SUMMARYIn a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two weeks of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n=14), polysomnography (n=22), actigraphy (n=13), sleep log (n=22), and subjective sleep quality (n=25). Mean dim light melatonin onset (DLMO) (±SD), before treatment, occurred at 23.17 hours (±138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.

End-stage renal disease (ESRD) is an increasing health problem worldwide. Given the increasing prevalence of this disease, the high cost of hemodialysis treatment and the burden of hemodialysis on a patient's life, more research on improving the clinical outcomes and the quality of life of hemodialysis-treated patients is warranted. Sleep disturbances are much more prevalent in the dialysis population than in the general population. Several studies investigating the effect and importance of sleep problems on quality of life in dialysis patients revealed that sleep disturbances have a major influence on the vitality and general health of these patients. Sleep disturbances in this patient group are caused both by the pathology of the renal disease and by the dialysis treatment itself. This Review focuses on circadian sleep-wake rhythm disturbances in individuals with ESRD. The possible external and internal influences on sleep-wake rhythmicity in patients with ESRD, such as the effect of dialysis, medications, melatonin and biochemical parameters, are presented. In addition, possible approaches for strengthening the synchronization of the circadian sleep-wake rhythm, such as nocturnal hemodialysis, exogenous melatonin, dialyzate temperature, exogenous erythropoietin, use of bright light and exercise during dialysis treatment, are explored. Further research in this area is warranted, and a greater awareness of sleep problems is needed to improve the quality of life of patients with ESRD.

As melatonin amplitude and melatonin rhythm decreased with advancing renal dysfunction, follow-up research into circadian rhythms in patients with CKD is warranted.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Disturbances of sleep-wake rhythm are frequently reported in daytime haemodialysis patients. • The melatonin rhythm, which plays an important role in synchronization of the sleep-wake rhythm, is disturbed in this patient group. • In other patient groups with disturbed melatonin rhythm, use of exogenous melatonin resulted in an improvement of sleep quality and melatonin rhythm. WHAT THIS STUDY ADDS • This is the first study on the effects of exogenous melatonin on sleep-wake rhythm in haemodialysis patients. • Due to exogenous melatonin, sleep parameters such as sleep fragmentation, sleep onset latency and subjective sleep quality improved. • Nocturnal melatonin rise was recovered. AIM The aim of this study was to investigate the effects of exogenous melatonin on sleep-wake rhythm in haemodialysis patients. METHODS The study design is a randomized, double-blind, placebo-controlled, cross-over study of 3 ¥ 6 weeks melatonin 3 mg at 22.00 h every night. Haemodialysis patients were asked to fill out a sleep questionnaire and to wear an actometer to record their sleep problems objectively. Furthermore, melatonin concentrations in saliva were sampled the night after daytime haemodialysis and the consecutive night. Actometers, the sleep questionnaire and melatonin concentrations were repeated during the study. RESULTS In total, 20 patients (six female, median age 71 years) completed the investigation. On nights after daytime dialysis, objective sleep onset latency decreased significantly from a median of 44.5 (placebo) to a median of 15.5 min with melatonin (P < 0.01). Sleep efficiency increased from 67.3 to 73.1% with melatonin (P < 0.05). Actual sleep time increased from 376 min (placebo) to 388 min with melatonin (P < 0.01), and sleep fragmentation decreased from 4.5 to 3.1 (P < 0.01). Furthermore, subjective sleep parameters improved also. Patients reported less time needed to fall asleep (P < 0.05) and fewer wake periods (P < 0.05) on the nights with and without daytime dialysis and an increase in sleep time on the night of daytime dialysis (P < 0.05). Furthermore, the nocturnal melatonin rise was recovered. CONCLUSION Treatment with melatonin resulted in an improvement of subjective and objective sleep parameters, as well as a recovered nocturnal melatonin rhythm.

Exogenous melatonin, which can be used to treat certain circadian rhythm disorders, maximally advances delayed rhythms when administered 5 hours before the endogenous melatonin starts to increase. The time of the start of the endogenously melatonin is defined as Dim Light Melatonin Onset (DLMO). The DLMO concentration has been defined in serum to be 10 pg/ml. Because of the greater practicability of frequent saliva sampling over blood sampling, we have validated radioimmunoassay (RIA) measurements of melatonin in saliva in patients diagnosed as suffering from a typical circadian rhythm disorder: Delayed Sleep Phase Syndrome (DSPS). Based on these results we have defined the equivalent salivary DLMO concentration to be 4 pg/ml.