Chronobiology Discipline - Chronotherapy - Circadian Clocks - Clock Genes - Sleep
- Sleep Medicine
INTRODUCTION
“Whoever wishes to investigate medicine properly should proceed thus: In the first
place to consider the seasons of the year, and what effects each of them produces
for they are not all alike, but differ much from themselves in regard to their changes.”
- Hippocrates, (c. 460 - c. 370 BC)
From the earliest times, there has been a recognition that natural phenomena often
manifest in repetitive cycles, and that these are governed by both internal and environmental
forces. It was also appreciated that cyclical activity is critical for the functioning
of living organisms, including man. In the modern era, this chronobiological perspective
is increasingly being reintroduced into the life sciences. It is now known that almost
all species possess a genetically programmed timekeeping system, which responds to
the environmental rhythms generated by the Earth’s rotation around its axis[1],[2]. This endogenous timekeeping system regulates various biological processes including
the cell cycle, immunity, metabolism, neural growth and development, reproduction
and sleep/wake cycles. Many studies have now shown that adequate sleep is necessary
for the proper regulation of vital biological processes as well as for a normal life
expectancy[3],[4]. Sleep itself however responds to more basic processes. The architectural markers
of sleep, including its stages, timing, and duration, are periodic in nature[5], and these processes, in turn, are driven by the circadian clock, which itself is
influenced by a combination of genetic factors, as well as by repetitive events in
the environment[6].
As reviewed below, the various zeitgebers (environmental timekeepers or regulators)
of the circadian clock most importantly include ambient lighting, but other events,
such as the scheduling of meal times, or occurrences which have important social or
psychological significance, can also impact the clock’s circadian phase.
In earlier times, recurrent environmental events were fairly unitary and easy to identify:
the rising and setting of the sun, the changing of the seasons, or the migration of
animals. In the modern era, however, “timekeeper identification” is more challenging.
Humans have become “flooded” with signals reminding them of the passage of time, many
of them contradictory and often competitive. The broad array of technological advances
that have made our modern-day society possible, e.g., electric “all night” lighting,
jet travel, instantaneous news and communication, 24-hour internet access, and many
other inventions, have brought with them multiple psychological stresses, as well
as a perceived need to accomplish as much as possible in a limited amount of time.
This perspective, unfortunately, has also influenced attitudes toward sleep. For many
people, this natural biological need is increasingly viewed as a process that takes
away from available time that is necessary for “getting things done”. The consequences
of this outlook are that, throughout the world, major segments of the population are
sleeping less and are living under tremendous “sleep pressure”, i.e., a felt physiological
need to make up for prolonged periods of inadequate rest[7]. Over time, sleep deprivation has even broader consequences for human health. It
has been suggested that chronic sleep curtailment induces significant stress on pancreatic
tissues and that this stress, in turn, promotes the development of serious illnesses
such as type 2 diabetes[8]. Further, an increasing amount of evidence suggests that long-term sleep deprivation
is a major cause of a range of other clinical abnormalities, including psychiatric[9], metabolic[10],[11], and immunological disorders[12]-[14].
Increasingly, it is being recognized that normalization of disrupted circadian rhythms
might be a key approach for treating sleep disorders. This approach in turn depends
on a chronopharmacological treatment strategy, which takes into account the entire
history of a patient’s disrupted circadian rhythms. This perspective emphasizes the
importance of dealing not only with the complications that result from sleep disorders
and their immediate biological sequelae, but also with the broader process of managing
the environmental and physiological timekeepers of day to day life, factors which
can be primary causes of inadequate sleep. The purpose of this review is to summarize
what is known about how timing mechanisms influence basic biological processes, and
how disruptions to these mechanisms may present in patients who are seen in clinical
practice.
