Psychometric Properties of the Athens Insomnia Scale in Occupational Computer Users.

Background: Various studies have shown that insomnia is associated with computer use. The Athens Insomnia Scale (AIS) is an 8-item tool that has been widely used for screening insomnia. No studies have investigated the psychometric validity of AIS in occupational computer users. Objective: the current research aimed to test the psychometric properties of the AIS among occupational computer users. Materials and Methods: a sample of four hundred and twenty-four occupational computer users (age: 20-65 years and body mass index: 21.6 ± 3.5 kg/m2) completed an AIS and a socio-demographic questionnaire in this cross-sectional study. Results: a confirmatory factor analysis demonstrated that the three-factor model had an adequate fit (the goodness of fit index (0.95), incremental fit index (0.90) and χ2/df (2.61)). Evidence was found for configural, scalar and metric invariance of the 3-factor model across gender groups. A moderate level of internal consistency was implied by a Cronbach's alpha of 0.66. Conclusion: the findings of the present research support the validity of AIS for screening insomnia, as demonstrated by the scale's psychometric properties; its internal consistency, internal homogeneity, item discrimination, and factorial validity.

Psychometric properties of the Epworth sleepiness scale in Ethiopian university students.

BACKGROUND: Daytime sleepiness is highly prevalent across the globe. The Epworth sleepiness scale (ESS) is the most widely used tool for screening daytime sleepiness. The psychometric properties of the ESS have not been comprehensively examined in African populations. MATERIAL AND METHODS: A cross-sectional design with simple random sampling was used in the present study. The study recruited 600 students from Mizan-Tepi University, Ethiopia, of which 329 (age = 18-28 years and body mass index = 21.19 ± 3.17 kg/m2) completed the study. ESS, a semi-structured socio-demographics questionnaire and a clinical interview to diagnose insomnia according to the International Classification of Sleep Disorders were employed. RESULTS: All except one item of the ESS showed a floor effect, while only one item score showed ceiling effect. However, no ceiling/floor effect was observed in the ESS total score. The Cronbach's alpha (0.75) and composite reliability (0.75), indicated good internal consistency, while a moderate item-total score correlation (r = 0.55-0.67) implied favorable internal homogeneity. The known-group validity was established by significantly higher scores for all the ESS item scores and the ESS total scores among those with symptoms of insomnia than among non-symptomatic students. Fit indices along with the consideration of inter-factor correlation coefficient, measures of item retention favored the unidimensional structure of the ESS. CONCLUSION: The ESS has excellent psychometric validity for screening daytime sleepiness in Ethiopian university students.

Dimensionality of the Pittsburgh Sleep Quality Index in the collegiate young adults.

PURPOSE: To explore and validate the factor structure of the Pittsburgh Sleep Quality Index (PSQI) in the collegiate young adults. METHODS: Six hundred university students were initially contacted and invited to participate in a survey of their sleep experience and history. Of this preliminary sample 418 of the students (age = 20.92 ± 1.81 years, BMI = 23.30 ± 2.57 kg/m(2)) fulfilled the screening criteria and ultimately completed the Pittsburgh Sleep Quality Index (PSQI), a self-report survey of respondents' sleep habits and sleep quality. The students were enrolled in various undergraduate and postgraduate programs at Jamia Millia Islamia, New Delhi, India. Exploratory factor analysis (EFA) investigated the latent factor structure of the scale. Confirmatory factor analysis evaluated both of the models found by EFA. RESULTS: The Kaiser's criteria, the Scree test, and the cumulative variance rule revealed that a 2-factor model accounted for most of the variability in the data. However, a follow up Parallel Analysis found a 1-factor model. The high correlation coefficient (r = 0.91) between the two factors of the 2-factor model and almost similar values of the fit indices supports the inference that the PSQI is a unidimensional scale. CONCLUSIONS: The findings validate the 1-factor model of the PSQI in the collegiate young adults.

