OBJECTIVE: To assess the efficacy and safety of perioperative melatonin and melatonin agonists in preventing postoperative delirium (POD).
METHODS: We conducted a systematic search for randomized controlled trials (RCTs) published through December 2022. The primary outcome was efficacy based on the incidence of POD (POD-I). Secondary outcomes included efficacy and safety according to the length of hospital or intensive care unit stay, in-hospital mortality, and adverse events. Subgroup analyses of POD-I were based on the type and dose of drug (low- and high-dose melatonin, ramelteon), the postoperative period (early or late), and the type of surgery.
RESULTS: In the analysis (16 RCTs, 1981 patients), POD-I was lower in the treatment group than in the control group (risk ratio [RR] = 0.57). POD-I was lower in the high-dose melatonin group than in the control group (RR = 0.41), whereas no benefit was observed in the low-dose melatonin and ramelteon groups. POD-I was lower in the melatonin group in the early postoperative period (RR = 0.35) and in patients undergoing cardiopulmonary surgery (RR = 0.54).
CONCLUSIONS: Perioperative melatonin or melatonin agonist treatment suppressed POD without severe adverse events, particularly at higher doses, during the early postoperative period, and after cardiopulmonary surgery.

OBJECTIVE: Causes of nocturia may extend beyond primary bladder pathology and it has been commonly associated as a side effect of sleep disorders. This has led to the study of melatonin and melatonin receptor agonists as a primary treatment for nocturia hypothesized to be secondary to sleep disorders. We aim to systematically review the efficacy and reported safety of melatonin and melatonin receptor agonists in the treatment of nocturia.
METHODS: A search strategy of EMBASE and Pubmed/Medline databases was utilized to identify eligible studies. Two thousand and twenty-eight unique references were identified in concordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines for systematic reviews, of which nine papers met the inclusion criteria. The Cochrane Collaboration risk of bias criteria in the open label and nonplacebo studies was used to assess bias.
RESULTS: The nine studies identified included 3 randomized double-blinded placebo-controlled trials, 2 randomized non-placebo trial, and 4 prospective open-label trials. Three utilized the melatonin-receptor agonist ramelteon (8 mg) and six utilized melatonin (four 2 mg extended release, two 2 mg normal release). Nocturia improved in 8 studies varying from moderate to low efficacy related to reduction in nocturia episodes. Five studies evaluated sleep parameters finding improvement in both nocturia and sleep quality. Male subjects represented 76.8% of 371 total subjects in prospective and randomized trials. Ramelteon and melatonin were both reported as well tolerated during nocturia treatment. A meta-analysis was not able to be performed due to the heterogeneity of bladder diagnoses.
CONCLUSIONS: At this time, there is insufficient evidence to routinely recommend melatonin as an effective treatment for nocturia given the limitations of current clinical studies. Randomized placebo-controlled trials and prospective open label studies in non-neurogenic populations report a trend towards nocturia improvement with good tolerability and rare side effects. Therefore, further larger scale randomized trials with focused urologic diagnoses in well-characterized patient populations are warranted.

Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta-analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = -6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = -5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = -8.74 min), and oSOL (p = 0.017; weighted difference = -14 min). Regarding long-term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes.

To assess the efficacy of melatonin and melatonergic agonist for the treatment of delirium in hospitalized patients.
Embase, MEDLINE, PsycINFO, PubMed, CENTRAL, Cochrane Database of Systematic Reviews, TRIP Medical Database, ClinicalTrials.gov and Google were searched from inception to October 2022. Randomized controlled trials (RCT) and observational studies with any type of comparator evaluating melatonin or melatonergic agonist (ramelteon) enrolling any populations (ICU, surgery, geriatric) were included. Two reviewers independently selected and extracted data using the Cochrane risk of bias tools (RoB2 and ROBINSI).
Out of the 650 screened publications, three RCTs and six observational studies were included (n = 1211). All three RCTs compared melatonin to placebo, as the majority of observational studies compared melatonin or ramelteon to antipsychotics. Two RCTs reported the duration of delirium and a meta-analysis provided a statistical difference between melatonin and placebo (-1.72 days, 95% CI -2.66 to -0.77, p = 0.0004). Five observational studies reported the duration of delirium but only one reported a statistical reduction in the duration of delirium.
Although melatonin and ramelteon may be effective treatments for delirium, particularly to shorten the duration of delirium and to limit the use of rescue medication, current data is limited in number and in its quality. Clinicians should wait until higher quality data from ongoing RCTs are available before prescribing melatonin to delirious patients.

Delayed sleep-wake phase disorder (DSWPD) is a common circadian sleep-wake phase disorders brings serious social impairment of the patients. Melatonin is the main medication option; however, it has not been approved in some countries, and over-the-counter melatonin is under poor quality control. The melatonin receptor agonist ramelteon might be a potential treatment option, but there are few reports regarding its use in DSWPD patients. Existing pharmacological and chronobiological studies suggest that an ultra-low dose of ramelteon in the early night is beneficial for DSWPD. Here, we present our clinical experience together with a pharmacological review and discussion. Twenty-three DSWPD patients, of whom 18 patients had a treatment history of a normal dose of ramelteon, were prescribed low-dose ramelteon (median: 0.571 mg, 1/14 of a tablet) to be taken in the early night (mean: 18:10). After the treatment, the mean sleep schedule was significantly advanced, and clinical symptoms were improved.
Shimura A, Kanno T, Inoue T. Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. J Clin Sleep Med. 2022;18(12):2861-2865.

