Efficacy of Melatonin for Sleep Disturbance in Children with Persistent Post-Concussion Symptoms: Secondary Analysis of a Randomized Controlled Trial.

Sleep disturbances are commonly reported in children with persistent post-concussion symptoms (PPCS). Melatonin treatment is often recommended, yet supporting evidence is scarce. We aimed to evaluate the efficacy of treatment with melatonin for sleep disturbance in youth with PPCS following mild traumatic brain injury (mTBI). This article is a secondary analysis of a clinical trial of melatonin compared with placebo to treat PPCS. Youth (8-18 years of age) with PPCS and significant sleep-related problems (SRPs) at 4-6 weeks post-injury were eligible. Exclusion criteria: significant medical/psychiatric history; previous concussion/mTBI within 3 months. Treatment groups were: placebo, melatonin 3 mg, or melatonin 10 mg. Primary outcome was change in SRPs measured using the Post-Concussion Symptom Inventory (PCSI) after 2 weeks of treatment. Secondary outcomes included change in actigraphy sleep efficiency, duration, onset latency, and wake-after-sleep-onset. Behavior was measured using Behaviour Assessment for Children (2nd edition). Seventy-two participants (mean age 14.0, standard deviation [SD] = 2.6) years; 60% female) with PPCS and significant sleep disturbance were included in the secondary analysis: placebo (n = 22); melatonin 3 mg (n = 25); melatonin 10 mg (n = 25). Sixty-four participants had actigraphy data. SRPs decreased across all groups over time with a significant effect of melatonin 3 mg (3.7; 95% confidence interval [CI]: 2.1, 5.4) compared with placebo (7.4; 95% CI: 4.2, 10.6) and melatonin 10 mg (6.4; 95% CI: 3.6, 9.2). Sleep duration increased in the melatonin 3 mg (43 min; 95% CI: 6, 93) and melatonin 10 mg groups (55 min; 95% CI: 5, 104) compared with placebo. A per protocol analysis demonstrated improved sleep efficiency in the melatonin 10 mg group (p = 0.029). No serious adverse events were reported. Depressive symptoms significantly decreased with melatonin 3 mg (-4.7; 95% CI: -9.2, -.2) but not with melatonin 10 mg (-1.4, 95% CI: -5.9, 3.2) treatment compared with placebo. Changes in cognition or behavior were otherwise not significantly different between treatment groups. Short-term melatonin is a well-tolerated treatment for sleep disturbance in youth with PPCS following mTBI. In this context, it may also be associated with a reduction in depressive symptoms.

Associations of Urinary Phytoestrogen Concentrations with Sleep Disorders and Sleep Duration among Adults.

Current evidence on the relationship of phytoestrogens with sleep is limited and contradictory. In particular, studies on individual phytoestrogens and sleep have not been reported. Thus, this study aimed to appraise the associations of individual phytoestrogens with sleep disorders and sleep duration. This cross-sectional study comprising 4830 adults utilized data from the National Health and Nutrition Examination Survey 2005-2010. Phytoestrogens were tested in urine specimens. Sleep disorders and sleep duration were based on a self-reported doctor's diagnosis and usual sleep duration. The main analyses utilized logistic and multinomial logistic regression models and a restricted cubic spline. In the fully adjusted model, compared with tertile 1 (lowest), the odds ratios (95% confidence intervals (CIs)) of sleep disorders for the highest tertile of urinary concentrations of enterolactone, enterodiol, and O-desmethylangolensin were 0.64 (0.41-1.00), 1.54 (1.07-2.21), and 1.89 (1.26-2.85), respectively. Linear inverse, approximatively linear positive, and inverted L-shaped concentration-response relationships were found between enterolactone, enterodiol, and O-desmethylangolensin and sleep disorders, respectively. Compared with normal sleep (7-8 h/night), the relative risk ratio (RRR) (95% CI) of very short sleep for enterolactone was 0.56 (0.36-0.86), and the RRR (95% CI) of long sleep risk for genistein was 0.62 (0.39-0.99). Furthermore, negative associations of genistein with sleep disorders and enterolactone with long sleep risk, as well as positive associations of enterodiol with both long and very short sleep, were observed in the stratified analysis by age or gender. Finally, a notable finding was that urinary O-desmethylangolensin concentration was positively related to sleep disorders in both females aged 40-59 years and non-Hispanic Whites but inversely associated with sleep disorders in both females aged 60 years or over and other Hispanics. Our findings suggested that enterolactone and genistein might be beneficial for preventing sleep disorders or non-normal sleep duration among adults, and enterodiol might be adverse toward this goal. However, the association of O-desmethylangolensin with sleep disorders might be discrepant in different races and females of different ages.