Effect of zeitgebers on the circadian clock
Zeitgebers are the environmental agents, and most often physical, such as the level
of ambient light, which serve as timekeepers for the biological clock. These external
zeitgebers however can also be linked to events that have social or psychological
meaning. The timing of the occurrence of these zeitgebers determines the appropriate
regulation of the endogenous oscillator[15]. Therefore, sleep and neurobehavioral processes are deeply affected by the regularity
of the entrainment[16]. Light tends to be the dominant zeitgeber for entraining the master clock, the brain’s
suprachiasmatic nucleus (SCN), with the daily succession of light and dark periods
having been shown to significantly regulate human circadian rhythms[17]. The size and degree of the phase changes of the circadian clock are closely determined
by specific time that the zeitgeber occurs. This can then be plotted in a diagram,
which, is known as a phase response curve. In clinical applications, manipulation
of the time at which light is introduced can be used to either advance or delay the
circadian phase. Environmental influences such as degrees of latitude, seasonal changes
to the times of sunrise and sunset, continuing exposure to bright artificial light
which is kept on until late at night, or if lighting is turned on when the individual
is in the early stages of sleep, are all examples of events which could delay the
rest phase of the internal clock for 60 min or longer. Conversely, exposure to bright
natural or artificial light very early in the morning, before an individual’s normal
waking time, can advance the circadian phase for an hour or longer. Finally, light
exposure during the middle of the day usually has no effect on the circadian phase[18].
Recent research has shown that in addition to physical stimuli, more complex, non-photic
stimuli can have a substantial entraining effect. The so-called social zeitgebers,
such as relationships with individuals, social interaction or working atmosphere can
additionally synchronize biological rhythms. Life events, which have a deep psychological
impact, such as the death of a family member or loved one, can additionally disrupt
the circadian clock. Early studies on the effects of bereavement were in fact focused
on the adverse impact that its associated emotions had on the body’s biological rhythms.
The initial hypotheses on this point emphasized that rhythm disruptions were the first
manifestations of this particular type of life stress[19]. The theory of social zeitgebers was further expanded by Monk and co-workers, who
defined social rhythms as habitual behaviors (“social zeitgebers”), which might occur
somewhat irregularly (e.g., having breakfast at a certain time on one day and another
time on the next day, versus constant timing each day), rather than other behavioral
events which have a predictable sequence (for instance, the daily taking of breakfast)[20].
Taken together, these studies show that the various features of zeitgebers, including
their exposure, timing, and duration, can be imbued with psychological significance,
which in turn entrain internal circadian cycles, and can thus have a regulatory effect
on important biological functions such as sleep.
Interactive theory of homeostasis and circadian regulation in the process of sleep
The quantity and timing of sleep are regulated by circadian and homeostatic factors,
and have been integrated into a theory of sleep known as the two-process model of
sleep, which was proposed by Borbély[21]. This model postulates that the need for sleep increases during wakefulness due
to homeostatic processes, known as “S”, in the brain, whereas circadian modification
is regulated by the circadian process, or “C”.
In a recent reappraisal, Borbély et al.[22] stated that the conceptualization of process S paralleled recent discoveries regarding
topographic differences in brain function. It has been found, for instance, that both
increases and decreases in process S are localized in the cortical regions of the
brain. Borbély and coworkers have suggested that these regional differences are reflective
of changes that occur in slow wave activity, and that such activity can be predicted
based on which area of the brain is chosen for analyzing this activity[22]. In the update to their theory, Borbély et al.[22] have suggested that the two processes are continuously interacting and provided
further speculation on the nature of this interaction. This revision of the basic
theory is based on the premise that lower circadian amplitude parallels increases
in sleep pressure while, conversely, a decline would accompany reductions in sleep
pressure. The concept of sleep pressure, which appears to be consistent with evidence
regarding the topographical specialization of brain functioning, underscores the importance
of the influence of the clock on behavior and physiology.
