhythm management is
expanding alongside growing research into adjunc-
tive psychosocial treatments for BD (112, 171–
173). Rhythm stabilization is a core component in
most adjunctive psychosocial treatments for BD
(113), including cognitive behavioural therapy.
Improving sleep quality is an important compo-
nent of rhythm stabilization, and has functional
benefits in its own right (102, 103). Interestingly,
management of the sleep-wake cycle is a commonly
reported well-being strategy amongst people with
BD (174). Our qualitative investigations suggest
that this strategy is appealing not only because it is
judged effective, but also because it is empowering
for patients to understand that a core element of
BD biology is partly under their control (175).
Particularly interesting are treatments for bipo-
lar depression [the most common and most resis-
tant manifestation of BD (176)] using
combinations of zeitgeber manipulation and phar-
macotherapy. For example, Benedetti and col-
leagues (177) have shown that progressive sleep
phase advance across three days can sustain the
antidepressant effects of total sleep deprivation,
and that the chronobiological mechanism is
enhanced by lithium.
Chronotherapeutic interventions are therefore
an important target for further study. Future
research into these interventions should seek to
identify moderators (e.g., light sensitivity, severity
and diagnosis, temperament, gender) and media-
tors (e.g., light-dark cycle exposure, sleep quality,
sleep architecture, circadian rhythmicity, daytime
arousal) of treatment outcome. Our knowledge of
possible interactions between behavioural and
pharmacological treatments is also limited (171).
Finally, the recent discovery that lightÕs neurobio-
logical effects are blue-shifted (178, 179) encour-
ages a more sophisticated investigation of light
treatment for BD. One aspect of this investigation
must be the potential toxicity of blue-enhanced
light (see 180).
Summary and conclusions
Four main themes can be drawn from the present
review. First, standard laboratory protocols for
separating sleep and circadian function are not

feasible in vulnerable populations, so the biologi-
cally important distinction between these processes
is difficult to investigate. Fundamental questions
can instead be addressed by careful extrapolation
from well populations, perhaps quantified by their
degree of risk for BD. Second, biological rhythm
pathways are interwoven with other pathways
implicated in BD (e.g., monoamines, GSK-3b),
and future research should actively address this
complexity. Third, the wide variety of evidence
demonstrating biological rhythm involvement in
BD is a rich source of hypotheses for future work
in this burgeoning area. Research in humans has
yet to discover mechanisms of large effect, but
preclinical studies suggest the reward · circadian
interaction may be particularly fruitful. Finally,
interventions built on chronobiological principles
should be energetically investigated. These inter-
ventions are theoretically plausible, benign, eco-
nomical, and attractive to patients.
In conclusion, research into sleep and circadian
function in BD is an exciting, challenging and
rewarding avenue for the future. It has the
potential to significantly broaden understanding
of a particularly serious mental illness and to
improve the quality of life and functioning of
patients.
References
1. Goodwin F, Jamison K. Manic-Depressive Illness. New
York: Oxford University Press, 1990.
2. Goodwin FK, Jamison KR. Manic-Depressive Illness:
Bipolar Disorders and Recurrent Depression. New York:
Oxford University Press, 2007.
3. American Psychiatric Association. Diagnostic and statis-
tical manual of mental disorders: DSM-IV-TR. 4th Text
Revision ed. Washington, DC: APA, 2000.
4. Goodwin GM. Evidence-based guidelines for treating
bipolar disorder: revised second edition. Recommenda-
tions from the British Association for Psychopharmacol-
ogy. J Psychopharmacol 2009; 23: 346–388.
5. Yatham LN, Kennedy SH, OÕDonovan C et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT)
guidelines for the management of patients with bipolar
disorder: update 2007. Bipolar Disord 2006; 8: 721–739.
6. Harvey AG, Schmidt DA, Scarna A, Semler CN, Good-
win GM. Sleep-related functioning in euthymic patients
with bipolar disorder, patients with insomnia, and sub-
jects without sleep problems. Am J Psychiatry 2005; 162:
50–57.
7. Suto M, Murray G, Hale S, Amari E, Michalak EE. What
works for people with bipolar disorder? Tips from the
experts. J Affect Disord 2010; 124: 76–84.
8. Moore-Ede MC. Physiology of the circadian timing
system: predictive versus reactive homeostasis. Am J
Physiol 1986; 250: R737–R752.
9. Reppert SM, Weaver DR. Coordination of circadian
timing in mammals. Nature 2002; 418: 935–941.
10. Takahashi JS, Hong H-K, Ko CH, McDearmon EL. The
genetics of mammalian circadian order and disorder:
Circadian rhythms and sleep in BD
implications for physiology and disease. Nat Rev Genet
2008; 9: 764–775.
11. Hu K, Scheer FA, Buijs RM, Shea SA. The endogenous
circadian pacemaker imparts a scale-invariant pattern of
heart rate fluctuations across time scales spanning minutes
to 24 hours. J Biol Rhythms 2008; 23: 265–273.
12. Liu AC, Welsh DK, Ko CH et al. Intercellular coupling
confers robustness against mutations in the SCN circa-
dian clock network. Cell 2007; 129: 605–616.
13. Mrosovsky N. Critical assessment of methods and con-
cepts in nonphotic phase shifting. Biol Rhythms Res 1999;
30: 135–148.
14. Bechtel W. The downs and ups of mechanistic research:
circadian rhythm research as an exemplar. Erkenntnis, in
press.
15. Roennebert T, Foster RG. Twilight times: light and the
circadian system. Photochem Photobiol 1997; 66: 549–
561.
