Selective Melatonin Receptor Agonist Research Articles

Agomelatine augmentation of sertraline in the treatment of moderate to severe obsessive-compulsive disorder: a randomized double-blinded placebo-controlled clinical trial

BackgroundAs 40–60% of the patients with obsessive-compulsive disorder (OCD) do not adequately respond to the first-line treatment, finding an effective second-line treatment is required. Our aim was to assess the efficacy and safety of agomelatine (a selective melatonin receptor agonist and a 5-hydroxytryptamine (HT)2 C antagonist) augmentation of sertraline in the treatment of patients with moderate to severe OCD.MethodsIn this 12-week randomized, double-blinded, placebo-controlled, parallel-group clinical trial, 65 patients with moderate to severe OCD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM–5) criteria and a Yale-Brown obsessive compulsive scale (Y-BOCS) score of over 21, were included. They were assigned with sertraline (100 mg/day for the first 4 weeks and 200 mg/day for the next 8 weeks) and either agomelatine (25 mg/day) or placebo. The primary outcome was OCD symptoms measured by the Y-BOCS.ResultsFifty patients (24 in agomelatine group and 26 in placebo group) completed the trial. The Y-BOCS scores in total (MD (95% CI) = 12.25 (11.00, 13.49) (P < 0.001) vs. MD (95% CI) = 12.46 (6.65, 15.74) (P < 0.001)), the obsession subscale (MD (95% CI) = 5.04 (4.19, 5.88) (P < 0.001) vs. MD (95% CI) = 5.00 (3.84, 6.16) (P = 0.0001)), and compulsion subscale (MD (95% CI) = 7.21 (6.34, 8.07) (P < 0.001) vs. MD (95% CI) = 7.460 (6.50, 8.42) (P < 0.001)) significantly decreased in both groups. Although, at the end of the trial, no significant difference was observed between the scores of the two groups in total (MD (95% CI) = 0.480 (-1.23, 2.19) (P = 0.78)), the obsession subscale (MD (95% CI) = 1.020 (-0.15, 2.19) (P = 0.38)), and the compulsion subscale (MD (95% CI) = 0.540 (-0.34, 1.42) (P = 0.54)). No major adverse effects were recorded, and the frequency of side effects was not significantly different between the groups.ConclusionAgomelatine in augmentation with sertraline is safe and tolerable in patients with moderate to severe OCD. However, our study does not support its efficacy in improving OCD symptoms, compared to placebo.Trial registrationThe trial was registered at the Iranian Registry of Clinical Trials on 14/07/2020 (www.irct.ir; IRCT ID: IRCT20170123032145N5).

Shumian Capsule Improves the Sleep Disorder and Mental Symptoms Through Melatonin Receptors in Sleep-Deprived Mice.

Healthy sleep is vital to maintaining the body's homeostasis. With the development of modern society, sleep disorder has gradually become one of the most epidemic health problems worldwide. Shumian capsule (SMC), a kind of traditional Chinese medicine (TCM) commonly used for insomnia, exhibits antidepressant and sedative effects in clinical practice. However, the underlying mechanisms have not been fully clarified. With the aid of a network pharmacology approach and function enrichment analysis, we identified the involvement of melatonin receptors in the antidepressant and sedative effects of SMC. In sleep-deprived mice, SMC treatment significantly alleviated insomnia and relevant mental alterations by improving both sleep latency and sleep duration. However, ramelteon, a selective melatonin receptor agonist that has been approved for the treatment of insomnia, only improved sleep latency. Additionally, SMC exhibited comparable effects on mental alterations with ramelteon as determined by an open-field test (OFT) and forced swimming test (FST). Mechanistically, we revealed that the melatonin receptor MT1 and MT2 signaling pathways involved the therapeutic effects of SMC. In addition to the single effect of traditional melatonin receptor agonists on treating sleep onset insomnia, SMC had therapeutic potential for various sleep disorders, such as sleep onset insomnia and sleep maintenance insomnia. Convergingly, our findings provide theoretical support for the clinical application of SMC.