Melatonin and sleep
Melatonin is a pleiotropic molecule, which is released by the pineal gland and possesses
a broad range of functions[23]-[25]. Among these functions are its actions in adjusting the timing of the central clock
that in turn can produce changes in the sleep/wake cycle[26]-[28]. Consequently, disruption to melatonin’s activities is likely to produce a broad
range of sleep disorders.
Moreover, melatonin can cross the placenta and plays a potent role in synchronizing
the fetal biological clock[29]. The synthesis of melatonin is closely affected by ambient light, and can be disrupted
if such light is increased above critical levels[30],[31] thus melatonin’s activities represent a complex interplay between physiological
need and environmental cues. In addition, to its regulation of the sleep-wake cycle,
melatonin closely affects numerous activities throughout the body. These include,
but are not limited to, blood pressure and autonomic regulation, and immune system
regulation, which is accomplished through enhanced production of cytokines and interleukins.
Additionally, melatonin has a role in obesity and control of energy expenditure. Other
melatonin effects include detoxification of free radicals and antioxidant actions,
which can protect the gastrointestinal tract from ulcers[32]. These broad-ranging effects underscore melatonin’s significance as a major regulator
of bodily activities.
Human circadian rhythm sleep disorders (CRSDs)
The International Classification of Sleep Disorders (ICSD-3) redefined this group
of sleep disorders into “sleep-wake” disorders to underscore the importance of the
physiologic impact, which occur throughout the 24-h cycle.
Circadian rhythm sleep-wake disorders occur when the internal circadian clock becomes
desynchronous due to endogenous dysfunctions, or when it is disrupted by exogenous
factors in the environment. These include delayed sleep phase disorder (DSPS), advanced
sleep phase disorder (ASPS), irregular sleep-wake rhythm disorder, non-24-h sleep-wake
rhythm disorder, jet lag disorder, and shift work disorder[33]. Among the symptoms of clock desynchronization are atypical clinical symptoms, including
persistent fatigue, chronic insomnia, poor appetite, or mood disorders. Nevertheless,
some cases of desynchronization do not manifest in any of these clinical signs[26].
Delayed sleep phase disorder
One of the most common of the circadian rhythm sleep-wake disorders (CRSDs) is delayed
sleep phase disorder (DSPS), a condition that is often mistaken for sleep initiation
insomnia. The DSPS typically is a common complaint that emerges during teenage years,
but may also persist into adulthood. Affected individuals find it difficult to initiate
sleep at an appropriately early time, and, additionally, may have difficulty in rising
at a desirable time in the morning. The consequence of these problems is a chronic
and often quite severe sleep restriction; all resulting from efforts adhere to socially
expected waking schedules. The resulting sleep debt tends to drive compensatory efforts
to obtain extra sleep on weekends and free days. Despite the obvious inconvenience,
which the disorder poses to affected individuals, the associated sleep quality and
duration are essentially normal but are simply delayed[34].
Advanced sleep phase disorder
ASPS is characterized by major advances in the major sleep period in which the individual
habitually and involuntarily initiates sleep and experiences wakeup times that are
considerably earlier than the desired clock time. This condition is found more frequently
in middle aged and older adults. Affected individuals complain of sleepiness in the
late afternoon or early evening and find it difficult to stay asleep during the early
morning hours. Most patients with this condition report that they have a sleep onset
occurring between 6pm and 9pm, and tend to awaken between 2am and 5am. If the sleep
time is restricted because of social or occupational obligations, individuals with
ASPS continue to wake up at a time that is earlier than desired and consequently resulting
in sleep deficiency over a prolonged period[35].
Irregular sleep-wake rhythm disorder
Patients who experience multiple periods of sleep within a 24-hour period are referred
to as having an irregular sleep-wake rhythm disorder. Affected individuals show symptoms
of insomnia, which may include difficulties with sleep initiation or sleep maintenance,
and excessive sleepiness during the day. The condition affects many categories of
patients, including children with neurodevelopmental disorders but occurs particularly
in older adults with neurodegenerative disorders[36].
