The Effects of Melatonin Supplementation on Sleep Quality and Assessment of the Serum Melatonin in ICU Patients: A Randomized Controlled Trial.

OBJECTIVES: To evaluate whether the use of exogenous melatonin affects sleep, reduces the prevalence of delirium, and decreases the need for analgosedation and to assess whether serum melatonin indices correlate with exogenous administration in critically ill patients. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: Multicenter ICUs of two tertiary hospitals. PATIENTS: A total of 203 adult patients who were admitted to the ICU and administered with analgesics and/or sedatives. INTERVENTIONS: Oral melatonin (10 mg) or placebo for up to seven consecutive nights. MEASUREMENTS AND MAIN RESULTS: The number of observed sleeping hours at night was assessed by the bedside nurse. Sleep quality was evaluated using the Richards Campbell Questionnaire Sleep (RCSQ). The prevalence of delirium, pain, anxiety, adverse reactions, duration of mechanical ventilation, length of ICU and hospital stays, and doses of sedative and analgesic drugs administered were recorded. The use of analgesics and sedatives was assessed daily. Melatonin levels were determined by enzyme-linked immunosorbent assay. Based on the RCSQ results, sleep quality was assessed to be better in the melatonin group than that in the placebo group with a mean (SD) of 69.7 (21.2) and 60.7 (26.3), respectively (p = 0.029). About 45.8% and 34.4% of participants in the melatonin and placebo groups had very good sleep (risk ratio, 1.33; 95% CI, 0.94-1.89), whereas 3.1% and 14.6% had very poor sleep (risk ratio, 0.21; 95% CI, 0.06-0.71), respectively. No significant difference was observed regarding the days free of analgesics or sedatives, the duration of night sleep, and the occurrence of delirium, pain, and anxiety. Melatonin serum peak levels at 2 AM were 150 pg/mL (range, 125-2,125 pg/mL) in the melatonin group and 32.5 pg/mL (range, 18.5-35 pg/mL) in the placebo group (p < 0.001). CONCLUSIONS: Melatonin was associated with better sleep quality, which suggests its possible role in the routine care of critically ill patients in the future.

Assessment of Circadian Rhythms.

Circadian rhythms are observed in most physiologic functions across a variety of species and are controlled by a master pacemaker in the brain called the suprachiasmatic nucleus. The complex nature of the circadian system and the impact of circadian disruption on sleep, health, and well-being support the need to assess internal circadian timing in the clinical setting. The ability to assess circadian rhythms and the degree of circadian disruption can help in categorizing subtypes or even new circadian rhythm disorders and aid in the clinical management of the these disorders.

Assessment of diurnal melatonin, cortisol, activity, and sleep-wake cycle in patients with and without diabetic retinopathy.

OBJECTIVE: To assess the diurnal melatonin, cortisol, and activity/rest levels, as well as sleep quality, in patients with and without nonproliferative diabetic retinopathy (DR). METHODS: We included 25 diabetic patients with DR and 29 without DR. A total of 21 healthy subjects constituted the control group. We assessed the circadian rhythm by actigraphy and diurnal salivary melatonin and cortisol measurements. Sleep quality was evaluated by actigraphy and the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires. Light exposure was quantified by actigraphy. The primary outcome was peak salivary melatonin level. Secondary outcomes were mean melatonin and cortisol levels during dark hours, activity-rest rhythm, sleep quality, as well as level of white, red, green, and blue light exposure. RESULTS: Peak melatonin concentration at 04:00 and mean nocturnal melatonin level were significantly reduced in all diabetic patients, regardless of retinopathy stage (p < 0.001). Levels of light exposures during dark hours were not significantly different in patients with and without DR and healthy controls. Only patients with DR showed increased intradaily variability in their activity-rest interval, indicating circadian misalignment (p = 0.04). Neither the objective actigraphic sleep quality parameters nor the subjective PSQI or ESS scores were significantly different between healthy controls and diabetic patients. CONCLUSIONS: Reduced nocturnal melatonin concentration and increased fragmentation of activity-rest intervals revealed circadian rhythm disturbance in diabetic patients with DR.

