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Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting...
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Eduard Gamper (1887–1938) was Head of the Department of Neuropsychiatry at the Charles University’s German Faculty of Medicine in Prague. He had trained in Innsbruck, where he undertook groundbreaking work on the midbrain in an anencephalic child and in a series of patients who had died from Wernicke’s encephalopathy. Gamper identified the mamillar...
Citations
... Even assuming that the findings of this study are compatible with the initial trea tmen t out c ome report ed by Er den [ 14 ], the effectiv eness of melatonin in reducing bruxism activity has not yet been supported by evidence. It is known that melatonin supplemen ta tions are used particulary in insomnia and various circadian sleep disorders as an external synchronizer [ 45 ]. Ac c ording t o an int ernational position paper including the recommendations of experts in the field of sleep medicine and neur opsy chiatric disor ders, the use of melatonin has also been suggested in a wide range of indications such as anxiety disorders, autism spectrum disorder, delirium, eating disorders, schizophrenia and neuroc og nitive disorders [ 39 ]. ...
... Besides, MTN biosynthesis and level are reduced with increasing body mass due to disturbance of circadian rhythm (Mohammadi et al. 2021). In addition, sleep disturbances are associated reduction of MTN levels with subsequent metabolic defragment and glucose variability (Palagini et al. 2021). Circulating MTN is metabolized by liver CYP1A2 to 6-hydroxy melatonin, inhibition of this enzyme, for example, by caffeine, increases MTN, while activation of this enzyme by cigarette smoking reduces circulating MTN level (Jiang et al. 2021). ...
Melatonin (MTN) is a neuro-hormone released from the pineal gland. MTN secretion is regulated by different neuronal circuits, including the retinohypothalamic tract and suprachiasmatic nucleus (SCN), which are affected by light. MTN is neuroprotective in various neurodegenerative diseases, including Parkinson’s disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD.
... Melatonin has been used in comorbid insomnia, with various medical conditions [16]. Studies support this notion that either immediate or prolonged release of melatonin at the dose f 1-10 mg, not only can be prescribed safely, but also can improve sleep quality, sleep latency, and day-time sleepiness in patients with neuropsychiatric disorders like Parkinson's disease, respiratory disorders such as Chronic Obstructive Pulmonary Diseas (COPD), and sulfur mustard lung injuries [17][18][19][20][21][22][23][24][25]. ...
Background
COMISA is a common disorder that results in nighttime awakenings ,daytime sleepiness and PAP intolerance. Cognitive behavioral therapy for insomnia is used to improve PAP adherence and no medication has been evaluated in such population yet. Melatonin with its chronobiotic and antioxidant effects may have potential benefits on COMISA consequences at the appropriate dose and time. This study aimed to evaluate the effect of melatonin on sleep quality, daytime sleepiness and PAP Compliance in patients with COMISA.
Methods
This double-blind placebo trial randomly assigned eligible OSA patients who suffered from insomnia despite using PAP for over a month to receive either melatonin 10 mg or placebo. The primary outcomes were measured by changes in the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire (FOSQ-10) over one month. Adherence to PAP was measured by the results of the PAP device reports on the average length of time and number of nights that the device was used.
Results
Thirty patients were enrolled in the study after randomization. The melatonin arm showed significant improvement in all four primary outcomes compared to the placebo arm. The PSQI score was 3.836±1.839 in the melatonin arm versus 10.522±3.626 in the placebo arm ( P value<0.001). The ISI score was 8.476±3.568 in the melatonin arm versus 14.47±4.50 in the placebo arm ( P value<0.001). The ESS score was 6.854±4.334 in the melatonin arm versus 13.298±5.119 in the placebo arm ( P value<0.001). The FOSQ-10 score was 24.93±5.02 in the melatonin arm versus 19.87±4.24 in the placebo arm ( P value= 0.006). Additionally, nighttime consequences such as sleep latency and awakenings showed significant improvement in the melatonin arm. PAP devices results revealed improvement in duration of PAP use overnight.
Conclusions
Administering melatonin has been shown to improve self-reported sleep quality and PAP adherence in patients with COMISA.
Trial registration
Registration number IRCT20220105053635N1 was issued by the Iranian Registry of Clinical Trials (IRCT).
... For example, when taken in the morning, the antipsychotic drug aripiprazole resulted in significantly favorable lipid and cholesterol measures compared to evening dosing (138), while evening dosing of risperidone was associated with greater weight gain and elevated glycosylated hemoglobin when compared to morning dosing (139). Melatonin taken in the evening promotes phase-advance of the circadian clock in delayed sleep-wake phase disorder and may have beneficial effects on psychopathology in other disorders where comorbid sleep-circadian disturbance is suspected (140). ...
Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep—circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep—circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.
... Sleep problems are managed via pharmacological, non-pharmacological, or combined interventions, as reviewed in the following sections. Clinical guidelines recommend that, especially in children and young people with autism, non-pharmacological interventions are tested first before considering pharmacological options [30][31][32] . ...
