Circadian Rhythms Across the Lifespan

Significance for Practicing Psychiatrists

Circadian Related Sleep Disorders and Useful Screening Tools

Figure.

Impact on Sleep and Psychiatric Disorders

Circadian rhythms have a profound effect on our mental and physical health. This is not surprising due to our evolution under a 24-hour light/dark cycle. Almost every cell in the body contains a molecular circadian clock, which is influenced by the master circadian clock in the suprachiasmatic nucleus in the anterior hypothalamus. At least half of all genes in the genome oscillate with a circadian rhythm.¹

There is growing recognition that circadian health, which is defined as robust ~24-hour rhythms that are stably and appropriately timed with respect to both the external light-dark cycle and social rhythms (eg, sleep times), is a key pillar of health. This ensures that human behaviors and biological processes are optimized by occurring at biologically appropriate times. Indeed, mental health and circadian health are tightly entwined, and circadian interventions can improve mood and well-being, even in healthy people.

Infancy

The human suprachiasmatic nucleus starts oscillating in utero, in synchrony with time cues from the mother. With birth, newborns lose this time cue and have irregular sleep patterns, which begin to consolidate around 3 to 5 months. The emergence of a stable sleep-wake pattern is likely to reflect the development of the infant’s endogenous circadian system. Increased daily exposure to light is associated with a faster transition to a stable sleep-wake pattern, and a stronger, more well-defined circadian pattern in infant activity levels. This suggests the possibility that increasing daytime exposure to moderate light intensities and maximizing light-dark differences in the 24-hour day may promote circadian entrainment in infants.² Needless to say, a consolidated sleep pattern in infants is associated with less sleep disruption and improved mood in caregivers.

Adolescence

With the onset of puberty, circadian rhythms shift later in time (phase delay). This is at least in part physiologically driven by sex hormones, as it is also observed in other mammals.³ Behaviors such as staying up later and the associated increased exposure to evening light also shifts the timing of the clock later.⁴

The increased use of blue-light–emitting electronic devices close to the face in the evening will phase delay the clock, as the circadian clock is maximally sensitive to blue light.⁵ Phase delays in circadian timing (a later circadian clock and more “eveningness”) are associated with increased incidence of depression, anxiety, and substance use, and may well be a transdiagnostic risk factor.⁶

When circadian phase delays lead to chronic complaints of difficulties in falling asleep and waking up at desired, often socially mandated earlier clock times, the patient may have delayed sleep-wake phase disorder (DSWPD). DSWPD affects approximately 7% to 16% of adolescents and young adults.⁷ Indeed, these later sleep onsets in combination with early school or work start times result in chronic sleep deprivation. Adolescents and young adults are arguably the most sleep-deprived segment of society. The major sleep and circadian disruption that occurs in adolescence and young adulthood likely contributes to the emergence of many psychiatric illnesses during this developmental stage.

Adulthood

Circadian rhythms drift back earlier with aging. Eveningness tends to peak in the late teens or earlier twenties, and thereafter there is a progressive drift towards earlier circadian rhythms-or more “morningness”-with aging.⁸ In general, females tend to have slightly earlier timed circadian rhythms than males. Most healthy adults (~70%), have an endogenous circadian period that is greater than 24 hours.⁹ This suggest that the majority of adults need to shift earlier (phase advance) to stay in synchrony with the external light-dark cycle. Despite increased time spent indoors, endogenous circadian timing in humans is still influenced by the external light/dark cycle. Later sunsets lead to later sleep onsets and, in the face of socially mandated fixed wake times, also to shorter sleep durations.

Historically, only adults engaged in shift work were considered to suffer from chronic circadian disruption. Rotating shift work or irregular shifts lead to a constantly changing light/dark cycle to which the circadian clock continually tries to adjust. Even stable permanent shifts, whether morning, evening, or night shifts, can be difficult, particularly as most shift workers prefer to sleep at socially normative night-time hours on days off. Thus, shift work is associated with sleep disruption and worse mental (particularly depressive symptoms) and physical health.^10,11 If possible, shift work should be avoided, particularly in patients with or at risk for mental health conditions.

