![]() Expression of downstream effectors to melatonin receptors was also affected. The transcription and expression of melatonin receptors were reduced, and circadian rhythm related genes were altered. Tryptophan and 5-hydroxytryptamine levels were increased in the hypothalamus, while melatonin level was decreased. Sleep fragmentation, circadian rhythm disorders, and insomnia exhibited in CRS-treated mice formed sleep disorders. Mice undergoing chronic restraint stress modeling for 28 days showed body weight loss and reduced locomotor activity. The study explored the melatonin-related mechanisms of stress-associated sleep disorders on a mouse model of chronic stress by exploring the alteration in sleep architecture, melatonin, and related small molecule levels, transcription and expression of melatonin-related genes as well as proteins. Stress may trigger sleep disorders and are also risk factors for depression. 4Department of Surgery, University of Toronto, Toronto, TO, Canada.3Institute of Molecular Medicine and Innovative Pharmaceutics, Qingdao University, Qingdao, China.2Institute of Drug Discovery Technology, Ningbo University, Ningbo, China.1Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.Histamine receptor inverse agonists (APD-125, eplivanserin, and LY2624803) improve slow-wave sleep but, for various reasons, the drug companies withdrew their products.Tian-Ji Xia 1, Zhi Wang 1, Su-Wei Jin 1, Xin-Min Liu 2, Yong-Guang Liu 1, Shan-Shan Zhang 1, Rui-Le Pan 1, Ning Jiang 1, Yong-Hong Liao 1, Ming-Zhu Yan 1*, Li-Da Du 3,4* and Qi Chang 1* Piromelatine may improve sleep maintenance. Phase II studies of dual orexin receptor antagonists (almorexant, lemborexant, and filorexant) have shown some improvement in sleep maintenance and sleep continuity. Valerian is relatively safe but has equivocal benefits on sleep quality. Tryptophan decreases sleep onset in adults, but data in the elderly are not available. Melatonin slightly improves sleep onset and sleep duration, but product quality and efficacy may vary. Non-FDA-approved hypnotic agents that are commonly used include melatonin, diphenhydramine, tryptophan, and valerian, despite limited data on benefits and harms. Tiagabine, sometimes used off-label for insomnia, is not effective and should not be utilized. Trazodone, a commonly used off-label drug for insomnia, improves sleep quality and sleep continuity but carries significant risks. Benzodiazepines should not be used routinely. Low-dose zolpidem sublingual tablets or zaleplon can alleviate middle-of-the-night awakenings. Eszopiclone or zolpidem extended release can be utilized for both sleep onset and sleep maintenance. Suvorexant or low-dose doxepin can improve sleep maintenance. Ramelteon or short-acting Z-drugs can treat sleep-onset insomnia. The choice of a hypnotic agent in the elderly is symptom-based. We review the indications, dosing, efficacy, benefits, and harms of these drugs in the elderly, and discuss data on drugs that are commonly used off-label to treat insomnia, and those that are in clinical development. This review focuses on Food and Drug Administration (FDA)-approved drugs for insomnia, including suvorexant, low-dose doxepin, Z-drugs (eszopiclone, zolpidem, zaleplon), benzodiazepines (triazolam, temazepam), and ramelteon. Current drugs for insomnia fall into different classes: orexin agonists, histamine receptor antagonists, non-benzodiazepine gamma aminobutyric acid receptor agonists, and benzodiazepines. Pharmacotherapy plays an adjunctive role when insomnia symptoms persist or when patients are unable to pursue cognitive behavioral therapies. ![]() Various specialty societies view psychological/behavioral therapies as the initial treatment intervention. The main modalities in the treatment of insomnia in the elderly are psychological/behavioral therapies, pharmacological treatment, or a combination of both. Chronic insomnia burdens society with billions of dollars in direct and indirect costs of care. ![]() Chronic insomnia affects 57% of the elderly in the United States, with impairment of quality of life, function, and health. ![]()
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