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Author(s): Lisa Burry [sup.1] [sup.2], Romain Sonneville [sup.3] [sup.4], E. Wesley Ely [sup.5] [sup.6] [sup.7] Author Affiliations: (1) grid.416166.2, 0000 0004 0473 9881, Departments of Pharmacy and Medicine, Mount Sinai [...]

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT 1 /MT 2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress. • Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. • Ramelteon markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. • Activation of melatonin receptors balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. • Ramelteon protects RSDS-elicited behavioral changes through the MT 1 receptor in the hippocampus. [ABSTRACT FROM AUTHOR]

Sleep disorders adversely affect daily activities and cause physiological and psychiatric problems. The shortcomings of benzodiazepine hypnotics have led to the development of ramelteon, a melatonin MT1 and MT2 agonist. Although the sleep-promoting effects of ramelteon have been documented, few studies have precisely investigated the structure of sleep and neural oscillatory activities. In this study, we recorded electrocorticograms in the primary motor cortex, the primary somatosensory cortex and the olfactory bulb as well as electromyograms in unrestrained rats treated with either ramelteon or vehicle. A neural-oscillation-based algorithm was used to classify the behavior of the rats into three vigilance states (e.g., awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep). Moreover, we investigated the region-, frequency- and state-specific modulation of extracellular oscillations in the ramelteon-treated rats. We demonstrated that in contrast to benzodiazepine treatment, ramelteon treatment promoted NREM sleep and enhanced fast gamma power in the primary motor cortex during NREM sleep, while REM sleep was unaffected. Gamma oscillations locally coordinate neuronal firing, and thus, ramelteon modulates neural oscillations in sleep states in a unique manner and may contribute to off-line information processing during sleep.

BackgroundThe effectiveness of melatonin and its analogs in preventing postoperative delirium (POD) following cardiac surgery is controversial. The purpose of this systematic review and meta-analysis was to confirm the benefits of melatonin and its analogs on delirium prevention in adults who underwent cardiac surgery.MethodsWe systematically searched the PubMed, Cochrane Library, Web of Science, Embase, and EBSCOhost databases, the last search was performed in October 2021 and repeated before publication. The controlled studies were included if investigated the impact of melatonin and its analogs on POD in adults who underwent cardiac surgery. The primary outcome was the incidence of delirium. The Stata statistical software 17.0 was used to perform this study.ResultsThis meta-analysis included eight randomized controlled trials (RCTs) and two cohort studies with a total of 1,714 patients. The results showed that melatonin and ramelteon administration were associated with a significantly lower incidence of POD in adults who underwent cardiac surgery (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.29–0.74; P = 0.001). The subgroup analyses confirmed that melatonin 3 mg (OR, 0.37; 95% CI, 0.18–0.76; P = 0.007) and 5 mg (OR, 0.34; 95% CI, 0.21–0.56; P < 0.001) significantly reduced the incidence of POD.ConclusionMelatonin at dosages of 5 and 3 mg considerably decreased the risk of delirium in adults who underwent cardiac surgery, according to our results. Cautious interpretation of our results is important owing to the modest number of studies included in this meta-analysis and the heterogeneity among them.Systematic Review RegistrationPROSPERO registration number: CRD42021246984.

Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta‐analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case–control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case–control studies involving 2594 patients were included in this meta‐analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14–0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23–0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37–0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11–1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964). [ABSTRACT FROM AUTHOR]

Aim: A melatonin receptor agonist ramelteon is a drug that is also used in urinary tract infections. Melatonin is known to have an effect on smooth muscle contraction. In this study, we aimed to question whether ramelteon exerts a melatonin-like effect on bladder contractions. Material and Methods: Wistar-albino (n = 8) intact female rats were used in the study. After decapitation, 1.5x5 mm bladder strips were examined in an isolated organ bath in which there was Krebs-Henseleit solution. After the regulation period, ramelteon was applied non-cumulatively in two separate doses of 0.2µM, 1µM. The area under the curve (AUC) and peak to peak (p-p) values before and after the application were normalized as % change. Results: Exposure of bladder strips to ramelteon significantly increased contractions. Ramelteon caused a statistically significant increase in p-p, AUC values of spontaneous bladder contractions at a dose of 0.2 and 1µM (p < 0.05). Conclusion: Ramelteon has an activator effect on spontaneous bladder contractions unlike melatonin. The physiopathological mechanisms under activator activity need to be investigated with further studies. This effect should be taken into account in clinical use. [ABSTRACT FROM AUTHOR]

Objective: Metabolic side effects are a limiting factor in the use of antipsychotics, which remain the cornerstone of long‐term management of patients with severe mental illness. There is contrasting evidence on a possible role of melatonin and melatonin‐agonists in attenuating antipsychotic‐induced metabolic abnormalities. Design: We conducted a systematic review (PubMed, PsycInfo, Cochrane databases, up to August 2020) and a random‐effect meta‐analysis of double‐blind, randomized placebo‐controlled trials (RCTs) involving melatonin and melatonin‐agonists in the treatment of antipsychotic‐induced metabolic changes. The primary outcome was the standardized mean difference (SMD) of composite metabolic outcomes built with metabolic syndrome components. Secondary outcomes were individual metabolic syndrome components, and other anthropometric, glucose metabolism, lipid profile, and psychopathology measures. Results: Out of the initial 41 studies, six documented five separate RCTs randomizing 248 patients (126 to melatonin/ramelteon, 122 to placebo) affected by schizophrenia‐spectrum disorders and bipolar disorder. Melatonin/ramelteon outperformed placebo on the primary outcome (SMD −0.28, 95% CI = −0.39 ÷ −0.168), as well as on all individual components of metabolic syndrome (systolic blood pressure MD −3.266, 95% CI = −6.020 ÷ −0.511; fasting glucose MD −3.766, 95% CI = −5.938 ÷ −1.593; triglycerides MD −9.800, 95% CI = −19.431 ÷ −0.169; HDL MD 2.995, 95% CI = 0.567 ÷ 5.423), except waist circumference. Conclusions: Melatonin/ramelteon augmentation may be beneficial for non‐anthropometric metabolic syndrome components in patients treated with antipsychotics. [ABSTRACT FROM AUTHOR]

