This is a revised competitive renewal of NIMH grant MH40161. Our original renewal was disapproved, mainly because we lacked a fully- functional standard temporal isolation unit (TIU) and sufficient input from a statistician/methodologist. By deleting studies that might optimally require a fully-functional standard TIU and by more extensive consultations with Dr. McFarland, we have hopefully satisfied all of the concerns of the study section, which encouraged us to re-apply. Measurement of plasma melatonin levels (by our extremely sensitive and accurate GCMS assay) In the evening under dim light to determine the onset of nighttime melatonin production (the dim light melatonin onset, or DLMO) is an excellent marker for its circadian phase position and accurately reflects the phase shifting effects of Light. The goals of the present proposal are to assess the roles of photic and nonphotic time cues on shifting the DLMO in normal subjects and to compare phase shifting effects of bright light in normal subjects to winter depressive patients. In addition, normal subjects will be studied on repeated occasions, before and after one week of standardized conditions, in order to evaluate inter- and intra-subJect variability, as well as time of year effects. We propose to test at least four hypotheses: 1) Intra-individual variability in the DLMO can be decreased by a week of standardized light-dark conditions; 2) shifts in light but not in sleep or meal times shift the DLMO; 3) winter depressive patients preferentially respond to the antidepressant effects of morning light compared to evening light; and 4) winter depressive patients have DLMOs that are phase delayed at baseline and have greater (more positive) A- D differentials (the A-D differential is the advance response to morning light minus the delay response to evening light) compared to normal controls. We propose to do three experiments: 1) melatonin production and its responses to light in normal subjects; 2) effect of shifting sleep and light on the DLMO in normal subjects; and 3) treatment of winter depressive patients with appropriately timed bright light. These investigations should help us to identify timing disturbances in the DLMO and abnormal responses to light in winter depressive patients and to decide how to optimally treat these patients with bright light. These studies will also lead to description of some general principles that may be useful in the evaluation and treatment of other putative circadian rhythm abnormalities.
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