... Effective in increasing total sleep time and sleep efficiency, reducing sleep-onset latency, reducing morning wakings in children and young people with autism, especially when they involve both children and their parents, and when based on individualized management strategies targeting the specific factors negatively impacting on sleep [29][30][31][32][33][34][35] Massage and physical activity Beneficial effects of massage therapy [30] , yoga [36] , physical activity [37] , aquatic exercise [38] in children and young people with autism; and physical exercise in adults [44] Psychological interventions Preliminary evidence of beneficial effects of mindfulness-based interventions [39] and cognitive behavioral therapy [29][30][31] in children and young people with autism. In adults, no evidence of the effectiveness of acceptance and commitment therapy intervention [43] Supplements and vitamins ...
... Effective in increasing total sleep time and sleep efficiency, reducing sleep-onset latency, reducing morning wakings in children and young people with autism, especially when they involve both children and their parents, and when based on individualized management strategies targeting the specific factors negatively impacting on sleep [29][30][31][32][33][34][35] Massage and physical activity Beneficial effects of massage therapy [30] , yoga [36] , physical activity [37] , aquatic exercise [38] in children and young people with autism; and physical exercise in adults [44] Psychological interventions Preliminary evidence of beneficial effects of mindfulness-based interventions [39] and cognitive behavioral therapy [29][30][31] in children and young people with autism. In adults, no evidence of the effectiveness of acceptance and commitment therapy intervention [43] Supplements and vitamins ...
Sleep problems are more common in people with autism spectrum disorder (ASD) as compared to the general population, and may contribute to worsening social functioning, emotional symptoms, and lower quality of life. To support healthcare professionals and researchers in the field, we provide an updated overview of sleep problems in the context of autism across the lifespan and their evidence-based management, as derived from evidence-synthesis studies and the most recent randomized controlled trials. Most studies to date have been conducted in children and adolescents with autism. Several studies suggest that behavioral interventions aiming at improving sleep hygiene and environment may be beneficial, especially when actively involving parents. Furthermore, there is an increasing body of literature showing that melatonin is an effective pharmacological option for improving sleep quality in children and adolescents with autism, in line with reports showing a reduced endogenous synthesis of this hormone. Unfortunately, studies in adults are more limited, and thus, the evidence base around non-pharmacological and pharmacological interventions remains mixed. Finally, there is a growing interest towards the use of complementary interventions or food supplements, but further studies are needed to test their effectiveness. In sum, most studies to date support the use of behavioral interventions and melatonin, especially in children and adolescents with autism. However, findings need to be validated in large-scale, rigorous and blinded trials and extended to the adult population. Non-pharmacological interventions remain the first treatment option and should adopt an individualized approach, considering individual characteristics and needs, including comorbidities, family dynamics, and sleep environment.
... Students report high rates of depressive and anxiety symptoms, with approximately 60% reporting insufficient and poor-quality sleep [5][6][7]. With evidence supporting the use of melatonin for sleep (e.g., [8,9]), many students have begun to use over-the-counter (OTC) melatonin supplements to manage their sleep problems. In fact, rates of melatonin usage across the U.S. have risen five-fold over the past 2 decades [10], and recent reports have questioned the relative safety of melatonin [11], particularly in regard to suicidal ideation [12]. ...
... As a dietary supplement, melatonin is generally well tolerated, has relatively few side effects, and has been shown to be effective for treating sleep disturbance and depression [8,9,21,22], supporting the hypothesis that melatonin might have robust efficacy. However, adverse effects of melatonin usage have been found [11]. ...
... To ensure that students' sleep-related habits would not unduly influence the results, we controlled for students' sleep hygiene when estimating this model. Given the evidence supporting melatonin's positive effect on sleep as well as mood [8,9,21], we expected the following regarding melatonin's robust effectiveness: Hypothesis 1a) ongoing melatonin users would report residual decreases in sleep disturbance and Hypothesis 1b) decreases in sleep disturbance would predict decreases in students' depressive symptoms. We contrasted those hypotheses with alternative hypotheses based on melatonin's questionable effectiveness, predicting that Hypothesis 2a) ongoing melatonin users would report residual increases in sleep disturbance and Hypothesis 2b) increases in sleep disturbance would predict corresponding increases in students' depressive symptoms. ...
With such high rates of undergraduate sleep problems, students have chosen to take melatonin, an over-the-counter supplement that can facilitate sleep. Questions remain as to the effectiveness of melatonin for sleep problems, and questions have emerged about its impact on mental health. Accordingly, the current study examined how ongoing melatonin usage might impact relative changes in college students’ sleep disturbance and ultimately their depressive symptoms. The two-wave (baseline and 2-month follow-up), online sample consisted of 331 undergraduates (86% female; Mage = 21.3, SD = 2.4), who reported on melatonin usage, sleep disturbance, and depressive symptoms. Controlling for sleep hygiene, socio-economic status, and gender, our model demonstrated a significant indirect effect from ongoing melatonin usage to depressive symptoms. Specifically, melatonin consumption predicted relative increases in sleep disturbance, which, in turn, predicted corresponding increases in students’ depressive symptoms. Given the increasing prevalence of melatonin usage, the potential for unforeseen consequences remains high. Results suggest that the negative consequences of melatonin use can include both college students’ mental health and their sleep. Given the efficacy of addressing sleep problems with cognitive or behavioral strategies, it is essential that student support services highlight alternatives to melatonin and the potential problems associated with its use.