Sleep-wake rhythm disorders (SWRD’s) can also occur at irregular times, i.e., in periods
other than a 24-h day. Any condition in this category is deemed to meet these criteria
according to ICSD-3:
-
A history of insomnia, excessive daytime sleepiness, or both, which alternate with
asymptomatic episodes, due to misalignment between the 24-h LD cycle and the non-entrained
endogenous circadian rhythm of sleep-wake propensity;
-
Symptoms, which persist over the course of at least 3 months;
-
A complete diagnosis is based on data from sleep diaries and actigraphy measurements
for a minimum period of two weeks. In the case of blind individuals a longer duration
of testing is required and actigraphy records must show that the sleep/wake episodes
occur daily. Further, the circadian period is longer than 24-h and is not better explained
by another current sleep disorder, medical or neurological disorder, mental disorder,
medication use, nor by the presence of a substance use disorder[37].
Jet lag disorder
Another condition is jet lag disorder (JLD), which is caused by circadian misalignment
due to crossing time zones too quickly for the adjustment of circadian system. This
may result in difficulties for circadian system resynchronization, depending on how
many time zones were crossed, and the direction of travel. Readjustment of the circadian
system may require several days in severe cases. Other factors which can exacerbate
the severity of jet lag symptoms include characteristics of the local environment,
including the saliency and availability of local time cues. Intra-individual factors
such as the ability to sleep while sitting upright in an airline seat or individual
differences in adaptability to phase changes can also contribute.
Shift work disorder
An increasingly common phenomenon in industrialized societies around the world is
the prevalence of work assignments occurring in the nighttime hours. Such work scheduling
is now known to produce a condition known as shift work disorder (SWD). Night work
assignments can result in excessive sleepiness during the day, or inability to sleep
when sleep time is allowed. To meet the criteria for this condition, the symptoms
must not be the result of any other sleep disorder, medical condition, nor of another
medication effect. More than 20% of shift workers have symptoms of SWD. The most salient
consequence of this disorder is inattentiveness and a decline in cognitive efficiency.
These symptoms in turn may lead to an increase in slip and fall injuries, mistakes,
or increases in industrial accidents. Furthermore, additional accidents may occur
to shift workers who, at the conclusion of their shift, are driving home from work
in the early morning hours, a period which coincides with their lowest level of alertness.
This combination of risk factors has been found to increase the likelihood that affected
individuals will have a motor vehicle collision[38]. Other long-term effects that have been found to be associated with shift work are
an increased susceptibility to various cancers[39], sleep disturbances[40], gastrointestinal problems[41], neuropsychological issues and cardiovascular symptoms[42].
These symptoms may be linked to desynchronization between the internal clock and the
LD cycle. It has been recommended that shift workers should avoid exposure to light
for 30 min prior to going to sleep following their work assignments. They should also
avoid taking an additional morning shift assignment that starts before 7am or to work
for more than three successive night shifts. Additionally, women who are pregnant
should avoid performing night shift work[43]. It has been found that glasses that restrict light in wavelengths of less than
680 nm, i.e., in the “blue” end of the visual spectrum, may reduce the severity of
these symptoms[44].
Clock genes and sleep
Many research reports have established that clock genes are expressed in several brain
regions, which are involved in sleep regulation, i.e., of its stages, structure and
duration[45]. Several animal model studies have shown that the homeostatic component of sleep
is substantially controlled by the circadian clock. The absence of CLOCK in mice was
found to significantly alter the sleep organization and particularly, it reduced NREM
sleep around 60 to 120 min compared to the control mice[46]. Deletion of BMAL1 results in a change in sleep architecture and sleep duration
in mice, and the BMAL1 mutant mice exhibited an increased duration of NREM sleep[47],[48].