Self-reported sleep disturbance in Crohn's disease is not confirmed by objective sleep measures.

Sleep disturbance and fatigue are commonly reported among patients with Crohn's disease (CD). In this prospective study, we aimed to define sleep quality in CD patients at various disease activity states and compare to healthy controls using objective and subjective measures. A prospective observational cohort study of CD patients seen at a tertiary academic inflammatory bowel diseases (IBD) clinic was compared to healthy volunteers. CD activity was assessed using the Harvey-Bradshaw Index (HBI). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) and objectively over 1-week using actigraphy (motion-based) and morning urinary melatonin metabolite. 121 subjects (CD patients N = 61; controls N = 60) completed the study. 34 had active CD (HBI > 4). Sleep disturbance was more frequently reported by CD subjects than controls (PSQI: 57% vs. 35%, p = 0.02) and in patients with active CD versus in remission state (PSQI 75.8% vs. 33.3%, p < 0.01; ESS: 45.5% vs. 19%, p = 0.03). Sleep parameters as measured by actigraphy and urine melatonin metabolite did not vary by group. Crohn's patients report significantly more disturbed sleep than controls. However, poor sleep was not confirmed by objective measures of sleep quality. Excessive daytime sleepiness in CD patients may be driven by factors beyond objectively measured poor sleep.

Urinary levels of 6-sulphatoxymelatonin and their associations with sleep disorders and behavioural impairments in children with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with sleep disturbances that may result from abnormalities in melatonin production. The correlations of melatonin levels with the severity of sleep disorder and/or severity of ASD were reported. OBJECTIVES: To evaluate urinary levels of the melatonin metabolite, 6-sulphatoxymelatonin (aMT6s), in children with ASD, and their associations with sleep abnormalities and behavioural impairments. METHODS: Study involved 77 children with ASD and 84 controls aged 2.5‒15.5 years. Sleep disorders were assessed by Children's Sleep Habits Questionnaire. Morning and afternoon levels of aMT6s were determined by radioimmunoassay method. Urinary creatinine levels were assessed by an enzymatic method. RESULTS: The urinary aMT6s/creatinine values indicate that the night-time melatonin levels are significantly lower in ASD than in controls, but there are no significant differences in the daytime levels. In the ASD group, on average, a 6.8-fold difference between night-time and daytime values of urinary aMT6s/creatinine was found, whereas for the controls a 12.5-fold difference was observed, indicating a lower night-time increase in melatonin levels. In ASD group, the difference in night-time-daytime aMT6s/creatinine value correlated with some types of sleep problems, but not with the severity of ASD. CONCLUSION: The results indicate that in ASD there are differences in the patterns of melatonin secretion that may be associated with sleep impairment (Tab. 4, Fig. 2, Ref. 28).

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study.

OBJECTIVE: This prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. METHODS: Breast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. RESULTS: This cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. CONCLUSION: The first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

Study protocol and rationale for a prospective, randomized, double-blind, placebo-controlled study to evaluate the effects of Ashwagandha (Withania somnifera) extract on nonrestorative sleep.

