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Journal of Affective Disorders 185 (2015) 219229

Contents lists available at ScienceDirect

Journal of Affective Disorders


journal homepage: www.elsevier.com/locate/jad

Review

The bipolarity of light and dark: A review on Bipolar Disorder and


circadian cycles
T. Abreu a,1, M. Bragana b
a

Department of Psychiatry and Mental Health, Centro Hospitalar do Tmega e Sousa, Penael, Portugal
Psychiatry and Mental Health Clinic, Centro Hospitalar So Joo, and Department of Clinical Neurosciences and Mental Health, Porto Medical School, Porto,
Portugal

art ic l e i nf o

a b s t r a c t

Article history:
Received 18 May 2015
Received in revised form
6 July 2015
Accepted 8 July 2015
Available online 26 July 2015

Background: Bipolar Disorder is characterized by episodes running the full mood spectrum, from mania
to depression. Between mood episodes, residual symptoms remain, as sleep alterations, circadian cycle
disturbances, emotional deregulation, cognitive impairment and increased risk for comorbidities. The
present review intends to reect about the most recent and relevant information concerning the biunivocal relation between bipolar disorder and circadian cycles.
Methods: It was conducted a literature search on PubMed database using the search terms bipolar,
circadian, melatonin, cortisol, body temperature, Clock gene, Bmal1 gene, Per gene, Cry
gene, GSK3, chronotype, light therapy, dark therapy, sleep deprivation, lithum and agomelatine. Search results were manually reviewed, and pertinent studies were selected for inclusion as
appropriate.
Results: Several studies support the relationship between bipolar disorder and circadian cycles, discussing alterations in melatonin, body temperature and cortisol rhythms; disruption of sleep/wake cycle;
variations of clock genes; and chronotype. Some therapeutics for bipolar disorder directed to the circadian cycles disturbances are also discussed, including lithium carbonate, agomelatine, light therapy,
dark therapy, sleep deprivation and interpersonal and social rhythm therapy.
Limitations: This review provides a summary of an extensive research for the relevant literature on this
theme, not a patient-wise meta-analysis.
Conclusions: In the future, it is essential to achieve a better understanding of the relation between bipolar disorder and the circadian system. It is required to establish new treatment protocols, combining
psychotherapy, therapies targeting the circadian rhythms and the latest drugs, in order to reduce the risk
of relapse and improve affective behaviour.
& 2015 Elsevier B.V. All rights reserved.

Keywords:
Bipolar disorder
Circadian cycles
Sleep/wake cycle
Clock genes
Chronotype
Chronotherapeutics

Contents
1.

2.
3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Bipolar Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.
Circadian cycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bipolar Disorder and circadian cycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
The inuence of circadian rhythms disturbances on Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

220
220
220
221
222
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Abbreviations: ACTH, Adrenocorticotrophic hormone; ARNTL, Aryl hydrocarbon receptor nuclear translocator-like; Bmal1, Brain and muscle aryl hydrocarbon nuclear
translocator-like 1 gene; BD, Bipolar Disorder; BD-I and BD-II, Bipolar Disorder type I and type II; C, Cytosine; Clock, Circadian locomotor output cycles kaput gene; Cry 1 and
2, Cryptochromes 1 and 2 genes; CSM, Composite Scale of Morningness; DRN, Dorsal raphe nuclei; DT, Dark Therapy; EEG, Electroencephalogram; GHT, Geniculohypothalamic tract; GSK3, Glycogen synthase kinase 3-beta; IGL, Intergeniculate leaet; IPSRT, Interpersonal and Social Rhythm Therapy; LT, Light Therapy; MRN, Median
raphe nuclei; MT1, Melatonin Receptor 1; MT2, Melatonin Receptor 2; Per1, 2 and 3, Period 1, 2 e 3 genes; REM, Rapid Eye Movement; RHT, Retinohypothalamic tract; ROR,
RAR-related orphan receptor alpha; SAD, Seasonal Affective Disorder; SCN, Suprachiasmatic nuclei; SNP, Single nucleotide polymorphism; T, Thymine; TEMPS-A, Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire; TSH, Thyroid stimulating hormone; vlSCN, ventrolateral Suprachiasmatic nuclei
E-mail address: taniacoelhoabreu@gmail.com (T. Abreu).
1
Address: Lugar do Tapadinho, Guilhufe, 4564-007 Penael, Portugal.
http://dx.doi.org/10.1016/j.jad.2015.07.017
0165-0327/& 2015 Elsevier B.V. All rights reserved.

220

T. Abreu, M. Bragana / Journal of Affective Disorders 185 (2015) 219229

3.2.
3.3.
3.4.
3.5.

Clock genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223


Sleep/wake cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Chronotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Chronotherapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
3.5.1.
Pharmacological treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
3.5.2.
Light therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
3.5.3.
Dark therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
3.5.4.
Sleep deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
3.5.5.
Interpersonal and Social Rhythm Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
5. Limitations of the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

1. Introduction
1.1. Bipolar Disorder
The concept of Bipolar Disorder (BD) has been in constant
evolution since the Ancient Greece. The ofcial classications are
based on Kraepelin's perspective of Manic Depressive Insanity,
but the emphasis has been shifting to the concept of bipolar
spectrum, which extends to the limits of normal temperament
(Akiskal and Pinto, 1999).
BD is a chronic disease characterized by shifts in mood, energy
and activity. It ranges from extreme elation, or mania, to severe
depression and it is possible to have opposite symptoms simultaneously, during mixed states. In severe cases, psychotic
symptoms can occur. Between mood episodes, residual symptoms
remain, as sleep alterations, circadian cycle disturbances, emotional deregulation, cognitive impairment and increased risk for
comorbidities (Leboyer and Kupfer, 2010).
Accordingly to the World Mental Health Survey, the total lifetime prevalence of type 1 BD is 0.6%, type II BD is 0.4% and subthreshold BD is 1.4%, yielding a total prevalence estimate for the
Bipolar Disorder Spectrum of 2.4% worldwide (Merikangas et al.,
2011). The average age of onset varies from 17 to 27 years, with no
differences for both sexes (Gelder et al., 2000).
The early onset, prevalence, frequent number of episodes and
prolonged duration of periods of depression contribute to BD
being the sixth leading cause of disability in the world. It therefore
has a major social impact, with a loss of social development, loss of
productivity, unemployment and high costs for governments.
Despite its lower prevalence compared with some other mental
disorders, BD causes more marked functional impairment and
greater reduction in quality of life (Miller et al., 2014). Moreover,
compared to the general population, there are several comorbidities associated with this disease, including obesity, diabetes, cardiovascular disease and metabolic syndrome (Janney et al., 2014).
This is a public health problem that requires the development
of better methods of diagnosis and more appropriate therapeutic
strategies. It is important to target symptoms between episodes in
order to increase the duration of the inter-episodes periods and
improve the diseases prognosis.
A crucial step is the search for a better understanding of the
relationship between BD and circadian cycles.
1.2. Circadian cycles
Chronobiology is the science that studies the rhythms and