In mice, genetic mutation of both Cry1 and Cry2 resulted in abnormal sleep stages
and structures producing an enhanced duration of NREM sleep than in the wild type
mice [49]. These findings thus suggest that clock genes have a functional significance in
the regulation of sleep homeostasis processes.
Dysregulation in the expression of circadian clock genes in the hypothalamic suprachiasmatic
nucleus (SCN) has been shown to be associated with disrupted circadian activity. Per3
polymorphism studies have shown positive correlations with preferences for morningness
and eveningness[50],[51]. Genetic variation recognized at Clock, Per2, Per3, and Npas2 has been found to
be associated with the sleep/wake scheduling of seasonal affective disorder (SAD)
patients[52]. The condition known as familial advanced sleep phase syndrome (FASPS) has been
found to be associated with a polymorphism identified at the locus of Per2[53] and CKIδ[54]. The creation of a mutation at the locus of CKIδ in mice produced a reduction in
the circadian period[54]. In drosophila, the experimental generation of the same mutation produced a lengthening
of the circadian period[92]. Alleles identified at Per3 gene was found to influence the prevalence of DSPS[55],[56]. In bipolar patients, clock mutant was correlated with delays in their sleep phase
for 79 min and the patients showed a reduction in their sleep length of 1.25 h[57]. Taken together, this evidence demonstrates that clock genes are either directly
or closely involved in the timing, duration, architecture, stages and homeostatic
mechanisms of sleep.
Chronotype and sleep
Based on the preference of behavioral attributes of sleep/wake schedule, individuals
are classified into different phenotypes referred to as morning types (larks) and
evening types (owls). Morning type individuals prefer to sleep early in the night
and to awaken early in the morning, whereas evening type individuals prefer to go
to sleep late in the night and to awaken late in the morning. In 1976, a questionnaire
was developed to assess these preferences[58]. Individuals could thus be categorized into morning, evening and intermediate types
depending on their activities and scoring pattern of the questionnaire[58]. Due to variations in genetic machinery, a wide distribution exists in the occurrence
of chronotypes. Questionnaire testing has revealed the existence of individuals (“subtypes”)
with preferences for the moderate morning, extreme morning, moderate evening, extreme
evening and intermediate waking times[15],[58]. The chronotype is influenced by genetic vulnerability[50],[53],[59], environment[60], age and gender[15],[61]. Morning type and evening type individuals have been shown to exhibit significant
differences in their rectal temperatures and subjective alertness[59]. In addition, the sleep time of morning chronotypes has been shown to undergo advances
of at least 80 min[62].
Most children are categorized as early chronotypes, an indication that their circadian
clock is advanced. The main characteristic feature of adolescence is the ability to
stay awake until late at night and then to start to sleep in a bed[15]. There is a progressive change in the physiological functioning of the circadian
clock, and by age of 20, sleep timing tends to advance from the late status[15]. In a population study comprising 2135 university students, gender- based differences
between men and women were identified. The authors found that men have a greater preference
for evening times whereas women preferred morning time[61]. Some limited evidence has suggested that the sleep/wake cycle of short sleepers
and evening types are affected when social time schedules are changed to daylight
saving time[63]. In an analysis of 21, 600 chronotypes, it has been found that solar cues (sunlight
intensity and duration) are more important in determining the entrainment of the human
circadian clock than the social timing schedule of the society[60]. It has been suggested that the preference for morningness and eveningness is caused
by the phase of the circadian clock rather than by individual behavioral activity[64]. It should be noted that both schizophrenia and bipolar patients have a scoring
pattern more associated with eveningness preferences than control subjects[65]. These findings suggest that efforts, for instance, to improve efficiency in the
work environment or to treat clinically aberrant conditions, require an awareness
of the phase of affected individuals’ circadian clocks.
