MONOAMINE RECEPTOR SENSITIVITY AND ANTIDEPRESSANT DRUGS

当前提案的目标是开发方法并直接 评估长期服用抗抑郁药患者的受体敏感性 药物治疗。抗抑郁药物在许多生化和药物方面存在差异 生理参数，但在大鼠肾上腺素能和5-羟色胺能改变 长期治疗后的受体敏感性已被发现 大多数化合物。然而，目前还没有直接的临床证实 这些变化发生在患者身上。恒河猴的初步研究 将评估涉及确定相对敏感度的测试 血浆MHPG、生长激素和催乳素对肾上腺素和5-羟色胺能的影响 激动剂和拮抗剂药物及正确给药途径的确定 给药和剂量反应曲线。一旦那个敏感的挑战 试验表明，急性和慢性给药的效果分别为3 临床有效，但结构和生化不同 抗抑郁药物将在恒河猴身上进行研究。这些测试发现 无论是急性或慢性药物治疗都将被改变 用来控制受试者。抑郁症患者将用这些研究 同样研究的三种药物在慢性治疗前后的测试 在恒河猴身上。在患者中，受体测量的变化 敏感度将根据临床上直接的药物效应进行评估 改进，以及这两个维度的相互作用。这项研究是 旨在提供直接的临床证据来评估这一假设 生化上不同但临床上相同的共同机制 有效的抗抑郁药物治疗是提高患者的敏感性 肾上腺素能和5-羟色胺能受体。从这一点上获得的信息 研究将对更有效的开发具有重要意义 抗抑郁药物治疗。此外，我们还研究了植物的急性 碳酸锂治疗抑郁症的抗抑郁作用 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疗效的关系 色氨酸摄入量高低对高血压病疗效影响的研究 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.