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A new dawn in the sleep disorders pipeline?

Nature Reviews Drug Discovery volume 11, pages 595–596 (2012)Cite this article

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Pharmacological treatment options

Sleep is regulated by circadian biological clocks and homeostatic mechanisms that monitor the distribution of sleep and wakefulness. Aspects such as sleep duration and circadian preferences for sleeping patterns are determined by genetic polymorphisms. Some of the signalling molecules implicated in promoting wakefulness include noradrenaline, acetylcholine, histamine, dopamine, serotonin and the neuropeptides orexin A and B (also referred to as hypocretins). GABA (γ-aminobutyric acid) and adenosine, however, promote sleep. In addition, melatonin has a key role in the synchronization of biological rhythms with environmental cues. Virtually all molecules are not essential for the regulation of sleep, which is indicative of the redundancy of signalling molecules as well as the probable complexity of the spatiotemporal specificity in the regulation of different sleep states. This complexity, as well as the substantial overlap of the signalling molecules and specific receptor subtypes with other central nervous system (CNS) functions, has substantially contributed to a limited array of highly specific and validated molecular targets to treat sleep disorders. As a result, the current pharmacological interventions to treat sleep disorders, which are often accompanied by behavioural therapies, utilize a relatively small subset of the molecular targets and signalling pathways known to have a role in sleep. The vast majority of drugs used to improve sleep latency and/or sleep maintenance in insomnia patients are benzodiazepines and non-benzodiazepines such as zolpidem and eszopiclone. Both drug classes target the GABAergic signalling pathway and are allosteric modulators of GABAA receptor currents with similar efficacy profiles. Alternative pharmacological insomnia treatment options include the melatonin receptor (subtypes MT1 and MT2) agonist ramelteon (Rozerem; Takeda Pharmaceuticals), which has a very modest efficacy profile, or drugs targeting histamine receptors. Stimulant compounds for the treatment of hypersomnia-related sleep disorders include modafinil and armodafinil (Nuvigil; Teva Pharmaceuticals), which have undefined molecular targets but are likely to modulate dopamine transporters. These widely used drugs have a modest efficacy but a favourable safety profile. The GABAB and possibly γ-hydroxybutyrate receptor agonist sodium oxybate (Xyrem; Jazz Pharmaceuticals) is indicated for excessive daytime sleepiness and cataplexy in patients with narcolepsy. Also, drugs targeting catecholamine and serotonin signalling pathways are used to treat REM sleep disorders, narcolepsy and other hypersomnia-related sleep disorders. The pharmacological treatment options for circadian rhythm and parasomnia-related sleep disorders are largely limited to behavioural therapies and off-label drugs, representing significant unmet needs.

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Figure 1: The developmental pipeline for sleep disorders.

References

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Acknowledgements

GBI Research would like to thank M. Canal, Ph.D., at the University of Manchester for her scientific advice.

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  1. Waldemar Ockert, Ph.D., is an analyst at GBI Research, Knowsley House, Knowsley St, Bolton, BL1 2AH. wockert@gbiresearch.com,

    Waldemar Ockert

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The author declares no competing financial interests.

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Ockert, W. A new dawn in the sleep disorders pipeline?. Nat Rev Drug Discov 11, 595–596 (2012). https://doi.org/10.1038/nrd3789

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