Advances in the pharmacological management of non-24-h sleep-wake disorder

ABSTRACT

Introduction: Melatonin, a hormone that regulates circadian rhythms and the sleep-wake cycle, is produced mainly during the dark period in the pineal gland and is suppressed by light exposure. Patients with non-24-h sleep-wake disorder (non-24) fail to entrain the master clock with the 24-h light-dark cycle due to the lack of light perception to the suprachiasmatic nucleus typically in totally blind individuals or other organic disorders in sighted individuals, causing a progressive delay in the sleep-wake cycle and periodic insomnia and daytime sleepiness.

Areas covered: Herein, the authors review the pharmacological therapies including exogenous melatonin and melatonin receptor agonists for the management of non-24. They introduce a historical report about the effects of melatonin on the phase shift and entrainment for blind individuals with the free-running circadian rhythm.

Expert opinion: Orally administered melatonin entrains the endogenous circadian rhythm and improves nighttime sleep and daytime alertness for non-24. Currently, tasimelteon is the only approved medication for non-24 by the US Food and Drug Administration and the European Medicines Agency. Treatments that focus only on sleep problems are insufficient for the treatment of non-24, and aids to entrain the free-running rhythm with the light-dark cycle are needed.

KEYWORDS:

• Circadian rhythm
• daytime sleepiness
• free-running rhythm
• insomnia
• melatonin
• melatonin receptor agonist
• non-24-h sleep-wake disorder
• tasimelteon

Article highlights

• Non-24 fails to synchronize the endogenous biological clock with the environmental light-dark cycle due to the lack of light perception to the SCN in totally blind individuals, causing a progressive delay in the sleep-wake and melatonin secretion cycles.

• Melatonin is produced primarily at night in the pineal gland and is suppressed by light exposure.

• Melatonin is involved in the regulation of circadian rhythms.

• The MT1 and MT2 receptors in the SCN mediate the circadian phase-shifting and sleep-promoting effects of melatonin.

• The treatment strategies for non-24 aim to entrain the free-running rhythm with the 24 h light-dark cycle.

• Melatonin receptor agonists resynchronize the circadian phase shift and have the potential as a pharmacological agent for non-24.

• Tasimelteon is the only approved medication by the FDA and EMA for the treatment of non-24 in both sighted and blind individuals.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.