Nonrestorative sleep (NRS) is one of the cardinal symptoms of insomnia and can occur independent of other components of insomnia. Among the sleep disturbances, NRS has been little studied in the general population, even though this symptom plays an important role in several medical conditions associated with chronic inflammation such as heart disease, fibromyalgia, and chronic fatigue syndrome, as well as various sleep disorders. There is paucity in the literature about effective treatments for NRS. Ashwagandha (Withania somnifera) has been demonstrated to reduce anxiety and stress, allowing the body to settle down and prepare for sleep. This study will be a double-blind, randomized, placebo-controlled interventional study in NRS population.The NRS participants are identified using Restorative Sleep Questionnaire-weekly version (RSQ-W) questionnaire. Actigraphy and polysomnography are used for the objective assessment of sleep. The other assessments used are Hamilton Anxiety Depression Scale (HADS), World Health Organization Quality of Life (WHOQOL) scales, and C-reactive protein. Routine blood and urine analyses will be conducted to assess the safety of treatment. Duration of study for each participant will be 50 days with "day one" for screening followed by randomization for the treatment. The duration for medicine/placebo intake shall be 42 days.Primary outcome will be to evaluate effect of daily supplement of ashwagandha extract compared with placebo in subjects with NRS at 6 weeks from baseline, as assessed by the total score of RSQ-W. CTRI REGISTRATION NUMBER: CTRI/2017/02/007801.

Performance of the biological rhythms interview for assessment in neuropsychiatry: An item response theory and actigraphy analysis.

BACKGROUND: Biological rhythm disturbances are widely associated with the pathophysiology of mood disorders. The Biological Rhythms Interview for Assessment in Neuropsychiatry (BRIAN) is a self-report that indexes rhythm disturbance in sleep, activity, social and eating patterns. The aim of this study was to perform an Item Response Theory (IRT) analysis of the BRIAN and investigate its associations with objective sleep and rhythm disturbance measures. METHODS: 103 subjects (31 bipolar, 32 major depression and 40 healthy volunteers) wore an actiwatch for fifteen days, and completed a first morning urine sample and the BRIAN on day 15. IRT analysis assessed individual BRIAN items and their relationship to total score. Individual actiwatch records were processed to produce a sequence of transitions between rest/activity, and a likelihood of transitioning between states was calculated to investigate sleep-wake dynamics. Cosinor analysis produced daily activity rhythms (DARs). Spearman correlations were used to assess the association between sleep/DAR variables and the BRIAN. RESULTS: IRT analyses showed that 11 of 18 BRIAN items displayed a high level of discrimination between item options across a range of BRIAN total scores. Total BRIAN score correlated with wake after sleep onset, total activity count during sleep, and urinary 6-sulphatoxymelatonin. BRIAN Activity domain correlated with the daytime transition probability from rest to activity. LIMITATIONS: The sample size may have been underpowered for the graded-response model employed in IRT. The study lacked an objective comparison for BRIAN eating and social domain. CONCLUSION: The present study reveals the BRIAN displays promising external validity compared to objective parameters of circadian rhythmicity.

Analysis of Different Melatonin Secretion Patterns in Children With Sleep Disorders: Melatonin Secretion Patterns in Children.

The objective of this study was to analyze circadian patterns of urinary 6-sulphatoxymelatonin (aMT6s) excretion in children with primary sleep disorders in comparison with healthy controls. A total of 124 control children and 124 patients (aged 4-14 years) diagnosed with diverse primary sleep disorders were recruited. aMT6s concentrations were measured in diurnal and nocturnal urine, as well as in 24-hour urine. aMT6s levels were significantly higher and showed significantly more evident circadian variations in the control group ( P < .001). Four different melatonin (aMT) production and excretion patterns were distinguished in the group with sleep disorders: (1) standard aMT production pattern, (2) low aMT production pattern, (3) aMT production pattern with absence of circadian variation, and (4) aMT hyperproduction pattern. This study highlights the importance of analyzing specific alterations of aMT secretion in each sleep disorder and provides evidences to explain why not all children with sleep disturbances do respond to aMT treatment.

Association of Urinary 6-Sulfatoxymelatonin (aMT6s) Levels and Objective and Subjective Sleep Measures in Older Men: The MrOS Sleep Study.