periodic physical and biochemical phenomena that occur in living


things. There are several types of rhythms that rule our body.
When these rhythms have the approximate duration of twentyfour hours, they are called circadian (circa diem, about a day); infradian, if the duration is longer; and ultradian, if they have a
shorter length.
Circadian cycles manifest themselves in the temporal organization of physiological, cellular, neural, biochemical and behavioral
processes, allowing our bodies to anticipate the phase of the day,
organizing these processes proactively (Dibner et al., 2010). this
preview of the environmental changes, leading to the early preparation of numerous functions, is a highly functional feature,
present in many organisms, from bacteria to humans.
The circadian cycles are endogenously generated, however, if
there is no adaptation to the environment (entrainment), its
length does not match the expected twenty-four hours. For there
to be an integration of the internal time with the geophysical time,
our body has to capture environmental cues, called zeitgebers or
exogenous time signals. There are several zeitgebers such as temperature, food intake and the day/night cycle (or light/dark cycle),
the latter being the most important.
Virtually all cells in the body are autonomous circadian oscillators (Dibner et al., 2010). In order to the light information reach
all the cells, it has to be processed by a central clock, which is
located in a pair of small nuclei in the anterior region of the hypothalamus, the suprachiasmatic nuclei (SCN) (Foster and Hankins, 2007).
There are three main afferents of the SCN: the retinohypothalamic tract (RHT), the geniculohypothalamic tract
(GHT) and terminals of the dorsal raphe nuclei (DRN) and the
median raphe nuclei (MRN) (Dibner et al., 2010). RHT comes from
a small set of photosensitive retinal ganglion cells, which express
melanopsin (Foster and Hankins, 2007). The monossinaptic bers
of this tract go to the ventrolateral part of the SCN (vlSCN), trough
the optic nerve. RHT also projects to the intergeniculate leaet
(IGL), which, in turn, carry processed light information to the SCN,
trough GHT. The IGL also receive MRN stimuli, integrating photic
and nonphotic signals. The bers from the MRN and DRN ending
in SCN participate in the nonphotic regulation of this nucleus
(Morin and Allen, 2006).
The SCN processes the information and transmits it to the
peripheral clocks and to other clocks in the brain (located in other
hypothalamic nuclei, thalamus, amygdala and habenula) in order
to synchronize all individual endogenous rhythms. The transmission of circadian information is done via hormones and metabolites and also by direct neural control involving the autonomic

T. Abreu, M. Bragana / Journal of Affective Disorders 185 (2015) 219229

nervous system and neuroendocrine system (Dibner et al., 2010).


The melatonin is one of these circadian information pathways.
This hormone is predominantly produced in the pineal gland and
is released into the cerebrospinal uid and into circulation, exerting its actions in various target tissues. Melatonin's production
is suppressed by light, thus presenting a circadian variation.
Overnight, its levels gradually increase, peaking in the middle of
the night, and then decline until the beginning of the day (Kalsbeek et al., 2006). This hormone inuences the circadian rhythms
of other hormones, body temperature, glucose homeostasis, immune and cardiovascular function. It is also associated with the
propensity for sleep.
Similarly, melatonin has a circannual variation, increasing in
proportion to the duration of the night. One of the most important
roles of melatonin is to transmit information about the time of day
for the rest of the body. This way, it controls the seasonal physiological functions such as sleep, appetite, body weight and reproduction in animals.
At the molecular level, melatonin acts on the expression of
clock genes in the pars tuberalis of the pituitary and inuences the
SCN directly by binding to its melatonin receptor 1 (MT1) and 2
(MT2). It inhibits the electrical and metabolic activities of SCN
neurons, hence, altering the phase and amplitude of circadian
cycles (Kalsbeek et al., 2006).
Another SCN pathway includes the hypothalamic-pituitary axis.
This nucleus promotes the release of corticotropin-releasing hormone by the paraventricular nucleus, which stimulates the release
of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. In turn, ACTH enters the circulation and will stimulate the
production of glucocorticoids in the cortex of the adrenal glands.
Cortisol levels uctuate in a circadian rhythm, reaching its zenith
after waking up and its nadir in the night (Kalsbeek et al., 2006). In
addition to controlling the rhythm of cortisol production, SCN also
modulates the sensitivity of the adrenal gland to the ACTH (Buijs
et al., 2003; Nader et al., 2010).
Conversely, the hypothalamic-pituitary axis strongly inuences
the circadian system. Cortisol affects the peripheral clocks in almost all tissues and organs, adjusting the phase of the cycle under
stress situations. As cortisol does not reach the SCN, this keeps its
intrinsic circadian rhythm regardless of the changes in the rest of
the body, so that once the stress situation has been resolved, the
SCN resynchronizes the peripheral clocks (Nader et al., 2010).
It is contemplated that other hormones such as aldosterone,
testosterone, luteinizing hormone, growth hormone, thyroid stimulating hormone (TSH), and follicle stimulating hormone also
exhibit periodic variations throughout the day under the control of
the SCN (Nakagawa and Okumura, 2010).
The peripheral clocks are present in almost all tissues. Studies
have shown that liver, lungs, kidneys, spleen, pancreas, heart,
stomach, skeletal muscle, cornea, thyroid and adrenal display robust oscillations in clock genes expression. The most immature
tissues with a wide range of differentiating cells do not present
these oscillations (Dibner et al., 2010).
Several important physiological functions uctuate throughout
the day, such as blood pressure and heart rate; metabolism of
carbohydrates and lipids in the liver, muscle and adipose tissue;
detoxication of xenobiotics and endobiotics compounds by liver,
kidney and small intestine; renal ow and urine output; etc.
It is suggested that the three most important purposes of the
peripheral clocks (at least in metabolically active tissues) are: the
anticipation of metabolic pathways to optimize the processing of
food; limiting the metabolic processes with adverse effects for periods when strictly necessary; and the distribution of incompatible
chemical reactions at different periods (Schibler, 2007).
These peripheral functions are coordinated by the SCN. To do
so, it uses direct routes, such as neural and humoral signals already