Infant acetylcholine, dopamine, and melatonin dysregulation: Neonatal biomarkers and causal factors for ASD and ADHD phenotypes.

Autism spectrum disorders (ASD) and ADHD are common neurodevelopmental disorders that benefit from early intervention but currently suffer from late detection and diagnosis: neurochemical dysregulations are extant already at birth but clinical phenotypes are not distinguishable until preschool age or later. The vast heterogeneity between subjects' phenotypes relates to interaction between multiple unknown factors, making research on factor causality insurmountable. To unlock this situation we pose the hypothesis that atypical pupillary light responses from rods, cones, and the recently discovered ipRGC system reflect early acetylcholine, melatonin, and dopamine dysregulation that are sufficient but not necessary factors for developing ASD and/or ADHD disorders. Current technology allows non-invasive cost-efficient assessment already from the first postnatal month. The benefits of the current proposal are: identification of clinical subgroups based on cause rather than phenotypes; facilitation of research on other causal factors; neonatal prediction of later diagnoses; and guidance for targeted therapeutical intervention.

Assessment of 6-sulfatoxymelatonin rhythms and melatonin response to light in disease states: lessons from cirrhosis.

Circadian rhythmicity and non-visual sensitivity to light can be assessed, in healthy subjects, by measuring the rhythm of the urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) and by determining the response of plasma melatonin to nocturnal retinal light exposure, respectively. However, the validity of these techniques has not been assessed in disease states in which disruption of the circadian rhythm is known or suspected to occur. Thus, the aims of this study were as follows: (i) to assess the reliability of circadian aMT6s profile estimates derived from 36 h versus 56 h urine collections and (ii) to test different models for calculating melatonin suppression in response to light in healthy volunteers and patients with cirrhosis. Twenty patients with biopsy-proven cirrhosis and 10 matched healthy volunteers undertook: (i) separate 36 - and 56-h urine collections, under controlled conditions, for cosinor analysis of the urinary aMT6s profile; (ii) a melatonin suppression test, comprising of a baseline night, during which subjects were woken and asked to sit in front of a switched off light sphere, and an experimental night, identically executed, except that the light sphere was switched on and the subjects were exposed to white light (4.1 × 10(14) photons/cm(2)/s) for 30 min. Alternative approaches to the calculation of melatonin suppression were taken, with/without inclusion of the baseline night. Eighteen patients and eight healthy volunteers had matched analysable 36 - and 56-h urinary samples. Cosinor analysis showed a significant fit in 88% of the remaining 56 h collections, and 48% of the remaining 36-h collections. Thus, eight patients and five healthy volunteers had matched analysable samples for cosinor analysis. In the healthy volunteers, aMT6s profile indices obtained using the 36 - and the 56-h collections did not differ significantly. In contrast, considerably more variability was observed in patients [i.e. the difference in the aMT6s peak time was 0.5 ± 1.7 h (limits of agreement: -3.9; +2.9 h)]. No difficulties were encountered in obtaining suppression estimates by use of the experimental night only. In contrast, suppression estimates obtained by use of both nights were considered inaccurate in one (11%) healthy volunteer and in 5 (28%) patients, primarily because: (i) melatonin concentrations at the beginning of light administration were significantly different on baseline and experimental night; (ii) the rise in melatonin was inconsistent on baseline night; and (iii) the shape of the rising phase of melatonin was different on baseline and experimental night. In conclusion, shorter urine collections lead to a higher number of profiles with no significant cosinor fit, and differences in cosinor indices obtained from the 36 - and 56-h collections were considerable, especially in patients. Thus, 56-h collections are probably advisable. Use of both baseline and experimental nights to calculate melatonin suppression often resulted in increased variation and confounding, due to point oscillations in melatonin concentration and lack of repeatability of the melatonin profiles on the two nights. Thus, use of the experimental night only is probably advisable.

