Melatonin rhythms in delayed sleep phase syndrome.

The aim of this study was to compare circadian and sleep characteristics between patients with delayed sleep phase syndrome (DSPS) and healthy controls. The authors studied 8 DSPS patients and 15 normal controls. Serum melatonin concentration was assessed every hour for 24 h under dim light conditions. The sleep phase and the melatonin rhythm in DSPS patients were significantly delayed compared to those in normal controls. Sleep length was significantly greater in DSPS patients compared to that in controls, but the duration of melatonin secretion did not differ between the two groups. The final awakening, relative to melatonin onset, melatonin midpoint, and melatonin offset, was significantly longer in DSPS patients than in controls. By contrast, the timing of sleep onset relative to melatonin rhythm did not differ between the two groups. The authors found a significant positive correlation between sleep phase markers and melatonin phase markers in DSPS. They postulate that a delayed circadian pacemaker may be responsible for delayed sleep phase syndrome. The alteration of phase angle between melatonin rhythm and sleep phase suggested that not only the delay of the circadian clock but also a functional disturbance of the sleep-wake mechanism underlies DSPS.

Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle.

BACKGROUND: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. METHODS: We applied an ultrashort sleep-wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. RESULTS: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. CONCLUSIONS: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.

Poor compensatory function for sleep loss as a pathogenic factor in patients with delayed sleep phase syndrome.

OBJECTIVE: Delayed sleep phase syndrome (DSPS) is a condition in which the patient is unable to reset or phase-advance his/her sleep timing properly after transient sleep delay and consequently shows persistent sleep phase delay. Prior studies suggested that DSPS is associated with a phase delay in the circadian pacemaker, but there was no evidence to explain the patient's inability to reset sleep phase. SUBJECTS AND METHODS: We used an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation to allow the differential observation of diurnal sleep propensity fluctuation both from circadian and homeostatic aspects in 11 patients with DSPS (17-37 years; 8 men, 3 women) and 15 healthy controls (19-32 years; 8 men, 7 women). SETTING: NA. PATIENTS OR PARTICIPANTS: NA. INTERVENTIONS: NA. RESULTS: DSPS patients showed less ability to compensate for previous sleep loss during their circadian day and first hours of their circadian nighttime determined by dim light melatonin onset compared with controls, while controls compensated for previous sleep loss at most circadian times. Though shapes of dim light melatonin rhythm did not differ between the groups, phase angle between melatonin and sleep propensity rhythms was wider in DSPS patients than in controls. CONCLUSIONS: These findings suggest that poor compensatory function for sleep loss predisposes DSPS patients to failure to reset their sleep phase. Our results provide implications for understanding not only the pathophysiology of DSPS but also the biological basis for why some people can change their sleep schedule easily according to personal or social demands while others cannot.

Prevalence and correlates of sleep problems in Chinese schoolchildren.

STUDY OBJECTIVES: This study examined the prevalence and correlates of sleep problems in Chinese schoolchildren. DESIGN AND SETTING: A cross-sectional questionnaire survey was undertaken in Shandong Province, People's Republic of China. PARTICIPANTS: A total of 2004 elementary school children (998 boys and 1006 girls) participated in the survey. MEASUREMENTS AND INTERVENTIONS: The parents completed a questionnaire that asked about sleep problems, and characteristics of the family and child. Teachers completed a questionnaire that included the Modified Conners Hyperkinesis Index (MCHI), whether the child slept in class, and school achievement. RESULTS: Parent-reported sleep problems that occurred "sometimes" or "often" were sleep walking/talking, 14.2%; too little sleep, 14.0%; too much sleep, 12.5%; nightmares, 12.0%; trouble sleeping, 6.1%; and nocturnal enuresis, 4.5%. Teachers reported that 9.4% of children slept in class "sometimes" or "often". Approximately 11% of children were reported to have any sleep problem "often". Children with sleep problems were more frequently reported to be hyperactive, and to have poorer child-parent relations, poorer peer relations, and poorer social competency and school achievement. Multivariate logistic regression analysis indicated that sleep problems were significantly correlated with following factors: poor parental relations, crowded homes, bedwetting cessation after age 4, chronic physical diseases, reported hyperactivity and poor peer relations. CONCLUSIONS: Parent-reported sleep problems in Chinese children were less prevalent than those reported in Western countries, and associated with multiple family, prenatal, and child developmental factors. Children with sleep problems were reported to be more hyperactive, and to have social and academic problems more frequently. <=

Sleep and mood disorders.