221

mentioned and indirect routes such as feeding, body temperature


and activity rhythms.
Temperature variations, inuenced directly by the SCN and by
activity cycles controlled also by SCN, appear to have a role in the
adjustment of peripheral clocks (Dibner et al., 2010).
Food intake is also a strong zeitgeber for various tissues such as
the liver, kidney, pancreas and heart. The food restriction limits the
duration of their availability, however, when an individual ingests
food daily only for a short period of time, in a few days the body
adapts to absorb the maximum fat during this period. Thus, having
fewer meals does not change the calorie consumption. Despite the
limited knowledge concerning the location and functioning of this
oscillator synchronizable by food, it is known that food restriction
affects the clock genes in peripheral tissues, however, has no effect
at the level of the SCN, causing a desynchronization between the
central and peripheral clocks. This suggests that the nutritional
regulation of oscillators in peripheral tissues may have a direct
role in the coordination of the metabolic oscillations. When the
availability of food is back to normal, the SCN resets the peripheral
clocks (Froy and Miskin, 2010).
At the molecular level, the SCN and peripheral clocks are controlled by negative feedback loops involving transcription and
translation of the clock genes. The main circuit includes the gene
circadian locomotor output cycles kaput (clock), and the brain and
muscle ARNT-like gene-1 (Bmal1) that translate the CLOCK and
BMAL1 proteins (also known as Aryl hydrocarbon receptor nuclear
translocator-like, ARNTL). These form a heterodimer that promotes
the transcription of period genes (per1, per2 and per3) and cryptochromes genes (cry1 and cry2) during the day. In the cytoplasm,
the proteins encoded by these genes form heterodimers which,
after reaching certain levels, move to the nucleus and interfere
with the action of the CLOCK/BMAL1 complex, blocking the transcription of their genes.
The PER and CRY proteins are subjected to change after translation, being phosphorylated by enzymes casein kinase 1 and
and the glycogen synthase kinase 3-beta (GSK3). This phosphorylation occurs rhythmically in synchronization with the daylight. The PER/CRY phosphorylated complex will be degraded
during the night in order to alleviate the inhibition of the heterodimer CLOCK/BMAL1, therefore allowing the resumption of
transcription of Per and Cry genes. This way, its formed a negative
feedback loop, which lasts about 24 h.
Other genes, including the Rev-Erb, timeless and ror are involved in auxiliary feedback loops, which stabilize and regulate
the main feedback loop (McClung, 2007; Dibner et al., 2010;
Westrich and Sprouse, 2010).
In conclusion, it can be said that, irrefutably, circadian cycles
inuence our body, determining the timing and rhythms of various physiological and behavioral processes. It is therefore clear
that maintaining health and balance is dependent on the correct
adaptation to the environment around us and on the effective
synchronization of this information throughout the body.

2. Methods
It was conducted a literature search on PubMed database for
articles between 2005 and 2014, using the search terms bipolar,
circadian, melatonin, cortisol, body temperature, clock
gene, Bmal1 gene, per gene, cry gene, GSK3, chronotype, light therapy, dark therapy, sleep deprivation, lithum and agomelatine.
Search results were manually reviewed, and pertinent studies
were selected for inclusion as appropriate. Other previously published articles were also consulted due to its importance within
the theme.

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T. Abreu, M. Bragana / Journal of Affective Disorders 185 (2015) 219229

3. Bipolar Disorder and circadian cycles


3.1. The inuence of circadian rhythms disturbances on Bipolar
Disorder
When the circadian system is in harmony, the peripheral clocks
are synchronized with the SCN. However, this balance can be
broken at different levels, both between the SCN and the geophysical time as between the SCN and the peripheral clocks (WirzJustice, 2003). Some factors, pathological or non-pathological,
endogenous or exogenous, can lead to desynchronization of circadian rhythms, causing them to last less or longer than the expected 24 h.
The external desynchronization occurs when the phase of internal rhythms is altered by manipulation of external synchronizers (Reinberg and Ashkenazi, 2003). A well-known example is Jet
Lag, which happens when an individual travels to different longitudes and suffers a transient desynchronization of circadian cycles. After adaptation to local time, the cycles are recomposed.
The internal desynchronization refers to differences in the
length of the internal rhythms in the same subject over time, even
in the presence of natural zeitgebers (Reinberg and Ashkenazi,
2003). Circadian rhythms are considered free-run when regulated
by endogenous rhythms, regardless of the inuence of zeitgebers
(Westrich and Sprouse, 2010). This dissociation between circadian
cycles and the day/night cycle can result in the dissociation of
several internal rhythms, which are not all equally affected. In a
study with rats exposed to cycles of 22 h, it was demonstrated an
internal desynchronization of rhythms of body temperature, locomotor activity, sleep and melatonin. The release of the latter was
controlled by two different oscillators, the light/dark cycle and
endogenous rhythms (Schwartz et al., 2009). A plausible explanation for this dissociation may be the fact that different subregions of SCN control different parameters. As mentioned above,
RHT projects to vlSCN, so the efferents of this sub-region will adapt
to the day/night cycle. In turn, the vlSCN projects to the dorsomedial SCN division. Abrupt changes in the day/night cycle can
induce dissociation in the expression of clock genes between the
two sub-regions (Schwartz et al., 2009). One study showed that,
under conditions of forced desynchronization, rapid eye movement sleep (REM), controlled by dorsomedial SCN division, follows
a free-run pace while the slow-wave sleep is synchronized by a
direct efferent of vlSCN (Lee et al., 2009).
External and internal desynchronization and consequential alteration of circadian cycles' phases have been studied within BD.
No signicant empirical evidence was yet found, but changes in
circadian function can predict disease recurrence, which is a factor
in favor of the discussed relation (Mansour et al., 2005).
Abnormal rhythmic activity can be a BD feature even during the
euthymic phase. Comparing individuals with BD in recovery with
healthy controls, signicant differences were found, including
advances in cycle phase (an earlier acrophase), higher percentage
of nocturnal sleep and lower average daily activity (Salvatore et al.,
2008). An assessment of the functional impact of circadian
rhythms disturbances on BD concluded that most of the deterioration of the functioning during the inter-episode period was
due to changes in circadian cycles. In agreement with previous
studies, it has been also demonstrated a high prevalence of sleep
disorders, even in patients in remission phase (Giglio et al., 2010a).
One theory emerged decades ago proposing that uctuations
between mania and depression would result in a pulsating effect
of the duration of the rhythms imposed by the patient SCN and the
24 h routine imposed by society. Early temporal isolation studies
observed that some Bipolar Disorder patients present a free-run
pace with less than 24 h (Kripke et al., 1978; Wehr et al., 1985) and
with loss of range (Wehr et al., 1983). This shortening of circadian

