Abstract
Exogenous melatonin (0.5-10 mg) has been shown to entrain the free-running circadian rhythms of some blind subjects, yet questions still remain as to the most effective dose and the most appropriate circadian time (CT) at which to commence melatonin treatment. Some melatonin phase response curves (PRCs) have been constructed by studying entrained sighted subjects and these show that melatonin produces phase delays if administered between CT18-6 and phase advances if administered between CT6-18. The protocols for these PRC studies are flawed, in that they do not conform to the classical PRC protocol whereby subjects should be free-running in constant lighting conditions. The aims of the present studies were to define further the properties of exogenous melatonin both as a phase shifting and an entraining agent in blind subjects with free-running circadian rhythms, together with one abnormally entrained individual. Specifically these aims were to investigate the entraining effects of daily administration of 0.5 mg melatonin on the free-running cortisol rhythm and its acute effects compared to placebo on the sleep-wake cycle in blind subjects. A study was also designed to assess whether a single dose of melatonin (5 mg) could shift the phase of endogenous circadian rhythms (melatonin and 6-suphatoxymelatonin) in free-running blind subjects, in order to construct a PRC. Melatonin (0.5 mg daily) administered to a blind subject with entrained, but abnormally advanced, circadian rhythms in a step-wise manner shifted the cortisol rhythm, probably by phase delay (cumulative phase delay of 2.5 h). This change of phase improved sleep by decreasing sleep latency, total number of night awakenings, the number and duration of night awakenings in the second half of the night and the number and duration of daytime naps. Most of the ten free-running blind subjects who took 0.5 mg melatonin daily for one full circadian beat cycle exhibited an entrained or shortened cortisol period during melatonin treatment. The subjects who entrained did so when melatonin treatment commenced in the phase advance portion of the melatonin PRC (CT6-18). Three subjects failed to entrain with initial melatonin treatment commencing in the phase delay portion of the PRC. During melatonin treatment there was a significant increase in night time sleep duration and a reduction in the number and duration of daytime naps. The CT of melatonin administration may be an important in determinant of entrainment. The efficacy of different doses, formulations and length of treatment need further investigation. The melatonin PRC was carried out in seven subjects, one of whom took part in the study twice. The majority of phase shifts were phase delays (6, compared to 3 phase advances), and some were opposite in direction to that expected on the basis of the most recently published PRC. This may be due to the fact that the original PRC was constructed from multiple doses of melatonin (0.5 mg daily for four days) and the subjects were all sighted and entrained. Moreover the current study used a higher (5 mg) single dose of melatonin. It is also possible that each individual has a different PRC based on individual circadian period. The assessment of more subjects should clarify these issues and enable the construction of a full PRC. These studies show that low dose melatonin can entrain free-running rhythms in blind people as well as improving sleep and confirm melatonin as the treatment of choice for non 24 hour sleep wake disorder in the blind. The results of the preliminary PRC study, if confirmed, suggest that the PRC for free-running people is different to that of entrained people. This may explain why some subjects do not entrain to melatonin taken at specific circadian times.