J. Sleep Res. (1998) 7, 135–143 Delayed sleep phase syndrome: A placebo-controlled cross-over study on the eﬀects of melatonin administered ﬁve hours before the individual dim light melatonin onset J. E. NAGTEGAAL 1 , G. A. KERKHOF 4 , M. G. SMITS 2 , A. C. W. SWART 3 and Y. G. VAN DER MEER 1 Department of Clinical Pharmacy, 1 Hospital ‘De Gelderse Vallei’, Ede/Bennekom, 2 Department of Neurology, 3 Department of Clinical Chemistry, Leiden University Medical Centre, 4 Department of Physiology, The Netherlands Accepted in revised form 4 March 1998; received 6 October 1997 SUMMARY In 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.  body temperature, delayed sleep phase syndrome (dsps), dim light melatonin onset, melatonin INTRODUCTION patients is well consolidated with normal sleep architecture and total sleep time, and no sleep pathology (Aldrich 1996). Delayed Sleep Phase Syndrome (DSPS) is a circadian rhythm In adolescents, a prevalence of greater than 7% is suggested disorder characterized by an abnormally delayed sleep-wake (Regestein and Pavlova 1995; Pelayo et al. 1988), whereas in rhythm. The major symptoms of DSPS are extreme diﬃculty middle aged adults a prevalence of 0.7% is found (Ando et al. to initiate sleep at a conventional hour of the night and great 1995). diﬃculty to wake up on time in the morning for school or Endogenous melatonin, a hormone produced by the pineal work (Weitzman et al. 1981). The aetiology of DSPS is mostly gland during the dark phase of the day-night cycle, is thought unknown (Aldrich 1996), although several developmental and to play a major role in the synchronisation of circadian rhythms. environmental factors have been suggested (Dahlitz 1991) like Its secretion is controlled by an endogenous oscillator that is e.g. long labour (Dahlitz 1991), infections (Dahlitz 1991) or entrained by light. The circadian rhythm of melatonin is highly shift work (DCSC 1990). Once initiated, the sleep of DSPS reproducible and generally not easily altered (Reiter 1992). From several studies (Aldrich 1996; Rosenthal et al. 1990; Alvarez et al. 1992; Czeisler et al. 1981) it has become clear Correspondence: J. E. Nagtegaal, Department of Clinical Pharmacy, that there are two methods to treat DSPS: with chronotherapy Hospital ‘De Gelderse Vallei’, P.O. Box 9501, 6720 GA Bennekom, The Netherlands and with administration of melatonin. Dahlitz (1991) published 135  1998 European Sleep Research Society