Melatonin and risk of mortality in subjects with aneurysmal subarachnoid hemorrhage

BackgroundDelayed cerebral ischemia (DCI) is a cause of morbidity associated with aneurysmal subarachnoid hemorrhage (aSAH). Neuroinflammation contributes to the development of DCI. Melatonin is a sleep-promoting hormone known to have cerebral anti-inflammatory properties. We hypothesized that synthetic melatonin (or the selective melatonin receptor agonist ramelteon) incidentally prescribed to improve sleep may lower the incidence of DCI among hospitalized aSAH patients. MethodsSubjects with a Hunt and Hess Grade I-III were identified from a data registry involving all aSAH patients admitted to our hospital between January 2015 and September 1, 2018. A cohort of patients who received either melatonin or ramelteon during their hospitalization was compared to a matched cohort that did not receive these drugs. The primary endpoint was incidence of DCI. Secondary outcomes included modified Rankin score (mRS) at discharge, discharge destination, and mortality at 6 weeks from discharge. The two groups were compared using univariate analysis. P < 0.05 was considered significant. ResultsThere was no significant difference in the incidence of DCI (15.8% vs. 16.9%, p = 1), discharge mRS (mRS 0–3: 51.3% vs. 45.1%, p = 0.59), discharge disposition (Home: 43.6% vs. 44.4, p = 0.47), or mortality (0% vs. 9.2%; p = 0.074) between the melatonin/ramelteon and non-melatonin groups. ConclusionThe use melatonin had no effect on DCI but may improve mortality in aSAH subjects. Prospective studies using a larger cohort are warranted to validate these findings.

The Protective Effects of Ramelteon Against Isoflurane-Induced Insults and Inflammatory Response in Brain Microvascular Endothelial Cells.

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.

Melatonin receptor ligands: A pharmaco-chemical perspective.

Melatonin MT1 and MT2 receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT2 -selective agents-agonists, antagonists, or partial agonists-were reported, the field was lacking MT1 -selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri- or tetra-cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype-selective melatonin receptor antagonists "active" in vivo, which are critical to our understanding of melatonin and melatonin receptors' role in basic physiology and disease.

Structure-based discovery of potent and selective melatonin receptor agonists.

Melatonin receptors MT1 and MT2 are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound 21 reaching EC50 of 0.36 nM. Six of these molecules displayed selectivity for MT2 over MT1. Moreover, two most potent agonists, including 21 and a close derivative of melatonin, 28, had dramatically reduced arrestin recruitment at MT2, while compound 37 was devoid of Gi signaling at MT1, implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists.

Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury.

Melatonin receptors (MTs) are potential drug targets for stroke therapy. Ramelteon is a selective melatonin receptor agonist used to treat insomnia. In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice. Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion (MCAO). We found oral administration of ramelteon (3.0 mg/kg) significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia. We showed that administration of ramelteon (3.0 mg/kg) displayed comparable protective efficacy and length of effective time window as administration of edaravone (10 mg/kg, i.p.), which was used in clinic to treat ischemic stroke. Chronic ischemic brain injury was induced in mice using photothrombosis. Oral administration of ramelteon (3.0 mg · kg−1 · d−1) for 7 days after ischemia significantly attenuated functional deficits for at least 15 days. The neuroprotection of ramelteon was blocked by 4-P-PDOT, a specific MT antagonist. We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. Intracerebroventricular injection of rapamycin, an autophagy activator, compromised the neuroprotection of ramelteon, suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death. These data demonstrate for the first time the potential benefits of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.

Structure-based discovery of potent and selective melatonin receptor agonists

Structure-based discovery of potent and selective melatonin receptor agonists

Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use.

In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists’ actions as cardioprotective therapeutic agents.

A Cluster Headache Responsive to Ramelteon, a Selective Melatonin MT&lt;sub&gt;1&lt;/sub&gt;/MT&lt;sub&gt;2&lt;/sub&gt; Receptor Agonist

Patients with cluster headaches occasionally fail to respond to conventional preventive treatments. We herein report a case of a patient with a cluster headache in which the symptoms were refractory to conventional preventive treatments except for high-dose glucocorticoids. The headache attacks occurred daily while sleeping, thus the patient suffered from insomnia. Ramelteon, a selective melatonin receptor agonist and a member of a new class of insomnia therapies, completely suppressed the attacks during sleep and provided rapid relief from insomnia. This is the first English case report to describe the efficacy of ramelteon as a preventive treatment for cluster headaches.

The melatonin receptor agonist ramelteon effectively treats insomnia and behavioral symptoms in autistic disorder.

Children with autism spectrum disorders (ASD), including autistic disorder, frequently suffer from comorbid sleep problems. An altered melatonin rhythm is considered to underlie the impairment in sleep onset and maintenance in ASD. We report three cases with autistic disorder in whom nocturnal symptoms improved with ramelteon, a selective melatonin receptor agonist. Insomnia and behavior, assessed using the Clinical Global Impression-Improvement Scale, improved in two cases with 2 mg ramelteon and in the third case with 8 mg ramelteon. Our findings demonstrate that ramelteon is effective not only for insomnia, but for behavioral problems as well, in patients with autistic disorder.

