tasimelteon and Sleep-Wake-Disorders

Depression has become one of the most commonly prevalent neuropsychiatric disorders, and the main characteristics of depression are sleep disorders and melatonin secretion disorders caused by circadian rhythm disorders. Abnormal endogenous melatonin alterations can contribute to the occurrence and development of depression. However, molecular mechanisms underlying this abnormality remain ambiguous. The present review summarizes the mechanisms underlying the antidepressant effects of melatonin, which is related to its functions in the regulation of the hypothalamic-pituitary-adrenal axis, inhibition of neuroinflammation, inhibition of oxidative stress, alleviation of autophagy, and upregulation of neurotrophic, promotion of neuroplasticity and upregulation of the levels of neurotransmitters, etc. Also, melatonin receptor agonists, such as agomelatine, ramelteon, piromelatine, tasimelteon, and GW117, have received considerable critical attention and are highly implicated in treating depression and comorbid disorders. This review focuses on melatonin and various melatonin receptor agonists in the pathophysiology and treatment of depression, aiming to provide further insight into the pathogenesis of depression and explore potential targets for novel agent development.

Topics: Animals; Antidepressive Agents; Antioxidants; Benzofurans; Chronobiology Disorders; Cyclopropanes; Depression; Humans; Hypothalamo-Hypophyseal System; Indenes; Melatonin; Pituitary-Adrenal System; Receptors, Melatonin; Sleep Wake Disorders

Sleep and wake are two fundamental states of human existence. Conditions such as insomnia and hypersomnia can have profound negative effects on human health. Many pharmacological interventions impacting sleep and wake are available or are under development. This brief digest surveys early approaches to sleep modulation and highlights recent developments in sleep modulating agents.

Topics: Animals; Humans; Sleep; Sleep Aids, Pharmaceutical; Sleep Wake Disorders; Wakefulness-Promoting Agents

To investigate the efficacy of exogenous administration of melatonin and melatonin receptor agonists for the improvement of delirium, sleep, and other clinical outcomes of subjects in the intensive care unit (ICU). We carefully searched three electronic databases, i.e., Pubmed/Medline, Embase, and Cochrane library, to retrieve randomized controlled trials (RCTs) administrating melatonin or melatonin receptor agonists to adult subjects admitted to the ICU. Useful data such as the prevalence of delirium, duration of sleep, number of awakenings per night, duration of mechanical ventilation, and ICU stay as well as in-ICU mortality were extracted and pooled by using a random effect model. Eight RCTs were included in the qualitative analysis. Administration of exogenous melatonin and melatonin receptor agonists was associated with a trend towards elongated duration of sleep (pooled weighted mean difference/WMD = 0.43; 95% confidence intervals/CIs, - 0.02~0.88, p = 0.063) and could decrease the number of awakenings per night (pooled WMD = - 2.03; 95% CIs, - 3.83~- 0.22, p = 0.028). Meanwhile, participants in the treatment group showed a significantly reduced prevalence of delirium (pooled risk ratio/RR = 0.49; 95% CIs, 0.28~0.88, p = 0.017) and duration of ICU stay (pooled WMD = - 0.32; 95% CI, - 0.56~- 0.07, p = 0.002) in comparison with those in the control group. Exogenous administration of melatonin and melatonin receptor agonists could improve the sleep of subjects in the intensive care units, which may play an important role in decreasing the prevalence of delirium and shortening duration of ICU stay.

Topics: Adult; Benzofurans; Case-Control Studies; Correlation of Data; Cross-Sectional Studies; Cyclopropanes; Delirium; Hospital Mortality; Humans; Indenes; Intensive Care Units; Length of Stay; Melatonin; Randomized Controlled Trials as Topic; Receptors, Melatonin; Respiration, Artificial; Risk Factors; Sleep; Sleep Wake Disorders; Treatment Outcome; Wakefulness

Non-24-h sleep-wake disorder (non-24) is a circadian rhythm disorder occurring in 55-70% of totally blind individuals (those lacking conscious light perception) in which the 24-h biological clock (central, hypothalamic, circadian pacemaker) is no longer synchronized, or entrained, to the 24-h day. Instead, the overt rhythms controlled by the biological clock gradually shift progressively earlier or later (free run) in accordance with the clock's near-24-h period, resulting in a recurrent pattern of daytime hypersomnolence and night-time insomnia. Orally administered melatonin and the melatonin agonist tasimelteon have been shown to entrain (synchronize) the circadian clock, resulting in improvements in night-time sleep and daytime alertness. We review the basic principles of circadian rhythms necessary to understand and treat non-24. The time of melatonin or tasimelteon administration must be considered carefully. For most individuals, those with circadian periods longer than 24 h, low-dose melatonin should be administered about 6 h before the desired bedtime, while in a minority, those with circadian periods shorter than 24 h (more commonly female individuals and African-Americans), melatonin should be administered at the desired wake time. Small doses (e.g., 0.5 mg of melatonin) that are not soporific would thus be preferable. Administration of melatonin or tasimelteon at bedtime will entrain individuals with non-24 but at an abnormally late time, resulting in continued problems with sleep and alertness. To date, tasimelteon has only been administered 1 h before the target bedtime in patients with non-24. Issues of cost, dose accuracy, and purity may figure into the decision of whether tasimelteon or melatonin is chosen to treat non-24. However, there are no head-to-head studies comparing efficacy, and studies to date show comparable rates of treatment success (entrainment).

Topics: Benzofurans; Blindness; Circadian Clocks; Cyclopropanes; Humans; Melatonin; Sleep Wake Disorders

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

Topics: Acetamides; Benzofurans; Circadian Rhythm; Cyclopropanes; Dietary Supplements; Humans; Receptors, Melatonin; Sleep Wake Disorders

Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions.

Topics: Acetamides; Animals; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Humans; Hypnotics and Sedatives; Indenes; Melatonin; Neurodegenerative Diseases; Receptors, Melatonin; Sleep Wake Disorders

Topics: Benzofurans; Blindness; Circadian Rhythm; Cyclopropanes; Cytochrome P-450 CYP1A2; Humans; Receptors, Melatonin; Sleep Wake Disorders