Objective Methotrexate (MTX) used anti-metabolite, causes bone morbidity, including growth arrest and reduced bone mineral density. Melatonin, produced by the pineal gland, has also multiple positive effects in human bone cells, and positive effects on bone. Ramelteon (RMT) is a non-selective melatonin receptor agonist. In this study, we investigated whether ramelteon, a melatonin agonist, has a protective effect on MTXinduced bone toxicity. Material and Methods The rats divided into 4 groups, including Group 1 control group; Group 2 MTX group (20 mg/kg); Group 3 MTX+RMT (20 mg/kg + 10 mg/kg); Group 4 RMT (10 mg/kg). Oral ramelteon and intraperitoneal mtx were applied to the rats on the second day according to the groups. After 7 days, long bones were evaluated histologically with hematoxylin-eosin (HE) staining and immunohistochemically with Catepsin K and RUN X2 staining. For statistical analysis immunohistochemical scores of the groups were compared between the groups for this purpose, the Oneway ANOVA Duncan test was used by SPSS-22.00 package program. Results There was no significant difference between the control group (group I) and the experimental groups (group II-group III-group IV) in H&E staining of bone tissue sections (p>0.05). No positive staining was observed in any of the groups in CAT-K and RUN-X immunostaining (p>0.05). Conclusion It was showed that ramelteon has no anabolic function in bone turnover, histopathological and immunohistochemical, in bone toxicity induced by high-dose methotrexate on intact bone tissue. [ABSTRACT FROM AUTHOR]

As the COVID‐19 pandemic grows, several therapeutic candidates are being tested or undergoing clinical trials. Although prophylactic vaccination against SARS‐CoV‐2 infection has been shown to be effective, no definitive treatment exists to date in the event of infection. The rapid spread of infection by SARS‐CoV‐2 and its variants fully warrants the continued evaluation of drug treatments for COVID‐19, especially in the context of repurposing of already available and safe drugs. Here, we explored the therapeutic potential of melatonin and melatonergic compounds in attenuating COVID‐19 pathogenesis in mice expressing human ACE2 receptor (K18‐hACE2), strongly susceptible to SARS‐CoV‐2 infection. Daily administration of melatonin, agomelatine, or ramelteon delays the occurrence of severe clinical outcome with improvement of survival, especially with high melatonin dose. Although no changes in most lung inflammatory cytokines are observed, treatment with melatonergic compounds limits the exacerbated local lung production of type I and type III interferons, which is likely associated with the observed improved symptoms in treated mice. The promising results from this preclinical study should encourage studies examining the benefits of repurposing melatonergic drugs to treat COVID‐19 and related diseases in humans. [ABSTRACT FROM AUTHOR]

Abstract Introduction Non‐24‐hour sleep‐wake disorder (N24SWD) is often observed in the visually impaired and those who isolate indoors. Melatonin receptor agonists may be used for treatment, but there is currently no evidence that they are effective in patients without visual impairment. Case We report a case of a 23‐year‐old woman who withdrew from her social life owing to autism spectrum disorder and experienced an unusual sleep rhythm. She presented with N24SWD. The N24SWD cycle averaged 25.6 days but was extended to 42 days using ramelteon. However, this was not enough. We prescribed the addition of suvorexant and the sleep cycle returned to normal. Conclusion N24SWD is a disease that seriously impairs social life and productivity. We propose a possible treatment strategy for N24SWD using ramelteon and suvorexant.

Abstract Background It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection. Methods VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated. Results Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody. Conclusions Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production.

Insomnia, also called sleeplessness, is a sleep disorder with very diverse sleep problems and is classified into seven categories. Circadian rhythm sleep-wake disorder (CRSWD) is a type of insomnia characterized by the misalignment of the body's circadian clock with the external 24-hour environmental cycle. CRSWD encompasses seven subtypes, among which delayed sleep-wake phase disorder (DSWPD) is prominently recognized for its impact on sleep patterns. Sleep disturbances, particularly insomnia, are prevalent in depressed patients, often serving as a primary symptom that prompts clinical consultation. CRSWD frequently leads to significant social dysfunction, often making it impossible for students to attend school and difficult for working adults to find employment. Effective treatments for CRSWD include bright light therapy, cognitive-behavioral therapy for insomnia (CBT-I), and melatonin receptor agonists, particularly for certain CRSWD subtypes. In this case report, the melatonin receptor agonist ramelteon was administered to a high school student with DSWPD and comorbid depression, resulting in the successful management of symptoms. Following treatment, the patient resumed high school, pursued a university education, and secured employment post-graduation. These findings indicate that ramelteon may be a promising treatment option for CRSWD in patients with comorbid depression, warranting further clinical investigation., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Matsumoto et al.)

Despite advancement in anti-seizure medications, 30% of patients continue to experience recurrent seizures. Previous data indicated the antiepileptic properties of melatonin and its agonists in several animal models. However, the underlying mechanisms of melatonin and its agonists on cellular excitability remain poorly understood. In this study, we demonstrated the electrophysiological changes of two main kinds of ion channels that are responsible for hyperexcitability of neurons after introduction of melatonin agonists- ramelteon (RAM). In Neuro-2a cells, the amplitude of voltage-gated Na + ( I Na ) and delayed-rectifier K + currents ( I K (DR) ) could be suppressed under RAM. The IC 50 values of 8.7 and 2.9 μM, respectively. RAM also diminished the magnitude of window Na + current ( I Na (W) ) elicited by short ascending ramp voltage, with unchanged the overall steady-state current-voltage relationship. The decaying time course of I Na during a train of depolarizing pulses arose upon the exposure to RAM. The conditioning train protocol which blocked I Na fitted the recovery time course into two exponential processes and increased the fast and slow time constant of recovery the presence of RAM. In pituitary tumor (GH 3 ) cells, I Na amplitude was also effectively suppressed by the RAM. In addition, GH3-cells exposure to RAM decreased the firing frequency of spontaneous action potentials observed under current-clamp conditions. As a result, the RAM-mediated effect on INa was closely associated with its ability to decrease spontaneous action potentials. Collectively, we found the direct attenuation of I Na and I K (DR) caused by RAM besides the agonistic action on melatonin receptors, which could partially explain its anti-seizure activity., (© 2024 The Authors. FASEB BioAdvances published by Wiley Periodicals LLC on behalf of The Federation of American Societies for Experimental Biology.)

