Totally blind people have sleep problems that are caused by desynchronized (non 24-hour) circadian rhythms. Without photic time cues; the internal body clock tends to """"""""free-run"""""""" on about a 24.5-hour cycle; as a result, circadian rhythms move in and out of phase with desired sleep times, causing recurrent insomnia and impaired daytime alertness. Nightly oral administration of melatonin may act as a """"""""darkness signal"""""""" that can synchronize internal rhythms to desired sleep times. In addition to this """"""""clock resetting"""""""" (phase-shifting) action, melatonin may benefit insomnia in blind patients by a direct sleep-promoting (sedative) action. The goal of this project is to demonstrate the safety and efficacy of oral melatonin administration for circadian rhythm sleep disorders in totally blind people, and to elucidate the most relevant mechanism of action (phase-shifting or direct sedation). The experimental protocol will consist of clinical trials in which melatonin is administered at bedtime to blind subjects who have free-running circadian rhythms with related sleep complaints. The trials will test doses of 0.5 and 10 mg., employing a within-subject placebo-controlled, cross-over design. The phase relationships between endogenous circadian rhythms and sleep will be monitored by periodic measurement of the endogenous melatonin rhythm, concurrent with indicators of sleep time, quality and quantity. Treatment effects on circadian phase will be assessed three times during each trial by measuring the timing of endogenous melatonin secretion. Treatment effects on sleep and alertness will be assessed by daily diaries, daily wrist actigraphic monitoring, polysomnography (PSG) and multiple sleep latency testing (MSLT). Subjective benefits will be assessed with daily ratings of alertness and vigor. Safety will be assessed by close monitoring for side effects and by periodic clinical evaluation and laboratory testing.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
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Oregon Health and Science University
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Lewy, A J (2007) Melatonin and human chronobiology. Cold Spring Harb Symp Quant Biol 72:623-36
Schoenhard, John A; Muldowney 3rd, James A S; Emens, Jonathan S et al. (2007) Plasminogen activator inhibitor-1 has a circadian rhythm in blind individuals. Thromb Haemost 98:479-81
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
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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
Emens, Jonathan S; Lewy, Alfred J; Lefler, Bryan J et al. (2005) Relative coordination to unknown ""weak zeitgebers"" in free-running blind individuals. J Biol Rhythms 20:159-67
Lewy, Alfred J; Emens, Jonathan S; Bernert, Rebecca A et al. (2004) Eventual entrainment of the human circadian pacemaker by melatonin is independent of the circadian phase of treatment initiation: clinical implications. J Biol Rhythms 19:68-75
Lewy, Alfred J; Emens, Jonathan; Sack, Robert L et al. (2003) Zeitgeber hierarchy in humans: resetting the circadian phase positions of blind people using melatonin. Chronobiol Int 20:837-52
Lewy, Alfred J; Emens, Jonathan S; Sack, Robert L et al. (2002) Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int 19:649-58

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