Modern lifestyles and circadian clock complications
Modern technological devices such as portable telephones, computers with light-emitting
screens, and numerous other devices can negatively impact sleep quality. This is particularly
the case when they are used late at night inasmuch as the associated light exposure
can affect the phase and amplitude of the melatonin cycle, thus resulting in poor
quality of sleep and reduced sleep duration. Numerous studies now show that simulated
monochromatic light at late nighttime hours affects the synthesis of melatonin, a
major feedback regulator of circadian clock[66]. The associated suppression in melatonin levels produces increased alertness, which
in turn can impair sleep length and quality[67]-[69]. A study has demonstrated that reading with the help of light-emitting electronic
(LEE) devices delays the secretion of melatonin for 1.5 h[69]. In addition, people who have used LEE devices for reading reported delays in their
sleep onset and poor sleep quality in the evening when compared to those subjects
who read with the printed version on paper[69]. The prevalence of jet lag in individuals has provided researchers with an opportunity
to study the internal clock in humans. Evidence from numerous studies in this area
strongly points to the need for appropriate entrainment with the environmental cues[70].
Misalignment of the circadian system can adversely affect sleep/wake cycles, which
in turn can have broader effects on overall health. Behavioral choices affecting sleep
times are major contributors to this process. Prolonged shift work can accelerate
the development of type 2 diabetes (T2DM)[71],[72]. In addition, individuals having a long-term circadian disruption are vulnerable
to psychiatric disorders[16],[73],[74], metabolic disorders, including obesity[75],[76], and T2DM[77]-[83], cardiovascular disorders[84],[85] and cancer[86],[87]. In individuals who work rotating shifts, adaptation to the new work schedule is
complicated by the fact that they encounter natural light exposure while they return
to the home in broad daylight. This, in turn, can interfere with the entrainment of
the circadian clock, and often leads to circadian disruption. Those who are assigned
to work rotating shifts often have problems in adapting to a new and unaccustomed
sleep schedule. Modern society has provided many benefits that have reduced the difficulties
of living that prevailed for many centuries previously. These benefits have come at
a cost, however, inasmuch as trends such as shift work, jet travel, the availability
of nighttime shopping and entertainment, and other pressures of our 24/7 society,
are now known to interfere with the natural functioning of the circadian system. These
consequences have unfortunately increased the risk of health problems for individuals
as well as adding to the costs of public health care.
Mealtime and circadian rhythm
Cumulative evidence reveals that mealtime closely interacts with the circadian clock[88]. “Chrononutrition”, which means meal timings, is a recently proposed specialty that
focuses the interaction between mealtime, circadian clock and metabolism. Additionally,
mealtimes affect metabolism and body weight[89]. Eating at the wrong time of day results in a misalignment between the peripheral
circadian clocks and the central biological clock in the SCN. The resultant desynchronization
enhances the risk of developing cardiometabolic disorders[88],[90]. Nocturnal species consume most of their daily food requirement at night. For example,
mice eat most of their daily consumption of food (70-80%) during the dark half of
the day (active phase)[91]. Therefore, when mealtime is limited to the light phase (inactive phase) of the
day, uncoupling between peripheral and central clocks takes place, and , in as little
as one week, mice put on more weight compared to their counterparts fed during the
dark phase in as little as one week[92]. Moreover, one more study in mice revealed that confining food accessibility to
the active phase (8-9 h) was protective against weight gain and metabolic syndrome,
secondary to atherogenic food ingestion [93]. The benefical effect of confining food to the active phase is not due to to caloric
restriction. Hatori et al.[94] subjected mice to either an ad libitum dietary access or constrained their feeding
time to 8-h per day (active phase) of a high-fat-diet. Intriguingly, mice with limited
feeding time ate similar calories to their counterparts with ad libitum food access,
yet limiting food access to 8 h had a protective effect against weight gain, increased
insulin levels, hepatic steatosis, and systemic inflammation[94].
