New Treatment Options for Circadian Rhythm Sleep Disorders

by Anne Lambert, MS

Insomnia is a common condition, characterized by difficulty falling asleep, increased nighttime wakefulness, or inadequate sleep duration. Up to 75% of adults report symptoms of acute insomnia that occur a few nights per week or more, while approximately 10% to 15% have chronic insomnia, which is sleep difficulty lasting at least three nights per week for one month or more.(1,2) Significant personal and socioeconomic burdens are associated with insomnia, yet it remains largely underrecognized and inadequately treated. Daytime fatigue, difficulty concentrating, irritability, increased healthcare utilization, reduced work productivity, lower quality of life or quality of social relationships, and decrements in memory, mood, or cognitive function have all been noted.(2,3)

In an international study, interviewers found that insomnia was reported by 27.1% of respondents in the United States. Sleep maintenance was the most predominant symptom (73%), followed by difficulty falling asleep (61%), and poor sleep quality (48%). The majority of individuals with sleep problems reported being “somewhat” or “very” bothered by their symptoms, and reported that their sleep problems impacted on their daily quality of life either “somewhat” or “a lot.” Among individuals with a history of insomnia, the rate of reporting insomnia symptoms to physicians was generally low and of those who did consult a physician, few were prescribed any medication.(4)

Neurobiology of Sleep
The American Academy of Sleep Medicine (AASM) recently updated the Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders.(5) Two in-depth review papers accompanied the updated parameter. The first focused on “exogenous” circadian rhythm sleep disorders, including shift work disorder and jet lag disorder;(6) and the second focused on “endogenous” circadian rhythm sleep disorders, including advanced sleep phase disorder, delayed sleep phase disorder, irregular sleep-wake rhythm, and the non-24-hour sleep-wake syndrome (nonentrained type) or free-running disorder.(7)

Circadian rhythms are synchronized (entrained) by light and darkness and are critical to the sleep cycle. Endogenous circadian rhythms are controlled by the suprachiasmatic nucleus (SCN), a bilateral region of the brain located in the hypothalamus. The SCN sends information to other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and adenosine. Circadian arousal increases in the morning, dips in the afternoon, and peaks in the late evening. The regulation of body temperature throughout the day by the SCN is one key circadian arousal signal—with decreases in temperature in the evening inducing sleep and early-morning increases in temperature signaling the time to awaken. Combined with this, a morning pulse of cortisol, which binds to circadian hypothalamic receptors, stimulates arousal from sleep with levels declining throughout the day, therefore inducing sleep in the evening when cortisol levels decrease. Adenosine, a byproduct of energy metabolism, increases to an evening high when it inhibits neuronal activity, switching on sleep circuits.(8) The neuronal and hormonal activities generated by the SCN regulate many different body functions over a 24-hour period, including core body temperature and functioning of the autonomic, endocrine, cardiovascular, hepatic, pulmonary, and renal systems.(9) All of these systems work together to control the sleep-wake cycle and dysregulation or disturbances to of any of these systems can cause sleep irregularities.

Management Options
Depending on the symptoms reported by the patient, sleep hygiene education, behavioral interventions, keeping a sleep diary for one to two weeks, and cognitive behavioral therapy are initial options.(3) Interestingly, in the 2005 Sleep in America Poll, 7% of respondents reported using prescription sleep medication at least a few nights each month, 9% reported using over-the-counter (OTC) sleep aids, 11% reported using alcohol, beer, or wine specifically to help them sleep, and 2% reported using melatonin for sleep.(10) Clearly, there is a need for targeted, effective therapies that can address the unmet needs of patients with insomnia.

Currently, pharmacological agents include benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, antihistamines, antidepressants, melatonin, herbal products, and nutritional supplements.(3,11) Although highly effective at reducing sleep latency, benzodiazepines and the non-benzodiazepine benzodiazepine receptor agonists are associated with varying degrees of residual daytime sedation, abuse liability, and toxicity.(12) Antidepressants and antihistamines are also effective in some patients, but have troublesome adverse effects.(3,12) In 2006, AASM issued a position statement on the use of OTC and herbal medications citing insufficient evidence of effective treatment and the possibility of side effects or adverse drug interactions when used without the advice of a physician.(13) New data suggests that melatonin receptor agonists promote sleep by influencing homeostatic sleep signaling mediated by the SCN, and have been shown to be effective in the treatment of insomnia.(14,15) Clinicians need to stay up-to-date on the available agents and look to the evidence to choose the appropriate agent for each patient.

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References

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