16. Mistlberger RE, Antle MC, Glass JD, Miller JD. Behav-
ioral and serotonergic regulation of circadian rhythms.
Biol Rhythms Res 2000; 31: 240–283.
17. Rutter J, Reick M, Wu LC, McKnight SL. Regulation of
clock and NPAS2 DNA binding by the redox state of
NAD cofactors. Science 2001; 293: 510–514.
18. Panda S, Hogenesch JB. ItÕs all in the timing: many
clocks, many outputs. J Biol Rhythms 2004; 19: 374–
387.
19. Hunt AE, Al-Ghoul WM, Gillette MU, Dubocovich ML.
Activation of MT(2) melatonin receptors in rat suprach-
iasmatic nucleus phase advances the circadian clock. Am J
Physiol Cell Physiol 2001; 280: C110–C118.
20. Roenneberg T, Merrow M. The network of time: under-
standing the molecular circadian system. Curr Biol 2003;
13: R198–R207.
21. Bechtel W, Abrahamsen A. Decomposing, recomposing,
and situating circadian mechanisms: three tasks in devel-
oping mechanistic explanations. In: Leitgeb H, Hieke A
eds. Reduction and Elimination in Philosophy of Mind
and Philosophy of Neuroscience. Frankfurt: Ontos Ver-
lag, 2009: 173–186.
22. Sakamoto K, Oishi K, Shiraishi M et al. Two circadian
oscillatory mechanisms in the mammalian retina. Neuro-
report 2000; 11: 3995–3997.
23. Murray G, Michalak EE, Levitt AJ et al. O sweet spot
where art thou? Light treatment of Seasonal Affective
Disorder and the circadian time of sleep. J Affect Disord
2006; 90: 227–231.
24. Murray G, Michalak EE, Levitt AJ et al. Therapeutic
mechanism in Seasonal Affective Disorder: do fluoxetine
and light operate through advancing circadian phase?
Chronobiol Int 2005; 22: 937–943.
25. Frank E, Swartz HA, Boland E. Interpersonal and social
rhythm therapy: an intervention addressing rhythm dys-
regulation in bipolar disorder. Dialogues Clin Neurosci
2007; 9: 325–332.
26. Frank E, Kupfer DJ, Thase ME et al. Two-year outcomes
for interpersonal and social rhythm therapy in individuals
with bipolar I disorder. Arch Gen Psychiatry 2005; 62:
996–1004.
27. Murray G, Harvey A. Circadian rhythms and sleep in
bipolar disorder. In: Yatham LN, Maj M eds. Bipolar
Disorder: Clinical and Neurobiological Foundations.
New York: John Wiley & Sons, in press.
28. Rial RV, Nicolau MC, Gamundi A et al. The trivial
function of sleep. Sleep Med Rev 2007; 11: 311–325.
29. Maquet P. Sleep function(s) and cerebral metabolism.
Behav Brain Res 1995; 69: 75–83.
467
Murray and Harvey
30. Durmer JS, Dinges DF. Neurocognitive consequences of
sleep deprivation. Semin Neurol 2005; 25: 117–129.
31. Wagner U, Gais S, Haider H, Verleger R, Born J. Sleep
inspires insight. Nature 2004; 427: 352–355.
32. Stickgold R, Walker MP. Sleep-dependent memory con-
solidation and reconsolidation. Sleep Med 2007; 8: 331–
343.
33. Stickgold R. Sleep-dependent memory consolidation.
Nature 2005; 437: 1272–1278.
34. Hu P, Stylos-Allan M, Walker MP. Sleep facilitates
consolidation of emotional declarative memory. Psychol
Sci 2006; 17: 891–898.
35. Frank MG, Benington JH. The role of sleep in memory
consolidation and brain plasticity: dream or reality?
Neuroscientist 2006; 12: 477–488.
36. Shneerson JM. Handbook of Sleep Medicine. Oxford:
Blackwell, 2000.
37. Borbely AA. Sleep: circadian rhythm versus recovery
process. In: Koukkou M, Lehmann D, Angst J eds.
Functional States of the Brain: Their Determinants.
Amsterdam: Elsevier, 1980: 151–161.
38. Dijk D-J, Franken P. Interaction of sleep homeostasis and
circadian rhythmicity: dependent or independent systems?
In: Kryger MH, Roth T, Dement WC eds. Principles and
Practice of Sleep Medicine. Philadelphia: Saunders, 2005:
418–434.
39. Borbely AA. A two process model of sleep regulation.
Human Neurobiol 1982; 1: 195–204.
40. Edgar DM, Dement WC, Fuller CA. Effect of SCN
lesions on sleep in squirrel monkeys: evidence for oppo-
nent processes in sleep-wake regulation. J Neurosci 1993;
13: 1065–1079.
41. Czeisler CA, Buxton OM, Khalsa SBS. The human
circadian timing system and sleep-wake regulation. In:
Kryger MH, Roth T, Dement WC eds. Principles and
Practice of Sleep Medicine, 4th ed. Philadelphia: Elsevier,
2005: 375–394.
42. Czeisler CA, Duffy JF, Shanahan TL et al. Stability,
precision, and near-24-hour period of the human circa-
dian pacemaker. Science 1999; 284: 2177–2181.
43. Coull JT, Jones ME, Egan TD, Frith CD, Maze M.
Attentional effects of noradrenaline vary with arousal
level: selective activation of thalamic pulvinar in humans.
Neuroimage 2004; 22: 315–322.
44. Aston-Jones G, Chen S, Zhu Y, Oshinsky ML. A neural
circuit for circadian regulation of arousal. Nat Neurosci
2001; 4: 732–738.
45. Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-
wake cycle: sleep architecture, circadian regulation, and
regulatory feedback. J Biol Rhythms 2006; 21: 482–493.
46. Saper CB, Scammell TE, Lu J. Hypothalamic regulation
of sleep and circadian rhythms. Nature 2005; 437: 1257–
1263.
47. Gooley JJ, Saper CB. Anatomy of the mammalian
circadian system. In: Kryger MH, Roth T, Dement WC
eds. Principles and Practice of Sleep Medicine, 4th ed.
Philadelphia: Elsevier, 2005: 335–350.
48. Landolt HP. Sleep homeostasis: a role for adenosine in
humans? Biochem Pharmacol 2008; 75: 2070–2079.
49. Heller HC. A global rather than local role for adenosine
in sleep homeostasis. Sleep 2006; 29: 1382–1383.
50. Miklowitz DJ, Johnson SL. The psychopathology and
treatment of bipolar disorder. Ann Rev Clin Psychol
2006; 2: 199–235.
51. Phillips ML. The neural basis of mood dysregulation in
bipolar disorder. Cogn Neuropsychiatry 2006; 11: 233–
249.
468
52. Murray G, Goldstone E, Cunningham E. Personality and
the predisposition(s) to bipolar disorder: heuristic benefits
of a two-dimensional model. Bipolar Disord 2007; 9: 453–
461.
53. Murray G, Allen NB, Trinder J. Mood and the circadian
system: investigation of a circadian component in positive
affect. Chronobiol Int 2002; 19: 1151–1169.
54. Thayer RE. Problem perception, optimism, and related
states as a function of time of day (diurnal rhythm) and
moderate exercise: two arousal systems in interaction.
Motiv Emot 1987; 11: 19–36.
55. Murray G, Nicholas CL, Kleiman J et al. NatureÕs clocks
and human mood: the circadian system modulates reward
motivation. Emotion 2009; 9: 705–716.
56. Boivin DB, Czeisler CA, Dijk D-J et al. Complex inter-
action of the sleep-wake cycle and circadian phase
modulates mood in healthy subjects. Arch Gen Psychiatry
1997; 54: 145–152.
57. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I,
Cardinali DP. Jet lag: therapeutic use of melatonin and
possible application of melatonin analogs. Travel Med
Infect Dis 2008; 6: 17–28.
58. Reinberg A, Ashkenazi I. Internal desynchronization of
circadian rhythms and tolerance to shift work. Chrono-
biol Int 2008; 25: 625–643.
59. Meyrer R, Demling J, Kornhuber J, Nowak M. Effects of
night shifts in bipolar disorders and extreme morningness.
Bipolar Disord 2009; 11: 897–899.
60. Ehlers CL, Frank E, Kupfer DJ. Social zeitgebers and
biological rhythms. Arch Gen Psychiatry 1988; 45: 948–
952.
61. Sleipness EP, Sorg BA, Jansen HT. Diurnal differences in
dopamine transporter and tyrosine hydroxylase levels in
rat brain: dependence on the suprachiasmatic nucleus.
Brain Res 2007; 1129: 34–42.
62. Yoshida K, McCormack S, Espana RA, Crocker A,
Scammell TE. Afferents to the orexin neurons of the rat
brain. J Comp Neurol 2006; 494: 845–861.
63. Saper CB, Cano G, Scammell TE. Homeostatic, circa-
dian, and emotional regulation of sleep. J Comp Neurol
2005; 493: 92–98.
64. Dinges DF, Pack F, Williams K et al. Cumulative
sleepiness, mood disturbance, and psychomotor vigilance
performance decrements during a week of sleep restricted
to 4–5 hours per night. Sleep 1997; 20: 267–277.
65. Drake CL, Roehrs TA, Burduvali E, Bonahoom A,
Rosekind M, Roth T. Effects of rapid versus slow
accumulation of eight hours of sleep loss. Psychophysiol-
ogy 2001; 38: 979–987.
66. Hamilton NA, Catley D, Karlson C. Sleep and the
affective response to stress and pain. Health Psychol 2007;
26: 288–295.
67. Novati A, Roman V, Cetin T et al. Chronically restricted
sleep leads to depression-like changes in neurotransmitter
receptor sensitivity and neuroendocrine stress reactivity in
rats. Sleep 2008; 31: 1579–1585.
68. Franzen PL, Siegle GJ, Buysse DJ. Relationships between
affect, vigilance, and sleepiness following sleep depriva-
tion. J Sleep Res 2008; 17: 34–41.
69. El-Sheikh M, Buckhalt JA, Mark Cummings E, Keller P.
Sleep disruptions and emotional insecurity are pathways
of risk for children. J Child Psychol Psychiatry 2007; 48:
88–96.
70. Zohar D, Tzischinsky O, Epstein R, Lavie P. The effects
of sleep loss on medical residentsÕ emotional reactions
to work events: a cognitive-energy model. Sleep 2005; 28:
47–54.

71. Dahl RE, Lewin DS. Pathways to adolescent health sleep
regulation and behavior. J Adolesc Health 2002; 31: 175–
184.
72. Yoo SS, Gujar N, Hu P, Jolesz FA, Walker MP. The
human emotional brain without sleep–a prefrontal amyg-
dala disconnect. Curr Biol 2007; 17: R877–R878.
73. Harvey AG, Mullin BC, Hinshaw SP. Sleep and circadian
rhythms in children and adolescents with bipolar disorder.
Dev Psychopathol 2006; 18: 1147–1168.
74. Cartwright R, Agargun MY, Kirkby J, Friedman JK.
Relation of dreams to waking concerns. Psychiatry Res
2006; 141: 261–270.
