Malberg Jessica E, Blendy Julie A
Neuroscience Discovery, Wyeth Research, Princeton, NJ 08543, USA.
Trends Pharmacol Sci. 2005 Dec;26(12):631-8. doi: 10.1016/j.tips.2005.10.005. Epub 2005 Oct 21.
After decades of effort, the field of depression research is far from understanding how antidepressant drugs mediate their clinical effects. The time lag of 2-6 weeks of therapy that is necessary to obtain antidepressant efficacy indicates a requirement for long-term regulation of molecules activated by drug treatment. The focus of antidepressant research has thus expanded from examining acute monoamine-mediated mechanisms to include long-term transcriptional regulators such as cAMP response element-binding protein (CREB) and trophic factors such as brain-derived nerve growth factor and insulin-like growth factor. In addition, the recent discovery of antidepressant-induced neurogenesis provides another avenue by which antidepressants might exert their effects. Current efforts are aimed at understanding how CREB and trophic factor signaling pathways are coupled to neurogenic effects and how alterations in behavioral, molecular and cellular endpoints are related to the alleviation of the symptoms of depression.
经过数十年的努力,抑郁症研究领域距离理解抗抑郁药物如何介导其临床效果仍有很大差距。获得抗抑郁疗效所需的2至6周治疗时间滞后表明需要对药物治疗激活的分子进行长期调节。因此,抗抑郁研究的重点已从研究急性单胺介导的机制扩展到包括长期转录调节因子,如环磷酸腺苷反应元件结合蛋白(CREB),以及营养因子,如脑源性神经营养因子和胰岛素样生长因子。此外,最近发现的抗抑郁药诱导的神经发生提供了抗抑郁药可能发挥作用的另一条途径。目前的研究致力于了解CREB和营养因子信号通路如何与神经发生效应相关联,以及行为、分子和细胞终点的改变如何与抑郁症症状的缓解相关。