Assessment of the relationship between melatonin, hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes, and osteoprotegerin and its ligand sRANKL in girls with anorexia nervosa.

BACKGROUND: It has been suggested that disturbances in melatonin (MEL) secretion might play a role in osteoporosis development in females with anorexia nervosa (AN). It might be hypothesized that changes in the levels of hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes might mediate the potential relationship between MEL and bone tissue. AIM: We investigated whether a relationship existed between MEL and LH, FSH-E2, TSH-FT3, FT4 and ACTH-cortisol axes in girls with AN. We also aimed to establish whether such a relationship might adversely affect the balance of the OPG/sRANKL system. MATERIAL/METHODS: Eighty-six girls with AN and 21 healthy subjects aged 12.6 to 18.2 years participated in the study. The serum levels of hormones as well as OPG and sRANKL were determined by radioimmunoassay (RIA), immunoradiometric assay (IRMA) or enzyme-linked immunosorbent assay (ELISA) methods. DISCUSSION: Our study participants with AN showed a significant reduction in body mass and body mass index (BMI), a decrease in LH, E2 and FT3 concentrations, increased MEL concentration at 02.00 hours and increased amplitude between its nocturnal and morning levels (Δ MEL2.00/9.00) as well as an increase in cortisol concentration. These changes were associated with a significant increase of OPG and sRANKL levels and a decrease in the OPG/sRANKL ratio. BMI values correlated positively with LH, FSH, E2, FT3 and the OPG/sRANKL ratio while the correlation between BMI and cortisol was negative. Δ MEL2.00/9.00 correlated positively with cortisol and negatively with LH, FSH, E2, FT3 concentrations and the OPG/sRANKL ratio. A positive correlation was observed between LH, E2 and the OPG/sRANKL ratio as well as between cortisol and sRANKL while the correlation between LH and OPG as well as between cortisol and the OPG/sRANKL ratio was negative. E2 and LH were shown to be significant and independent predictors of Δ MEL2.00/9.00. LH turned out to be a significant and independent predictor of OPG, cortisol and FT3 were significant and independent predictors of sRANKL, while LH, E2, Δ MEL2.00/9.00 and FT3 were significant predictors of the OPG/sRANKL ratio. CONCLUSIONS: Alterations in OPG and sRANKL levels observed in girls with AN are associated with changes in nocturnal MEL secretion, the circadian rhythm of MEL, and LH, E2, FT3 and cortisol levels. Dysregulation of the relationships between MEL and LH, E2, FT3 and cortisol found in girls with AN might affect the balance of the OPG/sRANKL system. Low values of the OPG/sRANKL ratio associated with high OPG and sRANKL levels suggest some defect in the mechanism compensating for bone remodeling disturbances.

Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin.

We compared the period of the rhythm of plasma melatonin, driven by the hypothalamic circadian pacemaker, to in vitro periodicity in cultured peripheral fibroblasts to assess the effects on these rhythms of a polymorphism of PER3 (rs57875989), which is associated with sleep timing. In vitro circadian period was determined using luminometry of cultured fibroblasts, in which the expression of firefly luciferase was driven by the promoter of the circadian gene Arntl (Bmal1). The period of the melatonin rhythm was assessed in a 9-d forced desynchrony protocol, minimizing confounding effects of sleep-wake and light-dark cycles on circadian rhythmicity. In vitro periods (32 participants, 24.61±0.33 h, mean±SD) were longer than in vivo periods (31 participants, 24.16±0.17 h; P<0.0001) but did not differ between PER3 genotypes (P>0.4). Analyses of replicate in vitro assessments demonstrated that circadian period was reproducible within individuals (intraclass correlation=0.62), but in vivo and in vitro period assessments did not correlate (P>0.9). In accordance with circadian entrainment theory, in vivo period correlated with the timing of melatonin (P<0.05) at baseline and with diurnal preference (P<0.05). Individual circadian rhythms can be reliably assessed in fibroblasts but may not correlate with physiological rhythms driven by the central circadian pacemaker.