75. Nishida M, Pearsall J, Buckner RL, Walker MP. REM
Sleep, Prefrontal theta, and the consolidation of human
emotional memory. Cereb Cortex 2009; 19: 1158–1166.
76. Wagner U, Born J. Memory consolidation during sleep:
interactive effects of sleep stages and HPA regulation.
Stress 2008; 11: 28–41.
77. Cantero JL, Atienza M, Stickgold R, Kahana MJ,
Madsen JR, Kocsis B. Sleep-dependent theta oscillations
in the human hippocampus and neocortex. J Neurosci
2003; 23: 10897–10903.
78. Maquet P, Ruby P, Maudoux A et al. Human cognition
during REM sleep and the activity profile within frontal
and parietal cortices: a reappraisal of functional neuro-
imaging data. Prog Brain Res 2005; 150: 219–227.
79. Maquet P, Péters J-M, Aerts J et al. Functional neuro-
anatomy of human rapid-eye-movement sleep and dream-
ing. Nature 1996; 383: 163–166.
80. Stickgold R, Hobson JA, Fosse R, Fosse M. Sleep,
learning, and dreams: off-line memory reprocessing.
Science 2001; 294: 1052–1057.
81. Stickgold R. Why we dream. In: Kryger MH, Roth T,
Dement WC eds. Principles and Practice of Sleep Med-
icine. Philadelphia: Elsevier, 2005: 579–587.
82. Hobson JA, Pace-Schott EF, Stickgold R. Dreaming and
the brain: toward a cognitive neuroscience of conscious
states. Behav Brain Sci 2000; 23: 793–842.
83. Ashby FG, Isen AM, Turken AU. A neuropsychological
theory of positive affect and its influence on cognition.
Psychol Rev 1999; 106: 529–550.
84. Barbano MF, Cador M. Opioids for hedonic experience
and dopamine to get ready for it. Psychopharmacology
2007; 191: 497–506.
85. Bressan RA, Crippa JA. The role of dopamine in
reward and pleasure behaviour–review of data from
preclinical research. Acta Psychiatr Scand Suppl 2005;
111: 14–21.
86. Lima MM, Andersen ML, Reksidler AB et al. Blockage
of dopaminergic D(2) receptors produces decrease of
REM but not of slow wave sleep in rats after REM sleep
deprivation. Behav Brain Res 2008; 188: 406–411.
87. Monti JM, Monti D. The involvement of dopamine in the
modulation of sleep and waking. Sleep Med Rev 2007; 11:
113–133.
88. Dahan L, Astier B, Vautrelle N, Urbain N, Kocsis B,
Chouvet G. Prominent burst firing of dopaminergic
neurons in the ventral tegmental area during paradoxical
sleep. Neuropsychopharmacology 2007; 32: 1232–1241.
89. Yuferov V, Butelman ER, Kreek MJ. Biological clock:
biological clocks may modulate drug addiction. Eur J
Hum Genet 2005; 13: 1101–1103.
90. Yujnovsky I, Hirayama J, Doi M, Borrelli E, Sassone-
Corsi P. Signaling mediated by the dopamine D2
receptor potentiates circadian regulation by CLOCK:
BMAL1. Proc Natl Acad Sci USA 2006; 103: 6386–
6391.
Circadian rhythms and sleep in BD
91. Charney DS. Psychobiological mechanisms of resilience
and vulnerability: implications for successful adaptation
to extreme stress. Am J Psychiatry 2004; 161: 195–216.
92. Sprouse J, Braselton J, Reynolds L. Fluoxetine modulates
the circadian biological clock via phase advances of
suprachiasmatic nucleus neuronal firing. Biol Psychiatry
2006; 60: 896–899.
93. Yuan Q, Lin F, Zheng X, Sehgal A. Serotonin modulates
circadian entrainment in Drosophila. Neuron 2005; 47:
115–127.
94. Adrien J. Neurobiological bases for the relation between
sleep and depression. Sleep Med Rev 2002; 6: 341–351.
95. Brummett BH, Krystal AD, Ashley-Koch A et al. Sleep
quality varies as a function of 5-HTTLPR genotype and
stress. Psychosom Med 2007; 69: 621–624.
96. Machado RB, Tufik S, Suchecki D. Chronic stress during
paradoxical sleep deprivation increases paradoxical sleep
rebound: association with prolactin plasma levels and
brain serotonin content. Psychoneuroendocrinology 2008;
33: 1211–1224.
97. Meerlo P, Sgoifo A, Suchecki D. Restricted and disrupted
sleep: effects on autonomic function, neuroendocrine
stress systems and stress responsivity. Sleep Med Rev
2008; 12: 197–210.
98. Roman V, Walstra I, Luiten PG, Meerlo P. Too little
sleep gradually desensitizes the serotonin 1A receptor
system. Sleep 2005; 28: 1505–1510.
99. Berk M, Dodd S, Kauer-SantÕanna M et al. Dopamine
dysregulation syndrome: implications for a dopamine
hypothesis of bipolar disorder. Acta Psychiatr Scand
Suppl 2007; 116: 41–49.
100. Oquendo MA, Hastings RS, Huang YY et al. Brain
serotonin transporter binding in depressed patients with
bipolar disorder using positron emission tomography.
Arch Gen Psychiatry 2007; 64: 201–208.
101. Cousins DA, Butts K, Young AH. The role of dopamine
in bipolar disorder. Bipolar Disord 2009; 11: 787–806.
102. Harvey A, Murray G, Chandler RA, Soehner A. Sleep
disturbance as transdiagnostic: consideration of neurobi-
ological mechanisms. Clin Psychol Rev 2010; doi:
10.10161j.cpr.2010.04.003.