Mood disorders are found in one-third to one-half of patients with chronic sleep problems. Likewise, most patients with mood disorders experience insomnia, but a minority obtain significantly increased amounts of sleep. Although mood disorders cause significant morbidity and mortality, they often go undiagnosed. Attention to sleep complaints could lead to better identification of mood disorders. Management of sleep problems in patients with mood disorders should focus on treating underlying mood disorders with attention to the nature of the sleep complaint. Patients with depression show characteristic abnormalities in sleep continuity, slow-wave sleep and REM sleep patterns. Differences in sleep patterns cannot reliably distinguish patients with depression from those with other psychiatric disorders, but sleep changes may provide a window on neurobiologieal abnormalities in depression.

Diurnal preference, sleep habits, circadian sleep propensity and melatonin rhythm in healthy human subjects.

After 24-h sleep deprivation, 33 healthy young subjects entered the 10/20 min ultra-short sleep-wake schedule for 26 h. Melatonin rhythm was hourly assessed simultaneously. Results indicated that morning preference was significantly correlated with habitual sleep onset (r=-0.41, P=0.04), habitual sleep offset (r=-0.52, P=0.002), melatonin peak time (r=-0.36, P=0.04), and sleep propensity onset time (r=-0.36, P=0.04). The intervals between habitual sleep mid-point and melatonin peak time and between habitual sleep mid-point and sleep propensity onset time were significantly longer in morning-preference subjects than in evening-preference subjects (P<0.05). These findings suggest that the variance of diurnal preference may be related to differences in phase relations between habitual sleep timing and the circadian pacemaker.

Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep-wake syndrome in humans.

Changes in the phase relation between sleep timing and the circadian pacemaker are suspected to have an etiological significance in circadian rhythm sleep disorders. Simultaneous recordings of rest-activity and rectal temperature in seven sighted delayed sleep phase syndrome (DSPS) patients, seven sighted non-24-h sleep-wake syndrome (non-24) patients, and 14 healthy controls were made for 10-14 days continuously in the subjects' homes. We found that sleep length and the interval from the body temperature (BT) trough to sleep offset were significantly longer in both non-24 and DSPS patients than in the controls, and that the interval between sleep onset and the BT trough was significantly less in the non-24 patients than in the DSPS patients and the controls. We postulate these alterations in phase relation to be associated with phase changes of the circadian pacemaker via different illumination timings.

Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls.

Recent studies suggest that melatonin 1b (Mel1b) receptor, as well as melatonin 1a (Mel1a) receptor, is involved in the modulation of circadian rhythms in mammals. Mutational analysis was performed in the entire coding region of the human Mel1b receptor gene using genomic DNA from sleep disorder subjects. We have identified two missense mutations, G24E and L66F. However, neither is likely to be associated with sleep disorders in our study population. One of the subjects with non-24-h sleep-wake syndrome carries missense mutations in both the Mel1a and Mel1b receptor genes.

Psychometric assessment of subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) in psychiatric disordered and control subjects.

Subjective sleep quality has been identified as an important clinical construct in psychiatric disordered patients. The Pittsburgh Sleep Quality Index (PSQI), one of the most widely used standardized measures to assess subjective sleep quality, generates a global score and scores seven components. The present study psychometrically assessed clinical profiles of subjective sleep quality in 82 control and 92 psychiatric disordered subjects (primary insomnia, n=14; major depression, n=30; generalized anxiety disorder, n=24; and schizophrenia, n=24), using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J). The overall reliability coefficient of the PSQI-J was high (Cronbach's alpha=0.77). Correlation coefficients between the PSQI-J global and component scores were statistically significant. The PSQI-J global and component mean scores were significantly higher in psychiatric disordered subjects than control subjects, except for the component of sleep duration. Using a cut-off point of 5.5 in the PSQI-J global score, estimations of sensitivity and specificity provided 85.7 and 86.6% for primary insomnia, 80.0 and 86.6% for major depression, 83.3 and 86.6% for generalized anxiety disorder, and 83.3 and 86.6% for schizophrenia, respectively. The present study supports the utility of the PSQI-J as a reliable and valid measure for subjective sleep quality in clinical practice and research.

Sleep loss and daytime sleepiness in the general adult population of Japan.