Sleep and circadian rhythm dysregulation in schizophrenia.

Sleep-onset and maintenance insomnia is a common symptom in schizophrenic patients regardless of either their medication status (drug-naive or previously treated) or the phase of the clinical course (acute or chronic). Regarding sleep architecture, the majority of studies indicate that non-rapid eye movement (NREM), N3 sleep and REM sleep onset latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged. Many of these sleep disturbances in schizophrenia appear to be caused by abnormalities of the circadian system as indicated by misalignments of the endogenous circadian cycle and the sleep-wake cycle. Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep in schizophrenic patients could be partly related to a presumed hyperactivity of the dopaminergic system and dysfunction of the GABAergic system, both associated with core features of schizophrenia and with signaling in sleep and wake promoting brain regions. Since multiple neurotransmitter systems within the CNS can be implicated in sleep disturbances in schizophrenia, the characterization of the neurotransmitter systems involved remains a challenging dilemma.

Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.

The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.

Sleep architecture of consolidated and split sleep due to the dawn (Fajr) prayer among Muslims and its impact on daytime sleepiness.

BACKGROUND: Muslims are required to wake up early to pray (Fajr) at dawn (approximately one and one-half hours before sunrise). Some Muslims wake up to pray Fajr and then sleep until it is time to work (split sleep), whereas others sleep continuously (consolidated sleep) until work time and pray Fajr upon awakening. AIM: To objectively assess sleep architecture and daytime sleepiness in consolidated and split sleep due to the Fajr prayer. SETTING AND DESIGN: A cross-sectional, single-center observational study in eight healthy male subjects with a mean age of 32.0 ± 2.4 years. METHODS: The participants spent three nights in the Sleep Disorders Center (SDC) at King Khalid University Hospital, where they participated in the study, which included (1) a medical checkup and an adaptation night, (2) a consolidated sleep night, and (3) a split-sleep night. Polysomnography (PSG) was conducted in the SDC following the standard protocol. Participants went to bed at 11:30 PM and woke up at 7:00 AM in the consolidated sleep protocol. In the split-sleep protocol, participants went to bed at 11:30 PM, woke up at 3:30 AM for 45 minutes, went back to bed at 4:15 AM, and finally woke up at 7:45 AM. PSG was followed by a multiple sleep latency test to assess the daytime sleepiness of the participants. RESULTS: There were no differences in sleep efficiency, the distribution of sleep stages, or daytime sleepiness between the two protocols. CONCLUSION: No differences were detected in sleep architecture or daytime sleepiness in the consolidated and split-sleep schedules when the total sleep duration was maintained.

Evaluation of blood antioxidant defense and apoptosis in peripheral lymphocytes on exogenous administration of pineal proteins and melatonin in rats.

In view of the significant health impact of oxidative stress and apoptosis dysfunction, and further, because of suggestions that administration of antioxidants might reduce apoptosis rate through up-regulation of body antioxidant defense systems, therefore the purpose of this study was to compare the effect of buffalo (Bubalus bubalis) pineal proteins (PP at 100 µg/kg BW, i.p.) with melatonin (MEL at 10 mg/kg BW, i.p.) on blood (erythrocytes) antioxidant defense system and apoptosis in isolated peripheral blood lymphocytes of female Wistar albino rats. The cell viability index (%) and apoptosis index (%), which are directly related to the apoptosis rate of the cells, were used as dependent measures for inferring PP and MEL activity. The total cell viability index did not differ between rats treated with MEL and PP from control animals. The percentage of apoptotic cell death through fluorescence microscopy also did not change in MEL and PP groups as compared with control. DNA fragmentation as an index of apoptosis was detected with propidium iodide staining and assessed by flow cytometry. Pineal proteins and MEL administration caused significant (p < 0.05) reduction in lipid peroxidation and increased level of catalase, superoxide dismutase, glutathione peroxidase, and glutathione in erythrocytes as compared with control. Interestingly, we did not observe increase in the non-viable cells and percentage of apoptotic cell death in PP-treated group, controls or in animals in which MEL had been administered. Therefore, the present study confirmed the up-regulation of erythrocytes (blood) antioxidant defense systems and absence of adverse effect on rate of apoptosis in PP and MEL-administered rats under absence of stress or toxicant exposure. Hence, these test agents can be tested for further therapeutic values against adverse apoptosis rate under stress or toxicants exposures.

