CLINICAL
Philip Boyce
Erin Barriball
Circadian rhythms
and depression
Background
Depression is a common disorder in primary care. Disruptions to the circadian rhythms
associated with depression have received little attention yet offer new and exciting
approaches to treatment.
Objective
This article discusses circadian rhythms and the disruption to them associated with
depression, and reviews nonpharmaceutical and pharmaceutical interventions to shift
circadian rhythms.
Discussion
Features of depression suggestive of a disturbance to circadian rhythms include early
morning waking, diurnal mood changes, changes in sleep architecture, changes in
timing of the temperature nadir, and peak cortisol levels. Interpersonal social rhythm
therapy involves learning to manage interpersonal relationships more effectively
and stabilisation of social cues, such as including sleep and wake times, meal times,
and timing of social contact. Bright light therapy is used to treat seasonal affective
disorders. Agomelatine is an antidepressant that works in a novel way by targeting
melatonergic receptors.
Keywords: circadian rhythm, depression
However, current treatments have been developed
on the basis of a causal model for depression.
Focused psychological treatments target those
depressions that arise from psychosocial
difficulties. Examples include:
• cognitive behavioural therapy (CBT), which
corrects maladaptive thinking patterns
• behavioural treatments that aim to overcome
‘depressogenic’ behaviours such as avoiding
pleasurable activities, and
• lifestyle modifications, particularly work-life
balance, diet and exercise and sleep-wake
cycle management.5
Antidepressant medications target the
neurotransmitter disturbances (serotonin or
noradrenaline) considered to underlie biological
depression. While the focus of biological
aspects of depression has centred on changes in
neurotransmitters, there has been relatively little
attention paid to the changes in circadian rhythms
associated with depression that offer new and
rational treatment options for depression.
Circadian rhythms
Over the past 5–10 years, there has been
growing community awareness about
depression, with an increased emphasis
on its treatment in primary care. Evidence
based pharmacological and psychological
treatments for depression have been
outlined in clinical practice guidelines.1,2
These treatments are recommended on the
basis of severity rather than depression type.
While such an approach makes treatment
decisions relatively straightforward, it
does not take into account the different
causal explanations for depression;
particularly whether the depression is
predominantly biological, such as that seen
in melancholia3,4 and bipolar depression, or
the result of psychosocial factors.
The regular rhythm of night (dark) and day (light)
regulates our life, as it does for most living
organisms. Associated with this are regular
changes in core body temperature, hormonal
secretions, heart rate, renal output and gut
motility. Our mental ability and energy levels
are highest during daylight hours, when we
engage in exercise and social interactions, with
our metabolism and physiology adapted to this.
During the night, when activity levels drop, core
body temperature falls and reaches its nadir,
while cortisol levels rise before awakening.
There are cyclic changes in the level of sleep (as
shown by changes on an electroencephalogram
[EEG]) with hormonal release, such as the
release of growth hormone linked to specific
phases of the regular sleep cycle.6–8 When our
Reprinted from AusTrAliAn FAmily PhysiCiAn Vol. 39, no. 5, mAy 2010 307
CLINICAL Circadian rhythms and depression
sleep-wake cycle is out of phase with the daynight cycle (eg. due to jetlag or shift work), we
can experience dysphoria, poor functioning and
increased health risk.7,9
Regulating circadian rhythms
These rhythmic changes in metabolism and
psychological activity are under the control of
a circadian clock; this ensures that our body is
attuned to the level of mental and physical activity
associated with a particular time of day or night.
When free of external environmental clues,
the amplitude of our daily rhythm is longer than
the 24 hour day-night cycle (hence the name
circa diem – about a day) as demonstrated in
experiments when individuals were placed
in temporal isolation10 or in conditions of
permanent darkness such as subjects wintering
in the Antarctic.11
The human circadian pacemaker or ‘clock‘ is
located in the suprachiasmatic nucleus of the
anterior hypothalamus. This regulates the key
circadian rhythmic changes such as cortisol,
thyroid hormone and core body temperature.
The mechanism for this is governed by a set of
genes that operate through a series of feedback
mechanisms with a regular cycle of about (but not
exactly) 24 hours.12–14
The circadian pacemaker has to be
resynchronised regularly to compensate
for the slightly longer than 24 hour cycle
of the ‘endogenous’ circadian rhythm. This
synchronisation to the external environment is
mediated through the retinohypothalamic tract.