Acute ischemic stroke is a challenging disease that threatens the life of older people. Dysfunction of brain endothelial cells is reported to be involved in the pathogenesis of acute ischemic stroke. Ramelteon is a novel agonist of melatonin receptor developed for the treatment of insomnia. Recently, the promising protective effect of Ramelteon on brain injury has been widely reported. The present study aims to investigate the protective effect of Ramelteon against free fatty acid (FFA)–induced damages in brain vascular endothelial cells and the underlying mechanism. Firstly, we discovered that Ramelteon administration remarkably reversed the decreased cell viability, increased LDH release, activated oxidative stress, and excessive released inflammatory factors caused by FFAs. Secondly, Ramelteon extensively suppressed the attachment of U937 monocytes to bEnd.3 brain endothelial cells induced by FFAs. In addition, the elevated expression of E-selectin and the reduced expression of KLF2 induced by FFAs were pronouncedly alleviated by Ramelteon. Lastly, silencing of KLF2 abolished the protective effects of Ramelteon against FFA-induced expression of E-selectin and the attachment of U937 monocytes to bEnd.3 brain endothelial cells. In conclusion, Ramelteon mitigated FFA-induced attachment of monocytes to brain vascular endothelial cells by increasing the expression of KLF2 and reducing the expression of E-selectin. [ABSTRACT FROM AUTHOR]

• Melatonin regulates circadian processes and strongly influences the sleep-wake cycle. • Delirium and sleep-wake disturbances share a strong relationship, especially in acute illness. • Melatonin supplementation can help prevent delirium in selected groups of hospitalized older adults. • Consider using melatonin or ramelteon along with high-quality multicomponent delirium prevention efforts. Alterations in circadian rhythm play an important role in the development of delirium. In this umbrella review, we examined the efficacy of melatonin and ramelteon for delirium prevention in hospitalized older adults. Umbrella review methodology from the Joanna Briggs Institute guided the review process. Only meta-analyses were included. Risk of bias was evaluated using the AMSTAR-2 checklist. Three meta-analyses were included in this review. The quality of studies was low-to-moderate. Two meta-analyses reported a significant reduction in delirium using melatonin or ramelteon (pooled OR and 95% confidence intervals ranged from 0.41 [0.19-0.86] to 0.63 [0.46-0.87]). Melatonergics significantly reduced delirium on medical units (OR = 0.25, 95% CI 0.07-0.88) but not surgical units (OR = 0.62, 0.16-2.43). Heterogenity was high, with I2 ranging from 72.14% to 84%. Melatonergics appear to prevent delirium among hospitalized older adults, particularly those on medical units. Based on these results, providers may consider using melatonergics as complements to high-quality multicomponent delirium prevention. [ABSTRACT FROM AUTHOR]

Background: An impaired sleep-wake cycle may be one factor that affects the development of delirium in critically ill patients. Several small studies suggest that exogenous melatonin or ramelteon may decrease the incidence and/or duration of delirium. Objective: To compare the effect of prophylactic administration of melatonin, ramelteon, or no melatonin receptor agonist on the development of delirium in the intensive care unit (ICU). Methods: This was a single-center, retrospective, observational cohort study of nondelirious patients in the ICU who received melatonin, ramelteon, or no melatonin receptor agonist. The primary end point was the incidence of delirium. Secondary end points included assessments of daily level of sedation and daily utilization of antipsychotic, sedative, and opioid agents. Results: No difference was observed in the incidence of delirium among the melatonin, ramelteon, and placebo cohorts (18.7% vs 14.3% vs 13.8%; P = 0.77). A difference was observed in the rate of agitation and sedation among the 3 groups, with the greatest observed in the melatonin cohort. Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids. Overall, there was no difference in clinical outcomes, including duration of mechanical ventilation and ICU or hospital length of stay. Conclusion and Relevance: Therapy with melatonin, ramelteon, and no melatonin receptor agonist resulted in similar rates of delirium in a mixed ICU population. Despite significant differences in agitation, sedation, and medication utilization, there was no differences in the clinical outcomes evaluated. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) is important for protecting the brain tissue by selectively exchanging substances between the blood and brain. The integrity of the BBB can be damaged by multiple factors, including oxidative stress and inflammation. Ramelteon is an oral hypnotic drug, and in the present study, we investigated its protective effect on BBB damage, as well as the underlying mechanism. LPS was used to induce BBB damage on mice and stimulate injury on endothelial cells. Evans blue staining assay was used to measure the brain permeability. The expressions of ZO-1 and Occludin were evaluated using immunostaining and Western blot in the brain tissue and endothelial cells, respectively. qRT-PCR and ELISA were used to detect the production of IL-1β and MCP-1 in the brain vessels. TBA assay was utilized to examine the concentration of MDA in the brain tissue and endothelial cells. The expression of Nrf2 in the nucleus and NQO1 were determined using Western blot assay. The endothelial permeability of the monolayer was examined using the FITC-dextran permeation assay. Firstly, the increased brain permeability and downregulated expression of tight junction proteins in the brain tissue induced by LPS were significantly reversed by treatment with Ramelteon, accompanied by the decrease in the production of IL-1β and MCP-1 in the vessels in mice. Also, the Nrf2 signaling was activated and oxidative stress in the brain vessels was alleviated by treatment with Ramelteon. Secondly, LPS-induced increase in endothelial monolayer permeability and decrease in tight junction protein expression in bEnd.3 brain endothelial cells were significantly reversed by Ramelteon, accompanied by activated Nrf2 signaling and alleviated oxidative stress. Lastly, the protective effects of Ramelteon against LPS-induced reduction of ZO-1 and Occludin, and the increase in endothelial monolayer permeability were dramatically abolished by silencing Nrf2. Ramelteon might ameliorate LPS-induced hyperpermeability of the BBB by activating the Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Background and purpose Parkinson's disease (PD) is a severe neurodegenerative disease with high morbidity in the elderly population. 6‐OHDA‐induced cell senescence is reported to be involved in the pathogenesis of PD. Ramelteon is an oral hypnotic agent that specifically targets the receptors of the suprachiasmatic nucleus in the human hypothalamus. Here, an investigation is made to see whether Ramelteon possesses a beneficial effect against 6‐OHDA‐induced cellular senescence in human SH‐SY5Y neuronal cells. Methods The release of LDH was detected to assess cytotoxicity and flow cytometry was conducted to evaluate the cell cycle. The telomerase activity and the SA‐β‐Gal assay were performed to determine the state of cell senescence. Oxidative stress was evaluated by detecting the release of H2O2. The expressions of p21, p53, and Nrf2 were measured using the qRT‐PCR and Western blotting assay. siRNA technology was used to knock down the expression level of Nrf2 in SH‐SY5Y neuronal cells. Results First, it was found that Ramelteon mitigated cell cycle arrest in the G0/G1 phase in 6‐OHDA‐challenged SH‐SY5Y neuronal cells. Second, treatment with Ramelteon alleviated cellular senescence in 6‐OHDA‐treated SH‐SY5Y neuronal cells by increasing telomerase activity and reducing the activity of SA‐β‐gal. It was also found that Ramelteon reduced the expressions of p21 and p53. Notably, Ramelteon attenuated 6‐OHDA‐induced oxidative stress by increasing the expression of Nrf2. Silencing of Nrf2 abolished the protective effects of Ramelteon against 6‐OHDA‐induced cellular senescence. Based on these findings, it was concluded that Ramelteon alleviated 6‐OHDA‐induced cellular senescence by increasing the expression of Nrf2 in human SH‐SY5Y neuronal cells. Conclusion Ramelteon protected against 6‐OHDA‐induced cellular senescence in human SH‐SY5Y neuronal cells through activating the Nrf2 signaling pathway.