More recently, irregular sleep timing has been recognized as a subtle, but chronic form of circadian disruption. Irregular sleep timing in general is associated with poorer mental and physical health, which is likely to be due in part to the circadian shifting in response to the associated irregular light/dark cycle.¹² A subtype of irregular sleep timing is known as “social jet lag,” which refers to shifts in sleep times from work or school days to free days.¹³ Typically, socially mandated work or school schedules push sleep to earlier clock times, while sleep drifts back to later more circadian appropriate clock times on free days.

Shifts of two hours or more in the midpoint of sleep between work days and free days is associated with depression, greater substance use, and worse physical health, and is estimated to occur in approximately 30% of the general population.¹³ Irregular sleep timing and social jet lag appear to be risk factors for psychiatric disorders, but longitudinal studies are needed.

Elderly

In the elderly, several factors can contribute to circadian disruption. Circadian rhythms continue to drift earlier in time. If this morningness leads to complaints of falling asleep too early in the evening and waking too early in the morning, the patient may have advanced sleep-wake phase disorder (ASWPD).⁷ Aging is also associated with reduced light exposure, as less time is spent outdoors and indoor lighting can be very dim.¹⁴

The lenses in the eyes yellow with aging; this reduces exposure to the most potent, blue wavelengths of light.¹⁴ In the extreme case of dementia, these factors, in addition to a potentially disintegrating suprachiasmatic nucleus, can result in irregular sleep-wake rhythm disorder (ISWRD).⁷ This consists of a less robust circadian rhythm with multiple episodes of sleep during the day and multiple periods of wake during the night.

Screening tools

Circadian timing is currently difficult to objectively measure outside of specialized sleep and circadian research laboratories. There are several approaches in development to address this problem. A home saliva collection kit to assess dim light melatonin onset, the current gold standard marker of circadian timing in humans, is in development.¹⁵

Blood-based transcriptomic biomarkers and algorithms to analyze data from wearables are starting to be validated against the dim light melatonin onset kit. Meanwhile, the Morningness-Eveningness Questionnaire (MEQ) asks people to consider their “feeling best” rhythms and indicate preferred clock times for sleep and engagement in various hypothetical situations (eg, physical exercise, exams, work).¹⁶ The questionnaire also assesses morning alertness, morning appetite, evening tiredness, and alarm clock dependency. Lower MEQ scores indicate more eveningness, and higher scores indicate greater morningness. Although morningness or eveningness correlates with dim light melatonin onset (r = -0.70) there can be up to a 4-hour range in dim light melatonin onset for a given MEQ score.¹⁷

The Munich ChronoType Questionnaire (MCTQ) focuses on sleep timing and the regularity of one’s work schedule, number of workdays per week, and sleep timing and alarm clock use on workdays and free days.¹⁸ Sleep timing on free days can give a sense of endogenous circadian timing, although sleep on free days can also be influenced by alarm clock use, or by recovery from sleep deprivation that may have built up over the work/school week. More easily, the MCTQ can help assess for social jet lag as the difference between usual sleep timing on work/school days versus usual sleep timing on free days.

Sleep timing and social jet lag can also be assessed over the short term with a 7-day sleep diary. For patients with shifting or irregular work schedules, a work diary (with commute times if they are long) can be also be useful.

A more recent questionnaire, SATED (Satisfaction, Alertness, Timing, Efficiency and Duration) may be useful to assess sleep and circadian issues.¹⁹ This brief questionnaire may pinpoint the sleep and circadian factors most bothersome to the patient. In general, asking patients about daily routines, what changes they would like to make to their sleep schedule, and what social factors affect their sleep times will be useful.

Circadian treatments

Overall, striving for bright light during daytime and minimizing nighttime light promotes wakefulness during the day and sleep at night and leads to a more robust circadian rhythm. Specific first-line treatments for circadian rhythm disorders include strategically timed light therapy and melatonin.⁷ Circadian treatments work best when they are integrated into the patient’s regular routine. A summary of circadian treatments and their effects is shown in Figure.

