Finding better answers for sleep disorders
The psychopharmacology of sleep disorders is awakening from a long slumber. Before now, you might have considered sleep disorders as somewhat exotic, to be diagnosed by sleep subspecialists with fancy and expensive equipment. Other than abusable stimulants or dependence-causing hypnotics, psychopharmacologic treatments were lacking.
Today, new treatments for patients with sleep and wakefulness problems are changing assumptions about what constitutes a treatable condition, what treatments are available, and how long to treat (see “When patients can’t sleep”). As sleep’s neurobiology becomes more clear,1,2 psychopharmacologists need to become experts in diagnosing and treating sleep disorders.
‘New’ treatable conditions
Narcolepsy and cataplexy have long been recognized as important—if rare—sleep disorders. We now know that several other diagnosable and treatable conditions are much more common causes of disrupted sleep and impaired daytime wakefulness. These include:
- shift-work sleep disorder, treatable with modafinil,3
- obstructive sleep apnea, treatable with modafinil augmentation of continuous positive airway pressure (CPAP)3
- chronic insomnia, treatable with chronic administration of hypnotics such as eszopiclone and others in development that do not seem to cause dependence4
- restless legs syndrome, treatable with pramipexole and other dopamine agonists (Table 1).5
Consider these sleep disorders as the possible cause of symptoms when you evaluate a patient with treatment-resistant depression, cognitive dysfunction, insomnia, or excessive daytime sleepiness. Likewise, symptoms of nighttime wakefulness and excessive daytime sleepiness should be evaluated as possibly being secondary to another psychiatric or medical disorder, pain, or psychotropic medication.
Psychotropic agents now used or in testing for sleep disorders
Promote daytime wakefulness
Armodafinil (active renantiomer of modafinil; prolonged half-life)
Late clinical testing
H3 histamine antagonists
Early clinical and preclinical testing
For chronic insomnia
Eszopiclone (active senantiomer of hypnotic zopiclone)
Indiplon (immediate- and modified-release formulas)
Late clinical testing
Ramelteon (selective M1/M2 receptor melatonin agonist
Obstructive sleep apnea
CPAP at night
Modafinil in the daytime
Serotonin, alpha-adrenergic antagonists
Restless legs syndrome
Late clinical testing
*FDA-approved for treatment of insomnia; length of treatment not specified
CPAP: Continuous positive airway pressure
For sleep deprivation caused by partying or working overtime, no one would argue that a drug—rather than a good night’s sleep—is the treatment of choice. However, the 25% of shift workers who have shift-work sleep disorder have more than a lifestyle problem. They require evaluation for treatment of sleepiness during their working hours and when they drive to and from work.
Traffic accidents have been shown to be correlated with the daily rhythm of sleepiness (Figure 1), 6 suggesting that individuals who must sleep during odd hours, work during odd hours, and drive to and from work need to be evaluated for treatment. Such treatment would include hypnotics that promote sleep when these individuals have the time to sleep and wake-promoting agents such as modafinil when they must work and drive.
Even more remarkable are data showing that a person who has been awake for 24 hours has the psychomotor performance of someone who meets the legal definition of intoxication (Figure 2).7 This finding has implications for anyone who pulls an “all-nighter,” including medical interns working in intensive care units.8
Figure 1 Timing of traffic accidents correlates with daily sleepiness rhythm
Traffic fatalities (blue bars) occur most frequently from 10 p.m. to 6 a.m. and 4 to 6 p.m., corresponding with daily sleepiness patterns (red line).
Source: Prepared from National Center on Sleep Disorder Research/National Highway Traffic Safety Administration data, reference 6
Figure 2 Moderate fatigue and alcohol intoxication
have similar effects on performance
Hand-eye coordination compared in 40 subjects kept awake for 28 hours and after consuming enough alcohol to attain a mean blood alcohol concentration of 0.10%. Results expressed as percentage of performance at start of each testing session.
Source: Adapted and used with permission from Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997;388:235.
How does the clinician differentiate sleep disorders from other sleep-related problems, such as poor sleep hygiene, 24-hour consecutive overworkers, and chronic overworkers with huge sleep debts (the “I-can-sleep-when-I’m-dead” syndrome). We should not prescribe pharmacologic interventions for patients who accumulate huge sleep debts, enabling them to drive up their sleep debts even further. But shift-work sleep disorder affects many of us, at least intermittently, as our schedules change. This applies not just to classical shift workers such as police, fire, nursing, and factory workers, but also to those who:
- commute long distances across time zones and have vital work to do in the first few days after arrival or return, while suffering “jet lag”
- must intermittently work long hours, such as “on call” physicians and nurses, project managers, and programmers racing to meet a deadline.
By understanding the nature of true sleep disorders and their treatments, you will be in a strong position to decide whom to treat and with what.
- National Sleep Foundation. www.sleepfoundation.org
- Stahl SM, Higgins CM (eds). Illustrated insights in sleep: excessive sleepiness. San Diego, CA: NEI Press; 2005.
- National Institutes of Health. State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. June 2005. consensus.nih.gov/2005/2005InsomniaSOS026html.htm
Drug brand names
- Eszopiclone • Lunesta
- Modafinil • Provigil
- Pramipexole • Mirapex
- Ramelteon • Rozerem
- Ropinirole • Requip
- Zaleplon • Sonata
- Zolpidem • Ambien
Dr. Stahl receives grant/research support or serves as a consultant to Asahi, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb Co., Cephalon, Cyberonics, Cypress Bioscience, Pierre Fabre, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Nova Del Pharma, Otsuka, Pfizer Inc., Sanofi Synthelabo, Sepracor Inc., Shire Pharmaceuticals, Solvay Pharmaceuticals, and Wyeth.
Adapted and reprinted with permission from PsychEd Up: Psychopharmacology Educational Update 2005;1(5):6-7. Copyright 2005, NEI Press.
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7. Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997;388:235.-
8. Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 2004;351:1838-48.