period results in phase advances and usually precedes an hypomanic or manic episode (Westrich and Sprouse, 2010).
The hypothesis of the phase advance of the circadian cycles in
bipolar patients considers that there are two sets of circadian
rhythms that may become misaligned. A set of rhythms mainly
metabolic and which is closely connected to the SCN; and another
set of rhythms, less connected to the SCN, the sleep/wake cycle
evoked responses. The circadian rhythm of sleep propensity goes
on the rst group, the second concerns the actual hours of sleep
that are inuenced by stress and the demands of social time (Lewy,
2009). Several parameters can be assessed to characterize the rst
group, as body temperature and cortisol and melatonin levels.
Melatonin is a potent endogenous synchronizer whose production is affected by light, so that it has been abundantly studied
in the context of mood disorders. Bipolar individuals may show
changes in the levels and phases of melatonin secretion. There are
some studies that argue that the changes in this hormone are
characteristics of the stages of the disease. One study found an
advance of the night melatonin peak and an increase of its levels
during episodes of mania (Lewy, 2009; Novakova et al., 2014). On
the other hand, a study compared unipolar depression with BD
and concluded that the latter had signicantly lower levels and
later onset of melatonin secretion (Robillard et al., 2013). In euthymic patients, there is a delayed melatonin's peak (Dallaspezia
and Benedetti, 2009).
Another line of thought is more inclined to consider changes in
levels of melatonin as an inherent feature of BD and not just one of
the stages of the disease. Lower levels of melatonin were found in
euthymic patients, depression episodes and even mania when
compared with healthy controls (Nurnberger et al., 2000). Hence,
there are permanently reduced levels across the different phases
of the disease.
A topic discussed repeatedly on this matter is the hypersensitivity of bipolar patients to light. After exposing these patients to a
light source during the night, it is noted a greater suppression of
melatonin synthesis than in healthy subjects (Lewy et al., 1985).
This suppression is reduced by treatment with lithium carbonate
(Hallam et al., 2005a, 2005b) and sodium valproate (Hallam et al.,
2005a, 2005b), which led to the conclusion that the therapeutic
effect of these drugs would be partially explained by this chronobiological action. There is also no agreement in this matter, because this suppression of melatonin by light in euthymic patients
was not conrmed in every studies (Nurnberger et al., 2000).
Cortisol is also one of the most widely used marker of the
circadian cycles. A study in patients experiencing a manic episode
has shown that these had higher cortisol levels at night and an
early nadir compared to a control group (Linkowski et al., 1994).
Other studies extend this cortisol hypersecretion also to depressive episodes (Gallagher et al., 2007). A recent study showed that
daytime cortisol levels and reactivity to daily events were similar
in remitted bipolar patients and healthy controls, but bipolar patients showed atter diurnal slopes and larger cortisol uctuations. Patients with many previous episodes had higher overall
cortisol levels, reduced cortisol reactivity to negative daily events,
and atter diurnal slopes than patients with fewer episodes (Havermans et al., 2011). Therapeutic benets have been obtained in
BD by decreasing cortisol levels or through the use of antagonists
(Young, 2006).
The patterns of locomotor activity and body temperature may
also be used to evaluate dysfunction of circadian rhythms. It was
suggested a relationship between mood state symptom severity
and rhythm disturbances of locomotor activity in subjects suffering from Bipolar Disorder. A greater severity of manic symptoms is
related to a less robust circadian rhythm. Clinical features that
correlated with rhythm disturbances included decreased need for
sleep, disturbances in content of thought and thought disorder,