From the Guest Editor

Back to table of contents Next article From the Guest EditorFull AccessFrom the Guest EditorKarl Doghramji, M.D.Karl DoghramjiSearch for more papers by this author, M.D.Published Online:1 Jan 2014https://doi.org/10.1176/appi.focus.12.1.1AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail This issue of Focus is dedicated to the update and review of major developments in our understanding and management of sleep disorders, with an emphasis on those disorders that are commonly confronted by psychiatrists and other mental health practitioners. A staggering one-third of all humans are affected by sleep disorders. Sleep-related complaints are also disproportionately high in prevalence in psychiatric practice, and are actively expressed by patients suffering from almost all major psychiatric conditions. Proper identification, clinical evaluation, and effective management of sleep disorders are, therefore, of significant importance for psychiatrists.In the first paper, “Recent Advances in the Understanding of Insomnia,” I explore key developments in clarifying the pathophysiology of insomnia, and explain how these have led to an evolution of our view of the relationship between co-occurring insomnia and medical/psychiatric disorders from a model of unidirectional causality to one of autonomous disorders interacting in a bidirectional fashion. I also clarify how these constructs are reflected in the newly introduced DSM-5 diagnostic nosology. Pharmacological agents have played a crucial role in the management of insomnia for many decades; in his paper, “Novel Developments in the Pharmacological Management of Insomnia,” Dr. David Neubauer explores the many available agents and provides an evidence-based approach in their selection and use. Whereas GABA receptor agonists have dominated the therapeutic armementarium, Dr. Neubauer reviews novel and investigational agents with mechanisms traversing the receptor systems that are involved in the control of sleep and arousal, such as selective histamine H1 receptor antagonists, selective melatonin receptor agonists, and dual orexin receptor antagonists. “Natural” compounds enjoy a significant allure by virtue of their widespread availability, and the perception that they are safer than prescription medications for insomnia. In his “Ask the Expert” column, Dr. Milton Erman explores the array of products most commonly utilized for sleep-related complaints and provides empirical data to guide practitioners through the morass of widespread claims regarding the benefits of these agents. Although less widely utilized than pharmacological agents, cognitive and behavioral therapies are of clear benefit in insomnia. In her paper entitled, “Psychological and Behavioral Treatments for Insomnia,” Dr. Brenda Byrne explores the principles underlying these techniques and guidelines in their implementation. She also reviews exciting new evidence demonstrating the lasting benefit of these therapies for extended periods of time following termination of treatment. Dr. John Khoury and myself, in our paper entitled, “Circadian Rhythms in Health and Disease,” review our current understanding of the neurophysiology of the circadian regulation system, which encompasses a complex array of physiological and psychological variables including core body temperature, hormone secretion, hunger, mood, and sleep, among others. We then explain how misalignments in the timing of these variables can lead to circadian rhythm disorders, and explore many of the treatment modalities that can be utilized in the context of psychiatric practice for these disorders. Finally, in their paper, entitled “Parasomnias, A Review for Psychiatrists,” Drs. Thomas Hurwitz, Michael Howell, and Imran Khawaja review a fascinating group of behavioral disturbances that occur in the borderlands between sleep and wakefulness that are often confused with psychiatric disorders. The authors explore a systematic approach for the evaluation and management of these disorders, which can lead to serious injury, and which often disrupt relationships.I am grateful to the contributors of this issue of Focus, all of whom are prominent researchers, educators, and clinicians in the field of sleep medicine. I am confident that you will find their state-of-art papers to be informative and clinically relevant. FiguresReferencesCited byDetailsCited ByNone Volume 12Issue 1 Winter 2014Pages 1-1Disorders of Sleep PDF download

Melatonin Receptors Mediate Improvements of Survival in a Model of Polymicrobial Sepsis

Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice. Prospective, randomized, controlled study. University research laboratory. Male Sprague-Dawley rats (200-250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22 g). Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme-linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision. Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response. Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release.

Marked improvement in delirium with ramelteon: five case reports

Delirium is a common and serious acute neuropsychiatric syndrome characterized by inattention and global cognitive dysfunction. Delirium is associated with higher morbidity, higher mortality and longer hospitalization, but its aetiology remains unclear. We successfully treated five cases of delirium within 1 day with ramelteon, a novel selective melatonin receptor agonist. This suggests that correction of the circadian rhythm disturbance, one of the main symptoms of delirium, plays a crucial role in its treatment and sheds new light on a therapeutic strategy for treatment of delirium.

