30 In the absence of light input to the clock, nonphotic time cues are obviously a potential therapeutic option to treat non-24-hour circadian rhythms disorder

in the blind. There are currently no therapeutic guidelines, but some preliminary research suggests that it may be beneficial for patients to try to maintain a regular 24-hour schedule. Klerman Inhibitors,research,lifescience,medical and colleagues92 showed that the circadian system of a blind man with a period of 24.1 h became entrained when he lived on a 23.8 h “day.” AU aspects of his schedule were shifted simultaneously in this protocol including the sleep-wake cycle, meal times, activity, posture, and interaction with staff, precluding identification of the effective time signal, but collectively at least they were able to induce a phase advance. Other attempts to entrain circadian rhythms in blind people using a “potential complex ”zeitgeber“ including exercise (bicycle riding, 50 W over 15 mins), a strict social routine, a cold shower, and a heavy protein breakfast37 appeared to have induced a shift in Inhibitors,research,lifescience,medical the timing of sleep and temperature rhythms, find more although it is not clear whether entrainment occurred. Inhibitors,research,lifescience,medical The relative weakness of nonphotic time cues is readily observed; however, in the majority of totally blind people who are not entrained when living in society (see above), where they are exposed to many 24-hour time cues

such as work or school schedules, mealtimes, sleepwake schedules, activity, alarm clocks, family and social interaction, and so on. The inability to entrain to these schedules is dependent on an individual’s intrinsic circadian period as the weak nonphotic time cues with have narrow ”limits of entrainment,“ the range of periods over which nonphotic Inhibitors,research,lifescience,medical cues can have an effect. If an individual’s circadian period is too far from 24 hours, the weak nonphotic time Inhibitors,research,lifescience,medical signals will be unable to entrain it. Treatment of circadian rhythm disorders in the blind While some other drugs have been shown to shift

the timing of the clock (for review, see ref 30) the most promising therapeutic strategy for treatment found of non-24hour sleep-wake disorder is daily administration of melatonin. Although it was shown more than 20 years ago that melatonin treatment could entrain free running rhythms in rats93 and could cause phase advance shifts in humans,94,95 demonstration of entrainment in free running humans took longer to prove. Initial experiments using daily treatment with 5 mg or higher doses either failed to affect the circadian pacemaker at all56,96 or shortened period without inducing entrainment.97,98 These and other cases99-104 did report some improvement or stabilization of the sleep-wake cycle in these patients,105 most likely through the direct soporific effects of melatonin.105,108 In 1996, we began a re-examination of the entraining effects of melatonin in seven men with non-24-hour rhythms with a period >24 hours.