Utility of salivary melatonin measurements in the assessment of the pineal physiology in newborn infants.

SUBJECTS: The aim of this study was to assess whether salivary melatonin could be used as a reliable alternative to serum melatonin to study the pineal physiology in newborn infants. DESIGN AND METHODS: The 95 newborn infants were allocated to four groups according to the time of sampling (09-11am, 03-05pm, 09-11pm, and 03-05am). RESULTS: The median melatonin levels in serum and saliva were not significantly different between groups: median (interquartile range), 18.4pg/mL (13.9-26.0pg/mL) and 10.6pg/mL (7.5-14.9pg/mL); 13.3pg/mL (11.5-19.0pg/mL) and 9.1pg/mL (7.8-14.2pg/mL); 16.0pg/mL (12.4-18.7pg/mL) and 12.3pg/mL (8.2-16.8pg/mL); 13.0pg/mL (8.8-27.4pg/mL) and 11.2pg/mL (7.7-16.6pg/mL) for groups 1, 2, 3, and 4, respectively (p>0.05). The results revealed a highly significant correlation between the serum and salivary melatonin levels (Pearson's correlation coefficient, r=0.763; P<0.001). CONCLUSION: Melatonin levels in saliva reflect those in serum at any time of the day and like serum melatonin levels do not increase at night.

Melatonin for nondippers with coronary artery disease: assessment of blood pressure profile and heart rate variability.

The aim of this study was to assess the effects of 5 mg melatonin before sleep in patients with coronary artery disease (CAD) and with an abnormal circadian pattern of blood pressure (BP) on changes in circadian BP profile and heart rate variability (HRV). Sixty patients with CAD, nondippers aged 48-80 years (male 75%), were included. In addition to previous treatment, they were randomly allocated to melatonin or placebo. After 90 days, a second 24-h BP monitoring was carried out. Each patient had two sessions (before randomization and at the end of study) of 24-h ECG monitoring to assess the changes in HRV. Inclusion of melatonin led to BP pattern normalization in 35% of patients in the melatonin group and in 15% of controls (P=0.609). This effect was reached not only by a decrease in nighttime BP, but also by an increase in daytime BP (significant in the melatonin group). A nonoptimal effect for BP profile was observed in 12.5% of patients: extreme- or reverse dippers. In patients with conversion from nondippers to dippers (responders), an increase in standard deviation of normal-to-normal intervals between initial and final HRV analyses was observed. Nonresponders represented an increase in the mean circadian heart rate. To avoid nonoptimal effects, the inclusion of melatonin in pharmacotherapy of patients with CAD should be based on monitoring of circadian BP profile, before and during treatment. As melatonin caused not only a nocturnal decrease in BP but also a daytime increase, it should not be recommended in patients with 'high normal' values of BP because of the danger of induction of arterial hypertension.

Assessment of the effects of physiological release of melatonin on arterial distensibility and blood pressure.

AIM: The aim of our study was to investigate the effects of endogenous melatonin on arterial distensibility using measurements of the velocity of the aortic pulse wave between the carotid and femoral arteries in healthy young students assessed in the supine position. MATERIAL AND METHODS: We studied 29 healthy young students, aged between 18 and 27 years, with 19 being male. The measured the velocity of the aortic pulse wave between the carotid and femoral arteries, along the blood pressures and heart rate, while the subjects were in the supine position at two time points, namely from 01.30-02.30 and 13:30-14:30 hours, during a day, also taking plasma to measure the concentrations of melatonin. The velocity of the pulse waves was determined using an automatic device, the Complior Colson (France), which allowed on-line recording and automatic calculation of the velocity, the calculations being made by measuring the transit time of the pulse wave as it traversed the distance between two sites of recording according, the velocity of the pulse wave in meter per second being equal to the distance in meters divided by the time of transit in seconds. RESULTS: Although the velocity of the pulse wave, systolic, diastolic, and mean blood pressures, and heart rate were all increased in the morning relative to measurement made later in the day, levels of melatonin in the plasma were increased in the night. There was negative correlation between diurnal levels of melatonin and the velocity of the pulse wave. CONCLUSION: Our findings indicate that increased levels of melatonin during the night may cause a decreased velocity of the aortic pulse wave, along with blood pressures and heart rate.

