Resetting the Clock: Addressing Circadian Disorders

Phyllis Zee, MD

Associate Director, Center for Sleep & Circadian Biology, Professor, Northwestern University Institute for Neuroscience

This interview was conducted by Peter Cook on July 7, 2006.

Background

Dr. Phyllis Zee’s interest in circadian rhythms began in graduate school, after which she completed a residency in neurology and fellowship in sleep medicine. Her career has combined clinical care, research, and education in the area of circadian rhythms and sleep.

Circadian rhythms

A healthy person’s ability to sleep for a consolidated 7–8 hours a night and to maintain wakefulness during the day is the product of the interaction between two regulatory processes: the build up of sleep drive (sleep homeostasis) and circadian sleep propensity. “Circadian rhythms time physiological and behavioral rhythms, as well as promote alertness during the day and sleep at night” Dr. Zee says. “All physiological, behavioral, and cellular activity exhibit circadian rhythmicity.”

The epicenter of circadian rhythm governance in the brain is the suprachiasmatic nucleus (SCN), which is located in the hypothalamus. The SCN is home to a set of rhythmic neurons. “They’re literally pace-makers and produce a near 24-hour endogenous rhythm,” Dr. Zee says. “What we know now is that these circadian rhythms are actually regulated at a molecular level. Circadian rhythms are genetically regulated, self-sustaining, and the product of the interaction of a number of circadian clock genes.”

The usual frequency of oscillation (period) of human circadian rhythms is slightly longer than 24 hours (24.1–24.2 hrs). However, the rhythm can be “entrained” to our standard 24-hour light/dark cycle. “If you lived in a cave,” Dr. Zee says, “you wouldn’t operate on a 24-hour cycle. Every day you’d wake up and go to bed a little later than the previous day. We call this free-running, or non-entrainment.” Light and melatonin (produced by the pineal gland) are important time givers (or “zeitgebers”) that adjust the timing of the circadian clock on a daily basis. Light is the strongest zeitgeber and it has been shown that it can regulate the speed at which circadian genes are turned on or turned off.

Circadian Rhythm Sleep Disorders

Circadian rhythms regulate the timing of the sleep wake cycle and both sleep and wake propensity. Although the exact mechanism by which this occurs is not yet clear, Dr. Zee explains that “there are neural pathways between the SCN and other areas in the brain that regulate sleep and wakefulness.” In addition, the SCN regulates the timing of melatonin secretion from the pineal gland. Once secreted, melatonin exerts its action on SCN neurons. “These SCN neurons contain melatonin receptors, which when activated affect their timing as well as the level of electrical activity.” It has been proposed that the ability of melatonin to attenuate the firing rate of SCN neurons is responsible for its sleep promoting effects.

Unsurprisingly, when the regulation of circadian rhythms is altered, sleep disorders, called “circadian rhythm sleep disorders” can result. One of the more common types are phase disorders such as delayed sleep phase and advanced sleep phase. In these disorders, the major sleep period comes either hours later or earlier, respectively, than is generally socially acceptable.

“Delayed sleep phase is more common in adolescents and young adults and may be comorbid with depression and other mood disorders. Advanced sleep phase, is more often seen in older individuals, and it should be differentiated from early insomnia associated with depression,” Dr. Zee says.

Another common circadian sleep disorder is shift-work sleep disorder. This occurs mostly in those who work night shifts. Individuals with shift-work sleep disorder complain of difficulty sleeping during the day, and difficulty staying awake during the night, particularly in the early morning hours. “There are many comorbidities attendant to shift-work sleep disorder,” Dr. Zee says. “Obesity, GI disorders, cardiac disorders, substance abuse in effort to induce wakefulness or sleepiness, and mood disorders are common.”

Patients with neurological disorders, such as Alzheimer’s disease, and older people in nursing homes, sometimes fall prey to irregular sleep wake cycle disorder. They don’t have a consolidated bout of nightly sleep, and when they do sleep, it’s in short, irregular bursts. There is data to suggest that in Alzheimer’s Disease, this condition may at least in part due to deterioration of the SCN.

“Due to the lack of light perception, non-entrainment is mostly seen in blind people,” Dr. Zee says. “Patients will complain of insomnia, excessive sleepiness, or both, depending on the time of the month. Because their sleep and wake times are delaying every day, alignment with the 24 hour external day is also changing.” Non-entrainment is rare in sighted individuals who may have alterations in their response to circadian synchronizing agents, or alternatively are not exposed to bright light or structured social and physical activities.

The Cause

Although the exact underlying mechanisms responsible for many of the circadian rhythm sleep disorders are not well understood, the evidence suggests that a combination of endogenous and exogenous factors are involved. For example, while the degradation of neurons in the SCN may in part explain irregular sleep disorder, the lack of structured activities and bright light exposure can also promote irregular cycles in the elderly with dementia.

“Several possibilities may also be involved in the development of delayed sleep phase,” says Dr. Zee. “An unusually long circadian period, decreased sensitivity to entraining agents, or lack of light exposure can all contribute to the delayed phase.”

Certain behaviors can perpetuate delayed and advanced sleep phase. Those with the former don’t get the light they need in the morning, and those with the latter get too much light in the morning. Both conditions appear to have a genetic basis. Delayed and advanced sleep phase can run in families. Recently, mutations in circadian clock genes have been reported in families with advanced sleep phase, and scientists are looking for more genes involved in both disorders.

Treatment

“For both delayed and advanced sleep phase light therapy is the first-line treatment,” Dr. Zee says. “Because light in the morning usually advances the timing of circadian rhythms, and light in the evening delays circadian rhythms, we can use timed light exposure to realign circadian rhythms.”

Patients with delayed sleep need to get more light in the early morning and less in the evening, and vice versa for advanced phase patients. Melatonin has been shown to be useful for the treatment of delayed sleep phase. However, most studies of melatonin for the treatment of sleep phase disorders have been smal, and its use is not currently approved by the FDA for these indications. Light therapy during the night has been shown to help re-align circadian rhythms and increase alertness in night shift-workers. Studies have shown that melatonin can help night shift workers sleep during the day, but does not improve performance or alertness during night. Caffeine and scheduled naps can also help improve alertness during the night. More recently, modafinil, a wake promoting agent, was approved by the FDA for the excessive sleepiness that most of these patients experience during the night and early morning. For treating irregular sleep disorder, light therapy is, again, very useful. “When the patients are older, or in a nursing home,” Dr. Zee says, “structured physical and social activities during the day, keeping them engaged, has been shown to be very helpful.”

Conclusion

“This is an exciting time to be studying circadian rhythms,” Dr. Zee says. “We’re learning more about the genetics and pathophysiology of sleep and other circadian disorders, though we’ve got a ways to go yet. Of particular interest, it turns out that the genes which regulate circadian rhythms aren’t just in the SCN or the CNS—they’re in cells of other tissues and organs. Thus, biological timing is likely to have important implications for conditions ranging from sleep and mood disorders to respiratory, metabolic and cardiovascular disorders. The future of this field of study lies in integrating an understanding of biological timing with psychiatric and medical disorders beyond sleep.”

Disclosure: Dr. Zee has received financial support from Boehringer Ingelheim, the NIH, Schwarz Bioscience, and Takeda; has been on the speaker’s bureau for sanofia aventis, Sepracor, and Takeda; and has been a consultant to Boehringer Ingelheim, GlaxoSmithKline, Neurocrine, Pfizer, sanofi aventis, Sepracor, and Takeda.