VARIABILITY OF THE HUMAN MELATONIN PHASE-RESPONSE CURVE

我们最近发现，适当的时间管理 生理剂量的外源性褪黑激素（M）可引起昼夜节律时相 有视力的人的变化 事实上，我们的试验数据描述了一个阶段 响应曲线（PRC），其与人类的相位相差约12小时 PRCs代表光。 这条曲线上的三十个时间点来自九个 平均每人只有3 - 4分的人。 我们现在 建议测试每人12个时间点，以精确描述 人类M PRC的形状。 我们将在15个人中进行， 以确定PRC形状的可变性。 这项研究至关重要 在进行下一步工作前， 和治疗冬季抑郁症的生物机制和其他 时间生物学紊乱，包括时差反应、轮班工作适应不良 和某些类型的睡眠障碍。 从对M PRC的进一步研究中获得的数据最终也将使 可能使用M管理，以测试领先-但 有争议的--冬季抑郁症的相移假说。 根据 根据这一假设，大多数冬季抑郁症患者在 由于昼夜节律的相位延迟， 一年中的这个时候。 同样根据这个假设， 应该是最抗抑郁的，因为它提供了一个纠正阶段 提前 在许多--但不是全部--研究中， 上级其他时间安排的曝光。 一些批评人士 然而，我认为早晨的上级抗抑郁作用 光可能与其相位超前效应无关。 本 该提案将使我们能够使相移假设服从一个 关键测试：如果我们不能证明一次服用褪黑激素 比褪黑激素更能抗抑郁 一次施用以引起相位延迟，然后相移 假设失败。 这项未来的研究将特别重要， 因为它可以很好地控制安慰剂的反应， 从一开始就困扰着光治疗研究。 即使褪黑激素在治疗冬天方面证明是不成功的， 抑郁症，我们需要划定M PRC，这将是非常 在开发褪黑激素作为其他昼夜节律的治疗中很重要 相位紊乱 用M治疗应该有明显的优势， 避免了与目前使用的药物相关的问题。 镇静剂/催眠药有许多严重的副作用，包括混乱 (in老年人群），酒精中毒增强， 耐受性、习惯性、成瘾和记忆障碍;抗抑郁药 具有抗胆碱能和心脏毒性副作用， 问题 相反，低剂量M的唯一已知副作用是 轻度嗜睡，这在极低（0.5）mg剂量下很少见 我们使用。 最后，为了实现我们的目标， 评估和治疗昼夜节律紊乱，我们建议继续 验证M作为昼夜节律相位标记，并继续建立 MRIA和唾液M测定，使得M将在MRIA中变得更有用。 临床设置。

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.