Zopiclone as positive control in studies examining the residual effects of hypnotic drugs on driving ability.

Zopiclone (7.5 mg) is frequently used as a positive control in studies that examine the residual effects of hypnotic drugs on driving ability and related skills. This review summarizes studies examining the effects of zopiclone, and discusses its usefulness as a comparator drug for investigations of residual effects of novel sleep medication. A literature review (Pubmed and Embase) was conducted searching for studies that tested zopiclone on driving. Cross references were checked for additional papers. Eight studies utilizing the standardized on-the-road driving test consistently showed that in the morning following bedtime administration zopiclone (7.5 mg) significantly impaired driving performance. A total of 191 healthy volunteers were tested after placebo and zopiclone (7.5 mg). Meta analyses showed no significant differences in driving performance after zopiclone (7.5 mg) between adult and elderly healthy volunteers. The combined effect size (ES) and 95% confidence interval (95%CI) for healthy volunteers was 0.782 (0.620, 0.944). Relative to placebo, an average increment of 3.0 cm in Standard Deviation of Lateral Position (SDLP) was observed when treated with zopiclone (7.5 mg). This deviation was higher than the increment in SDLP reported for drivers with a blood alcohol concentration of 0.05% (+2.4 cm). Results from driving simulators and psychometric tests are consistent with the on-road driving test results. In conclusion, zopiclone (7.5 mg) is a reliable positive control, that consistently shows significant and meaningful impairment on the on-the-road driving test.

Therapeutic potential of melatonin and its analogs in Parkinson's disease: focus on sleep and neuroprotection.

Sleep disorders constitute major nonmotor features of Parkinson's disease (PD) that have a substantial effect on patients' quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT(1) and MT(2) receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed.

Melatonin in mitochondrial dysfunction and related disorders.

Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.

Melatonin agonists in primary insomnia and depression-associated insomnia: are they superior to sedative-hypnotics?

Current pharmacological treatment of insomnia involves the use of sedative-hypnotic benzodiazepine and non-benzodiazepine drugs. Although benzodiazepines improve sleep, their multiple adverse effects hamper their application. Adverse effects include impairment of memory and cognitive functions, next-day hangover and dependence. Non-benzodiazepines are effective for initiating sleep but are not as effective as benzodiazepines for improving sleep quality or efficiency. Furthermore, their prolonged use produces adverse effects similar to those observed with benzodiazepines. Inasmuch as insomnia may be associated with decreased nocturnal melatonin, administration of melatonin is a strategy that has been increasingly used for treating insomnia. Melatonin can be effective for improving sleep quality without the adverse effects associated with hypnotic-sedatives. Ramelteon, a synthetic analog of melatonin which has a longer half life and a stronger affinity for MT1 and MT2 melatonergic receptors, has been reportedly effective for initiating and improving sleep in both adult and elderly insomniacs without showing hangover, dependence, or cognitive impairment. Insomnia is also a major complaint among patients suffering from depressive disorders and is often aggravated by conventional antidepressants especially the specific serotonin reuptake inhibitors. The novel antidepressant agomelatine, a dual action agent with affinity for melatonin MT1 and MT2 receptors and 5-HT2c antagonistic properties, constitutes a new approach to the treatment of major depressive disorders. Agomelatine ameliorates the symptoms of depression and improves the quality and efficiency of sleep. Taken together, the evidence indicates that MT1/MT2 receptor agonists like ramelteon or agomelatine may be valuable pharmacological tools for insomnia and for depression-associated insomnia.

