MONOAMINE RECEPTOR SENSITIVITY AND ANTIDEPRESSANT DRUGS

本提案的目标是制定方法， 评估接受长期抗抑郁药治疗的患者的受体敏感性 药物治疗 抗抑郁药在许多生化和 生理参数，但在大鼠中，肾上腺素能和肾上腺素能 长期治疗后的受体敏感性已被发现， 大多数化合物。 然而，没有直接的临床证实， 这些变化发生在患者身上。 在恒河猴中的初步研究 将评估涉及确定以下相对灵敏度的试验： 血浆MHPG、生长激素和催乳素对肾上腺素能和肾上腺素能 激动剂和拮抗剂药物和确定适当的途径 给药和剂量反应曲线。 一旦这个敏感的挑战 测试开发，急性和慢性给药的效果3 临床有效，但结构和生物化学不同 将在恒河猴中研究抗抑郁药物。 这些测试发现 无论是急性或慢性药物治疗改变， 给控制对象。 抑郁症患者将与这些研究 在使用相同的三种药物进行慢性治疗之前和之后的测试 在恒河猴身上。 在患者中，受体测量的变化 将相对于直接药物作用、临床 改善，以及这两个方面的相互作用。 本研究 旨在提供直接的临床证据，以评估以下假设： 一种生化上不同但临床上相同的 有效的抗抑郁药物治疗是增加敏感性， 肾上腺素能和肾上腺素能受体。 从这获得的信息 研究将是重要的发展更有效的 抗抑郁药物治疗。 此外，我们还研究了植物的急性 碳酸锂对抑郁症患者的抗抑郁作用 对长期抗抑郁药物治疗无反应，并评估 5-羟色胺代谢与抗抑郁药物作用的关系 研究高和低色氨酸摄入量对 抗抑郁药物治疗。

The objective of the current proposal is to develop methods and directly assess receptor sensitivity in patients receiving long-term antidepressant drug treatment. Antidepressant drugs differ on many biochemical and physiologic parameters, but in rats changes in adrenergic and serotonergic receptor sensitivity following long-term treatment have been found with most compounds. However, there is no direct clinical confirmation that these changes are occurring in patients. Initial studies in rhesus monkeys will evaluate tests involving determination of the relative sensitivity of plasma MHPG, growth hormone and prolactin to adrenergic and serotonergic agonist and antagonist drugs and determination of proper routes of administration and dose response curves. Once that sensitive challenge tests are developed, the effect of acute and chronic administration of 3 clinically effective but structurally and biochemically dissimilar antidepressant drugs will be studied in rhesus monkeys. Those tests found to be altered with either acute or chronic drug treatments will then be given to control subjects. Depressed patients will be studied with these tests before and after chronic treatment with the same three drugs studied in rhesus monkeys. In patients, the changes in the measures of receptor sensitivity will be evaluated relative to direct drug effects, clinical improvement, and the interaction of these two dimensions. This study is designed to provide direct clinical evidence evaluating the hypothesis that a common mechanism of biochemically different but equally clinically effective antidepressant drug treatments is to increase the sensitivity of adrenergic and serotonergic receptors. The information obtained from this study will be important for the development of more efficacious antidepressant drug treatments. In addition, we plant to study the acute antidepressant effects of lithium carbonate treatment in depressed patients not responding to long-term antidepressant drug treatment and to assess the relationship of serotonin metabolism to antidepressant drug effects by studying the effects of high and low tryptophan intake on the efficacy of the antidepressant drug treatment.