Background and purpose: Parkinson's disease (PD) is a severe neurodegenerative disease with high morbidity in the elderly population. 6‐OHDA‐induced cell senescence is reported to be involved in the pathogenesis of PD. Ramelteon is an oral hypnotic agent that specifically targets the receptors of the suprachiasmatic nucleus in the human hypothalamus. Here, an investigation is made to see whether Ramelteon possesses a beneficial effect against 6‐OHDA‐induced cellular senescence in human SH‐SY5Y neuronal cells. Methods: The release of LDH was detected to assess cytotoxicity and flow cytometry was conducted to evaluate the cell cycle. The telomerase activity and the SA‐β‐Gal assay were performed to determine the state of cell senescence. Oxidative stress was evaluated by detecting the release of H2O2. The expressions of p21, p53, and Nrf2 were measured using the qRT‐PCR and Western blotting assay. siRNA technology was used to knock down the expression level of Nrf2 in SH‐SY5Y neuronal cells. Results: First, it was found that Ramelteon mitigated cell cycle arrest in the G0/G1 phase in 6‐OHDA‐challenged SH‐SY5Y neuronal cells. Second, treatment with Ramelteon alleviated cellular senescence in 6‐OHDA‐treated SH‐SY5Y neuronal cells by increasing telomerase activity and reducing the activity of SA‐β‐gal. It was also found that Ramelteon reduced the expressions of p21 and p53. Notably, Ramelteon attenuated 6‐OHDA‐induced oxidative stress by increasing the expression of Nrf2. Silencing of Nrf2 abolished the protective effects of Ramelteon against 6‐OHDA‐induced cellular senescence. Based on these findings, it was concluded that Ramelteon alleviated 6‐OHDA‐induced cellular senescence by increasing the expression of Nrf2 in human SH‐SY5Y neuronal cells. Conclusion: Ramelteon protected against 6‐OHDA‐induced cellular senescence in human SH‐SY5Y neuronal cells through activating the Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Older surgical patients are at high risk of developing postoperative delirium. Non-pharmacological strategies are recommended for delirium prevention, but no pharmacological agents have compelling evidence to decrease the incidence of delirium. The purpose of this study was to assess whether perioperative melatonin decreases the incidence of delirium in older adults undergoing surgical procedures. Methods A systematic search using PubMed/Medline, Embase, PsycINFO, CINAHL, and references of identified articles published in English between January 1990 and October 2017 was performed. Two independent reviewers screened titles and abstracts, and then extracted data following a full-text review of included articles with consensus generation and bias assessment. Studies reporting outcomes for melatonin or ramelteon use to prevent delirium in postoperative hospitalized patients (mean age ≥ 50 years) were eligible for inclusion. Data were pooled using a fixed-effects model to generate a forest plot and obtain a summary odds ratio for the outcome of interest (delirium incidence). Cochran’s Q and I2 values were used to investigate heterogeneity. Results Of 335 records screened, 6 studies were selected for the qualitative analysis and 6 were included in the meta-analysis (n = 1155). The mean age of patients in included studies ranged from 59 to 84 years. Patients in intervention groups typically received melatonin or ramelteon at daily doses of two to eight milligrams around cardiothoracic, orthopedic, or hepatic surgeries for one to nine days, starting on the evening before or the day of surgery. The incidence of delirium ranged from 0 to 30% in the intervention groups versus 4–33% in the comparator groups, and was significantly reduced in the melatonin group, with a summary effect of the meta-analysis yielding an odds ratio of 0.63 (95% CI 0.46 to 0.87; 0.006; I2 = 72.1%). A one study removed analysis reduced overall odds ratio to 0.310 (95% CI 0.19 to 0.50), while reducing heterogeneity (Cochran’s Q = 0.798, I2 = 0.000). Conclusion Perioperative melatonin reduced the incidence of delirium in older adults in the included studies. While optimal dosing remains an unanswered question, the potential benefit of melatonin and melatonin receptor agonists may make them a reasonable option to use for delirium prevention in older adults undergoing surgical procedures.

Taro Kishi,1 Ikuo Nomura,1 Kenji Sakuma,1 Tsuyoshi Kitajima,1 Kazuo Mishima,2 Nakao Iwata11Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, JapanObjective: This study was a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials, investigating the efficacy and tolerability/safety of melatonin receptor agonists, such as ramelteon and melatonin, for patients with bipolar disorder.Methods: We carried out a literature search through PubMed and the Cochrane Library from the date of inception to January 6, 2019. The risk ratio (RR), number needed to treat (NNT), and standardized mean difference (SMD) ±95% CI were calculated. The primary outcome was all-cause discontinuation.Results: We identified three ramelteon (n=746) and two melatonin (n=53) studies. One of these two melatonin studies reported only data on all-cause discontinuation, whereas the other study did not report data relevant for a meta-analysis. We found no significant differences between the treatment and placebo groups regarding all-cause discontinuation, neither individually (p: ramelteon=0.86, melatonin=1.00) nor pooled together (p=0.85). Although we found no significant differences between ramelteon and placebo regarding the relapse due to mania/hypomania or mixed episode; Pittsburgh Sleep Quality Index scores; depression scales scores; Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form scores; and the incidence of individual adverse events, such as headaches, insomnia, somnolence, anxiety, and dizziness, ramelteon was associated with a lower incidence of relapse due to depression than placebo (RR=0.67, 95% CI=0.48–0.94, p=0.02, NNT=14).Conclusion: Ramelteon might prevent relapse due to depression in patients with bipolar disorder. However, because of the small number of studies included in the present systematic review and meta-analysis, further studies comparing ramelteon and placebo with larger samples of patients with bipolar disorder are warranted. We also did not evaluate the efficacy and safety of melatonin for patients with bipolar disorder in detail.Keywords: ramelteon, melatonin, bipolar disorder, relapse, systematic review, meta-analysis

