VARIABILITY OF THE HUMAN MELATONIN PHASE RESPONSE CURVE

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We have recently discovered that appropriately-timed administration of a physiological dose of exogenous melatonin (M) can cause circadian phase shifts in sighted humans. In fact, our pilot data describe a phase response curve (PRC) that is about 12 hours out of phase with the human PRCs for light. The thirty time points on this curve come from nine individuals who average only three - four points per person. We now propose to test 12 time points per person to precisely delineate the shape of the human M PRC. We will do this in 15 individuals, in order to determine the variability in PRC shape. This study is essential before undertaking the next step in our on-going work , the examination and treatment of biological mechanisms of winter depression and other chronobiologic disorders, including jet lag, maladaptation to shift work and certain types of sleep disorders. Data obtained from further study of the M PRC will also eventually make possible the use of M administration in order to test the leading -- but controversial -- phase-shift hypothesis for winter depression. According to this hypothesis, most winter depressives become depressed in the winter because of a circadian phase delay cued to the later dawn at this time of the year. Also according to this hypothesis, morning light should be most antidepressant because it provides a corrective phase advance. In many -- but not all -- studies, morning light has been shown to be superior to light exposure scheduled at other times. Some critics have argued, however, that the superior antidepressant effect of morning light may be unrelated to its phase-advancing effect. The present proposal will enable us to subject the phase-shift hypothesis to a critical test: if we cannot show that melatonin administered at a time to cause a phase advance is more antidepressant than melatonin administered at a time to cause a phase delay, then the phase-shift hypothesis fails. This future study will be particularly important, because it will provide a very good control for the placebo response that has plagued light treatment studies from the outset. Even if melatonin proves unsuccessful in the treatment of winter depression, we need to delineate the M PRC which will be extremely important in developing melatonin as a treatment for other circadian phase disorders. Treatment with M should have the distinct advantage of avoiding problems commonly associated with currently used medications. Sedative/hypnotics have many serious side effects, including confusion (in the geriatric population), potentiation of alcohol intoxication, tolerance, habituation, addiction and memory impairment; antidepressants can have anticholinergic and cardiotoxic side effects, among many other problems. In contrast, the only known side effect of low doses of M is mild drowsiness and this is rarely seen at the very low (0.5) mg dose that we use. Finally, towards our goal of developing techniques for assessing and treating circadian phase disorders, we propose to continue validating M as a circadian phase marker and to continue establishing a M RlA and a salivary M assay, so that M will become more useful in the clinical setting.