Evidence that membrane‐bound G protein‐coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral ischemia

Melatonin is synthesized and released by the pineal gland in a circadian rhythm, and many of its peripheral actions are mediated via membrane MT1 and MT2 receptors. Apart from its metabolic functions, melatonin is a potent neuroprotective molecule owing to its antioxidative actions. The roles of MT1 and MT2 in the neuroprotective effects of melatonin and cell signaling after cerebral ischemia remain unknown. With the use of MT1 and MT2 knockout (mt1/2(-/-) ) mice treated with melatonin, we evaluated brain injury, edema formation, inducible nitric oxide synthase (iNOS) activity, and signaling pathways, including CREB, ATF-1, p21, Jun kinase (JNK)1/2, p38 phosphorylation, resulting from ischemia/reperfusion injury. We show that the infarct volume and brain edema do not differ between mt1/2(-/-) and wild-type (WT) animals, but melatonin treatment decreases infarct volume in both groups and brain edema in WT animals after middle cerebral artery occlusion. Notably, melatonin's neuroprotective effect was even more pronounced in mt1/2(-/-) animals compared to that in WT animals. We also demonstrate that melatonin treatment decreased CREB, ATF-1, and p38 phosphorylation in both mt1/2(-/-) and WT mice, while p21 and JNK1/2 were reduced only in melatonin-treated WT animals in the ischemic hemisphere. Furthermore, melatonin treatment lowered iNOS activity only in WT animals. We provide evidence that the absence of MT1 and MT2 has no unfavorable effect on ischemic brain injury. In addition, the neuroprotective effects of melatonin appear to be mediated through a mechanism independent of its membrane receptors. The underlying mechanism(s) should be further studied using selective melatonin receptor agonists and antagonists.

Critical appraisal of ramelteon in the treatment of insomnia

Ramelteon is the first member of a novel class of hypnotics and acts as a selective melatonin receptor agonist. In 2005, ramelteon was approved by the US Food and Drug Administration for the treatment of insomnia characterized by sleep onset problems. Its unique mechanism of action made it a promising candidate compared with the widely used hypnotics that act on the benzodiazepine receptor complex. Several studies have examined its efficacy and safety as a hypnotic agent. The primary efficacy of ramelteon was found to lie in a decrease in latency to persistent sleep, as measured by polysomnographic tests. Other sleep-related measures, such as total sleep time and number of nightly awakenings, show less pronounced improvement when treated with ramelteon. In addition, no rebound insomnia or abuse potential was observed in clinical studies. Although additional studies are necessary, current data on the acute and next-morning effects of ramelteon did not indicate cognitive or psychomotor impairment. Overall, ramelteon is safe and well tolerated, although some questions remain regarding its long-term efficacy and safety. These issues and possibilities for use in other patient groups should be addressed in future research.

Insomnia medication use and the probability of an accidental event in an older adult population

Objective:This study examined the risk of accidental events in older adults prescribed a sedating antidepressant, long-acting benzodiazepine, short-acting benzodiazepine, and nonbenzodiazepine, relative to a reference group (selective melatonin receptor agonist).Methods:This was a retrospective cohort analysis of older adults (≥65 years) with newly initiated pharmacological treatment of insomnia. Data were collected from the Thomson MarketScan® Medicare Supplemental and Coordination of Benefits databases (January 1, 2000, through June 30, 2006). Probit models were used to evaluate the probability of an accidental event.Results:Data were analyzed for 445,329 patients. Patients taking a long-acting benzodiazepine (1.21 odds ratio [OR]), short-acting benzodiazepine (1.16 OR), or nonbenzodiazepine (1.12 OR) had a significantly higher probability of experiencing an accidental event during the first month following treatment initiation compared with patients taking the reference medication (P < 0.05 for all). A significantly higher probability of experiencing an accidental event was also observed during the 3-month period following the initiation of treatment (1.62 long-acting benzodiazepine, 1.60 short-acting benzodiazepine, 1.48 nonbenzodiazepine, and 1.56 sedating antidepressant; P < 0.05).Conclusions:Older adults taking an SAD or any of the benzodiazepine receptor agonists appear to have a greater risk of an accidental event compared with a reference group taking an MR.