T. Abreu, M. Bragana / Journal of Affective Disorders 185 (2015) 219229

increase in rate and amount of speech, and increased motor activity and energy (Gonzalez et al., 2014).
The temperature in patients with bipolar depression often
shows an increase at night and a decrease in the last hours of the
morning, with a reduction in the amplitude of the rhythm (Nikitopoulou and Crammer, 1976; Souetre et al., 1988). There is an
anticipation of the normal daily pattern of body temperature,
which, during the remission of depressive symptoms, is normalized (Dallaspezia and Benedetti, 2009).
Changes have been detected in the circadian rhythms of other
hormones in patients with BD, including prolactin, TSH, growth
hormone and also of several urinary metabolites. These variations
apparently normalize with improved patients clinical status
(Dallaspezia and Benedetti, 2009).
Although there is no uniform agreement among the various
studies, there is no denying that the anomalies in the secretion of
melatonin, disruption of the hypothalamic-pituitary axis and
changes in thermoregulation may be involved in the pathophysiology BD.
3.2. Clock genes
With the development of molecular genetic techniques that
allow cloning and characterization of clock genes individually, we
have the possibility to explore the molecular mechanisms behind
the relationship between BD and circadian cycles.
The clock gene has been widely investigated in patients with
BD. Several studies were conducted on a single nucleotide polymorphism (SNP), in which there is a substitution of thymine nucleotide (T) for cytosine (C) at position 3111 of this gene (SNP
T3111C). Some of these studies have revealed that patients with BD
which have at least one copy of allele 3111C have an evening
chronotype (Katzenberg et al., 1998; Benedetti et al., 2003, 2007;
Lee et al., 2010), with a relatively late onset of sleep and an inferior
total sleep time (Benedetti et al., 2007). The homozygous for this
allele 3111C present several differences from the 3111T allele
homozygous or heterozygous, in particular, show a doubling of the
rate of recurrence of bipolar episodes (Benedetti et al., 2003) and
an increased recurrence of insomnia (Serretti et al., 2003, 2005). In
contrast, other studies have not conrmed the role of this polymorphism in these circadian phenotypes nor have found any association with mood disorders (Bailer et al., 2005; Kishi et al.,
2009; Calati et al., 2010; Choub et al., 2011).
No signicant associations have also been demonstrated for
several SNPs and haplotypes of the clock gene and typical BD circadian phenotypes (Shi et al., 2008; Soria et al., 2010). While
common variants of circadian genes apparently do not confer a
substantial risk at an individual level, multilocular interaction
between the clock gene, BHLHB2 and CSNK1E has been observed,
suggesting an additive effect on susceptibility to BD (Shi et al.,
2008).
Also with respect to the clock gene, it was demonstrated that
mice with mutations in this gene show similar behavior to mania,
with hyperactivity, decreased sleep behavior, increased specic
exploration, reduced sensorimotor gating and greater sensitivity to
altered photoperiod. It has also been demonstrated that chronic
administration of lithium decreases many of these behaviors
(Roybal et al., 2007; van Enkhuizen et al., 2013).
The Bmal1 gene (ARNTL) has been associated with BD (Mansour
et al., 2005, 2006, 2009; Nievergelt et al., 2006; Le-Niculescu et al.,
2009; Soria et al., 2010) and sleep disorders, particularly, sleep/
wake cycle attenuation, sleep fragmentation, increased total sleep
time and strengthening the electroencephalogram's (EEG) delta
waves (Laposky et al., 2005). More recently, a study investigated a
possible association between multiple SNPs of clock genes and
temperamental dimensions of the Temperament Evaluation of

223

Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPSA) in bipolar patients. It was found an association between three
SNPs of the ARNTL gene with hyperthymic temperament and four
SNPs with anxious temperament (Rybakowski et al., 2014a,
2014b). The ARNTL gene may be also associated with the lithium
prophylactic response in BD (Rybakowski et al., 2014a, 2014b).
As for period genes, the most associated with BD is per3
(Mansour et al., 2006, 2009; Nievergelt et al., 2006). Mutations in
this gene were related to the age of onset of the disease, response
to treatment, circadian uctuations of mood and temperament
characteristics (Artioli et al., 2007, Rybakowski et al., 2014a,
2014b). Per2 has also been more recently related to the therapeutic
effect of lithium (McCarthy et al., 2013) (detailed in Section 3.5.1).
Period genes are also linked to chronotype, with a polymorphism in per1 associated with the morning chronotype (Carpen et al., 2006) and a polymorphism in per3 associated with the
evening chronotype (Archer et al., 2003). In what concerns sleep/
wake cycle, there is a sleep phase advance in patients with a per1
polymorphism (Carpen et al., 2006), with a mutation in per2 (Toh
et al., 2001) and with the long allele of a length polymorphism in
per3. In contrast, patients with the short allele of the same polymorphism, present delayed sleep phase (Archer et al., 2003).
About cryptochromes genes, cry2 has been the most related to
BD (Nievergelt et al., 2005; Mansour et al., 2009). It has been associated with rapid cyclers (Sjoholm et al., 2010). More recently, a
variant in CRY1 (rs8192440) was nominally associated with good
treatment response to lithium (McCarthy et al., 2011). Both are
involved in the homeostatic regulation of sleep, cry1 is associated
with advanced sleep phase and cry2 with delayed sleep phase
(Okamura et al., 1999).
Several studies have focused on GSK3 enzyme, which plays an
important regulatory role in the transcription of clock genes in the
SCN. It was suggested a relationship between this enzyme and
BD's age of onset (Benedetti et al., 2004a, 2004b), however, it has
not been found direct and signicant associations of variants of its
gene with this disease (Lee et al., 2006). The activity of GSK3 is
inhibited by lithium, which probably has therapeutic relevance
(Mansour et al., 2005). One study concluded that this enzyme is a
plausible target for the therapeutic actions of lithium and also
suggested that the circadian cycles are signicative modulators of
the clinical benets of this drug (Kaladchibachi et al., 2007).
However, other studies have not found associations between
polymorphisms in the gene of this enzyme and the degree of response to lithium prophylaxis (Michelon et al., 2006; Szczepankiewicz et al., 2006).
Concerning the additional feedback loops previously mentioned, these include the nuclear receptors Rev-Erb (Nr1d1) and
Ror (Rora). Rev-Erb is a negative component of the circadian
clock phosphorylated and stabilized by GSK3. A study showed
that lithium treatment leads to rapid degradation of Rev-Erb and
activation of clock gene Bmal1 and that a variant of Rev-Erb insensitive to lithium interferes with the expression of circadian
genes (Yin et al., 2006). A variant in the promoter of NR1D1 encoding Rev-Erb (rs2071427) was nominally associated with good
treatment response (McCarthy et al., 2011). A more recent study
demonstrated Rev-Erb's impact in midbrain dopamine production and mood-related behavior in mice (Chung et al., 2014). It has
been identied a molecular connection between the circadian
timing system and mood regulation and a connection between
lithium treatment and Rev-Erb activity, suggesting it could be an
important target in the treatment of BD.
A meta-analysis combining association studies showed a signicant association between TIMELESS (rs774045), RORA
(rs782931) and BD. The rst was also associated with eveningness
and languid circadian type, while rs782931 was associated with
rigid circadian type. It was suggested that these variants in the