There are few epidemiological studies on sleep loss and daytime sleepiness in the general adult population of Japan. A total of 4000 adult people, aged 20 and over, were randomly drawn from five areas of Japan, and 3030 individuals were interviewed and completed a questionnaire including information about sleep duration and sleep problems. Overall, 29% slept less than 6 h at night, 23% reported having insufficient sleep, and 6% took sleep enhancing medications. The prevalence rates were 21% for symptoms of insomnia and 15% for excessive daytime sleepiness. Symptoms of insomnia were more prevalent in the elderly, whereas young people were more likely to report short sleep duration, subjective insufficient sleep and excessive daytime sleepiness. A multiple logistic regression model revealed that excessive daytime sleepiness had significant associations with young people, short sleep duration, insomnia symptoms, subjective insufficient sleep and sleep enhancing medication use. Short sleep duration was the strongest predictor of excessive daytime sleepiness. The findings indicate that sleep loss and excessive daytime sleepiness in the Japanese adult population are common, and comparable to those reported in Western countries. Excessive daytime sleepiness in the general adult population seems more likely to be attributed to short sleep duration.

Periodic fatigue symptoms due to desynchronization in a patient with non-24-h sleep-wake syndrome.

A 43-year-old man complaining of recurrent fatigue symptoms and sleep disorders occurring periodically every 4 weeks was studied. Using a wrist worn actigraphy and an ambulatory rectal temperature monitoring apparatus, his sleep-wake cycle and rectal temperature were measured continuously for 4 months, while diagnostic evaluation and therapeutic interventions were conducted. It was found that after he gave up an attempt to keep to a 24-h-day, a free-running sleep wake pattern appeared but his fatigue symptoms disappeared. An analysis of the relationship between his sleep-wake cycle and the rectal temperature rhythm found that his fatigue symptoms did not appear when both rhythms were synchronized with each other. Artificial bright light therapy entrained him to a 24-h day without relapsing of fatigue symptoms. Desynchronization between a 24-h sleep-wake schedule and his circadian pacemaker may have caused his periodically appearing fatigue symptoms.

Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology.

Delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake rhythm are circadian rhythm sleep disorders that are common in adolescents. Most patients have difficulty adjusting to school life, poor class attendance or refuse to go to school. Since a treatment has not been established, the present paper is presented to propose a strategy for treating circadian rhythm sleep disorders in adolescents, based on our clinical studies. Twenty subjects (12 males and eight females, mean age 16.2+/-1.7 years) participated in the study. The onset of sleep disorder occurred between the ages of 11 and 17. The most common factors affecting the onset of disorders were changes in social environment. The subjects kept a sleep-log for the periods before and during treatments. The treatments were based on chronobiology: resetting the daily life schedule, chronotherapy, regulation of the lighting environment, methylcobalamin, and/or melatonin. Bright light exposure was successful in 10 patients, of whom four were treated with methylcobalamin. Melatonin treatment was successful in two patients (one with and one without chronotherapy). Thirteen of the 20 patients were successfully, treated with therapies based on chronobiology. After consideration of these results, a step-by-step procedure of combined treatments for the circadian rhythm sleep disorders is proposed.

Somatic and psychological complaints and their correlates with insomnia in the Japanese general population.

OBJECTIVE: This cross-sectional study was conducted to estimate the prevalence of somatic and psychological complaints (SPCs) and to investigate the association of SPCs with insomnia in a sample of the general adult population of Japan. METHODS: We randomly selected 4000 adult residents (-20 years old) from five areas of Japan using stratified sampling and conducted interviews using a structured questionnaire. The questionnaire solicited information about eight somatic symptoms, eight psychological symptoms, three sleep problems, and demographic and health-related information. A total of 3,030 subjects completed questionnaires, giving a response rate of 75.8%. RESULTS: Stiff neck/shoulder (45.3%), backache (35.1%), and fatigue (31.4%) were the most common complaints in this population. In general, SPCs were more prevalent in younger persons and in women. Logistic regression analyses, controlling for other factors, showed that insomnia was significantly associated with a number of SPCs: backache (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 1.1-1.6), epigastric discomfort (OR = 1.7, 95% CI = 1.3-2.2), weight loss (OR = 2.0, 95% CI = 1.2-3.3), headache (OR = 1.7, 95% CI = 1.3-2.2), fatigue (OR = 1.7, 95% CI = 1.4-2.1), worrying (OR = 1.6, 95% CI = 1.1-2.3), irritability (OR = 1.4, 95% CI = 1.1-1.7), and loss of interest (OR = 1.8, 95% CI = 1.2-2.7). CONCLUSIONS: SPCs were common and were largely associated with insomnia in the general adult population of Japan. Further study is needed to examine the causal links between SPCs and insomnia.