103. Harvey AG. Sleep and circadian rhythms in bipolar
disorder: seeking synchrony, harmony, and regulation.
Am J Psychiatry 2008; 165: 820–829.
104. Johnson SL. Mania and dysregulation in goal pursuit: a
review. Clin Psychol Rev 2005; 25: 241–262.
105. Walker MP. The role of sleep in cognition and emotion.
Ann NY Acad Sci 2009; 1156: 168–197.
106. Krystal AD, Thakur M, Roth T. Sleep disturbance in
psychiatric disorders: effects on function and quality of
life in mood disorders, alcoholism, and schizophrenia.
Ann Clin Psychiatry 2008; 20: 39–46.
107. Giglio LM, Andreazza AC, Andersen M et al. Sleep in
bipolar patients. Sleep Breath 2009; 13: 169–173.
108. Michalak EE, Murray G, Young AH, Lam RW. Quality
of life impairment in bipolar disorder. In: Ritsner M,
Awad AG eds. Quality of Life Impairment in Schizo-
phrenia, Mood and Anxiety Disorders: From Brain
Functions to Clinical Practice. New York: Springer,
2007: 253–274.
109. Horn M, Scharer L, Walser S, Scherer-Klabunde D,
Biedermann C, Walden J. Comparison of long-term
monitoring methods for bipolar affective disorder. Neu-
ropsychobiology 2002; 45 (Suppl. 1): 27–32.
110. Frank E, Gonzalez JM, Fagiolini A. The importance of
routine for preventing recurrence in bipolar disorder. Am
J Psychiatry 2006; 163: 981–985.
469
Murray and Harvey
111. Jones SH. Circadian rhythms, multilevel models of
emotion and bipolar disorder: an initial step towards
integration? Clin Psychol Rev 2001; 21: 1193–1209.
112. Grandin LD, Alloy LB, Abramson LY. The social
zeitgeber theory, circadian rhythms, and mood disorders:
review and evaluation. Clin Psychol Rev 2006; 26: 679–
694.
113. Miklowitz DJ, Goodwin GM, Bauer MS, Geddes JR.
Common and specific elements of psychosocial treatments
for bipolar disorder: a survey of clinicians participating in
randomized trials. J Psychiatr Pract 2008; 14: 77–85.
114. Kripke DF, Mullaney DJ, Atkinson M, Wolf S. Circadian
rhythm disorders in manic-depressives. Biol Psychiatry
1978; 13: 335–351.
115. Wehr TA, Wirz-Justice A, Goodwin FK. Phase advance
of the circadian sleep-wake cycle as an antidepressant.
Science 1979; 206: 710–713.
116. Lewy AJ, Sack RL, Singer CM, White DM, Hoban TM.
Winter depression and the phase-shift hypothesis for
bright lightÕs therapeutic effects: history theory and
experimental evidence. In: Rosenthal NE, Blehar MC
eds. Seasonal Affective Disorders and Phototherapy. New
York: Guilford Press, 1989: 295–310.
117. Czeisler CA, Kronauer RE, Mooney JJ, Anderson JL,
Allan JS. Biologic rhythm disorders, depression and
phototherapy: a new hypothesis. Psychiatr Clin North
Am 1987; 10: 687–709.
118. Teicher MH, Glod CA, Harper D et al. Locomotor
activity in depressed children and adolescents, I: Circa-
dian dysregulation. J Am Acad Child Adolesc Psychiatry
1993; 32: 760–769.
119. Murray G, Allen NB, Trinder J, Burgess H. Is weakened
circadian rhythmicity a characteristic of neuroticism?
J Affect Disord 2002; 72: 281–289.
120. Boivin DB. Influence of sleep-wake and circadian rhythm
disturbances in psychiatric disorders. J Psychiatry Neu-
rosci 2000; 25: 446–459.
121. Wirz-Justice A. Biological rhythm disturbances in mood
disorders. Int Clin Psychopharmacol 2006; 21 (Suppl. 1):
S11–S15.
122. Ehlers CL, Kupfer DJ, Frank E, Monk TH. Biological
rhythms and depression: the role of zeitgebers and
zeitstorers. Depression 1993; 1: 285–293.
123. Healy D, Waterhouse JM. The circadian system and
affective disorders: clocks or rhythms? Chronobiol Int
1990; 7: 5–10.
124. Shi J, Wittke-Thompson JK, Badner JA et al. Clock genes
may influence bipolar disorder susceptibility and dysfunc-
tional circadian rhythm. Am J Med Genet B Neuropsy-
chiatr Genet 2008; 147B: 1047–1055.
125. Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe
JR. Circadian polymorphisms associated with affective
disorders. J Circadian Rhythms 2009; 7: 2.
126. Kishi T, Kitajima T, Ikeda M et al. Association study of
clock gene (CLOCK) and schizophrenia and mood
disorders in the Japanese population. Eur Arch Psychiatry
Clin Neurosci 2009; 259: 293–297.
127. Benedetti F, Dallaspezia S, Fulgosi MC et al. Actimetric
evidence that CLOCK 3111 T ⁄ C SNP influences sleep
and activity patterns in patients affected by bipolar
depression. Am J Med Genet B Neuropsychiatr Genet
2007; 144B: 631–635.
128. Benedetti F, Serretti A, Colombo C et al. Influence of
CLOCK gene polymorphism on circadian mood fluctua-
tion and illness recurrence in bipolar depression. Am J
Med Genet B Neuropsychiatr Genet 2003; 123B: 23–26.
470
129. Benedetti F, Radaelli D, Bernasconi A et al. Clock genes
beyond the clock: CLOCK genotype biases neural corre-
lates of moral valence decision in depressed patients.