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timeless and ror genes may confer susceptibility to BD and impact


on circadian phenotypes in carriers who thus had lower ability to
properly adapt to external cues (Etain et al., 2014). Timeless was
also associated with cyclothymic temperament (Rybakowski et al.,
2014a, 2014b) and with the lithium prophylactic response in BD
(Rybakowski et al., 2014a, 2014b).
Other genes have been investigated in this context, but few
statistically signicant associations have been achieved. However,
the cumulative effect of changes in these genes has been increasingly accepted as a causal factor of BD.
3.3. Sleep/wake cycle
The sleep/wake cycle is regulated by circadian cycles and by
homeostatic self-modulation that, under normal conditions, operate in synchrony. The reciprocal interaction between the two
types of regulation predicts the onset, duration, internal structure
and propensity for sleep (Murray and Harvey, 2010). The neurobiology of this interaction is not yet fully understood, it has been
suggested that circadian signals in the SCN promote wakefulness
during the day and facilitate sleep at night. It has been proposed
an involvement of melatonin in the physiological sleep regulation
since there is an increase in this hormone secretion about two
hours before bedtime, followed by an intensication of the propensity for sleep (Pandi-Perumal et al., 2009).
Sleep disturbances are characteristic in BD, although not essential to the diagnosis. Regardless of the mood phase, individuals
present more sleep onset latency and wakening after sleep onset
in comparison to healthy controls (Seleem et al., 2014). It was
performed a compilation of studies on the changes of sleep in
different stages of BD. During episodes of mania, 6999% of patients had a decreased need for sleep. However, in depression, 23
78% of patients had hypersomnia and up to 100% of patients had
insomnia (Harvey, 2008).
Regarding mania, decreased need for sleep is a critical marker.
It is also known that sleep deprivation can trigger a manic episode
and that the total sleep time is a predictor of future episodes. This
last parameter is not only a key target for therapeutic as it is an
important point in the evaluation of treatment response (Plante
and Winkelman, 2008). Sleep abnormalities found in mania are a
decrease in total sleep time, delta sleep and REM latency. There is
also increasing density of REM sleep and the time spent in bed
unable to sleep (Levenson and Frank, 2010).
As for depression, sleep disturbances are key characteristics
and ranks in the Diagnostic and Statistical Manual of Mental Disorders. Depressed patients have the main symptoms of insomnia:
difculty falling asleep, difculty maintaining sleep and early
awakening. It has been demonstrated a reduction of sleep efciency, total sleep time and slow-wave sleep; a delayed sleep onset; and an increased night-time awakenings. REM sleep distribution is also changed, with a decrease in the period from sleep
onset to the rst REM sleep onset (Pandi-Perumal et al., 2009).
Sleep abnormalities are similar in unipolar and bipolar depression,
however, in the latter, there seems to be an increased frequency of
early awakenings and hypersomnia and a higher density in REM
sleep (Plante and Winkelman, 2008).
In the euthymic period, there is also a signicant alteration in
sleep, with the sleep pattern resembling more to people with insomnia than normal sleep (Harvey et al., 2005; Harvey, 2008;
Geoffroy et al., 2014). Euthymic patients have increased sleep
fragmentation, movement during sleep and activity levels during
their least active ve hours (2:00 a.m.7:00 a.m.) and lower circadian relative amplitude than healthy individuals (Jones et al.,
2005; Rock et al., 2014).
The duration of sleep is a parameter often altered in BD. A
study revealed that decrease in sleep duration is associated with

more severe clinical conditions, but both individuals with shorter


periods of sleep (short sleepers) as individuals with longer periods
of sleep (long sleepers) have a worse quality of life and greater
impairment in functioning than those with normal sleep duration
(Gruber et al., 2009).
There seems to be a signicant relationship between sleep
duration and changes in mood (Bauer et al., 2006, 2008). A study
showed that 42% of patients analyzed showed a change in mood
on the same day or the day after the change in sleep duration,
most commonly the next day. The decrease of sleep duration was
followed by a change in the direction of hypomania or mania. On
the other hand, the increase of sleep duration was followed by a
shift towards depression. Patients with a signicant correlation
between the duration of sleep and mood changes exhibited alterations of more than three hours of sleep and had a higher
percentage of days in mania or depression than euthymia (Bauer
et al., 2008).
Disturbances of sleep are pervasive in BD, worse during mood
episodes, but still present during euthymic periods.
3.4. Chronotype
Chronotype is the individual preference of the day's period for
carrying out activities. The morning individuals prefer daytime,
while evening individuals favor to wake up later and perform their
activities in the afternoon or evening. The methods for determining chronotype foreshadow the timing of each individual to
fall asleep and wake up and periods of higher or lower energy and
acuity (Levenson and Frank, 2010).
Studies have shown that chronotype is the result of the circadian system activity. It is not only inuenced by the duration of the
circadian cycle but also by cellular components that affect its
amplitude and phase (Brown et al., 2008). As discussed above,
polymorphisms in clock, per3 and timeless genes have been associated with eveningness while a per1 gene polymorphism was
associated with morningness.
It has been documented a relationship between the evening
chronotype and BD. One study evaluated patients with BD type I
(BD-I), schizophrenia and schizoaffective disorder and a control
group through the Composite Scale of Morningness (CSM) and
concluded that patients with BD-I had a distinct prole from patients with other diseases and controls. They had lower results in
the rating scale, reecting an evening orientation, particularly regarding age (Mansour et al., 2005). A similar study in Korean population evaluated 92 patients with BD-I through the same scale.
These patients had a greater percentage of evening chronotype
(with a later timing of sleep) than the control group (Ahn et al.,
2008). More recently, it was additionally detected an association of
the evening chronotype in BD with a longer sleep latency (Giglio
et al., 2010b) and irregular bed-rise time (Baek et al., 2014). Furthermore, bipolar patients exhibit not only abnormalities in phase
preference but also in amplitude, which usually is lower (Boudebesse et al., 2013).
The difference in chronotype between BD-I and BD type II (BDII) is unclear, with information towards no signicant difference
between the two (Wood et al., 2009) and, on the contrary, BD-II
showing more eveningness than BD-I (Chung et al., 2012).
It is interesting to notice that patients with co-morbid BD and
alcoholism tend to be more of the morning type (Hatonen et al.,
2008), unlike patients with BD alone.
It was also suggested that there is a relationship between
chronotype and uctuations of mood, given that the mood
symptoms are positively correlated with the results of the evaluation scales for chronotype (Levenson and Frank, 2010). A recent
study investigated the association of circadian preference with
emotional and affective temperament. Cyclothymic and euphoric