Light zeitgebers
light acts a ‘zeitgeber’ or timekeeper, falling
on the retina which then sends impulses to
the suprachiasmatic nucleus; a process that is
mediated through the protein melanopsin (rather
than rods or cones).15 Bright light also has an
effect by suppressing melatonin production.
For this to occur, a light intensity of at least
1500 lux (brighter than standard artificial
lighting) is required to switch off melatonin
production. Suppressing melatonin can have
an effect in changing circadian rhythms: bright
light administered in the early morning will
suppress melatonin and therefore advance
circadian rhythms. in this example, the nadir of
the temperature rhythm will be moved earlier
308 Reprinted from AusTrAliAn FAmily PhysiCiAn Vol. 39, no. 5, mAy 2010
in the day, while bright light applied in the
evening will have an opposite effect by delaying
circadian rhythms.16–18
Social zeitgebers
Regular patterns of social behaviour can also
affect circadian rhythms and aid in regulating
them. These cues are known as ‘social zeitgebers’
and include time of going to bed and waking,
social interactions, and meal times.
Disruption to circadian rhythms
in depression
Disruptions to circadian rhythms have been found
among patients with major depression.19 While
these changes are thought to be a contributing
factor to the depression (such as suggested
by the dysphoria triggered by jetlag) it is also
possible that they may arise as a consequence of
the depression.
Sleep
There are a number of features of depression
suggestive of a disturbance to circadian rhythms;
perhaps the most obvious are the changes in
sleep, in particular waking early in the morning
which is usually linked to a diurnal mood change.
Sleep and polysomnographic studies demonstrate
other changes in circadian rhythms, particular
to the sleep architecture that indicate a ‘phase
advance’ of such rhythms; specifically of the
temperature nadir and cortisol levels, which occur
earlier in the night.19 Sleep architecture also
reflects this with a shortened rapid eye movement
(rEm) latency and rEm sleep shifted to the first
third, rather than the latter third of the sleep
cycle. These observations, along with clinical
features, all support the notion of circadian
rhythm disturbance in depression.19
Seasonal change
The most compelling evidence for a rhythm
disturbance hypothesis of depression is the link
between mood disorders and seasonal change.20
in addition to the 24 hour daily rhythm, there
are also regular rhythms over a year. These
are known as circannual rhythms and reflect
the changing day length (photo period) during
the year. Circannual rhythms of depression are
seen most clearly in seasonal affective disorder
(characterised by episodes of depression in winter
with remission in spring and summer). some
patients with bipolar disorder also experience
episodes of depression or (hypo)mania at the
same time each year. These seasonal changes are
considered to be the result of a failure to adapt
the shift in day length that accompanies seasonal
change.20,21 This adaptive failure leads to
circadian rhythms becoming uncoupled, resulting
in the onset of mood disorder. For patients with
bipolar disorder, this has shown very clearly with
disruptions to the sleep-wake cycle triggering off
episodes of hypomania or mania.22 A phase delay
in circadian rhythms are proposed as a mechanism
for seasonal affective disorder as demonstrated
by the temperature nadir and timing of melatonin
secretion occurring later in the night.16
Manipulating circadian
rhythms
The circadian rhythms disturbances of depression
can be corrected by novel nonpharmacological and
pharmacological methods.
Social zeitgebers
The timing of social zeitgebers, for example
sleep or meal times, play a role in regulation and
disruption of circadian rhythms. individuals who
suffer from mood disorders show fewer routine
activities than controls, and social rhythm
regularity predicts time to prospective onset
of a bipolar episode.23 in addition, it is thought
these individuals are more sensitive to circadian
rhythm disruptions.24
The symptoms presented by patients with
unipolar and bipolar depression tend to display
circadian rhythmicity. For example, sleep,
hunger and concentration all have a propensity
to follow a 24 hour clock, and will be affected
by disruption to biological rhythms. The
implementation of frequent and stable social
rhythms has been shown to be an important
prophylactic treatment in affective disorders.24
These activities, when performed regularly, have
the ability to entrain biological rhythms such as
cortisol and body temperature.25
As a result, interpersonal social rhythm
therapy (iPsrT) was created.24 interpersonal
social rhythm therapy involves learning to manage
interpersonal relationships more effectively and
stabilisation of social cues, such that the patient
performs routine daily activities at the same time
Circadian rhythms and depression CLINICAL
each day26 in particular maintaining a stable
sleep-wake cycle. The therapy allows for no more
than a 45 minute variation each day for any given
activity, and aims to prevent relapse by providing
the patient with a stable environment. The social
rhythm metric (srm) is a tool designed to aid in
social rhythm stabilisation.27 in its entirety, the
srm contains 17 items, including sleep and wake
times, meal times, and timing of social contact.
