Seasonal behavior in mammals is regulated by changes in the duration of nocturnal melatonin secretion. The latter serve as a chemical signal of change in the length of the night, which mammals use as an external indicator of the change of season. The timing of melatonin secretion is programmed by circadian pacemaker cells in the suprachiasmatic nucleus of the hypothalamus, which receives input from the retina and acts on the pineal via a multi-synaptic neural pathway. We have tested the hypothesis that lengthening of duration of nocturnal melatonin secretion in winter causes symptoms of winter depression in patients with seasonal affective disorder. Our recent finding that the duration of melatonin secretion becomes longer in winter than summer in patients with seasonal affective disorder, but remains constant in healthy volunteers, raises the possibility that the same photo-neuroendocrine mechanism used by non human mammals underlies the pathogenesis of winter depression in humans. To test this hypothesis, a delayed-release formulation of the beta-blocker,propranolol, that meets study-requirements, has been successfully developed in vitro. Propranolol will be used to shorten the duration of nocturnal melatonin secretion in patients with winter depression, thereby converting a chemical signal of winter into a chemical signal of summer. This alteration is predicted to switch patients from their winter state of depression to a summer state of remission. After developing an appropriate delayed release formulation of propranolol in preliminary studies with healthy volunteers, the drug will be administered to patients with winter depression on a nightly basis for four weeks in a double-blind, placebo-controlled clinical trial. The effect of treatments on melatonin secretion and on clinical state will be assessed with repeated measures of 24-hour plasma melatonin profiles and depression ratings.
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