Japanese Society of Sleep Research

259

Melatonin

Melat onin treatment for circadian rhythm sleep disorders

MASAKO OKAWA, MD,' MAKOTO UCHIYAMA, MD,' SHIGERU OZAKI, MU,^ KAYO SHIBUI, MD,' YUICHIKAMEI, M D , ~ TASTURO HAYAKAWA, M D , ~ AND JUJIRO URATA, M D ~
'Deparfmenf($Psychophysiology, National Institute

..

of Neurology and Psychiatry, Chiba, japan

of Mental Health, and *Department of Neuropsychiatry, Kohnodai Hospital, National Center

Abstract

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. actigraph, body temperature, delayed sleep phase syndrome, melatonin, non-24-hour sleep-wake syndrome, sleep log.

Key words

INTRODUCTION
In recent years, there has been an increased awareness of circadian rhythm sleep disorders. Among these, delayed sleep phase syndrome (DSPS) and non-24 h sleep-wake syndrome (non-24) are troublesome because they are often associated with substantial educational, welfare, and social problems. Recently, melatonin has been used widely for circadian rhythm sleep disorders, especially jet lag syndromes. Furthermore, melatonin was reported to be effective for non-24 in blind people'*2 and for insomnia. We report the actions of melatonin on the sleepwake cycle in patients with DSPS and non-24, and propose melatonin treatment procedures for DSPS and non-24.

abrupt phase s w n g method. Using the former method, the subjects took melatonin 0.5-1 h before their habitual bedtime; once sleep onset time advanced, they took it in the same manner until the sleep onset time came to their desirable time. Using the latter method, they took melatonin 1-2 h before their desirable bedtime. Patients with non-24, during the gradual delay of sleep phase, started to take melatonin about 1 h before the desired bedtime, when their sleep period came to occur at night time. The method was derived from the melatonin administration for phase-shifting by Sack et a1.*

RESULTS
The treatment course of representative cases are shown in Fig. 1. Table 1 summarizes the melatonin treatment. Melatonin treatment was effective in 6/11 patients (five DSPS and one non-24). Tiredness at rising was observed in four patients, but these symptom did not disturb the continuation of taking melatonin. Body temperature showed prompt phase shift followed by the phase-shift of sleep-wake cycle in successful cases. In a case with DSPS, melatonin administration was combined with chronotherapy to achieve earlier entrainment.

SUBJECTS AND METHODS

Eleven patients with circadian rhythm sleep disorders (eight men, three women, aged 16-46 years) took part in this study; nine with DSPS and two with non-24. We asked the patients to record sleep logs throughout the study period. In order to evaluate the accuracy of the self-recording sleep-log, motor activity (rest-activity cycles) were recorded by an actigraph monitor (Ambulatory Monitoring Inc., Ardsley, NY,USA) on the non-dominant wrist. Rectal temperature were continuously recorded in five patients during the study, using rectal temperature monitoring system (Kohden Medical Co., Tokyo, Japan). After 2 weeks of clinical diagnostic evaluation, the patients received 1-3 mg melatonin. Patients with DSPS took melatonin either gradually using the advancing method or with
Correspondence address: Masako Okawa. MD, Department of Psychophysiology. National Institute of Mental Health, National Center of Neurology and Psychiatry, 1-7-3 Kohnodai. Ichrkawa-sh. Chiba 272. Japan.

DISCUSSION
The present study showed favorable effects of melatonin for DSPS and non-24. With regard to the mechanism of melatonin action to sleep-wake cycles, in the circadian rhythm sleep disorders, two factors should be considered: phase-setting effect and hypnotic effect. Sack et a1.* have previously reported clear evidence of the phase-setting effects of melatonin in human subjects with non-24 and Dahlitz et al. demonstrated significant phase advancing effect in patients with DSPS taking melatonin

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Psychatry and Clinical Neurosciences

Table 1. Summary of melatonin treatment

Age/sex 34/m 16/m 30/m 31/f 30/f 34/11] 32/m 34/m 46/f 32/m 17/m Diagnosis DSPS DSPS DSPS Dose 3 mg 3 mg 1 mg 1 mg 1 nig Time 0.5-1 ha 0.5-1 ha constantb constantb constantb constantb 0.5-1 ha 1-2 ha 1-2 ha 0.5-1 ha constantb DSPS
1 mg

Eficacy

Side effects

Body temp Recorded Not recorded Recorded Recorded Recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Recorded

+
+ +

Tiredness

non-24 DSPS
DSPS DSPS (non-24) DSPS DSPS
non-24

+
+ -

Tiredness Bad feeling at rising

1 mg
3 mg --> 1 mg 3 mg 3 mg 3 mg

constantb

"Gradual advancing method by hours; bconstant timing of admmistration at 0.5-1 h before the desired bedtime.

Case KS 3Oy male

5 mg at 22.00 h.3 They speculated that exogenous administration of melatonin phase-shift or entrain the sleepwake rhythm in humans. Our DSPS patients were successfully treated by melatonin taken 1-2 h before their desired bedtime. Our patients definitely showed phase advance of the biological clock, which was supported by the advancement of rectal temperature rhythms in the unmasked condition. Hypnotic effects of melatonin at a dose of 1-3 mg are also shown in our patients who took melatonin 1 h before their habitual bedtime to gradually advance the sleep-onset time. In previous reports, the dose of melatonin broadly spread from 0.5 to 80 mg. Furthermore, melatonin is rapidly absorbed after oral administration, and peak plasma concentrations occur within 60 min, although sleep onset was delayed for 3-4 h after dosage.4 Further studies should be conducted to clarify these pharmacological characteristics.

REFERENCES
1. Palm L, Blennow 0,Wettenberg L. Correction ofnon-24-hour sleep/ wake cycle by melatonin in a blind, retarded boy. Atin. Neurol. 1991; 29: 336-339. 2. Sack RL, Lewy AJ, Blood ML, Stevenson J. Keith LD. Melatonin administration to blind people: Phase advances and entrainment.]. Bid. Rhyrhms 1991; 6: 249-261. 3. Dahlitz M, Alvarez B, Vignau J, Enghsh J, Arendt J. Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991; 333: 11211124. 4. Waldhauser F, Saletu B, Trinchar-Lugan I. Sleep laboratory investigations on hyponotic properties of melatonin. Psyrhopharmacoloxy 1990: 200: 333-336.

Figure 1. Treatment course of case 3, a 30 year-old male with delayed sleep phase syndrome. Black horizontal bars indicate sleep, and gray horizontal bars represent low-temperature (LT) zones below the overall mean of measuring period, whch are represented by double-plotted method. Crossed circles indicate temperature nadir measured under dim light ultrashort sleep-wake schedule. Early half of February, sleep onset and ofiet was irregularly delayed as well as low LT zone. W e administered 1 mg of nielatonin at 03.00 h for 5 days, and at 21.00 h thereafter. Sleep onset and LT zone advanced between 22.00 and 24.00 h. Temperature nadir also advanced from 12.00 to 05.00 h, which indicates advancement of biological clock.