This study aimed to determine the underlying mechanism of ramelteon on the competence of oocyte and subsequent embryo development in pigs during in vitro maturation (IVM). Our results showed that the cumulus expansion index was significantly lower in the control group compared to the ramelteon groups (p < 0.05). Moreover, supplementation of 10−11 and 10−9 M ramelteon significantly increased the cumulus expansion and development-related genes expression, and reduced apoptosis in cumulus cells (p < 0.05). In oocytes, the nuclear maturation rate was significantly improved in 10−11, 10−9, and 10−7 M ramelteon groups compared to the control (p < 0.05). Additionally, the level of intracellular GSH was significantly increased and ROS was significantly decreased in ramelteon-supplemented groups, and the gene expression of oocyte development and apoptosis were significantly up- and down-regulated by 10−11 and 10−9 M ramelteon (p < 0.05), respectively. The immunofluorescence results showed that the protein levels of GDF9, BMP15, SOD1, CDK1, and PGC1α were significantly increased by 10−11 M ramelteon compared to the control (p < 0.05). Although there was no significant difference in cleavage rate, the blastocyst formation rate, total cell numbers, and hatching/-ed rate were significantly improved in 10−11 M ramelteon group compared to the control (p < 0.05). Furthermore, embryo development, hatching, and mitochondrial biogenesis-related genes were dramatically up-regulated by 10−11 M ramelteon (p < 0.05). In addition, the activities of lipogenesis and lipolysis in oocytes were dramatically increased by 10−11 M ramelteon compared to the control (p < 0.05). In conclusion, supplementation of 10−11 M ramelteon during IVM improved the oocyte maturation and subsequent embryo development by reducing oxidative stress and maintenance of lipid homeostasis.

Anesthetic-induced cognitive impairment has been observed clinically. The mechanism underlying anesthetic-induced cognitive impairment is closely associated with neuronal apoptosis and neuroinflammation. Ramelteon is a potent and highly selective melatonin receptor agonist that has been used for the treatment of insomnia and has been reported to have an anti-inflammatory effect. In this study, we aimed to investigate the protective effects of Ramelteon against the cytotoxicity induced by isoflurane in brain microvascular endothelial cells. Our results show that Ramelteon ameliorated oxidative stress by suppressing the generation of mitochondrial reactive oxygen species (ROS) in human brain microvascular endothelial cells (HBMVECs). In addition, Ramelteon displayed a robust anti-inflammatory capacity against isoflurane-induced insults and inflammation by reducing the generation of interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), monocyte chemotactic protein 1 (MCP-1), stromal cell-derived factor-1 (SDF-1), matrix metalloproteinase-2 (MMP-2), and MMP-9. Furthermore, Ramelteon reduced the expression of cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Importantly, Ramelteon downregulated the activation of the p38MAPK/NF-κB signaling pathway, which is the key transcriptional regulator in the inflammation process. Our findings in the present study provide new evidence for the use of Ramelteon in the prevention of isoflurane-induced insults in brain endothelial cells. [ABSTRACT FROM AUTHOR]

Patients with delayed sleep-wake phase disorder (DSWPD) suffer from difficulties in sleep initiation at night, difficulties in waking up at the socially required time, and daytime somnolence. About half of the patients resist conventional light therapy and melatonin therapy. Therapy using hypnotics is not recommended due to its adverse effects. Recently, suvorexant, an orexin receptor antagonist, has become available for clinical use. The drug is relatively safer than traditional hypnotics such as benzodiazepines. We report three DSWPD patients who were successfully treated by the combination therapy of suvorexant and ramelteon. The first case was a 19-year-old woman who was experiencing difficulties in sleep initiation, difficulty in waking up in the morning, and daytime somnolence. She showed a prompt response to the combination therapy of suvorexant and ramelteon. Her sleep phase advanced, and her daytime somnolence reduced. The second and third cases were 21-year-old and 17-year-old men, respectively, who also showed significant sleep phase advances. Although case 2 was resistant to ramelteon treatment, his sleep phase advanced after suvorexant started. His difficulty in falling asleep and his habit of daytime napping disappeared after the combination therapy of suvorexant and ramelteon was started. Case 3 also showed a prompt response. His difficulties in falling asleep and waking up in the morning were ameliorated immediately after suvorexant with ramelteon was started. No obvious side effects were observed. Therapy using the combination therapy of suvorexant and ramelteon might be a reasonable option for DSWPD patients. [ABSTRACT FROM AUTHOR]

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms.sup.1 by synchronization to environmental cues and is involved in diverse physiological processes.sup.2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function.sup.3. Melatonin is formed in the pineal gland in a light-regulated manner.sup.4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness.sup.5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT.sub.1) and type 1B (MT.sub.2).sup.3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden.sup.7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids.sup.8,9, and is one of the most popular supplements in the United States.sup.10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT.sub.1 in complex with four agonists: the insomnia drug ramelteon.sup.11, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine.sup.12,13. The structure of MT.sub.2 is described in an accompanying paper.sup.14. Although the MT.sub.1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT.sub.1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT.sub.1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors. The MT.sub.1 melatonin receptor differs markedly from 5-HT receptors and shows atypical ligand entry; its structure with various ligands sheds light on receptor specificity., Author(s): Benjamin Stauch [sup.1] [sup.2] , Linda C. Johansson [sup.1] [sup.2] , John D. McCorvy [sup.4] [sup.15] , Nilkanth Patel [sup.1] [sup.3] , Gye Won Han [sup.1] [sup.2] , Xi-Ping [...]

Melatonin is a human neurotransmitter and plant signalling metabolite that perceives and directs plant metabolism. The mechanisms of melatonin action in plants remain undefined. We hypothesized that roots have a melatonin-specific receptor and/or transporter that can respond to melatonin-mediating pharmaceuticals. To test this hypothesis Arabidopsis seedlings were grown with melatonin pharmaceutical receptor agonists: ramelteon and tasimelteon, and/or antagonists: luzindole and 4-P-PDOT. Ramelteon was found both to mimic and competitively inhibit melatonin metabolism in plants. Due to the higher selectivity of ramelteon for the MT1 receptor type in humans, a sequence homology search for MT1 in Arabidopsis identified the rhomboid-like protein 7 (RBL7). In physiological studies, Arabidopsis rbl7 mutants were less responsive to ramelteon and melatonin. Quantum dot visualizations of the effects of ramelteon on melatonin binding to root cell membranes revealed a potential mechanism. We propose that RBL7 is a melatonin-interacting protein that directs root architecture and growth in a mechanism that is responsive to environmental factors.