[The assessment of selected personality traits, coping and melatonin nocturnal secretion in patients with functional dyspepsia]. / Ocena wybranych cech osobowosci, stylów radzenia sobie ze stresem oraz nocnego wydzielania melatoniny u chorych z dyspepsjq czynnosciowa.

AIM: The main aim of the research was a characteristic of selected personality traits and coping as well as estimation of a level of melatonin in serum in patients with functional dyspepsia (FD). METHODS: 36 patients with FD (14 men and 24 women) at age 19-43 (mean: 31.6) were examined. The control group consisted of 30 healthy persons at age 21-23 (mean: 37.2). CO-16 and CISS questionnaires were used to diagnose selected traits of personality and coping styles. Furthermore, melatonin concentration in serum was examined at 10 p.m., 2 a.m. and at 6 a.m. with the immunoenzymatic method (ELISA). RESULTS: Coping style focused on problems and emotions were the most frequent ones in the examined group. Cyclothymia, tendency towards neuroticism and depression, submission and sensitivity were these that characterised patients with FD well. It was also stated that the level of melatonin was higher than in healthy subjects. CONCLUSIONS: There are common personality traits and coping styles in the group of patients with FD. A level of melatonin in serum is increased.

Genetically increased risk of sleep disruption in Alzheimer's disease.

STUDY OBJECTIVES: To investigate the role of a monoamine A oxidase promoter polymorphism in sleep disruption in Alzheimer's disease (AD). DESIGN: A case-control association analysis. SETTING: Sleep disturbance in AD is common, is extremely stressful for caregivers, and increases the risk of institutionalisation. It remains unclear why only some patients develop sleep disturbance; neuropathologic changes of AD are not typically seen in the areas of the brain responsible for sleep. We hypothesized that the risk of sleep disturbance is, at least in part, influenced by the availability of serotonin used for melatonin synthesis secondary to polymorphic variation at the enzyme monoamine oxidase A (MAO-A). PATIENTS: Patients with AD diagnosed according to standard criteria. INTERVENTIONS: Data were collected using the Sleep domain of the Neuropsychiatric Inventory with Caregiver Distress. Patients' cognition and function were assessed using the Mini-Mental State Examination and the Functional Assessment Staging. Genotyping of apolipoprotein E (APOE) and of the 30 bp variable number tandem repeat of the MAO-A promoter was by standard methods. MEASUREMENTS AND RESULTS: Of 426 patients surveyed, 54% experienced sleep disturbance. We found that the high-activity 4-repeat allele of the MAO-A VNTR promoter polymorphism confers increased susceptibility to sleep disturbance (p = .008). A quantitative sleep disturbance score was significantly higher in the patients possessing MAO-A 4-repeat allele genotypes. APOE had no influence on the development of an altered sleep phenotype. CONCLUSIONS: We conclude that sleep disturbance in AD is common and distressing and is associated with genetic variation at MAO-A.

Correlation of serum trace elements and melatonin levels to radiological, biochemical, and histological assessment of degeneration in patients with intervertebral disc herniation.

