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

• Published in: Nature reviews. Drug discovery Vol. 7; no. 6; pp. 530 - 540
• Main Authors: Wafford, Keith A., Ebert, Bjarke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2008; Nature Publishing Group
• Subjects: Antidepressive Agents - administration & dosage; Antidepressive Agents - adverse effects; Antidepressive Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Biotechnology; Brain Mapping; Cancer Research; Care and treatment; Clinical Trials as Topic; Cognitive Therapy; Dosage and administration; GABA Modulators - administration & dosage; GABA Modulators - adverse effects; GABA Modulators - therapeutic use; GABA-A Receptor Agonists; Histamine Antagonists - administration & dosage; Histamine Antagonists - adverse effects; Histamine Antagonists - therapeutic use; Humans; Hypnotics; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - therapeutic use; Insomnia; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; Physiological aspects; review-article; Sedatives; Sleep Initiation and Maintenance Disorders - drug therapy; Sleep Initiation and Maintenance Disorders - etiology; Sleep Initiation and Maintenance Disorders - metabolism; Sleep Initiation and Maintenance Disorders - therapy; Sleep Stages - drug effects; Sleep-wake cycle; Wakefulness; Wakefulness - drug effects
• DOI: 10.1038/nrd2464
• ISSN: 1474-1776; 1474-1784

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. In this Review Ebert and Wafford discuss the mechanisms of action of current and emerging hypnotic drugs, emphasizing the importance of taking into account the consequences of disrupted sleep on day-time performance (or quality of wakefulness) when developing new therapeutics. 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.