Likewise, in humans, previous reports have demonstrated comparable outcomes, where
eating at the wrong time (nighttime “in active phase”) was accompanied with a greater
risk of developing cardiometabolic dysfunction[90]. In a Swedish study of 3610 participants of both sexes, eating late at night was
associated with an increased obesity odds ratio (OR) of 1.62 (95% confidence interval
[CI], 1.10-2.39) compared to those who did not eat late at night[95]. A recent systematic review and meta-analysis of 10 observational and experimental
studies that evaluated the impact of mealtime on obesity and metabolic changes in
humans demonstrated a negative influence of late mealtime on weight and metabolism[96]. Furthermore, both observational and experimental studies demonstrated a link between
late meal timing with hyperglycemia and diabetes mellitus[96].
Chronotherapy
Chronotherapy refers to the use of treatments that are sensitive to the circadian
characteristics of the patient. The larger purpose of this effort is to enhance patients’
therapeutic responses, e.g., treatment of sleep and psychiatric disorders with either
light therapy or melatonin[97].
Chronotherapy focuses on the degree of synchronization of a patient’s rhythmic cycles.
These include circadian parameters such as sleep/wake cycles, as well as amplitude
changes in cortisol, melatonin and body temperature[26]. Among the tools of chronotherapy are, e.g., the time of sampling of bodily fluids,
the timing of therapy, and regular assessment of therapeutic responses. The goal of
chronotherapy is to restore the functional organization of clock genes by the proper
scheduling of zeitgebers and the avoidance of factors that may disrupt the clock.
A major focus of chronotherapy is thus to manage the effects of zeitgebers on biological
functioning, all with the purpose of strengthening the weakened circadian clock[98].
It is known that bright white light can entrain and shift human circadian rhythms.
When used for this purpose it is called a ‘chronobiotic’ (i.e., an agent or a substance
that corrects the timing or strengthens oscillations of the master biological clock)[99],[100].
Treatment involving bright light exposure is now used clinically and experimentally
for treating sleep disorders and to help older patients whose circadian rhythms have
been disrupted[101].
The application of strategically timed exposure to bright light has been used to assist
shift workers in adjusting to night shift work inasmuch as it has been found to be
effective for alleviating sleepiness and fatigue.
Disorders such as sleep phase advances or delays, which directly reflect disruptions
of the biological clock, can be remediated by administration of light treatment and
sleep restriction. These treatments can also be applied to the enhancement of mood
states in patients with psychiatric disorders[102]-[104]. In the treatment of DSPS, the sleep phase can be advanced by strategically exposing
patients to bright light at specific times in the morning over a period of two weeks
(2500 lux, 2 h duration within a 3 h period between 6:00 and 9:00am). During the same
treatment program the use of specially developed goggles (from 16:00 to dusk and only
bedside lamps from dusk to bedtime), which restrict exposure to light below the 680
nm range, can attenuate the melatonin-suppressant effects of nighttime light exposure.
The recovery process from jet lag can similarly be accelerated up by a planned regimen
of timed exposure to sunlight[105]. Sleep hygiene and management of the LD and sleep schedule are the behavioral techniques
that can be adopted. Re-entrainment of desynchronized rhythms uses both behavioral
and non-behavioral strategies. Insomnia and excessive daytime sleepiness can be treated
with several pharmacological agents while melatonin is used to realign circadian rhythms
and thus to promote normal sleep[28]. Exposure to bright light in the evening can rapidly delay the circadian system,
and thus has been used for the treatment of patients suffering from ASPS.
A growing amount of evidence has confirmed that disruptions to the circadian system
can contribute to mood disorders. Increasingly patients with depressed mood and related
disorders are being treated through programs aimed at realigning the internal clock[19],[106],[107]. Regulation of sleep/wake schedule has been shown to improve the mood profile of
bipolar disorder patients[108]. In a number of psychiatric and neurodegenerative diseases there are often disruptions
to the sleep-wake cycles, and it has been reported that light therapy has been used
to address these problems[109],[110]. Light is considered to be one of the best antidepressants due to its healing effect
on mood deterioration and thus it is considered as a treatment of choice for ameliorating
seasonal affective disorder (SAD)[107],[111].