Anticonvulsant effects of the selective melatonin receptor agonist ramelteon

Objective The endogenous hormone melatonin has previously been shown to exert anticonvulsant effects in a variety of experimental models. Accordingly, we asked whether ramelteon, a synthetic and selective melatonin receptor agonist, might also possess anticonvulsant and/or antiepileptogenic properties. Methods The effects of ramelteon (30 or 100 mg/kg intraperitoneally twice daily for 5 days) were evaluated in two animal models of epilepsy. In the rat rapid kindling model, baseline hippocampal afterdischarge properties, kindling progression, and hippocampal excitability in kindled animals were measured. Anti-ictogenic efficacy was assessed after acute administration in untreated kindled rats. In the spontaneously epileptic Kcna1-null mouse model, we determined seizure frequency and periodicity using continuous video/EEG monitoring over 72 hours. Further, circadian rest–activity rhythms in ramelteon-treated animals were studied with actigraphy. Results In kindled animals, ramelteon reversed kindling-induced hippocampal excitability; however, it did not modify baseline afterdischarge properties, the progression and establishment of the kindled state in the rapid kindling model. However, in Kcna1-null mice, ramelteon (200 mg/kg/day) significantly attenuated seizure periodicity and frequency and improved circadian rest–activity rhythms compared with control animals. Conclusions The selective melatonin receptor agonist ramelteon possesses anticonvulsant properties in a chronic epilepsy model. Our findings provide further support for melatonin receptors being potential novel targets for anticonvulsant drug development.

Ramelteon for the treatment of insomnia in menopausal women

Sleep disturbances have been reported to be one of the most troubling manifestations of menopause. While hormone replacement therapy (HRT) has historically been considered a first-line treatment for menopausal insomnia, many women are now seeking alternative treatments due to concerns about the risks and side-effects of HRT. The goal of this study was to evaluate the effect of ramelteon, a selective melatonin receptor agonist, for the treatment of menopausal insomnia. A total of 20 healthy peri- and postmenopausal women with insomnia participated in this six-week, prospective, open-label trial of ramelteon (8 mg) at an academic medical centre. Participants completed sleep-wake diaries on a daily basis for six weeks. Self-report measures of sleep impairment, daytime functioning, quality of life and mood were also completed on a bi-weekly basis. Significant improvements in latency to sleep onset, total sleep time and sleep efficiency were observed in diary data while gains in sleep quality, sleep impairment, daytime functioning, quality of life and mood were found in self-report measures. There was no evidence of tolerance or rebound over the course of the trial. Overall, results suggest that ramelteon is an effective non-hormonal approach for the treatment of insomnia in menopause. Randomized-controlled trials are needed to further evaluate the efficacy of this intervention.

Ramelteon: A Novel Approach in the Treatment of Insomnia

To review the pharmacology, pharmacokinetics, efficacy, and safety of ramelteon in the treatment of primary insomnia in adults, including elderly adults. MEDLINE (1966-July 2008) and PsycINFO (1985-July 2008) literature searches were conducted to identify clinical data involving ramelteon. The manufacturer provided a summary of clinical data and abstracts of unpublished studies. All primary literature, including abstracts, focusing on the pharmacology and pharmacokinetics of ramelteon and clinical trials evaluating its use was reviewed. Information deemed most relevant was incorporated. Our search revealed 5 controlled trials evaluating the short-term efficacy and safety of ramelteon in the treatment of primary insomnia: 3 in adults and 2 in geriatric patients. Additionally, 2 studies in abstract form that evaluated the long-term effects of ramelteon were included. Ramelteon is the first selective melatonin receptor agonist approved by the Food and Drug Administration. It has no affinity for the gamma-aminobutyric acid receptor complex or for receptors that bind acetylcholine, cytokines, dopamine, norepinephrine, neuropeptides, opiates, and serotonin. In the only published Phase 3 trial in adults, investigators found that latency to persistent sleep decreased with ramelteon to 31.5 +/- 2.91 minutes with 8 mg and 29.5 +/- 2.96 minutes with 16 mg compared with 42.5 +/- 2.97 minutes with placebo (p = 0.007 and p = 0.002, respectively). Total sleep time was not significantly different from that with placebo. Safety data from short-term studies showed advantages of ramelteon over other sleep agents including no potential for abuse, no rebound insomnia, and lack of effect on motor and cognitive function. The adverse effects seen most frequently in ramelteon clinical trials were headache, somnolence, fatigue, nausea, dizziness, and insomnia. The overall incidence was similar to that of placebo. Ramelteon offers a novel mechanism of action for the treatment of insomnia. Studies support its short- and long-term use in adults and elderly adults for the treatment of primary insomnia characterized by difficulty with sleep initiation. Efficacy studies comparing ramelteon with other sleep agents are needed to further solidify the role of ramelteon in the treatment of insomnia.