... On the other hand, four worldwide consensuses of experts in the sleep field were published from January 2020 to March 2023. One international consensus, which included Italian experts, regarded the use of melatonin in insomnia treatment [22]; one regarded the management of insomnia disorder in the primary care setting in USA [23]. One other consensus regarded the managing of insomnia disorder in Japan [24]. ...
Insomnia is the most reported sleep disorder in industrialized countries, affecting, in the chronic form, around 10% of the European population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is frequently described as comorbid condition and may precipitate, exacerbate, or prolong a broad range of physical and mental disorders. Evaluating and targeting insomnia in the Italian clinical practice should be a priority.
The present expert opinions and recommendations represent an update from 2020 and insights from Insomnia Expert Consensus Group, based on systematic reviews according to PRISMA on available options in Italy from January 2020 to March 2023.
We evaluated 28 papers among international guidelines, expert opinions, systematic reviews, and meta-analysis produced during the last 26 months.
Our findings suggest that symptoms of insomnia must be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions, and lifestyle. Cognitive behavioral therapy for insomnia should be the first option according to availability. The choice of the drug should be based on different factors including type of insomnia, age, comorbidities, and potential side effects. If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects < 65 years old), the use should be in the short term (≤ 4 weeks). Indeed, eszopiclone, as a new option in Italy, may present a different profile and may be used for up to 6 months, also in the elderly. If the choice is melatonin, it should be used melatonin 2 mg prolonged release in adults ≥ 55 years for up to 13 weeks. A new dual orexin antagonist, daridorexant, is available in Italy; it has been shown to be effective in adults and elderly and it can be used for at least 3 months and up to 1 year.
... Melatonin, the sleep-regulating hormone, regulates the circadian clock by directly acting on the SCN, making it a promising candidate for treating mood disorders [45]. Slow-release formulations of melatonin, like Circadin and its synthetic ligand, Agomelatine, have been demonstrated to have anxiolytic properties [46,47]. Ramelteon, a melatonin receptor agonist, is currently used in patients with insomnia comorbid with depression. ...
Mood disorders account for a significant global disease burden, and pharmacological innovation is needed as existing medications are suboptimal. A wide range of evidence implicates circadian and sleep dysfunction in the pathogenesis of mood disorders, and there is growing interest in these chronobiological pathways as a focus for treatment innovation. We review contemporary evidence in three promising areas in circadian-clock-based therapeutics in mood disorders: targeting the circadian system informed by mechanistic molecular advances; time-tailoring of medications; and personalizing treatment using circadian parameters. We also consider the limitations and challenges in accelerating the development of new circadian-informed pharmacotherapies for mood disorders.
... Especially, the profiles reported in our study for both galenic forms in adults aged between 20 and 45 years are close to those previously reported in adults aged over 55 years with a prolonged-release form and an immediaterelease form, each containing 2 mg of melatonin [1,19]. It was shown that the prolonged-release formulation containing 2 mg of melatonin resulted in a plasma peak 2.6 h after ingestion and levels were maintained for at least 3.5 h [33]. The order of magnitude of the pharmacokinetic constants with the prolonged-release and the immediate-release forms containing 2 mg of melatonin is similar to the constants reported in our study, although their measurements were performed in the elderly who are known to display a reduced metabolism (absorption of ingested melatonin reduced by up to 50% in the elderly [34]). ...
Background
The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism.Objective
The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin.Methods
In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters.ResultsThe observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (Cmax: 2332 ± 950 pg/mL; Tmax: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (Cmax: 1151 ± 565 pg/mL; Tmax: 64.2 ± 44.2 min; p < 0.001 for comparison of Cmax and Tmax) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC0–540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated.Conclusions
The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.Trial RegistryRegistration number: NCT04574141.
... They are defined as treatments that exert their effects on or through the biological timekeeping system Gottlieb et al., 2019). Among chronotherapeutics, melatonin has been a commonly used treatment for insomnia treatment due to its role in regulating the sleep-wake circadian rhythm Palagini et al., 2021). It is a neurohormone synthesised and secreted by the pineal gland at night and its primary role is to synchronise biological circadian clocks and circadian rhythms regulating various physiological and behavioural parameters including the sleep-wake circadian rhythm. ...
Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta-analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = -6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = -5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = -8.74 min), and oSOL (p = 0.017; weighted difference = -14 min). Regarding long-term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes.
