Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease

• Published in: Annual review of pharmacology and toxicology Vol. 64; no. 1; pp. 359 - 386
• Main Authors: Kron, Jarrah O.-Z.J, Keenan, Ryan J, Hoyer, Daniel, Jacobson, Laura H
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 23-01-2024
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - drug therapy; Alzheimer's disease; daridorexant; Humans; insomnia; lemborexant; orexin; Orexin Receptor Antagonists - pharmacology; Orexin Receptor Antagonists - therapeutic use; Orexin Receptors; Orexins - pharmacology; sleep; Sleep - physiology; sleep wake rhythm disorders; suvorexant; sleep; sleep/wake rhythm disorders; daridorexant; orexin; Alzheimer's disease; lemborexant; insomnia; suvorexant
• ISSN: 0362-1642; 1545-4304; 1545-4304
• DOI: 10.1146/annurev-pharmtox-040323-031929

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep wake dysregulation to reestablish good sleep wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.