Small prospective studies, case reports, as well as some randomized placebo-controlled trials and previous meta-analyses have shown that ramelteon, a melatonin agonist, may reduce the risk of developing delirium.
The goal of this systemic review and meta-analyses was to assess the current evidence supporting the use of ramelteon in delirium prevention by including data from larger (>100 subjects) and more recent trials since the most recent meta-analyses were published in 2019. There were no exclusions for trial size, age, ramelteon dose, length of treatment, or hospital setting.
Medline, Embase, PsycINFO, EBM Reviews, Scopus, and Web of Science databases were queried using the search terms delirium (with subterms including prevention and control), ramelteon, Rozerem, or melatonin receptor agonists, for English-language publications until March 16, 2021. Randomized placebo-controlled trials of hospitalized subjects receiving ramelteon for delirium prevention were included. The primary outcome of interest was delirium incidence. Odds ratios of the risk of developing incident delirium and 95% confidence intervals were calculated using a random effects model.
A total of 177 articles were identified by the literature search. Five studies (n = 443, 53.7% male) met criteria for inclusion in the final meta-analyses. The meta-analyses of the randomized placebo-controlled trials revealed that ramelteon did not result in a reduction in the risk of incident delirium (n = 443; odds ratio = 0.49; 95% confidence interval = 0.13-1.85). A moderate degree of heterogeneity was noted among the studies (I2 = 53%).
Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients.

BACKGROUND: Although a previous review illustrated the efficacy of melatonin receptor agonists (MRAs) in preventing delirium, some recent randomized controlled trials (RCTs) did not confirm these effects.
OBJECTIVE: This study systematically reviewed the efficacy, acceptability, and tolerability of MRAs for delirium prevention.
METHODS: We searched electronic databases, including Scopus, PubMed, CINAHL, and Controlled Trials Register, from their inception to February 20, 2022. The primary efficacy outcome was delirium incidence rate after MRA administration; relative risks (RRs), overall discontinuation, and discontinuation due to adverse events are also presented.
RESULTS: The overall pooled incidence rates of delirium in MRA-treated and placebo-treated groups were significantly different with RR (95% CI)=0.66(0.52, 0.84, ), I2=59%. Similarly, the incidence rate was significantly lower in the melatonin-treated group than in the placebo-treated group [RR (95% CI) =0.65 (0.49, 0.88), I2=65%]. Unfortunately, incidence rates were not significantly different between ramelteon-treated and placebo-treated groups [RR (95% CI) =0.67 (0.42, 1.08), I2=50%]. The pooled incidence rate of delirium in either melatonin or ramelteon-treated groups was not significantly different from the placebo-treated group in elderly patients. The pooled incidence rate of delirium was significantly lower in the melatonin-treated group than in the benzodiazepinetreated group.
CONCLUSIONS: Based on this review, melatonin could prevent delirium with a small effect size. However, ramelteon did not show efficacy in preventing delirium. Additionally, neither melatonin nor ramelteon individually showed effectiveness in preventing delirium in elderly patients. Therefore, using MRAs to prevent delirium in clinical practice should be cautious. However, future welldefined and large sample size studies could verify these findings.

Valeriana officinalis L. (Valerianaceae) is one of the most reputed ancient medicinal plants used in modern phytotherapy and traditional medicine. Its root extract is one of the most effective herbal sedatives and tranquilizers, where the plant is also used for the treatment of gastrointestinal spasms. V. officinalis has complex phytochemistry consisting of the esterified iridoid derivatives known as valepotriates (e.g., valtrate, didrovaltrate, isovalerenic acid), sesquiterpenes (e.g., valerenic acid), flavonoids (e.g., linarin, apigenin), lignans (e.g., pinoresinol, hydroxypinoresinol), alkaloids (e.g., actinidine, valerine), triterpenes (e.g., ursolic acid), monoterpenes (e.g., borneol, bornyl acetate). Among them, valerenic acid is a marker compound for standardization of the root extracts of the plant and has been reported in many in vitro/in vivo studies to be responsible for anxiolytic action of the plant. Although modulation of gamma-aminobutyric acid (GABA) receptors has been revealed to be the leading mechanism of the plant-based on the existence of valerenic acid, several studies described the interaction of valerenic acid with glutamergic receptors. In addition to valerenic acid, isovaleric acid, didrovaltrate, borneol, and some lignans have also been proposed to contribute to the anxiolytic effect of the plant. In the current review, the data selectively scrutinized from the in vitro/in vivo studies about identifying anxiolytic molecular mechanisms of V. officinalis is focused.

To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.
Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies.
In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo.
Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.

It remains unclear whether melatonin and its analogues prevent postoperative delirium (POD). Therefore, we conducted a systematic review and meta-analysis to evaluate the effect of melatonin and its analogues on POD prevention. PubMed, Cochrane Library, Web of Science, Embase and CINAHL databases were searched. Primary outcome was the incidence of POD. Six randomized controlled trials, 2 cohort studies and 1 case-control study were included in this meta-analysis. Results showed that melatonin and its analogue ramelteon decreased the incidence of POD in the entire adult surgical population (odds ratio [OR] = 0.45, 95% confidence interval [CI] 0.24-0.84, P = .01). When administered at a higher dose (5 mg), melatonin was effective in reducing the POD incidence (OR = 0.32, 95% CI 0.20-0.52, P < .00001). Melatonin administered less than 5 elimination half-lives before the surgery significantly reduced the POD incidence (OR = 0.31, 95% CI 0.19-0.49, P < .00001). Current literature supports the effectiveness of melatonin and its analogue ramelteon in POD prevention. However, the present study was limited by the significant heterogeneity of the included studies. More studies are needed to ascertain the preventive effect of melatonin and its analogues on the incidence of delirium after cardiac and noncardiac surgeries.