Objectives: Postoperative delirium, associated with negative consequences including longer hospital stays and worse cognitive and physical outcomes, is frequently accompanied by sleep-wake disturbance. Our objective was to evaluate the efficacy and short-term safety of ramelteon, a melatonin receptor agonist, for the prevention of postoperative delirium in older patients undergoing orthopedic surgery.Design: A quadruple-masked randomized placebo-controlled trial (Clinical Trials.gov NCT02324153) conducted from March 2017 to June 2019.Setting: Tertiary academic medical center.Participants: Patients aged 65 years or older, undergoing elective primary or revision hip or knee replacement.Intervention: Ramelteon (8 mg) or placebo MEASUREMENTS: Eighty participants were randomized to an oral gel cap of ramelteon or placebo for 3 consecutive nights starting the night before surgery. Trained research staff conducted delirium assessments for 3 consecutive days starting on postoperative day (POD) 0, after recovery from anesthesia, and on to POD2. A delirium diagnosis was based upon DSM-5 criteria determined by expert panel consensus.Results: Of 80 participants, five withdrew consent (one placebo, four ramelteon) and four were excluded (four ramelteon) after randomization. Delirium incidence during the 2 days following surgery was 7% (5 of 71) with no difference between the ramelteon versus placebo: 9% (3 of 33) and 5% (2 of 38), respectively. The adjusted odds ratio for postoperative delirium as a function of assignment to the ramelteon treatment arm was 1.28 (95% confidence interval: 0.21-7.93; z-value 0.27; p-value = 0.79). Adverse events were similar between the two groups.Conclusion: In older patients undergoing elective primary or revision hip or knee replacement, ramelteon was not efficacious in preventing postoperative delirium. [ABSTRACT FROM AUTHOR]

Extensive research has gone into proposing a promising link between melatonin administration and attenuation of epileptic activity, the majority of which suggest its propensity as an antiseizure with antioxidant and neuroprotective properties. In the past few years, a number of studies highlighting the association of the melatonergic ligands with epilepsy have also emerged. In this context, our review is based on discussing the recent studies and various mechanisms of action that the said category of drugs exhibit in the context of being therapeutically viable antiseizure drugs. Our search revealed several articles on the four major drugs i.e. melatonin, agomelatine, ramelteon and piromelatine along with other melatonergic agonists like tasimelteon and TIK-301. Our review is suggestive of antiseizure effects of both melatonin and its analogues; however, extensive research work is still required to study their implications in the treatment of persons with epilepsy. Further evaluation of melatonergic signaling pathways and mechanisms may prove to be helpful in the near future and might prove to be a significant advance in the field of epileptology. [ABSTRACT FROM AUTHOR]

Background: Patients in the intensive care unit (ICU) often experience poor sleep quality. Pharmacologic sleep aids are frequently used as primary or adjunctive therapy to improve sleep, although their benefits in the ICU remain uncertain. This review aims to provide a comprehensive assessment of the objective and subjective effects of medications used for sleep in the ICU, as well as their adverse effects. Methods: PubMed, Web of Science, Scopus, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from their inception until June 2023 for comparative studies assessing the effects of pharmacologic sleep aids on objective and subjective metrics of sleep. Results: Thirty-four studies with 3498 participants were included. Medications evaluated were melatonin, ramelteon, suvorexant, propofol, and dexmedetomidine. The majority of studies were randomized controlled trials. Melatonin and dexmedetomidine were the best studied agents. Objective sleep metrics included polysomnography (PSG), electroencephalography (EEG), bispectral index, and actigraphy. Subjective outcome measures included patient questionnaires and nursing observations. Evidence for melatonin as a sleep aid in the ICU was mixed but largely not supportive for improving sleep. Evidence for ramelteon, suvorexant, and propofol was too limited to offer definitive recommendations. Both objective and subjective data supported dexmedetomidine as an effective sleep aid in the ICU, with PSG/EEG in 303 ICU patients demonstrating increased sleep duration and efficiency, decreased arousal index, decreased percentage of stage N1 sleep, and increased absolute and percentage of stage N2 sleep. Mild bradycardia and hypotension were reported as side effects of dexmedetomidine, whereas the other medications were reported to be safe. Several ongoing studies have not yet been published, mostly on melatonin and dexmedetomidine. Conclusions: While definitive conclusions cannot be made for most medications, dexmedetomidine improved sleep quantity and quality in the ICU. These benefits need to be balanced with possible hemodynamic side effects., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author recently observed a case involving a 12-year-old sighted girl who exhibited symptoms typical of non-24-hour sleep-wake rhythm disorder (N24SWD). This disorder, more commonly found in blind individuals, presents a unique challenge when diagnosed in those with vision. Several interventions can be attempted, ranging from behavioral adjustments to light therapy. Although melatonin has been noted for its effectiveness in realigning the patient's sleep-wake cycle, the use of ramelteon, a melatonin receptor agonist, has seldom been reported in managing N24SWD. However, this case illuminates the potential of ramelteon as another therapeutic option for sighted individuals with N24SWD. Further study is suggested to determine the potential of ramelteon in managing this disorder among sighted individuals of varying age groups., Citation: Huang C-H. Managing non-24-hour sleep-wake rhythm disorder with ramelteon in a 12-year-old girl with Pierre Robin sequence and developmental delay: a case report. J Clin Sleep Med . 2024;20(6):995-997., (© 2024 American Academy of Sleep Medicine.)

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)., Conclusion: 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., Competing Interests: Declaration of conflicting interestsThe authors declare that they have no conflicting interests.

Introduction: Non‐24‐hour sleep‐wake disorder (N24SWD) is often observed in the visually impaired and those who isolate indoors. Melatonin receptor agonists may be used for treatment, but there is currently no evidence that they are effective in patients without visual impairment. Case: We report a case of a 23‐year‐old woman who withdrew from her social life owing to autism spectrum disorder and experienced an unusual sleep rhythm. She presented with N24SWD. The N24SWD cycle averaged 25.6 days but was extended to 42 days using ramelteon. However, this was not enough. We prescribed the addition of suvorexant and the sleep cycle returned to normal. Conclusion: N24SWD is a disease that seriously impairs social life and productivity. We propose a possible treatment strategy for N24SWD using ramelteon and suvorexant. [ABSTRACT FROM AUTHOR]