A first step in treatment is to stabilize sleep timing as much as possible and ensure that the patient has the opportunity to get 7 to 9 hours of sleep. It may also be necessary to slowly shift the sleep schedule in the desired direction (~15-30 min/d), as the associated changes in light/dark exposure will help shift the circadian clock.

Furthermore, light exposure across waking hours should be considered. If trying to shift rhythms earlier, evening light should be minimized; to shift rhythms later, morning light should be minimized. For example, older adults with ASWPD should be instructed to minimize light exposure prior to their desired wake time. Light exposure can be minimized by staying indoors, dimming room lights and light-emitting devices, wearing commercially available blue light blocking amber glasses, and of course by sleeping/keeping eyes closed.

Light therapy, which is indicated for ASWPD, DSWPD, and ISWRD in adults with dementia, is typically administered for 30 to 60 minutes using a bright light box or a wearable light device that permits ambulation during the light treatment (eg, Re-Timer). To shift circadian rhythms earlier (ie, for DSWPD treatment), light therapy should be administered in the morning, ideally at habitual wake time. Timing is adjusted as the wake time is advanced. To delay circadian rhythms (ie, for ASWPD treatment), light therapy should be used in the evening.

Contraindications for light therapy include eye disease, conditions that cause photosensitivity (eg, lupus), phototoxic medication use, and a history of hypomania/mania (unless patients are very carefully monitored).

Supplemental melatonin is available over the counter in the US and can be used to assist with phase shifting, particularly in DSWPD, although the phase shifts are smaller than those seen with light. Low doses (≤ 0.5 mg) of melatonin are usually recommended to avoid the soporific effects seen with higher doses.²⁰ Morning melatonin can shift rhythms later, whereas melatonin taken about 5 hours before usual sleep onset time can shift rhythms earlier.

Melatonin use is contraindicated in the elderly because of increased risk for falls and mood changes as well as patients with epilepsy, those taking anti-hypertensive medications or blood-thinners, and women who are pregnant or breastfeeding.

Circadian treatments can be difficult to implement because the treatment needs to be timed according to the individual’s endogenous circadian timing. Incorrect timing of treatment can worsen circadian rhythm disorders. For example, in an individual who habitually wakes around 7 am, light exposure at 7 am would be biologically interpreted as morning light, and result in phase advances. However, in an individual who habitually wakes at 11 am, 7 am light exposure could be biologically interpreted as late night light, and possibly result in phase delays. For this reason, we do not initiate morning light treatment any earlier than 1 hour before habitual wake time.

Physical activity may also shift circadian timing, although findings indicate that the effects of a 1-hour high intensity exercise on subsequent circadian timing were small.²¹ While meal timing may not shift circadian timing, restricting eating to during the biological day can lead to weight loss.²²

Social rhythms therapy, a treatment for mood disorders, focuses on regulating daily activities with potential impact on circadian timing such as closely scheduling the timing of bed/wake, meals, exercise, first social contact, and start of work so that these events occur at a consistent time and do not vary significantly day-to-day.²³ The therapy is considered potentially effective, although more comparative efficacy trials are needed.

Conclusion

Circadian health is a key pillar of well-being. Exposure to bright light during the daytime and minimizing light during the night can help strengthen circadian rhythmicity. Circadian rhythms change across the lifespan; adolescents and younger adults are more likely to experience circadian phase delays, whereas older adults are more vulnerable to circadian phase advances. Disruptions in the circadian system and its alignment with the sleep-wake cycle can contribute to psychiatric illness.

Treatment of circadian rhythm disorders can improve mental health. Treatments include bright light therapy and melatonin; however, the timing of such interventions is critically important to their success.

Acknowledgement-We thank Muneer Rizvydeen for his help with creating the figure.

Disclosures:

Dr Burgess is Professor, and Dr Swanson is Associate Professor, Sleep and Circadian Research Laboratory, Department of Psychiatry, University of Michigan, Ann Arbor, MI. Dr Burgess reports that she is a consultant for Natrol, LLC and MovingMindz, Pty, Ltd; Dr Swanson reports no conflicts of interest concerning the subject matter of this article.

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