In our recently published study, we have shown that nightly oral administration of 10 mg melatonin can entrain (synchronize) free-running circadian rhythms in eight of nine blind adults to the 24.0-hour day, resulting in improved nighttime sleep and daytime alertness. The one person who did not entrain had the longest pre-treatment free-running period (24.9 h). In addition, we have shown that 10 mg of melatomn has a direct soporific action given to blind subjects when their free-running circadian rhythms are inverted. Most recently, he has found that the dose can be """"""""stepped down"""""""" to 0.5 mg in three out of three of these people. We have further found that they could also be entrained to a novo 0.5 mg dose (their longest free-running period was 24.4 h). The pre-treatment period appears to predict the likelihood of entrainment to melatonin and the steady-state phase of entrainment, which is consistent with several important principles established in animal studies. Therefore, our projects are of both clinical and scientific importance. There are approximately 200,000 totally blind people in the U.S. About 50 percent have free-running circadian rhythms, and many are children. The goal of this project will be to determine the efficacy of melatonin treatment at three doses (0.5 mg, 10 mg and 20 mg), with the prediction that the 0.5 mg dose will work only in blind children with relatively short periods (<24.5 h). In treatment failures with the 0.5 mg dose, we will test the efficacy of higher doses. Blind subjects who successfully entrain with melatonin will be followed for one year to assess the long-term benefits and risks of melatonin administration. It is particularly important to study blind children, because they may be more susceptible to side effects of melatonin and they may respond differently to melatonin treatment. Among the many basic science questions that we will be addressing is the effect of age on circadian period. The study of melatonin rhythms in blind children provides an opportunity to understand the physiology of the circadian system in children unperturbed by the light/dark cycle - without having to use a temporal isolation facility

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1-BDCN-6 (01))
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Freund, Lisa S
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Oregon Health and Science University
Schools of Medicine
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Emens, Jonathan; Lewy, Alfred J; Laurie, Amber L et al. (2010) Rest-activity cycle and melatonin rhythm in blind free-runners have similar periods. J Biol Rhythms 25:381-4
Emens, Jonathan; Lewy, Alfred; Kinzie, John Mark et al. (2009) Circadian misalignment in major depressive disorder. Psychiatry Res 168:259-61
Boudreau, Eilis A; Johnson, Kyle P; Jackman, Angela R et al. (2009) Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. Am J Med Genet A 149A:1382-91
Lewy, Alfred J; Emens, Jonathan S; Songer, Jeannie B et al. (2009) Winter Depression: Integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model. Sleep Med Clin 4:285-299
Emens, Jonathan S; Yuhas, Krista; Rough, Jennifer et al. (2009) Phase angle of entrainment in morning- and evening-types under naturalistic conditions. Chronobiol Int 26:474-93
Lewy, A J (2007) Melatonin and human chronobiology. Cold Spring Harb Symp Quant Biol 72:623-36
Lewy, Alfred J (2007) Current understanding and future implications of the circadian uses of melatonin, a neurohormone discovered by Aaron B. Lerner. J Invest Dermatol 127:2082-5
Lewy, Alfred J; Emens, Jonathan; Jackman, Angela et al. (2006) Circadian uses of melatonin in humans. Chronobiol Int 23:403-12
Lewy, Alfred J; Lefler, Bryan J; Emens, Jonathan S et al. (2006) The circadian basis of winter depression. Proc Natl Acad Sci U S A 103:7414-9
Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J et al. (2005) Melatonin entrains free-running blind people according to a physiological dose-response curve. Chronobiol Int 22:1093-106

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