Clinical characteristics of circadian rhythm sleep disorders.

From our practice at the sleep disorders clinic in Kohnodai Hospital, National Center of Neurology and Psychiatry (NCNP), we report the clinical characteristics of circadian sleep-wake rhythm disorders. Nearly 90% of circadian rhythm sleep disorders were diagnosed as delayed sleep phase syndrome (DSPS) or as non-24 sleep-wake syndrome (non-24). While DSPS was equally common in males and females, non-24 was more frequently seen in men. It was of psychiatric interest that a considerable number of patients had depressive states in the course of their circadian rhythm sleep disorders. Difficulty in adapting to social life was more severe in patients with non-24 than in those with DSPS.

Continuous measurement of temperature in non-24 hour sleep-wake syndrome.

The onset of the low temperature (LT) zone which was defined as a period when the rectal temperature was below its daily mean is a convenient circadian phase marker. In this study, we document three cases of non-24 h sleep-wake syndrome in which identification of the LT zone as an evening circadian phase marker contributed to clinical judgments. We found that the LT zone was correlated well with dim light melatonin onset. Moreover, calculating the LT zone was useful in determining phase position in irregular sleep pattern and in determining the timing of bright light therapy.

Human time production under constant routine.

Previous reports have suggested that human time production of several seconds fluctuates across the day. In order to test whether human time production was controlled by the circadian process or by the homeostatic process, we investigate diurnal fluctuation of human time production under constant routine conditions. We found a common circadian feature in time production tests of 10 s by calculating Z-score for each subject; afternoon troughs and morning peaks. These results may suggest that human time production was modulated by the circadian process.

Twenty-four hour profiles of four hormones under constant routine.

We studied the circadian features of melatonin, cortisol, thyroid stimulating hormone (TSH), and growth hormone (GH) together with rectal temperature during 36 h continuous forced wakefulness without physical exercise under dim light condition (constant routine). Subjects consisted of four healthy men aged 22-24 years. Blood sampling was conducted hourly, and food and water were supplied bi-hourly during the constant routine. Melatonin, TSH and cortisol displayed clear circadian rhythms under constant routine condition. While GH secretion was unlikely to be driven solely by the circadian pacemaker, its suppression round BT nadir may indicate that GH secretion was modulated to some extent by circadian rhythm.

Melatonin treatment for circadian rhythm sleep disorders.

We administered 1-3 mg melatonin to 11 patients (eight men, three women, aged 16-46 years) with circadian rhythm sleep disorders; nine with delayed sleep phase syndrome and two with non-24-hour sleep-wake syndrome. Sleep logs were recorded throughout the study periods and actigraph and rectal temperature were monitored during treatment periods. Melatonin was administered 1-2 h before the desirable bedtime for expected phase-shifting, or 0.5-1 h before habitual bedtime for gradual advance expecting an hypnotic effect of the melatonin. Melatonin treatments were successful in 6/11 patients. Timing and dose of melatonin administration, together with its pharmacological properties for circadian rhythm sleep disorders, should be further studied.

Trials of bright light exposure and melatonin administration in a patient with non-24 hour sleep-wake syndrome.

We report a patient with non-24 h sleep-wake syndrome (non-24) whose free-running sleep-wake cycle was successfully treated with both scheduled bright light exposure and melatonin treatment. In the present study, morning bright light as well as evening melatonin phase-advanced sleep-wake cycles and melatonin rhythm. Both these procedures achieved appropriate entrainment to a 24 h day. However, the patient did not continue morning bright light therapy after the discharge. Rising at appropriate times in the morning for bright light therapy was difficult for him to continue. Melatonin treatment was better tolerated because of its ease of application.

Melatonin treatment for circadian rhythm sleep disorders.

This study investigated the effects of melatonin administration on circadian rhythm sleep disorders, and aimed to clarify clinical characteristics of melatonin responders. The subjects were 46 patients with circadian rhythm sleep disorders: 30 Delayed Sleep Phase Syndrome (DSPS) and 16 non-24 h sleep-wake syndrome (non-24). Patients took 0.3-1.0 mg of melatonin 5, 3 and 1 h before habitual bedtime. Seventeen patients responded to melatonin (12 DSPS, five non-24). Comparison of clinical background between responders and non-responders revealed that the responders were characterized by short total sleep time and later onset age of clinical symptoms.