Genes Brain Behav 2008; 7: 20–25.
130. Beaulieu JM, Sotnikova TD, Yao WD et al. Lithium
antagonizes dopamine-dependent behaviors mediated by
an AKT ⁄ glycogen synthase kinase 3 signaling cascade.
Proc Natl Acad Sci USA 2004; 101: 5099–5104.
131. Gould TD, Manji HK. Glycogen synthase kinase-3: a
putative molecular target for lithium mimetic drugs.
Neuropsychopharmacology 2005; 30: 1223–1237.
132. Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor
Rev-ERB alpha is a critical lithium-sensitive component
of the circadian clock. Science 2006; 311: 1002–1005.
133. Li X, Bijur GN, Jope RS. Glycogen synthase kinase-
3beta, mood stabilizers, and neuroprotection. Bipolar
Disord 2002; 4: 137–144.
134. Coyle JT. What can a clock mutation in mice tell us about
bipolar disorder? Proc Natl Acad Sci USA 2007; 104:
6097–6098.
135. Yang S, Van Dongen HP, Wang K, Berrettini W, Bucan
M. Assessment of circadian function in fibroblasts of
patients with bipolar disorder. Mol Psychiatry 2009; 14:
143–155.
136. Benedetti F, Bernasconi A, Lorenzi C et al. A single
nucleotide polymorphism in glycogen synthase kinase
3-beta promoter gene influences onset of illness in patients
affected by bipolar disorder. Neurosci Lett 2004; 355:
37–40.
137. Benedetti F, Serretti A, Colombo C, Lorenzi C, Tubazio
V, Smeraldi E. A glycogen synthase kinase 3-beta
promoter gene single nucleotide polymorphism is associ-
ated with age at onset and response to total sleep
deprivation in bipolar depression. Neurosci Lett 2004;
368: 123–126.
138. Severino G, Manchia M, Contu P et al. Association study
in a Sardinian sample between bipolar disorder and the
nuclear receptor REV-ERB alpha gene, a critical compo-
nent of the circadian clock system. Bipolar Disord 2009;
11: 215–220.
139. Kishi T, Kitajima T, Ikeda M et al. Association analysis
of nuclear receptor Rev-erb alpha gene (NR1D1) with
mood disorders in the Japanese population. Neurosci Res
2008; 62: 211–215.
140. Artioli P, Lorenzi C, Pirovano A et al. How do genes
exert their role? Period 3 gene variants and possible
influences on mood disorder phenotypes. Eur Neuropsy-
chopharmacol 2007; 17: 587–594.
141. Nievergelt CM, Kripke DF, Barrett TB et al. Suggestive
evidence for association of the circadian genes PERIOD3
and ARNTL with bipolar disorder. Am J Med Genet B
Neuropsychiatr Genet 2006; 141B: 234–241.
142. Mansour HA, Monk TH, Nimgaonkar VL. Circadian
genes and bipolar disorder. Ann Med 2005; 37: 196–205.
143. Baum AE, Akula N, Cabanero M et al. A genome-wide
association study implicates diacylglycerol kinase eta
(DGKH) and several other genes in the etiology of
bipolar disorder. Mol Psychiatry 2008; 13: 197–207.
144. Consortium WTCC. Genome-wide association study of
14,000 cases of seven common diseases and 3,000 shared
controls. Nature 2007; 447: 661–678.
145. Sklar P, Smoller JW, Fan J et al. Whole-genome associ-
ation study of bipolar disorder. Mol Psychiatry 2008; 13:
558–569.
146. McClung CA, Sidiropoulou K, Vitaterna M et al. Reg-
ulation of dopaminergic transmission and cocaine reward

by the Clock gene. Proc Natl Acad Sci USA 2005; 102:
9377–9381.
147. Roybal K, Theobold D, Graham A et al. Mania-like
behavior induced by disruption of CLOCK. Proc Natl
Acad Sci USA 2007; 104: 6406–6411.
148. Falcon E, McClung CA. A role for the circadian genes in
drug addiction. Neuropharmacology 2009; 56 (Suppl. 1):
91–96.
149. Brown ES. Bipolar disorder and substance abuse. Psychi-
atr Clin North Am 2005; 28: 415–425.
150. Abarca C, Albrecht U, Spanagel R. Cocaine sensitization
and reward are under the influence of circadian genes and
rhythm. Proc Natl Acad Sci USA 2002; 99: 9026–9030.
151. Andretic R, Chaney S, Hirsh J. Requirement of circadian
genes for cocaine sensitization in Drosophila. Science
1999; 285: 1066–1068.
152. Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine
reward circuit in depression. Biol Psychiatry 2006; 59:
1151–1159.
153. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ,
Monteggia LM. Neurobiology of depression. Neuron
2002; 34: 13–25.
154. Lamont EW, Legault-Coutu D, Cermakian N, Boivin
DB. The role of circadian clock genes in mental disorders.
Dialogues Clin Neurosci 2007; 9: 333–342.
155. Hampp G, Ripperger JA, Houben T et al. Regulation of
monoamine oxidase A by circadian-clock components
implies clock influence on mood. Curr Biol 2008; 18: 678–
683.
156. McClung CA. Circadian genes, rhythms and the biology
of mood disorders. Pharmacol Ther 2007; 114: 222–232.
157. Kendler KS. ‘‘A gene for...’’: the nature of gene action in
psychiatric disorders. Am J Psychiatry 2005; 162: 1243–
1252.
158. Gottesman II, Gould TD. The endophenotype concept in
psychiatry: etymology and strategic intentions. Am J
Psychiatry 2003; 160: 636–645.