In intensive care unit (ICU) patients, delirium contributes to prolonged hospitalization, long-term cognitive impairment and increased mortality. Sleep disturbance, a risk factor for delirium, has been attributed to impaired melatonin secretion in critically ill patients. Ramelteon, a synthetic melatonin receptor agonist, is indicated for insomnia; there is limited, but growing evidence, to support its use for the prevention of delirium. The primary objective of this study is to describe the use of ramelteon and the incidence of delirium, assessed by Confusion Assessment Method for the ICU (CAM-ICU) scores, in adult surgical ICU patients from May 22, 2016 to June 30, 2018. The primary endpoint is the number of delirium free days in the week prior to and post first ramelteon administration. A total of 231 patients were included in the study with 201 (87%) positive for delirium at least once during the study timeframe. The median number of CAM-ICU negative days in the week pre-ramelteon administration was 4 days (IQR 2-7 days) compared to 6 days (IQR 3-7 days) in the week post-first ramelteon administration (P <.05). The time to CAM-ICU positive increased slightly to 3 days (IQR 1-7 days) following ramelteon initiation compared to 2 days (IQR 1-5 days) from initial ICU admission. Additionally, the median number of antipsychotic doses per patient decreased from 4 doses (IQR 1.25-14 doses) prior to ramelteon to 2 doses (IQR 1-4 doses) after ramelteon. Ramelteon administration was associated with a greater number of CAM-ICU negative days in surgical ICU patients. These findings describe a potential role for ramelteon in mitigating delirium in this patient population. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the effect of an intervention consisting of bright light exposure, sleep schedule shifts, and ramelteon on sleep disturbances after a transition of 12 time zones. Two groups, which flew from Tokyo to Rio, participated in this study. The experimental group received the treatment, whereas the control group did not receive any treatment. The experimental group members were exposed to bright light at night and their sleep-wake schedules were gradually delayed for 4 days before their flight. They also took 8mgof ramelteon once a day for 5 days fromthe day of their first flight. Both groups departed Tokyo at 14:05, transiting through Frankfurt and arriving in Rio at 05:05. In Rio, it was recommended that they go to bed earlier than usual if they experienced sleepiness. Nocturnal sleep variablesmeasured bywristwatch actigraphy and subjective morning tirednesswere compared between groups. Statistical analysis revealed shorter sleep onset latencies (SOLs) in the experimental group (p<0.01). The SOLs inRio were 7.762.5minutes for the experimental group and 16.363.7minutes for the control group (d50.89, effect size: large). Sleep efficiency for the first 3 nights in Rio was 88.5 ± 1.2% for the experimental group and 82.9 ± 3.0% for the control group (p<0.01, d51.09, effect size: large). These results suggest that the intervention reduced sleep disturbances in Rio. Our intervention may increase the options for conditioning methods for athletic events requiring time zone transitions. [ABSTRACT FROM AUTHOR]

We performed a network meta-analysis to build clear hierarchies of efficacy and tolerability of pharmacological interventions for the treatment and prevention of delirium. Electronic databases including PubMed, Google Scholar, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and MEDLINE were searched published up to February 22, 2019. A total of 108 randomized controlled trials (RCTs) investigating pharmacotherapy on delirium were included for analysis, and the strength of evidence (SoE) was evaluated for critical outcomes. In terms of treatment, quetiapine (low SoE), morphine (low SoE), and dexmedetomidine (moderate SoE) were effective in the intensive care unit (ICU) patients. In terms of prevention, dexmedetomidine (high SoE) and risperidone (high SoE) significantly reduced the incidence of delirium in ICU surgical patients, while ramelteon (high SoE) reduced the incidence of delirium in ICU medical patients. Despite the efficacy, dexmedetomidine and risperidone demonstrated higher drop-out rate (moderate to high SoE). Haloperidol and other antipsychotics, except for quetiapine and risperidone, showed no benefit. None of the agents showed benefit in non-ICU patients. In conclusion, dexmedetomidine may be a drug of choice for both treating and preventing delirium of the ICU and postsurgical patients. However, it may be less tolerable, and side-effects should be adequately managed. Current evidence does not support the routine use of antipsychotics. For medical patients, oral ramelteon might be useful for prevention. • This is first network meta-analysis (NMA) to provide strength of evidence for pharmacological interventions on delirium. • Our NMA does not support routine use of antipsychotics for treating and preventing delirium. • Dexmedetomidine may be a drug of choice for both treating and preventing delirium of the ICU and postsurgical patients. • For ICU medical patients, oral ramelteon can be potential alternative for antipsychotics. • None of the agents showed benefit in non-ICU patients. [ABSTRACT FROM AUTHOR]

Aim: The intensive care unit (ICU) environment contributes to the development of sleep disturbances. Sleep disturbances, sleep fragmentation, and multiple awakening episodes lead to the circadian rhythm disorder, which increases the risk of delirium. Melatonin and melatonin receptor agonist is widely used agent in the therapy of sleep disturbances. However, there is also some for its efficacy in ICU delirium. Enteral melatonin and ramelteon supplementation eliminates (partially) the delirium inducing factors.Methods: PubMed/MEDLINE, OVID, Embase, Cochrane Library, and Web of Science databases were searched using adequate key words. We reviewed the literature on the role of melatonin and ramelteon in the prevention of sleep disturbances and delirium in intensive care units and analysed the methods of melatonin therapy in an ICU setting. Review followed the PRISMA statement. A review written protocol was not drafted.Results: Originally 380 studies were searched in five scientific databases. After rejecting the duplicate results, 125 results were obtained. Finally, 10 scientific studies were included in the review. In selected articles, the leading topics analysed were the role of melatonin and ramelteon in the prevention of delirium and sleep disorders. In addition, the noted effect of therapy with these agents on reducing the ventilation time of mechanical time and the demand for psychoactive substances in the ICU environment.Conclusion: Reduction of either the incidence or the severity of delirium course is possible by eliminating its risk factors. Risk factors are directly related to sleep disorders. To reduce the problem, therefore, a holistic approach to the source is necessary. The efficacy of melatonin therapy in an ICU setting requires confirmation in studies including a greater number of participants as the impact of melatonin on these factors is yet to be fully elucidated. However, the prognosis is predictive because this concept provides patients with a minimally invasive and natural form of therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sleep plays an important role in the recovery of critically ill patients. However, patients in the intensive care unit (ICU) often suffer sleep disturbances and abnormal circadian rhythms, which may increase delirium and lengthen ICU stay. Nonpharmacologic strategies for preventing and treating sleep disturbances and delirium, such as overnight eye masks and ear plugs, are usually employed first, given the lack of adverse effects. However, a multimodal approach to care including pharmacotherapy may be necessary. Despite the limited available data supporting their use, medications such as melatonin, ramelteon, suvorexant, and dexmedetomidine may promote sleep and improve a variety of patient-centric outcomes such as delirium. This narrative review focuses on these nonbenzodiazepine agents used for sleep in the ICU. Practical application of each of these agents is described for when providers choose to utilize one of these pharmacotherapies to promote sleep or prevent delirium. [ABSTRACT FROM AUTHOR]