The aim of our study was to assess the blood concentrations of some trace elements and melatonin (MLT) in patients with intervertebral disc herniation (IDH) and to investigate the interaction of histological and biochemical degeneration findings with aging. The present study was carried out on 13 subjects (8 women and 5 men) diagnosed with IDH. They were divided into three groups according to their ages. Nighttime serum MLT, zinc (Zn), and magnesium (Mg) levels were determined in all patients. In addition, computed tomography (CT) scan of the brain and magnetic resonance imaging examination of the lumbar spine were obtained in this study. The Zn level and Zn/Mg ratio showed a decline in patients with IDH with aging, whereas the serum Mg level and tissue hydroxyproline content increased. A positive correlation between serum Zn and MLT concentrations was found (r=0.104, p=0.734). In addition, there was a positive correlation between serum Zn level and Zn/Mg ratio (r=0.835 and p<0.01), and a negative correlation between serum Mg level and Zn/Mg ratio (r=-0.571, p<0.05). On CT study, both volume percentage of calcified pineal gland and density of calcification were found to increase progressively with advancing age. The results of semiquantitative evaluation of disc tissues of patients with IDH for histological degeneration findings showed that 66.7% of discs treated had slight degeneration in younger age group, but 75.0% and 100% of discs had moderate or marked degeneration in older age groups. Our data indicated that there is a close relationship between MLT and Zn or Mg levels in the serum samples of patients with IDH, and the levels of these elements might be affected by the presence of degeneration process and serum MLT level, or vice versa.

The validity and feasibility of saliva melatonin assessment in the elderly.

Recent work in young and middle-aged subjects suggests that melatonin levels in saliva may represent a viable alternative to serum melatonin measurement. We hypothesized that it may be a valid measure of melatonin levels in older adults as well, but features unique to the elderly may limit its utility. To study this, subjects were admitted to an academic medical center where saliva and serum specimens were collected concurrently in dim light conditions during a 14-hr overnight study period and analyzed for melatonin levels with radioimmunoassays (RIAs). Eighty-five subjects over the age of 65 with a broad range of medical conditions participated in the study. Subjects with dementia, depression and anemia were excluded. We found that saliva volume was inadequate for analysis (<200 microL) in 23.6% of specimens, with the majority of inadequate volume specimens occurring after midnight and inadequate specimens occurring more frequently in females than in males. The correlation coefficient for saliva melatonin and serum melatonin was r = 0.659 (Spearman, P < 0.001), and r = 0.466 for saliva dim light melatonin onset (DLMO) and serum DLMO. Saliva melatonin levels were 30.9% of serum melatonin levels, with a wide range of ratios noted between subjects. Overall melatonin levels influenced both the correlation and ratio of saliva melatonin to serum melatonin; higher correlations and lower ratios were noted when melatonin levels were high. Saliva specimens provide an economical and practical method for melatonin assessment, however, in older adults, issues such as hyposalivation and low melatonin levels limit the feasibility and validity, respectively, of saliva melatonin.

Assessment of the relationship between dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in a rat model of postmenopausal osteoporosis.

BACKGROUND: Lately, there have been suggestions that bone mass changes occurring in postmenopausal women may remain related to melatonin. OBJECTIVE: To assess the relationship between the dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in ovariectomized rats--a model of postmenopausal osteoporosis. METHODS: Mature Wistar female rats were either ovariectomozed or underwent a sham operation. Following this they were killed at 02:00AM at weekly intervals for 8 weeks after surgery. Serum levels of MEL at death related to the chosen biochemical markers of bone formation (alkaline phosphatase--ALP; carboxyterminal propeptide of type I procollagen--PICP, both in serum) and resorption (cross-linked carboxyterminal telopeptide of type I collagen--ICTP in serum; hydroxyproline--HYP and total calcium--Ca, both excreted in urine). RESULTS: In all ovariectomized rats changes of examined indices of bone tissue metabolism were found to be dynamic and statistically significant relative to the control group; however the changes were more pronounced regarding resorption markers. Following ovariectomy, the increase in ALP and PICP values was found to begin at the 4th and the 1st week, while that in ICTP, HYP and Ca at the 2nd, the 1st and the 1st week, respectively. The ALP and PICP values remained at a similar level until the end of observation, whereas ICTP, HYP and Ca gradually decreased. MEL levels were decreased during the 2nd week following surgery and slightly increased 2 weeks later. The serum MEL levels in the ovariectomized group were significantly and negatively correlated with serum ICTP and both urinary HYP and Ca levels. CONCLUSION: Our findings in rats seem to corroborate the concept of secondary changes in MEL levels co-participating in the development of bone mass changes characteristic for postmenopausal osteoporosis.