BACKGROUND: Sleep and melatonin have been associated with healthy aging. In this study, we examine the association between melatonin levels and sleep among older men. METHODS: Cross-sectional study of a community-dwelling cohort of 2,821 men aged 65 years or older recruited from six U.S. centers. First morning void urine samples were collected to measure melatonin's major urinary metabolite, 6-sulfatoxymelatonin (aMT6s). We also assessed objective and subjective sleep parameters. We used logistic regression models to calculate multivariate (MV) odds ratios (ORs), and 95% confidence intervals (CIs) adjusted for important demographic variables and comorbidities. RESULTS: In the overall sample, the only significant finding in fully adjusted models was that aMT6s levels were inversely associated with subjectively measured daytime sleepiness (sleepiness mean score of 5.79 in the top aMT6s quartile, and 6.26 in the bottom aMT6s quartile, MV OR, 1.32; 95% CI, 0.95-1.84; p trend ≤ .02). When restricting to men without ß-blocker use (a known melatonin suppressant), aMT6s levels were significantly associated with shorter sleep time, that is, less than 5 hours (MV OR, = 1.90; 95% CI, 1.21-2.99; p trend = .01), and worse sleep efficiency, that is, less than 70% (MV OR, 1.58; 95% CI, 1.28-2.65; p trend < .001). aMT6s were not associated with subjective sleep quality or respiratory disturbance in any of our analyses. CONCLUSION: Lower nocturnal melatonin levels were associated with worsened daytime sleepiness, sleep efficiency, and shorter sleep time in older men. The role of circadian interventions, and whether melatonin levels are a modifiable risk factor for poor sleep in older men, warrants further study.

A preliminary study on the relationships between diurnal melatonin secretion profile and sleep variables in patients emergently admitted to the coronary care unit.

To clarify the significance of melatonin secretion under intensive care conditions, we investigated melatonin secretion profiles and sleep parameters of 23 patients just after admission to the coronary care unit (CCU) and 19 age-matched controls. Sleep parameters were evaluated by actigraphy, and melatonin secretion was assessed by measuring the urinary 6-sulphatoxy melatonin (6-SMT). 6-SMT secretion was lower and nocturnal sleep parameters were less satisfactory in the subjects than those in the controls, and there were positive correlations between these variables, particularly in the subject patients. The lowered melatonin secretion might be involved in the mechanism of insomnia in CCU patients.

Sleep disruption in tetraplegia: a randomised, double-blind, placebo-controlled crossover trial of 3 mg melatonin.

STUDY DESIGN: Randomised, double-blind, placebo-controlled crossover trial of melatonin supplementation to people with complete tetraplegia. OBJECTIVES: To investigate the effect that 3 mg melatonin supplementation has on objective and subjective sleep, quality of life and mood of people living with complete tetraplegia. SETTING: Austin Hospital Sleep Laboratory and participants' homes, Melbourne, Victoria, Australia. METHODS: Two week run-in followed by 3 week nightly administration of 3 mg melatonin or placebo, 2-week washout and further 3 week administration of the opposite treatment. Four testing sessions were conducted; the last nights of the run-in, treatment and washout periods. Testing sessions involved recording full polysomnography, completing a questionnaire battery and collecting urine and blood samples. The questionnaires assessed mood, sleep symptoms and health-related quality of life, and the urine and plasma samples assayed 6-sulphatoxymelatonin (aMT6s) and melatonin levels, respectively. A sleep diary was completed throughout the study. RESULTS: Eight participants (mean (s.d.): age 49.5 years (16), postinjury 16.9 years (7.1)) were recruited in which seven concluded the protocol. Endogenous-circulating melatonin was significantly higher (P < or = 0.01) following melatonin (urine: 152.94 µg h(-1) (74.51), plasma: 43,554.57 pM (33,527.11)) than placebo (urine: 0.86 µg h(-1) (0.40), plasma: 152.06 pM (190.55)). Subjective sleep improved significantly following melatonin specifically for duration of sleep per night and psychological wellbeing. Objective sleep showed a significant increase in light sleep with melatonin, with all other sleep parameters being unchanged. CONCLUSION: These results suggest that increasing melatonin in people with complete tetraplegia is beneficial, especially for subjective sleep. Investigation of the pharmacokinetics of melatonin metabolism in this population is warranted. SPONSORSHIP: This project is proudly supported by the Transport Accident Commission.

Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study were likely to belong to one of three symptom severity classes: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); moderate levels of all but hot flashes (moderate severity); and low levels of all (low severity). We tested models of the differential effects of hypothalamic-pituitary-ovarian (HPO) axis, hypothalamic-pituitary-adrenal (HPA) axis, and autonomic nervous system (ANS) biomarkers on the three symptom severity classes. METHODS: The Seattle Midlife Women's Health Study participants recorded symptoms monthly in diaries and provided overnight urine samples several times per year that were analyzed for estrone, follicle-stimulating hormone (FSH), cortisol, testosterone, epinephrine, and norepinephrine. Multilevel latent class analysis with multinomial regression was used to determine the effects of HPO axis, HPA axis, and ANS biomarkers on symptom severity class membership. RESULTS: Having lower estrogen and higher FSH levels was significantly associated with belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine and higher norepinephrine levels increased the likelihood of belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine levels was significantly associated with belonging to the moderate-severity class versus the low-severity class. Cortisol and testosterone were unrelated to symptom severity class membership. CONCLUSIONS: The association of HPO axis biomarkers (estrogen and FSH) with the high-severity hot flash class is anticipated based on prior hot flash research, and the associations of HPA axis biomarkers are as expected based on earlier laboratory studies. The association of lower epinephrine levels with the moderate-severity class suggests that these symptoms may be mediated by the ANS.

Relation of melatonin to sleep architecture in children with autism.

Children with autism often suffer from sleep disturbances, and compared to age-matched controls, have decreased melatonin levels, as indicated by urine levels of the primary melatonin metabolite, 6-sulfatoxymelatonin (6-SM). We therefore investigated the relationship between 6-SM levels and sleep architecture in children with autism spectrum disorders (ASD). Twenty-three children, aged 4-10 years, completed two nights of polysomnography and one overnight urine collection for measurement of urinary 6-SM excretion rate. Parents completed the Children's Sleep Habits Questionnaire. We found that higher urinary 6-SM excretion rates were associated with increased N3 sleep, decreased N2 sleep, and decreased daytime sleepiness. The results warrant further examination to examine the effects of supplemental melatonin on sleep architecture and daytime sleepiness.

A dietary supplement to improve the quality of sleep: a randomized placebo controlled trial.

BACKGROUND: To evaluate the effect of a dietary supplement containing polyunsaturated fatty acids, in association with Humulus lupulus extract, on the quality of sleep using the Leeds sleep evaluation questionnaire (LSEQ) in subjects with moderate to severe sleep disorders. METHODS: Randomized placebo-controlled trial, in a Population-based setting. Participants were adult patients 25 to 65 years old with a chronic primary insomnia who volunteered for the study. The tested intervention consisted of two soft gelatine capsules per day, containing either the dietary supplement (active group) or olive oil (placebo group) for a month. Subjects could also volunteer for two ancillary studies on melatonin and actigraphy. Evaluation criteria included i) perception of the quality of sleep at the end of treatment using the LSEQ questionnaire, ii) sleep efficiency measured by one-week actigraphic movement measurement performed before and during the treatment in a subsample of subjects, iii) night melatonin and 6 sulfatoxymelatonin (aMT6S) urine rates in a subsample of subjects. RESULTS: The average of Leeds score was similar in both groups (p = 0.95). A marked improvement in the quality of sleep was observed in both placebo (62%) and active (65%) group (p = 0.52). The evolution of urinary melatonin, aMT6S, and of the Mel/aMT6S ratio showed no differences between the two groups. Sleep efficiency, as measured by actigraphy, improved similarly in both groups during the treatment period, from 72% to 76% and 75% in the active and placebo group respectively (p = 0.91). CONCLUSIONS: The dietary supplement had neither effect on the perceived quality of sleep, nor on the melatonin metabolism and sleep-wake cycle. TRIAL REGISTRATION: clinical trials.gov:NCT00484497.

