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that despite no effect of melatonin (3 mg in the evening for 5 consecutive days) on the incidence of delirium (29.6% [55/186 patients scheduled for acute hip surgery] for the melatonin group vs. 25.5% [49/192] for the placebo group), a smaller proportion of patients in the melatonin group than in the placebo group experienced a long-lasting episode of delirium (> 2 days) (25.5% v. 46.9%; P = .02)6). Along the similar conception, we examined whether ramelteon, a melatonin agonist with 6- and 3-fold higher affinities for melatonin 1 (MT1) and melatonin 2 (MT2) receptors, respectively, compared to those of melatonin, is effective for the prevention of delirium in a multi-center, rater-blinded, randomized placebo-controlled clinical trial7). Eligible patients were 65-89 years old, newly admitted to intensive care units and regular acute wards in four university hospitals and one general hospital due to emergency, and able to take medi-cine orally. Patients were excluded from the study if they had an expected stay or life expectancy less than 48 h. Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/day; n=33) and placebo (n=34) every night for 7 days, and the main outcome measure was incidence of delirium as determined by the DSM-IV-TR. Ramelteon was associated with lower risk of delirium (3% vs. 32%, P =.003), with a relative risk of 0.09 (95% confi-dence interval [CI], 0.01-0.69). Even after controlling for risk factors such as age, diagnosis of dementia, and admission diagnosis of infection, ramelteon was still associated with a lower inci-dence of delirium (P =.01; odds ratio, 0.07; 95%CI, 0.008-0.54). Kaplan-Meier estimates of time to development of delirium were 6.94 days (95%CI, 6.82-7.06 days) for ramelteon and 5.74 days (5.05-6.42 days) for placebo. Comparison by log-rank test showed that the frequency of developing delirium was significantly lower in patients taking ramelteon than in those taking placebo (χ2=9.83, P =.002). Furthermore, ramelteon was associated with lower risk of delirium among patients with the Clinical Dementia Rating (CDR) ≥0.5 (the ramelteon group, 6% vs. the placebo group, 62%, P =.003), with a relative risk of 0.15 (95% CI, 0.02-0.96)8). Thus, these findings suggest that ramelteon administered nightly to elderly patients admitted for acute care provides protection against delirium, and support a possible pathogenic role of melatonin neurotransmission in delirium. One limitation in clinical practice, especially in an intensive care situ-ation, is the lack of intravenous formulations of melatonin and its agonists.Another possibility of mechanism for preventive effects of melatonin and ramelteon on delirium other than improvement in sleep-wake cycle is anti-microbial properties. Fink et al. reported that survival rate in rats experimentally having devel-oped sepsis was significantly improved after admin-istration of ramelteon or melatonin 1.0 mg/kg, compared with vehicle-treated animals, and that coadministration of melatonin receptor-antagonist luzindole abolished this effect completely9). As infection is a clinical factor that might precipitate delirium10), anti-septic effects of melatonin and ramelteon might be associated with the preventive effects on delirium. This finding can be partially explained through change in the balance between two pathways of tryptophan metabolism under inflammation. Tryptophan is metabolized through two major pathways, the kynurenine pathway and the methoxyindole pathway. The methoxyindole pathway generates serotonin, which is a further substrate for melatonin biosynthesis. The kynurenine pathway can be activated as a result of inflamma-tory stimuli11). This change in the balance between two pathways of tryptophan metabolism can decrease in melatonin biosynthesis. Therefore, administration of melatonin or ramelteon under systemic inflammation, which may cause delirium, can compensate for lack of melatonin, resulting in the prevention of delirium.Recent meta-analysis shows effectiveness of melatonin receptor agonists for delirium preven-tion12).Orexin is an alerting neuropeptide produced by neurons located predominantly in lateral hypotha-lamic area, perifornical area and posterior hypo-thalamus13). The orexin-A levels in cerebrospinal fluid (CSF) during active wake state are highest during the dark phase in nocturnal rodents and highest during the light phase in diurnal species14). As a primary arousal signal in wake control, orexin 133. Orexin receptor antagonists for delirium prevention