Chronopharmacology
Chronopharmacology deals with how drugs influence the circadian rhythms of individuals,
and has the further purpose of identifying the specific times at which a drug has
its optimal level of efficacy. The effects of the scheduled administration of psychoactive
drugs at various times have been examined in more detail[112]. Dawson and Armstrong, in 1996[99], following a review of the extant evidence, concluded that how a sleep disorder
manifests is connected to the phase-shifts of the circadian system. This view thus
pointed to the importance of the scheduling of drug administration. Clomipramine has
been found to provide the best response when administrated around mid-day, while the
side effects are greatest when it is administrated before bedtime[113].
Whether or not doses of neuroleptics are lethal has been shown to be reliant on the
time of administration[114]. The effectiveness of clinical therapies has been found to be critically dependent
on identifying the location of action of chronobiotics within the circadian system.
The circadian target sites chosen are in turn dependent on the specific physiological
objective of the therapy. These sites may be at the level of several functional areas
including: (a) input systems to the master oscillator, (b) the master clock itself,
(c) the entrainment mechanism, (d) coupling pathways, (e) slave oscillators, (f) passive
systems, or (g) feedback via overt rhythms in the retina by increasing or decreasing
the sensitivity to light. In the retinohypothalamic tract (RHT) these manipulations
can modulate the neurotransmitter glutamate and acetylcholine, which in turn can phase
shift the circadian timing. The geniculohypothalamic tract (GHT) is modulated by neuropeptide
Y while the SCN is stimulated by drugs acting on GABA and arginine vasopressin[115].
These findings demonstrate that treatment effectiveness for a range of disorders can
be enhanced when therapy selection for sleep disorders is based on the identification
of patients’ chronotypes. It is now evident that, before treatment is attempted, the
patients’ circadian functionality should be closely assessed and monitored. The goal
of such a diagnostic approach would include the tracking of the activity of melatonin
and its associated biochemical effects.
Taken together, these findings support the conclusion that the treatment of sleep
disorders can be improved and made most effective when the dynamic state of patients’
circadian timing systems are assessed and are made the focal determinant of how therapy
programs are developed.
Melatonin as a chronobiotic drug
Due to its influence on metabolic and electrical activity in the SCN, melatonin is
considered to be a chronobiotic drug[32]. Other studies have shown that repeated administration of exogenous melatonin can
entrain the rest/activity cycle, possibly through its effect as a “dark pulse”[99]. Lewy et al.[116] found that after four consecutive days of oral administration of melatonin the DLMO
(the first surge of melatonin output in the evening) was altered.
When administered in the evening and the early half of the night, melatonin has been
found to phase advance the endogenous clock, whereas, if given during the second half
of the night, the phase of the endogenous clock is delayed. It has been hypothesized
that adjustments to the circadian phase depend on the timing of melatonin administration,
which is either advanced or delayed[116]. Among the elderly, or in those who are chronically exposed to environmental stressors,
endogenous melatonin levels are typically at sub-optimal levels, a physiological state,
which is often associated with insomnia. In clinical cases such as these, exogenously
administered melatonin can be of benefit. Melatonin is also known to ameliorate the
deleterious effects of rotating shift work, including poor sleep quality and circadian
disruption.
Other associated studies have argued that melatonin hinders the elevation of core
body temperature, which is responsible for reducing sleep duration[117],[118]. Melatonin, which is now available in most countries as a non-prescription nutrient,
thus offers a convenient means for regulating the circadian clock, thereby providing
shift workers, particularly those who must work rapidly rotating shifts, the option
to enhance their sleep quality and duration. Among those who work slowly rotating
shifts, and thus who may experience more severe circadian disruption, it is recommended
that bright light exposure be combined with administration, of melatonin which has
been found to have additional protectant effects.