159. Lenox RH, Gould TD, Manji HK. Endophenotypes in
bipolar disorder. Am J Med Genet 2002; 114: 391–406.
160. Papadimitriou GN, Calabrese JR, Dikeos DG, Christo-
doulou GN. Rapid cycling bipolar disorder: biology and
pathogenesis. Int J Neuropsychopharmacol 2005; 8: 281–
292.
161. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji
HK. Toward constructing an endophenotype strategy for
bipolar disorders. Biol Psychiatry 2006; 60: 93–105.
162. Mitterauer B. Clock genes, feedback loops and their
possible role in the etiology of bipolar disorders: an
integrative model. Med Hypotheses 2000; 55: 155–159.
163. Bunney WE, Bunney BG. Molecular clock genes in man
and lower animals: possible implications for circadian
abnormalities in depression. Neuropsychopharmacology
2000; 22: 335–345.
164. Walker MP, van der Helm E. Overnight therapy? The role
of sleep in emotional brain processing. Psychol Bull 2009;
135: 731–748.
165. Wagner U, Fischer S, Born J. Changes in emotional
responses to aversive pictures across periods rich in slow-
wave sleep versus rapid eye movement sleep. Psychosom
Med 2002; 64: 627–634.
166. Wehr TA, Goodwin FK. Circadian Rhythms in Psychi-
atry. Pacific Grove: Boxwood Press, 1983.
167. Indic P, Forger DB, St Hilaire MA et al. Comparison of
amplitude recovery dynamics of two limit cycle oscillator
models of the human circadian pacemaker. Chronobiol
Int 2005; 22: 613–629.
Circadian rhythms and sleep in BD
168. Czeisler CA, Wright KP Jr. Influence of light on circadian
rhythmicity in humans. In: Turek FW, Zee PC eds.
Regulation of Sleep and Circadian Rhythms. New York:
Marcel Dekker, 1999: 149–180.
169. Frank E, Kupfer DJ, Ehlers CL et al. Interpersonal and
social rhythm therapy for bipolar disorder: Integrating
interpersonal and behavioural approaches. Behav Thera-
pist 1994; 17: 143–149.
170. Miklowitz DJ, Otto MW, Frank E et al. Psychosocial
treatments for bipolar depression: a 1-year randomized
trial from the Systematic Treatment Enhancement Pro-
gram. Arch Gen Psychiatry 2007; 64: 419–426.
171. Benedetti F, Barbini B, Colombo C, Smeraldi E. Chro-
notherapeutics in a psychiatric ward. Sleep Med Rev
2007; 11: 509–522.
172. Wirz-Justice A, Benedetti F, Berger MA et al. Chrono-
therapeutics (light and wake therapy) in affective disor-
ders. Psychol Med 2005; 35: 939–944.
173. Wirz-Justice A, Benedetti F, Terman M. Chronothera-
peutics for Affective Disorders: A ClinicianÕs Manual for
Light & Wake Therapy. Basel: Karger, 2009.
174. Russell SJ, Browne JL. Staying well with bipolar disorder.
Aust NZ J Psychiatry 2005; 39: 187–193.
175. Murray G, Suto M, Hole R, Hale S, Amari E, Michalak
EE. Self-management strategies used by Ôhigh functioningÕ
individuals with bipolar disorder: From research to
clinical practice. Clin Psychol Psychother 2010: doi:
10.1002/cpp.710.
176. Michalak EE, Murray G, Young AH, Lam RW. Burden
of bipolar depression: impact of disease and medications
on quality of life. CNS Drugs 2008; 22: 389–406.
177. Benedetti F, Barbini B, Campori E, Cigala Fulgosi M,
Pontiggia A, Colombo C. Sleep phase advance and
lithium to sustain the antidepressant effect of total sleep
deprivation in bipolar depression: new findings supporting
the internal coincidence model? J Psychiatr Res 2001; 35:
323–329.
178. Vandewalle G, Balteau E, Phillips C et al. Daytime light
exposure dynamically enhances brain responses. Curr Biol
2006; 16: 1616–1621.
179. Anderson JL, Glod CA, Dai J, Cao Y, Lockley SW. Lux
vs. wavelength in light treatment of Seasonal Affective
Disorder. Acta Psychiatr Scand 2009; 120: 203–212.
180. Terman M. Blue in the face. Sleep Med 2009; 10: 277–278.
181. Desan PH, Oren DA, Malison R et al. Genetic polymor-
phism at the CLOCK gene locus and major depression.
Am J Med Genet 2000; 96: 418–421.
182. Sitaram N, Nurnberger JI Jr, Gershon ES, Gillin JC.
Cholinergic regulation of mood and REM sleep: potential
model and marker of vulnerability to affective disorder.
Am J Psychiatry 1982; 139: 571–576.
183. Knowles JB, Cairns J, MacLean AW et al. The sleep of
remitted bipolar depressives: comparison with sex and
age-matched controls. Can J Psychiatry 1986; 31: 295–
298.
184. Millar A, Espie CA, Scott J. The sleep of remitted bipolar
patients: a controlled naturalistic study using actigraphy.
J Affect Disord 2004; 80: 145–153.
185. Jones SH, Hare DJ, Evershed K. Actigraphic assessment
of circadian activity and sleep patterns in bipolar disorder.
Bipolar Disord 2005; 7: 176–186.
186. Jones SH, Tai S, Evershed K, Knowles R, Bentall R.
Early detection of bipolar disorder: a pilot familial
high-risk study of parents with bipolar disorder and
their adolescent children. Bipolar Disord 2006; 8: 362–
372.
