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discretion of each patient. The primary outcome was incidence of delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, during the first 7 days. Among 526 patients-at-risk, those taking ramelteon and/or suvorexant developed delirium significantly less frequently than those who did not, after controlling for the effects of risk factors on the estimate of an independent association between the effects of ramelteon and/or suvorexant and the outcome of developing delirium (15.7% vs. 24.0%; odds ratio [OR]: 0.48, 95% confidence interval [CI]: 0.29–0.80, P = 0.005)27). Similar results were found among 422 patients-with-delirium (39.9% vs. 66.3%; OR: 0.36, 95%CI: 0.22–0.59; P < 0.0001). Thus, ramelteon and suvorexant appears to be effective for delirium prevention in real-world practice.5. ConclusionAccording to the evidence, we choose ramelteon first, and orexin receptor antagonists second for insomnia in elderly patients to prevent developing delirium. Thus, a potent melatonin agonist ramel-teon and orexin receptor antagonists play important roles not only in insomnia but also in the preven-tion of delirium.AcknowledgmentsNot applicable.This work was supported by the JSPS KAKENHI Grant Number 20K07927. The sponsor of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper for publica-tion.Author contributionsKotaro Hatta designed the study, obtained funding, analyzed the data, interpreted the data, drafted the report, and contributed to and have approved the final manuscript.Conflicts of interest statementDr Hatta has received lecture honoraria for Dain-ippon-Sumitomo, Eisai, Janssen, Meiji Seika, MSD, and Otsuka. 1) European Delirium Association; American Delirium Society. The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer. BMC Med, 2014; 12: 141. 2) Maldonado JR: Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry, 2013; 21: 1190-1222. 3) Inouye SK, Westendorp RG, Saczynski JS: Delirium in elderly people. Lancet, 2014; 383: 911-922. 4) Sultan SS: Assessment of role of perioperative mela-tonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth, 2010; 4: 169-173. 5) Al-Aama T, Brymer C, Gutmanis I, et al: Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry, 2011; 26: 687-694. 6) de Jonghe A, van Munster BC, Goslings JC, et al: Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind random-ized controlled trial. CMAJ, 2014; 186: E547-556. 7) Hatta K, Kishi Y, Wada K, et al: Preventive effects of ramelteon on delirium: a randomized placebo-con-trolled trial. JAMA Psychiatry, 2014; 71: 397-403. 8) Hatta K, Kishi Y, Wada K: Ramelteon for Delirium in Hospitalized Patients. JAMA, 2015; 314: 1071-1072. 9) Fink T, Glas M, Wolf A, et al: Melatonin receptors mediate improvements of survival in a model of poly-microbial sepsis. Crit Care Med, 2014; 42: e22-31.10) Young J, Murthy L, Westby M, et al: Diagnosis, preven-tion, and management of delirium: summary of NICE guidance. BMJ, 2010; 341: c3704.11) Lovelace MD, Varney B, Sundaram G, et al: Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology, 2016 Mar 16. pii: S0028-3908(16)30096-X. doi: 10.1016/j.neuropharm.2016.03.024. [Epub ahead of print]12) Khaing K, Nair BR: Melatonin for delirium prevention in hospitalized patients: A systematic review and meta-analysis. J Psychiatr Res, 2021; 133: 181-190.13) Ohno K, Sakurai T: Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuro-endocrinol, 2008; 29: 70-87.14) Gotter AL, Winrow CJ, Brunner J, et al: The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold. BMC Neurosci, 2013; 14: 90.15) Hunt NJ, Rodriguez ML, Waters KA, Machaalani R: Changes in orexin (hypocretin) neuronal expression with normal aging in the human hypothalamus. Neuro-biol Aging, 2015; 36: 292-300.16) Liguori C, Romigi A, Nuccetelli M, et al: Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol, 2014; 71: 1498-1505.17) Hamasaki MY, Barbeiro HV, Barbeiro DF, et al: Neuro-peptides in the brain defense against distant organ damage. J Neuroimmunol, 2016; 290: 33-35.18) Krystal AD, Benca RM, Kilduff TS: Understanding the sleep-wake cycle: sleep, insomnia, and the orexin system. J Clin Psychiatry, 2013; 74 Suppl 1: 3-20.15FundingReferences