Sleep symptoms during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

STUDY OBJECTIVES: Describe the severity of getting to sleep, nighttime awakening, and early morning awakening across the menopausal transition (MT) and early postmenopause (PM) and their relationship to age, menopausal transition factors, symptoms, stress-related factors, and health related factors. DESIGN: Cohort. SETTING: community. PARTICIPANTS: 286 women from the Seattle Midlife Women's Health Study cohort. MEASUREMENTS: Participants completed annual menstrual calendars for MT staging, diaries in which they rated their symptoms, stress levels, and perceived health multiple times per year from 1990-2007 and provided first morning urine samples assayed for E1G, FSH, cortisol, and catecholamines. Multilevel modeling (R program) was used for data analysis. RESULTS: Severity of self-reported problems going to sleep was associated with all symptoms, perceived stress, history of sexual abuse, perceived health (-), alcohol use (-) (all P < 0.001), and lower cortisol (P = 0.009), but not E1G or FSH. Severity of nighttime awakening was significantly associated with age, late MT stage, and early PM, FSH, E1G (-), hot flashes, depressed mood, anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-), and alcohol use (-) (all P < 0.001, except E1G for which P = 0.030). Severity of early morning awakening was significantly associated with age, hot flashes, depressed mood anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-) (all P < or = 0.001, except E1G for which P = 0.02 and epinephrine (P = 0.038), but not MT stages or FSH. Multivariate models for each symptom included hot flashes, depressed mood, and perceived health. CONCLUSION: Sleep symptoms during the MT may be amenable to symptom management strategies that take into account the symptom clusters and promote women's general health rather than focusing only on the MT.

On the origin and the consequences of circadian abnormalities in patients with cirrhosis.

OBJECTIVES: Plasma melatonin profile abnormalities have been described in patients with cirrhosis and generally attributed to impaired hepatic melatonin metabolism. The possibility that they might reflect circadian clock dysfunction has not been explored. In addition, the relationship between plasma melatonin profiles and the sleep disturbances observed in these patients remains unclear. The aims of this study were: (i) to evaluate circadian clock function and hepatic melatonin metabolism in cirrhotic patients, and (ii) to study the relationship between plasma melatonin profiles and sleep-wake behavior. METHODS: The study population comprised 20 patients with cirrhosis (mean (range) age, 59 (39-77) years) and 9 healthy volunteers (60 (38-84) years). Plasma melatonin/cortisol concentrations were measured hourly, for 24 h, in light/posture-controlled conditions. Urinary 6-sulfatoxymelatonin, the main melatonin metabolite, was measured simultaneously to determine clearance. The ability of light to suppress nocturnal melatonin synthesis was assessed. Habitual sleep quality/timing was evaluated using a questionnaire, actigraphy, and sleep diaries. RESULTS: There was evidence of central circadian disruption in patients compared with healthy controls: peak plasma melatonin/cortisol times were delayed (04:48+/-02:36 vs. 02:48+/-00:54, P=0.01; 10:18+/-02:54 vs. 08:54+/-01:24, P=0.06) and the plasma melatonin response to light was reduced (12%+/-19% vs. 24%+/-15%, P=0.09). However, the mean 24 h plasma melatonin clearance did not differ significantly between patients and healthy volunteers (0.22+/-0.10 vs. 0.28+/-0.17 l/kg per h, P=0.36). Finally, although patients showed a degree of misalignment between sleep and circadian timings, there was no association between circadian abnormalities and impaired sleep quality. CONCLUSIONS: Plasma melatonin profile abnormalities, predominantly central in origin, are observed in patients with mild to moderately decompensated cirrhosis. However, they are substantially unrelated to the sleep disturbances prevalent in this population.

Objective measures of disordered sleep in fibromyalgia.

OBJECTIVE: Patients with fibromyalgia syndrome (FM) complain of inadequate sleep, which could contribute to common symptoms including sleepiness, fatigue, or pain. However, measures that consistently and objectively distinguish FM patients remain elusive. METHODS: Fifteen women with FM and 15 age- and gender-matched controls underwent 3 nights of polysomnography; Multiple Sleep Latency Tests to assess sleepiness; testing of auditory arousal thresholds during non-REM stage 2 and stage 4 sleep; overnight assessment of urinary free cortisol; and analysis of 24-hour heart rate variability. RESULTS: On the second night of polysomnography, women with FM in comparison to controls showed more stage shifts (p = 0.04) but did not differ significantly on any other standard polysomnographic measure or on the Multiple Sleep Latency Tests. Alpha EEG power during deep non-REM sleep, alone or as a proportion of alpha power during remaining sleep stages, also failed to distinguish the groups, as did auditory arousal thresholds. Urinary free cortisol did not differ between FM and control subjects in a consistent manner. However, decreased short-term heart rate variability (HRV) and especially ratio-based HRV among FM subjects suggested diminished parasympathetic and increased sympathetic activity, respectively. Other HRV measures suggested decreased complexity of HRV among the FM subjects. CONCLUSION: Standard measures of sleep, a gold-standard measure of sleepiness, quantified alpha-delta EEG power, auditory arousal thresholds, and urinary free cortisol largely failed to distinguish FM and control subjects. However, HRV analyses showed more promise, as they suggested both increased sympathetic activity and decreased complexity of autonomic nervous system function in FM.

