Understanding sleep-wake mechanisms and drug discovery

Abstract

Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use. Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy. Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep medication.

Hypnotics with novel modes of action

“…triazolam, temazepam, estazolam, flurazepam, quazepam), and more recently with Z drugs (e.g. zolpidem, zaleplon, zopiclone and variations thereof) which all act on the same target, the GABA A receptor, but on different receptor subunits (see e.g …”

<p>Feasibility of Patient-Controlled Sleep with Dexmedetomidine in Treating Chronic Intractable Insomnia</p>

“…The depth of sedation (MOAAS decreasing from 5 to 2) was associated with increasing dosage of Dex. As shown in Figure 2, the mean dosages of Dex required to achieve MOAAS levels 4, 3 Figure 3.…”

“…1,2 The absence of sleep is associated with significant health and economic burdens, reduced work efficiency and quality of life. 3 Common pharmaceutical treatments of insomnia, based on the use of benzodiazepines and non-benzodiazepine hypnotics, 4 can cause residual effects, withdrawal reactions, tolerance, abuse potential and physical dependence. 5 Further, these drugs alter sleep structure and reduce the depth of non-rapid eye movement sleep.…”