471
Murray and Harvey
187. Ankers D, Jones SH. Objective assessment of circadian
activity and sleep patterns in individuals at behavioural
risk of hypomania. J Clin Psychol 2009; 65: 1071–1086.
188. Hallam KT, Olver JS, Chambers V, Begg DP, McGrath
C, Norman TR. The heritability of melatonin secretion
and sensitivity to bright nocturnal light in twins. Psycho-
neuroendocrinology 2006; 31: 867–875.
189. Nurnberger JI Jr, Adkins S, Lahiri DK et al. Melatonin
suppression by light in euthymic bipolar and unipolar
patients. Archiv Gen psychiatry 2000; 57: 572–579.
190. Wood J, Birmaher B, Axelson D et al. Replicable differ-
ences in preferred circadian phase between bipolar disor-
der patients and control individuals. Psychiatry Res 2009;
166: 201–209.
191. Pandi-Perumal SR, Moscovitch A, Srinivasan V, Spence
DW, Cardinali DP, Brown GM. Bidirectional communi-
cation between sleep and circadian rhythms and its
implications for depression: lessons from agomelatine.
Prog Neurobiol 2009; 88: 264–271.
192. Gruber J, Harvey AG, Wang PW et al. Sleep functioning
in relation to mood, function, and quality of life at entry
to the Systematic Treatment Enhancement Program for
Bipolar Disorder (STEP-BD). J Affect Disord 2009; 114:
41–49.
193. Riemann D, Voderholer U, Berger M. Sleep and sleep-
wake manipulations in bipolar depression. Neuropsycho-
biology 2002; 45 (Suppl. 1): 7–12.
194. Hudson JI, Lipinski JF, Frankenburg FR, Grochocinski
VJ, Kupfer DJ. Electroencephalographic sleep in mania.
Arch Gen Psychiatry 1988; 45: 267–273.
195. Hudson JI, Lipinski JF, Keck PE et al. Polysomnographic
characteristics of young manic patients. Arch Gen Psy-
chiatry 1992; 49: 378–383.
196. Murray G. Seasonality, Personality and the Circadian
Regulation of Mood. New York: Nova Science, 2006.
197. Jackson A, Cavanagh J, Scott J. A systematic review of
manic and depressive prodromes. J Affect Disord 2003;
74: 209–217.
198. Bauer M, Grof P, Rasgon N, Bschor T, Glenn T,
Whybrow PC. Temporal relation between sleep and mood
in patients with bipolar disorder. Bipolar Disord 2006; 8:
160–167.
199. Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi
E. Rate of switch from depression into mania after
therapeutic sleep deprivation in bipolar depression. Psy-
chiatry Res 1999; 86: 267–270.
200. Murray G, Judd F, Bullock B. Circadian and sleep ⁄ wake
variables as predictors of relapse in bipolar disorder.
472
Presented at the Australian Society for Bipolar Disorders
Conference 2007, Sydney, Australia, 20–22 September,
2007.
201. Perlman CA, Johnson SL, Mellman TA. The prospective
impact of sleep duration on depression and mania.
Bipolar Disord 2006; 8: 271–274.
202. Leibenluft E, Albert PS, Rosenthal NE, Wehr A.
Relationship between sleep and mood in patients with
rapid-cycling bipolar disorder. Psychiatry Res 1996; 63:
161–168.
203. Barbini B, Bertelli S, Colombo C, Smeraldi E. Sleep loss,
a possible factor in augmenting manic episode. Psychiatry
Res 1996; 65: 121–125.
204. Barbini B, Benedetti F, Colombo C et al. Dark therapy
for mania: a pilot study. Bipolar Disord 2005; 7: 98–101.
205. Wu JC, Kelsoe JR, Schachat C et al. Rapid and sustained
antidepressant response with sleep deprivation and chro-
notherapy in bipolar disorder. Biol Psychiatry 2009; 66:
298–301.
206. Terman M. Evolving applications of light therapy. Sleep
Med Rev 2007; 11: 497–507.
207. Wirz-Justice A, Quinto C, Cajochen C, Werth E, Hock C.
A rapid-cycling bipolar patient treated with long nights,
bedrest, and light. Biol Psychiatry 1999; 45: 1075–1077.
208. Padiath QS, Paranjpe D, Jain S, Sharma VK. Glycogen
synthase kinase 3b as a likely target for the action of
lithium on circadian clocks. Chronobiol Int 2004; 21:
43–55.
209. Abe M, Herzog ED, Block GD. Lithium lengthens the
circadian period of individual suprachiasmatic nucleus
neurons. Neuroreport 2000; 11: 3261–3264.
210. Manji HK, Moore GJ, Chen G. Bipolar disorder: leads
from the molecular and cellular mechanisms of action of
mood stabilisers. Br J Psychiatry 2001; 178: S107–S119.
211. Duncan JWC. Circadian rhythms and the pharmacology
of affective illness. Pharmacol Ther 1996; 71: 253–312.
212. Dokucu ME, Yu L, Taghert PH. Lithium- and valproate-
induced alterations in circadian locomotor behavior in
Drosophila. Neuropsychopharmacology 2005; 30: 2216–
2224.
213. Buysse DJ, Frank E, Lowe KK, Cherry CR, Kupfer DJ.
Electroencephalographic sleep correlates of episode and
vulnerability to recurrence in depression. Biol Psychiatry
1997; 41: 406–418.
214. Nofzinger EA, Schwartz RM, Reynolds CF III et al.
Affect intensity and phasic REM sleep in depressed men
before and after treatment with cognitive-behavioral
therapy. J Consult Clin Psychol 1994; 62: 83–91.