Melatonin level and pattern in postpartum versus nonpregnant nulliparous women.

OBJECTIVE: To compare 24-hour melatonin level and timing in postpartum and nonpregnant nulliparous women. Melatonin release provides information regarding circadian rhythm timing, which influences health. DESIGN: 2-group comparison of data derived from intensive within-subject data collection. SETTING: Participants' typical daily environment. PARTICIPANTS: 38 postpartum and 20 nonpregnant nulliparous women. Mothers' infants were 4 to 10 weeks of postnatal age. MAIN OUTCOME MEASURES: Urinary 6-sulfatoxymelatonin assayed from each voiding and corrected for volume using creatinine. RESULTS: Postpartum women had significantly higher baseline, lower maximum, lower percent rise, and differing pattern of 6-sulfatoxymelatonin than nonpregnant nulliparous women. CONCLUSION: Differences in melatonin suggest possible circadian rhythm disruption in the postnatal period.

Urinary 6-hydroxymelatonin sulfate excretion in intellectually disabled subjects with sleep disorders and multiple medications: validation of measurements in urine extracted from diapers.

The aim of this study was to examine the applicability of urinary 6-hydroxymelatonin sulfate (MT6s) measurements in the evaluation of melatonin secretion in intellectually disabled patients with sleep disorders. All 17 patients received drugs with potential interactions with melatonin metabolism. Serum melatonin 24-h profiles were determined at hourly intervals. The area under the curve (AUC) value, peak amplitude, half-rise time, and half-decline time were calculated individually. Urinary MT6s excretion was determined from samples collected from disposable diapers during three consecutive days at varying intervals. The average excretion rate for each hour of the day was calculated. The excretion profiles were characterized by total amount of MT6s excretion/24 h/kg body mass, amount of excreted MT6s during 6 h of maximum excretion (MAX 6h), and start time of the maximum excretion (start MAX 6h). There were significant positive correlations between serum melatonin AUC value and total excretion of MT6s/body mass, between serum melatonin amplitude and urinary MAX 6h, and between melatonin half-rise time and start MAX 6h; one patient on phenobarbital medication was out of line. The serum melatonin profiles of the patients were classified by comparing them with those of matched healthy volunteers (low-, normal-, or high secretors, normal or delayed rhythm). Similarly, the parameters of MT6s profiles were compared with those obtained from healthy controls, and the patients were reclassified as normal or aberrant. The classifications based on serum melatonin and urinary MT6s measurements were mostly concordant. The daily pattern of urinary MT6s excretion reliably reflected the phase of the serum melatonin rhythm irrespective of the medications, but in some cases, the total amount of excreted MT6s was lower than expected based on serum melatonin measurements.

Melatonin in older people with age-related sleep maintenance problems: a comparison with age matched normal sleepers.

STUDY OBJECTIVES: To determine whether older people with age-related sleep maintenance problems have significantly lower melatonin levels than comparable normal sleepers. DESIGN: Case-control study. SETTING: A largely urban population, Auckland, New Zealand. PARTICIPANTS: People over the age of 65 years, who either slept normally, or had age-related sleep maintenance problems. Participants were recruited through media advertising, and local interest groups. Initial screening was by mail (Pittsburgh Sleep Quality Index), followed by interviews at a hospital day clinic. Exclusions included those with depression, cognitive impairment, medical and/or environmental problems which might impair sleep. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A metabolite of plasma melatonin, 6-sulphatoxymelatonin (aMT6s) was measured in the urine of 57 normal sleepers, and 53 people with age-related problems over 24 hours in three aliquots: 12:00-19:00h, 19:00-07:00h, 07:00-12:00h. There were clear differences in self reported quality of sleep but no difference in mean aMT6s 24 hour or total night excretory levels, or night/day ratios. CONCLUSIONS: Older people with age-related sleep maintenance problems do not have lower melatonin levels than older people reporting normal sleep.