Background: It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection.Methods: VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated.Results: Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody.Conclusions: Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production. [ABSTRACT FROM AUTHOR]

• Depression and anxiety have been associated with misaligned circadian genes expression. • Disruption of of Immunity and neuroplasticity are associated with sleep disorders. • Melatonergic agonist restores the altered pro-inflammatory cytokines and neurotrophic factors. • The misaligned mRNA expressions of clock genes resynchronized after ramelteon treatment. Circadian dysfunction is a core manifestation and a risk factor for psychiatric disorders. Ramelteon (RMT), a melatonin receptor agonist, has been shown to induce sleep phase shifts and has been used to normalize sleep onset time. RMT has been used in sleep disorders, depression and anxiety. In this study, we aimed to investigate the effects of RMT in regulating gene expression profiles of the circadian clock and peripheral markers of inflammation and neuroplasticity. Sixteen patients with a diagnosis of primary insomnia comorbid with depression and anxiety and ten healthy controls were recruited in an 8-week open-label trial. The patients with primary insomnia received RMT 8 mg/day. The morning expression profiles of 15 core clock genes from peripheral blood mononuclear cells (PBMCs), urine and plasma levels of melatonin and its metabolite levels, and plasma inflammatory markers and neurotrophin levels were evaluated at baseline, 4th and 8th week of RMT treatment. RMT treatment was associated with significant clinical improvement in depression scores at 8th week (Hamilton depression rating scale scores (Mean ± SEM) from 21.5 ± 2.44 to 14.31 ± 2.25, p ≤ 0.05). The overall poor sleep quality (Pittsburgh sleep quality index) of the patient group significantly improved (p ≤ 0.05) following RMT treatment. The mRNA level analysis showed a significant association between RMT treatment and alterations of the nine core circadian genes (CLOCK, PER1, PER2, CRY1, CRY2, NR1D1, NR1D2, DEC1 and TIMELESS) in the patient group when compared with the control group (p ≤ 0.05). Compared with the controls, the patient group had a decrease in neurotrophins (brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and beta-nerve growth factor; p ≤ 0.05) but an increase in pro-inflammatory cytokine levels (interleukin-6, interleukin-1b, tumour necrosis factor-alpha and interferon gamma; p ≤ 0.05); RMT treatment normalized the levels of neurotrophins and cytokine levels. RMT treatment is able to restore phase-shifted melatonin markers, normalized the altered expression of the circadian genes, the levels of inflammatory cytokines and neurotrophins in patients with insomnia comorbid anxiety and depression. [ABSTRACT FROM AUTHOR]

• This study evaluated the effects of add-on ramelteon on sleep and circadian rhythm disturbances in schizophrenia. • A significantly greater improvement in serum melatonin, urinary melatonin, PSQI scores, serum AANAT and PANSS score were found in patients receiving add-on ramelteon. • Ramelteon may be considered as an add-on therapy with antipsychotic drugs for sleep and circadian rhythm disturbances in schizophrenia. The sleep and circadian rhythm disruptions in schizophrenia are attributed to a decrease in nocturnal melatonin level which may worsen if treated with conventional sedative drugs. This study was planned to evaluate the effects of add-on ramelteon on sleep and circadian rhythm disturbances in schizophrenia. A randomized, rater-blinded clinical trial was conducted on 120 patients with schizophrenia. Patients were categorized into predominantly positive (PG) or negative (NG) symptoms depending on Positive and Negative Syndrome Scale (PANSS) scoring, and then they were randomized into control (haloperidol/risperidone) or test (add-on ramelteon) groups. After recruitment, baseline serum melatonin, serum AANAT, urinary melatonin and Pittsburgh Sleep Quality Index (PSQI) were evaluated. Patients were reassessed after 4 weeks of therapy with antipsychotics with or without ramelteon. A significantly greater increase in night-time melatonin level (PG: 10·19; 95%CI: 1·42 to 18·97; p = 0·024; NG: 18·74; 95%CI: 8·48 to 29·0; p = 0·001), decrease in PSQI scores (PG: −1·57; 95%CI: −2·59 to −0·55; p = 0·003; NG: −2·49; 95%CI: −4·59 to −0·39; p = 0·021), increase in urinary melatonin (PG: 0·20; 95% CI: 0·056 to 0·35; p = 0·008; NG :0·15; 95% CI: 0·01 to 0·29; p = 0·034), increase in serum AANAT (PG: 4·61; 95%CI: 1·34 to 7·87; p = 0·007; NG:3·46; 95%CI: 1·30 to 5·63; p = 0·002) and improvement in PANSS score were found in patients receiving add-on ramelteon. The increase in serum melatonin and decrease in PSQI score were greater with predominantly negative symptom group in comparison to positive symptom group. Ramelteon may be considered as an add-on therapy with antipsychotic drugs for sleep and circadian rhythm disturbances in schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives: Melatonin is an endogenous hormone, which regulates circadian rhythms and promotes sleep. In recent years, several randomised controlled trials examining the prophylactic use of melatonin to prevent delirium were published with conflicting findings. The primary aim of this review was to determine the effect of melatonin on the incidence of delirium in hospitalised patients.Data Sources: MEDLINE, EMBASE and CENTRAL were systematically searched from their inception until December 2018.Review Methods: All randomised clinical trials were included.Results: Sixteen trials (1634 patients) were included in this meta-analysis. Incidence of delirium was not significantly lower in patients who received melatonin, with an odd ratio, OR (95%Cl) of 0.55 (0.24-1.26); ρ = 0.16, certainty of evidence = low, trial sequential analysis = inconclusive. However, patients who randomised to melatonin had a significantly shorter length of stay in intensive care units, with a mean difference, MD (95%CI) of -1.84 days (-2.46, -1.21); ρ < 0.001. No differences were demonstrated in the need for physical restraints (OR 95%Cl 0.65; 0.31-1.37; ρ = 0.26) and the requirement of sedative agents (OR 95%Cl 0.86; 0.48-1.55; ρ = 0.62).Conclusions: In summary, the results of this meta-analysis of sixteen trials neither support nor oppose the use of melatonin in the prevention of delirium of hospitalised patients. We identified high heterogeneity across all the included trials and low certainty of evidence with potential type II error. Future multi-centre, adequately powered randomised controlled trials are warranted to provide more certainty on the use of melatonin for the prevention of delirium.Prospero: CRD42019123546. [ABSTRACT FROM AUTHOR]