T. Abreu, M. Bragana / Journal of Affective Disorders 185 (2015) 219229

temperaments, which relate to BD, showed evening preference.


Temperament was more associated with absolute energy levels
than with chronotype. Evening types had less emotional control,
coping, volition and caution, and more affective instability and
externalization (Ottoni et al., 2012).
3.5. Chronotherapeutics
Over time, it has been demonstrated the efcacy of therapies
for BD targeting circadian cycles disturbances. This contributes to
the validation of the relationship between this condition and the
circadian system.
Chronotherapeutics bases itself on circadian rhythms stabilization, controlling the individuals exposure to environmental
stimuli that act on biological rhythms.
Experimental studies have been showing that sleep has an antimanic effect and that the wakefulness has an anti-depressant effect (Levenson and Frank, 2010). The mentioned therapies include
non-pharmacological treatments involving the controlled exposure of the patient to environmental stimuli that act on circadian rhythms, promoting sleep or wakefulness depending on the
desired effect (Benedetti et al., 2007).
3.5.1. Pharmacological treatments
Lithium carbonate is widely used in the treatment of BD, as it is
the rst choice in long-term treatment (Nivoli et al., 2012). Its
exact action mechanism has not been established, but some studies have shown that lithium acts directly in the SCN to increase
the free-run period of each neuron (Abe et al., 2000).
At the molecular level, lithium inhibits GSK3, an essential
component of circadian cycles, suggesting that this enzyme is one
of the mediators of therapeutic effect (Kaladchibachi et al., 2007).
It was also demonstrated that this drug promotes the expression
of Cry1 and Per2 genes; reduces the expression of Per3, Cry2,
Bmal1, Rev-Erb and E4BP4 genes; and prolongs the period and
enhance de amplitude of the rhythm of Per2 (Osland et al., 2010; Li
et al., 2012; McCarthy et al., 2013). These effects on the expression
of clock genes may be relevant to its inuence on biological
rhythms and may suggest new possibilities for future exploration
of its functions as a mood stabilizer. Another possible action mechanism of lithium is by reducing the suppression of melatonin by
light, as explained above (Hallam et al., 2005a, 2005b).
A study was conducted to evaluate the inuence of lithium in
the behavior of rodents. It alters the circadian rhythms and consistently decreases exploratory activity, aggression and has inuence on locomotion, among other actions. With regard to reward
behaviors, the data are less consistent (O'Donnell and Gould,
2007).
There are fewer studies regarding other mood stabilizers.
Valproic acid is used as an anticonvulsant and mood-stabilizing
drug. It has been demonstrated that it can also affect circadian
rhythms. Valproic Acid, in different circadian timings, can alter the
phase (delay or advance) and increase the amplitude of Per2 gene
rhythm (Johansson et al., 2011).
Quetiapine is an atypical antipsychotic that can be used in the
treatment of BD. A recent study found that quetiapine can alter
clock genes expression in mice, elevating Per1, Per2 and Bmal1
mRNA expression, depending on the circadian time (Moriya et al.,
2014).
Both valproic acid and quetiapine have different effects from
lithium. The latter, unlike the two other drugs, can lengthen the
period of Per2 expression.
Agomelatine is a potent agonist of melatonin receptors (MT1
and MT2) and an antagonist of 5-hydroxytryptamine receptor (5HT2C). It is able to re-synchronize circadian cycles, advancing its
phase (Calabrese et al., 2007; Zarate and Manji, 2008). After

225

administration of agomelatine, an increase of approximately two


hours was observed in the temperature prole and in the secretion
of cortisol and TSH (Leproult et al., 2005).
Studies have shown the effectiveness of agomelatine in treating
depression (Zupancic and Guilleminault, 2006; Calabrese et al.,
2007; San and Arranz, 2008; Zarate and Manji, 2008). A preliminary open label study concluded that agomelatine was an effective and well-tolerated adjunct to valproate or Li for acute depression in BD-II (Fornaro et al., 2013). Agomelanin also inuences
the quality and continuity of sleep, increasing its total length and
efciency, reducing latency and normalizing the distribution of
slow-wave sleep and delta EEG tracing (Zupancic and Guilleminault, 2006; Calabrese et al., 2007; Zarate and Manji, 2008).
3.5.2. Light therapy
Light therapy (LT) consists in the exposure of patients to a light
source. Many studies have used bright white light, however, recent
studies suggest that blue light (with E460 nm) leads more effectively to a change of phase. The optimum light dose and
duration of treatment should be adjusted for each individual
(Terman and Terman, 2005). For example, in Seasonal Affective
Disorder (SAD), a morning dose intensity of 5000 lx per hour is
used (Shirani and St Louis, 2009).
LT is the treatment of choice for SAD, but has also been prescribed for other conditions, including BD (Prasko, 2008). For
several years, it has been suggested that LT reduces depressive
symptoms in this disease (Kripke et al., 1983; Krauss et al., 1992). A
study in a group of women with BD-I and BD-II conrmed this
effect, however, highlighted the substantial risk of induction of
mixed states, indicating it will probably be a better approach to
initiate treatment for about fteen minutes (Sit et al., 2007).
The side effects of LT, when compared with drugs, are much
smaller. However, one should remain vigilant in order to prevent
the emergence of hypomania and autonomic hyperactivation,
especially during the beginning of treatment.
The combination of LT with drugs may result in a faster improvement of symptoms and a lower rate of residual symptoms
(Terman and Terman, 2005). A study also suggested combining LT
with light deprivation and sleep phase advance in medicated patients in order to accelerate and sustain the antidepressant response (Wu et al., 2009). It has also been proposed that combining
LT with total sleep deprivation would be useful in triggering an
acute response in drug-resistant patients (Benedetti et al., 2005).
3.5.3. Dark therapy
The deprivation of light, known as dark therapy (DT), consists
in a patient being in a place without light for a number of hours.
For example, the patient can stay in bed in the dark up to 14 h per
night (Levenson and Frank, 2010). Although there is still no concrete evidence, the darkness seems to organize and stabilize circadian rhythms (Phelps, 2008).
A single case study of a rapid cycler bipolar patient showed that
light deprivation decreases the mood recurrent pattern. This patient was submitted to enforced darkness, initially for 14 h each
night and later 10 h, and was assessed during several years. When
he followed his usual routine, he returned to his rapid cycling
pattern, but when he slept accordingly to the DT proposed, his
sleep and mood were stabilized (Wehr et al., 1998). In another
single case study, a rapid cycler bipolar patient, refractory to valproic acid, was exposed to a 10 h period of darkness. The rapid
cycling pattern rapidly stopped. Then, DT was augmented to a 14 h
period and LT was introduced in the morning, almost reaching
euthimia (Wirz-Justice et al., 1999).
Regarding specically the treatment of mania, one study recruited 32 patients and divided them in two groups, one group
that would be submitted to the usual pharmacological treatment

