Melatonin is a hormone produced by the pineal gland only during nighttime darkness. It acts like a dark signal and therefore resets the body clock, especially if administered during the day. Assessed by the endogenous melatonin onset, if melatonin is given in the morning, it causes the endogenous circadian pacemaker (ECP) to phase delay (shift to a later time), as if the ECP were perceiving a later dawn. If administered in the afternoon or evening, it causes the ECP to phase advance (shift to an earlier time), as if the ECP were perceiving an earlier dusk. These responses are described by a phase response curve (PRC). Our first grant in this area was to determine the PRC in normal subjects. We have found that the shape of the melatonin PRC does not vary with age; that is, older people are likely to benefit from melatonin in the same way as do younger individuals. However, little is known about optimal doses, particularly in the elderly. As described above, the melatonin PRC provides the correct administration times for treating circadian phase disturbances, including those found in the elderly, particularly advanced sleep phase syndrome. The melatonin PRC is also the basis for understanding the function of endogenous melatonin in humans. Given that the melatonin PRC is about 12 hours out of phase with the light PRC, the function of endogenous melatonin appears to be augmentation of entrainment of the ECP by the light/dark cycle. The investigators now propose to determine the optimal doses for inducing phase shifts in elderly humans. Specifically, they will determine the dose-response curve over a broad range, 0.05-30.0 mg. They hypothesize that this curve is log linear at low doses, above which a plateau is reached. If so, melatonin can be recommended for the treatment of circadian phase disorders at low -- and therefore extremely safe -- doses. In some (repeat) trials, the investigators plan to assess the entire melatonin curve, as well as other markers for circadian phase. In the present application, they plan to study the dose-response curve in people between 65 and 90. In a grant recently submitted to the NIMH, they hope to study the dose-response curve in younger individuals. These basic science investigations should form the basis for future clinical efficacy and safety studies of melatonin. Since people in vast numbers are already treating themselves with melatonin, we regard the proposed investigations as critical and timely, indeed, urgently needed. Based on these studies, melatonin may prove to be a safe and efficacious treatment for circadian phase disorders. Specifically, subjects for this study will include 20 to 24 elderly adults. Ten to 12 subjects each will participate in either in advance (A) or delay (D) set of dose response experiments. Each subject will have three types of evaluations: a one-day baseline evaluation of circadian phase; seven evaluations with different doses of melatonin or placebo; and repeat studies with placebo and melatonin 10.0 mg to assess effects on 24-hour measures of other circadian markers. Each dose-response study will include a three-day laboratory protocol with a baseline assessment of DLMO, a single administration of the melatonin dose on Day 2, followed by repeat measure of DLMO on Day 3. The major dependent measure of circadian phase is Day 3 DLMO. The dose response effect on phase shifting will be statistically assessed with ANOVA with seven levels (placebo plus 6 doses of melatonin). Body temperature will be analyzed with a two-way ANOVA for seven treatment conditions and eleven repeated measures time points.
|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|
|Lewy, A J; Hasler, B P; Emens, J S et al. (2001) Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin. Neurosci Lett 313:158-60|
|Kendall, A R; Lewy, A J; Sack, R L (2001) Effects of aging on the intrinsic circadian period of totally blind humans. J Biol Rhythms 16:87-95|
|Lewy, A J; Bauer, V K; Hasler, B P et al. (2001) Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin. Brain Res 918:96-100|
|Sack, R L; Brandes, R W; Kendall, A R et al. (2000) Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 343:1070-7|
|Lewy, A J (1999) The dim light melatonin onset, melatonin assays and biological rhythm research in humans. Biol Signals Recept 8:79-83|
|Lewy, A J (1999) Melatonin as a marker and phase-resetter of circadian rhythms in humans. Adv Exp Med Biol 460:425-34|