Light therapy
Bright artificial light of at least 1500 lux, has
been used to treat some forms of depression,
particularly seasonal affective disorder.28
This treatment was originally utilised on the
premise that seasonal affective disorder was a
consequence of the short day length of winter and
bright light would mimic the day length of summer.
While this proved to be effective it is now clear
that the mechanism for light therapy is in its effect
on shifting circadian rhythms. Thirty minutes of
bright light therapy (10 000 lux) in the morning
advances circadian rhythms and overcomes the
phase delay associated with seasonal affective
disorder, exhibiting its effect in 2–3 days.18
Role of melatonin
melatonin can be used to shift circadian rhythms
and melatonin is marketed as a hypnotic in
Europe. its ability to promote sleep can results
in improved mood.28,29 While there may be some
improvement in depression symptoms arising from
improving sleep with persons with depression,
melatonin administration during the day leads to
dysphoria and worsening of depressive symptoms,
indicating melatonin does not have an inherent
antidepressant action.30
melatonin is used to correct dysphoric
symptoms induced by circadian rhythm
disruption following transmeridian travel
(jetlag). Taken the night before departure,
(0.5–5.0 mg) it has been shown to be effective
in reducing symptoms of jetlag.31
Agomelatine
Theoretically, medications that target
melatonergic receptors in the brain will have an
affect on circadian rhythms. Agomelatine is an
agonist of melatonergic (mT1 and mT2) receptors
and a 5-hT2C antagonist. When taken at bed time,
it appears to have an effect by resynchronising the
circadian rhythms. it has been demonstrated to be
an effective antidepressant in placebo controlled
trials32,33 and equivalent efficacy compared to
selective serotonin reuptake inhibitors (ssris)33
and venlafaxine.34 it has a very short term
action (half life 2 hours) and must be taken at
night before going to sleep. While agomelatine
does improve sleep itself, its primary effect is
in synchronising circadian rhythms. At present,
the main studies on agomelatine have been
carried out on patients with major depression,
but this medication may prove to be useful where
circadian rhythm disturbances underpin the
patient’s clinical problem.
Agomelatine is indicated for use for the
treatment of major depression. it needs to be
taken at bed time with an initial dose of 25 mg
(which is the generally effective dose) that can
be increased to 50 mg if there is no response
within 2 weeks.
The side effect profile is favourable, with
no associated sexual side effects, day time
somnolence or weight gain.35 The most common
side effects associated with agomelatine
are: headache, nausea, diarrhoea, dry mouth,
constipation and nasopharyngitis.35 Agomelatine
has been found to increase serum transaminases
in some patients treated with 50 mg/day; it
is recommended that liver function tests are
conducted every 6 weeks while the patient is
taking it.36 it is metabolised by the cytochrome
P450 isoforms 1A1, 1A2 and 2C935 and
co-administration of potent CyP1A2 inhibitors
(such as fluvoxamine) is contraindicated.
Combination of agomelatine with oestrogens
(moderate CyP1A2 inhibitors) can increase
agomelatine levels.37
Agomelatine is currently undergoing further
evaluation, has recently been licensed for use in
Europe, and will offer a new therapeutic tool for
the treatment of depression when it is released
in Australia, especially for those who have been
unable to tolerate the side effects of current
antidepressants.
rhythm disruption as a proposed cause of
mood disorders presents an opportunity for
unique and efficacious treatment that includes
pharmacological, behavioural and novel
interventions such as bright light therapy.
Conclusion
13.
Depression is one of the most common reasons
for people to visit their general practitioner.
While diagnostically it is treated as a unitary
disorder, the varying aetiologies and treatments
for depression suggest it is not. Circadian
Authors
Philip Boyce mBBs, mD, FrAnZCP, is Professor
of Psychiatry, Discipline of Psychiatry, university
of sydney and the Department of Psychiatry,
Westmead hospital, sydney, new south Wales.
philip.boyce@sydney.edu.au
Erin Barriball BBsc, PGDipPsych, is research
Psychologist, Discipline of Psychiatry, sydney
medical school – Western, new south Wales.
Conflict of interest: this work was funded by an
unrestricted educational grant from Servier.
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