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  • Review Article
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Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time

Key Points

  • The incidence of insomnia in the general population is 10–30% and approximately 50% of cases complain of serious daytime consequences, such as inability to concentrate, reduced energy and memory problems. However, the development of hypnotic drugs tends to focus on the marginal and statistically significant increase in minutes slept during the night instead of the effects on the quality of wakefulness.

  • Current hypnotics, such as benzodiazepine receptor agonists, antihistamines and antidepressants, can be effective short-term treatments, but they can also cause next-day sedation, ataxia and cognitive impairment.

  • Advances in the understanding of sleep mechanisms have indicated new approaches for discovering novel hypnotic drugs. For example, the enhancement of slow-wave sleep and the modulation of circadian rhythms are strategies being pursued in the development of improved insomnia therapeutics.

  • The use of primary insomniacs as the key population for clinical development of hypnotics is limiting novel treatments of insomnia. Focus should be on the development of compounds with restorative effects on daytime function rather than on induction and maintenance of sleep only. Development of hypnotics in secondary insomniacs may address the relevant effects of sleep on quality of life and daytime performance.

Abstract

Sleep is essential for our physical and mental well being. However, when novel hypnotic drugs are developed, the focus tends to be on the marginal and statistically significant increase in minutes slept during the night instead of the effects on the quality of wakefulness. Recent research on the mechanisms underlying sleep and the control of the sleep–wake cycle has the potential to aid the development of novel hypnotic drugs; however, this potential has not yet been realized. Here, we review the current understanding of how hypnotic drugs act, and discuss how new, more effective drugs and treatment strategies for insomnia might be achieved by taking into consideration the daytime consequences of disrupted sleep.

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Figure 1: Sleep and arousal centres in the human brain.

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Correspondence to Bjarke Ebert.

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Competing interests

Both authors are employed by companies involved in the development of hypnotics.

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DATABASES

OMIM

Alzheimer's disease

familial advanced sleep phase syndrome

Parkinson's disease

Glossary

Primary insomnia

Patients who suffer from sleeplessness for at least 1 month that cannot be attributed to a medical, psychiatric or an environmental cause (such as drug abuse or medications).

Sedative

A substance that depresses the central nervous system, resulting in calmness, relaxation, reduction of anxiety and sleepiness.

Tolerance

Reduced drug responsiveness with repeated exposure to a constant drug dose.

Hypnotic drugs

A class of drug that induces sleep; used for the treatment of insomnia and to induce anaesthesia.

Sleep debt

The cumulative effect on the body of not getting sufficient sleep.

Sleep drive

The homeostatic mechanism that produces an increased tendency to fall asleep.

Narcolepsy

A sleep disorder that usually presents in young adulthood, consisting of recurring episodes of sleep during the day and often disrupted nocturnal sleep. Narcolepsy affects more than 100,000 people in the United States alone and seems to have a genetic basis.

Rotation adaptation task

A task in which subjects reach for visual targets using a hand-held cursor while unconsciously adapting to systematic rotations imposed on the perceived cursor trajectory.

Sleep hygiene

Sleep habits that promote healthy sleep such as fixed bedtime and awakening time, avoiding naps, blocking out noise and light, and avoiding caffeine and alcohol before sleep.

Polysomnographic variables

Physiological variables that are captured during electroencephalography sleep analysis, for example, brain electrical rhythms, eye movements, muscle activity or skeletal muscle activation, heart rhythm and breathing function or respiratory effort during sleep. These also include variables such as sleep latency and maintenance, duration of rapid eye movement (REM) and non-REM sleep.

Sleep latency

The time it takes to go from full wakefulness to being asleep.

Scheduled status

A controlled drug for which use and distribution is tightly regulated owing to its abuse potential or risk. Classified by the US Food and Drug Administration from I to V with Schedule I drugs exhibiting the highest risk. Most benzo-diazepines are Schedule IV meaning that they can only be supplied and produced by those authorized to do so.

Subjective sleep parameters

Using questionnaires, patients rate their feelings of time to sleep, time awake and number of awakenings during the night in addition to the quality of sleep and feeling 'refreshed' in the morning.

Phase-shift

An induced temporal shift of the normal circadian rhythm.

Montgomery–Åsberg depression rating scale

An 11-item clinician-administered questionnaire that is used to rate the severity of a patient's depression.

Sheehan disability scale

A patient self-reporting tool developed to assess functional impairment in work/school, social and family life. It uses a series of 10-point visual analogue scales.

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Wafford, K., Ebert, B. Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time. Nat Rev Drug Discov 7, 530–540 (2008). https://doi.org/10.1038/nrd2464

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