Beruflich Dokumente
Kultur Dokumente
Review
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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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.
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3.2.
3.3.
3.4.
3.5.
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
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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.
222
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,
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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226
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.
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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