Morning urinary assessment of nocturnal melatonin secretion in older women.

We evaluated the feasibility of using morning urine samples in epidemiological studies aimed at clarifying the relationship between nocturnal melatonin levels and breast cancer risk. Initially, a laboratory-based study of 29 women (40- 70 yr old) was performed to examine the correlation between plasma melatonin levels in hourly nocturnal blood samples and both melatonin and its major enzymatic metabolite, 6-hydroxymelatonin-sulfate (6-OHMS) in morning urine samples. In a companion field study, morning urine samples were collected from 203 healthy women to assess similarities and differences in laboratory versus field measures. Taken together, our results indicate: 1) levels of melatonin and of creatinine-corrected 6-OHMS in the first morning void urine are strongly correlated with total nocturnal plasma melatonin output (P < 0.001) and also with peak nocturnal melatonin values (P < 0.001); 2) similar ranges for 6-OHMS were found in the laboratory and the field; and 3) neither menopausal status nor hormonal replacement therapy altered 6-OHMS values in morning void urine. The inclusion of morning urine samples in epidemiological studies of cancer could allow cost-effective, widespread testing of the role played by melatonin in human health and disease.

The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement.

The present investigation used a placebo-controlled, double-blind, crossover design to assess the sleep-promoting effect of three melatonin replacement delivery strategies in a group of patients with age-related sleep-maintenance insomnia. Subjects alternated between treatment and "washout" conditions in 2-week trials. The specific treatment strategies for a high physiological dose (0.5 mg) of melatonin were: (1) EARLY: An immediate-release dose taken 30 minutes before bedtime; (2) CONTINUOUS: A controlled-release dose taken 30 minutes before bedtime; (3) LATE: An immediate-release dose taken 4 hours after bedtime. The EARLY and LATE treatments yielded significant and unambiguous reductions in core body temperature. All three melatonin treatments shortened latencies to persistent sleep, demonstrating that high physiological doses of melatonin can promote sleep in this population. Despite this effect on sleep latency, however, melatonin was not effective in sustaining sleep. No treatment improved total sleep time, sleep efficiency, or wake after sleep onset. Likewise, melatonin did not improve subjective self-reports of nighttime sleep and daytime alertness. Correlational analyses comparing sleep in the placebo condition with melatonin production revealed that melatonin levels were not correlated with sleep. Furthermore, low melatonin producers were not preferentially responsive to melatonin replacement. Total sleep time and sleep efficiency were correlated with the timing of the endogenous melatonin rhythm, and particularly with the phase-relationship between habitual bedtime and the phase of the circadian timing system.

Chronome assessment of circulating melatonin in humans.

BACKGROUND: Melatonin (MEL) production occurs mainly during the dark span. A prominent circadian variation is demonstrated in both blood and urine in humans. MATERIALS AND METHODS: The circadian, circannual, age and gender patterns of MEL were concomitantly investigated in 40 men and 132 women, each providing blood samples every 4 hours for 24 hours for conventional and cosinor analysis. RESULTS: Circulating MEL is circadian periodic (P < 0.001), peaking at night. The MESOR (rhythm-adjusted mean) is higher in women than in men. The circadian amplitude decreases with age. Both are modulated by a circannual variation, the MESOR peaking in winter (P < 0.001) and the circadian amplitude in summer (P < 0.05). CONCLUSIONS: Samples, unqualified as to gender, age and/or season, incompletely characterize the circadian MEL patterns. This chronome approach detects changes that may escape detection otherwise, checking whether a value is too high or too low, and also whether "swinging" occurs to the right extent.