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T. Abreu, M. Bragana / Journal of Affective Disorders 185 (2015) 219229

and other that would be also submitted to DT. These latter 16


patients were exposed to a 14 h period of darkness (from 6 p.m. to
8 a.m.) for three successive days. The mania symptoms decreased
signicantly faster than in the other group, but only in patients
that were treated within the rst 2 weeks of the episode (Barbini
et al., 2005).
Nevertheless, DT has disadvantages, as it is impractical and not
well accepted by patients (Phelps, 2008). Recently, a new approach
has been explored, using orange-tinted glasses that block blue
light. A case report describes a rapid decline in manic symptoms
with this technique, accompanied by regularization of the sleep
parameters (Henriksen et al., 2014).
3.5.4. Sleep deprivation
Sleep deprivation improves mood in patients with bipolar depression (Barbini et al., 1998, Papadimitriou et al., 2007). However,
depressive symptoms may return quickly after the patient has
slept (Harvey, 2008). It is also necessary monitoring because sleep
deprivation may be sufcient to trigger an episode of mania or
hypomania (Papadimitriou et al., 2007).
Most studies approach the association of sleep deprivation with
other therapies. One study found that the association between
sleep deprivation and LT lead to a faster antidepressant response
in 60% of patients (Benedetti et al., 2005). A more recent study
submitted 143 patients with a bipolar depressive episode to three
consecutive total sleep deprivation cycles with 36 hours duration,
combined with LT in the morning and lithium for two weeks. This
combination promptly triggered an antidepressant response and
decreased suicidality (Benedetti et al., 2014).

sleep/wake cycle, thermoregulation, cortisol secretion and melatonin secretion. It was also demonstrated the association between
altered circadian genes and BD. Likewise, an effective BD treatment generally involve the normalization of circadian function.
It remains to determine a causal association. However, it seems
that this is a two-way relationship, setting up a vicious cycle between changes of circadian cycles and symptoms and episodes of
BD.
At this time, our purpose should be using the existing knowledge to reduce the risk of disease recurrence and improve emotional functioning, thus contributing to a higher quality of life. In
the future, further investigation is needed to enlighten the addressed relationship. New treatment protocols should be established, combining psychotherapy, therapies targeting the circadian
rhythms and the latest drugs.

5. Limitations of the study


This review provides a summary of an extensive search for the
relevant literature on this theme, not a patient-wise meta-analysis.
The search was limited to PubMed database.

Conicts of interest
None.

Funding source
3.5.5. Interpersonal and Social Rhythm Therapy
The Interpersonal and Social Rhythm Therapy (IPSRT) is associated with the theory of social zeitgebers. This theory holds that
mania, hypomania and depression arise as a result of life events. A
change in patients life leads to a change in their usual routine,
such as mealtime or bedtime, which, in turn, leads to a disruption
of the circadian cycles, causing disease recurrence (Harvey, 2008).
Thus, it makes sense to use IPSRT in order to stabilize social
zeitgebers. This therapy combines psychotherapy with behavioral
strategies to regulate the daily routine (social routines, sleep/wake
cycle) and interpersonal psychotherapy to help patients in solving
their problems (Bottai et al., 2010).
Some studies have shown the IPSRT's effectiveness in the
prophylaxis of BD's recurrence (Frank et al., 2005, 2007, 2008;
Bouwkamp et al., 2013).
Recently, a group of patients with bipolar depression received
six IPSRT group sessions after two individual sessions, followed by
telephone calls for twelve weeks. In the end, depressive symptoms
improved signicantly (Hoberg et al., 2013).

4. Conclusions
A huge number of studies have highlighted the relationship
between BD and circadian cycles. Several data have not yet been
conrmed, leaving many questions unanswered. However, after
decades of research, it is impossible to ignore this relationship.
Being the circadian system an almost ubiquitous system in our
body, inuencing the behavior, physiology, cell biology, biochemistry, etc., it seems impossible that it does not inuence a condition like BD, also multisystemic itself. Almost all bipolar symptoms, including changes in mood, energy, sleep, appetite, ability to
concentrate, among others, present a circadian variation.
Different areas including physiology, pharmacology and genetics have shown that disturbances in circadian cycles are an
essential feature of BD. This condition is associated with altered

None.

Contributors
Tnia Abreu: conducted the literature search and wrote the
paper.
Miguel Bragana: supervised the process and revised the paper.

Acknowledgments
None.

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