CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS

抗抑郁药的临床药理学

• 批准号: 3944693
• 负责人: W Z POTTER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3944693
• 关键词: MAO inhibitors; adult human (21+); antidepressants; biological models; blood chemistry; combination chemotherapy; desipramine; dopamine; dosage; drug metabolism; electroconvulsive therapy; high performance liquid chromatography; human subject; human therapy evaluation; lithium; mental disorder chemotherapy; neuroendocrine system; neurotransmitter metabolism; norepinephrine; phenylethylamines; psychobiology; psychopharmacology; serotonin; urinalysis

The therapeutic mechanism of action of antidepressant medications in humans remains unknown. Comparison of effects on specific neurotransmitters and their metabolites in cerebrospinal fluid (CSF), plasma and urine in the same patients continues. Findings of special interest during the last year include the following: 1. Unique effects of electroconvulsive therapy (ECT) in humans continue to emerge: unlike all antidepressant drugs studied it does not reduce whole body norepinephrine (NE) turnover as measured in urine or NE and serotonin turnover as measured by MHPG and 5HIAA, respectively, in CSF. In fact ECT increases both 5HIAA and the dopamine (DA) metabolite, HVA in CSF. 2. Based on these clinical findings we carried out experiments on ECT in rats and found a selective increase in the D1 subtype of DA receptor in substantial nigra and caudate. Since ECT has been reported to have therapeutic effects in mania, psychosis and Parkinsonism as well as depression these DA effects likely have clinical and mechanistic implications. 3. In keeping with the theme that more than one neurotransmitter change is involved in antidepressant action, we have found that drugs with specific classes of initial biochemical effects have unique in vivo profiles of effects in humans only when changes of MHPG, 5HIAA and HVA are simultaneously taken into account. We have employed a 3-dimensional graph to obtain clear discrimination between five classes of drugs using these amine metabolites. 4. Alprazolam, a potent anti-anxiety agent with possible antidepressant properties, produces unusually robust decreases of ACTH and cortisol following intravenous administration. This finding may provide for a new test for the responsivity of the HPA axis; i.e. is it more difficult to suppress in certain psychiatric illnesses?

抗抑郁药的治疗机制 人类的药物治疗仍然未知。 效果对比 特定神经递质及其代谢物 同一患者的脑脊液 (CSF)、血浆和尿液 继续。 去年特别令人感兴趣的发现 包括以下内容： 1. 电休克治疗（ECT）对人体的独特作用 不断涌现：与研究过的所有抗抑郁药物不同 不会减少全身去甲肾上腺素 (NE) 的周转 通过尿液或 NE 测量以及血清素周转率测量 CSF 中分别有 MHPG 和 5HIAA。 事实上 ECT 会增加 脑脊液中的 5HIAA 和多巴胺 (DA) 代谢物 HVA。 2. 根据这些临床发现，我们进行了实验 对大鼠进行 ECT，发现 D1 亚型选择性增加 DA 受体位于黑质和尾状核。 自 ECT 以来 据报道对躁狂症、精神病和 这些 DA 效应可能会导致帕金森症和抑郁症 临床和机械影响。 3. 符合主题，不止一个 神经递质的变化与抗抑郁作用有关，我们 已经发现具有特定类别初始生化作用的药物 效果仅对人类具有独特的体内效果 同时进行 MHPG、5HIAA 和 HVA 变化时 考虑到。 我们使用 3 维图来获得 使用这些药物的五类药物之间有明确的区别 胺代谢物。 4. 阿普唑仑，一种有效的抗焦虑药，可能具有 抗抑郁特性，产生异常强劲的下降 静脉注射后 ACTH 和皮质醇。 这 这一发现可能为反应性提供新的测试 HPA轴；即在某些方面是否更难抑制 精神疾病？