Melatonin--a pleiotropic, orchestrating regulator molecule.

Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.

Pharmacotherapy of insomnia with ramelteon: safety, efficacy and clinical applications.

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon is the first melatonin receptor agonist approved by the Food and Drug Administration (FDA) for the treatment of insomnia characterized by sleep onset difficulties. Ramelteon is both a chronobiotic and a hypnotic that has been shown to promote sleep initiation and maintenance in various preclinical and in clinical trials. The efficacy and safety of ramelteon in patients with chronic insomnia was initially confirmed in short-term placebo-controlled trials. These showed little evidence of next-day residual effects, withdrawal symptoms or rebound insomnia. Other studies indicated that ramelteon lacked abuse potential and had a minimal risk of producing dependence or adverse effects on cognitive or psychomotor performance. A 6-month placebo-controlled international study and a 1-year open-label study in the USA demonstrated that ramelteon was effective and well tolerated. Other potential off-label uses of ramelteon include circadian rhythm sleep disorders such as shift-work and jet lag. At the present time the drug should be cautiously prescribed for short-term treatment only.

Measurement of melatonin in body fluids: standards, protocols and procedures.

BACKGROUND AND PURPOSE: The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulfatoxymelatonin (a6MTs) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the body's endogenous oscillatory pacemaker. The primary objective of this review is to ascertain the clinical benefits and limitations of current methodologies employed for detection and quantification of melatonin in biological fluids and tissues. DATA IDENTIFICATION: A search of the English-language literature (Medline) and a systematic review of published articles were carried out. STUDY SELECTION: Articles that specified both the methodology for quantifying melatonin and indicated the clinical purpose were chosen for inclusion in the review. DATA EXTRACTION: The authors critically evaluated the methodological issues associated with various tools and techniques (e.g. standards, protocols, and procedures). RESULTS OF DATA SYNTHESIS: Melatonin measurements are useful for evaluating problems related to the onset or offset of sleep and for assessing phase delays or advances of rhythms in entrained individuals. They have also become an important tool for psychiatric diagnosis, their use being recommended for phase typing in patients suffering from sleep and mood disorders. Additionally, there has been a continuous interest in the use of melatonin as a marker for neoplasms of the pineal region. Melatonin decreases such as found with aging are or post pinealectomy can cause alterations in the sleep/wake cycle. The development of sensitive and selective methods for the precise detection of melatonin in tissues and fluids has increasingly been shown to have direct relevance for clinical decision making. CONCLUSIONS: Due to melatonin's low concentration, as well as the coexistence of numerous other compounds in the blood, the routine determination of melatonin has been an analytical challenge. The available evidence indicates however that these challenges can be overcome and consequently that evaluation of melatonin's presence and activity can be an accessible and useful tool for clinical diagnosis.

Melatonin in septic shock: some recent concepts.

Melatonin is a versatile molecule, synthesized not only in the pineal gland, but also in many other organs. Melatonin plays an important physiologic role in sleep and circadian rhythm regulation, immunoregulation, antioxidant and mitochondrial-protective functions, reproductive control, and regulation of mood. Melatonin has also been reported as effective in combating various bacterial and viral infections. Melatonin is an effective anti-inflammatory agent in various animal models of inflammation and sepsis, and its anti-inflammatory action has been attributed to inhibition of nitric oxide synthase with consequent reduction of peroxynitrite formation, to the stimulation of various antioxidant enzymes thus contributing to enhance the antioxidant defense, and to protective effects on mitochondrial function and in preventing apoptosis. In a number of animal models of septic shock, as well as in patients with septic disease, melatonin reportedly exerts beneficial effects to arrest cellular damage and multiorgan failure. The significance of these actions in septic shock and its potential usefulness in the treatment of multiorgan failure are discussed.

Melatonin as a therapeutic tool in ophthalmology: implications for glaucoma and uveitis.

Several lines of evidence support the view that increased free radical generation and altered nitric oxide (NO) metabolism play a role in the pathogenesis of highly prevalent ocular diseases, such as glaucoma and uveitis. Data are discussed indicating that melatonin, being an efficient antioxidant that displays antinitridergic properties, has a promising role in the treatment of these ocular dysfunctions. Melatonin synthesis occurs in the eye of most species, and melatonin receptors are localized in different ocular structures. In view of the fact that melatonin lacks significant adverse collateral effects even at high doses, the application of melatonin could potentially protect ocular tissues by effectively scavenging free radicals and excessive amounts of NO generated in the glaucomatous or uveitic eye.

Malaria: therapeutic implications of melatonin.

Malaria, which infects more than 300 million people annually, is a serious disease. Epidemiological surveys indicate that of those who are affected, malaria will claim the lives of more than one million individuals, mostly children. There is evidence that the synchronous maturation of Plasmodium falciparum, the parasite that causes a severe form of malaria in humans and Plasmodium chabaudi, responsible for rodent malaria, could be linked to circadian changes in melatonin concentration. In vitro melatonin stimulates the growth and development of P. falciparum through the activation of specific melatonin receptors coupled to phospholipase-C activation and the concomitant increase of intracellular Ca2+. The Ca2+ signaling pathway is important to stimulate parasite transition from the trophozoite to the schizont stage, the final stage of intraerythrocytic cycle, thus promoting the rise of parasitemia. Either pinealectomy or the administration of the melatonin receptor blocking agent luzindole desynchronizes the parasitic cell cycle. Therefore, the use of melatonin antagonists could be a novel therapeutic approach for controlling the disease. On the other hand, the complexity of melatonin's action in malaria is underscored by the demonstration that treatment with high doses of melatonin is actually beneficial for inhibiting apoptosis and liver damage resulting from the oxidative stress in malaria. The possibility that the coordinated administration of melatonin antagonists (to impair the melatonin signal that synchronizes P. falciparum) and of melatonin in doses high enough to decrease oxidative damage could be a novel approach in malaria treatment is discussed.

Potential use of melatonergic drugs in analgesia: mechanisms of action.

Melatonin is a remarkable molecule with diverse physiological functions. Some of its effects are mediated by receptors while other, like cytoprotection, seem to depend on direct and indirect scavenging of free radicals not involving receptors. Among melatonin's many effects, its antinociceptive actions have attracted attention. When given orally, intraperitoneally, locally, intrathecally or through intracerebroventricular routes, melatonin exerts antinociceptive and antiallodynic actions in a variety of animal models. These effects have been demonstrated in animal models of acute pain like the tail-flick test, formalin test or endotoxin-induced hyperalgesia as well as in models of neuropathic pain like nerve ligation. Glutamate, gamma-aminobutyric acid, and particularly, opioid neurotransmission have been demonstrated to be involved in melatonin's analgesia. Results using melatonin receptor antagonists support the participation of melatonin receptors in melatonin's analgesia. However, discrepancies between the affinity of the receptors and the very high doses of melatonin needed to cause effects in vivo raise doubts about the uniqueness of that physiopathological interpretation. Indeed, melatonin could play a role in pain through several alternative mechanisms including free radicals scavenging or nitric oxide synthase inhibition. The use of melatonin analogs like the MT(1)/MT(2) agonist ramelteon, which lacks free radical scavenging activity, could be useful to unravel the mechanism of action of melatonin in analgesia. Melatonin has a promising role as an analgesic drug that could be used for alleviating pain associated with cancer, headache or surgical procedures.

Ramelteon: a review of its therapeutic potential in sleep disorders.

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT(1) and MT(2) melatonin receptors. Ramelteon's half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT(1) and MT(2) of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.