Blendy Julie A
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Biol Psychiatry. 2006 Jun 15;59(12):1144-50. doi: 10.1016/j.biopsych.2005.11.003. Epub 2006 Feb 2.
Major depressive disorder is a severe clinical problem across the globe, with a lifetime risk of 10%-30% for women and 7%-15% for men. The World Health Organization ranks major depression at the top of the list in terms of disease burden, and this burden is expected to rise in the next decade as the prevalence of the disorder grows. Since the late 1950s, a wide range of antidepressant medications targeting the monoamine systems has been available to alleviate the symptoms of major depressive disorder. Although widely prescribed, such antidepressant medications are accompanied by a delay in effectiveness, as well as varied side effects. Therefore, further characterization of the biological mechanisms behind their function is crucial for the development of new and more effective treatments. One protein that could serve as a convergence point for multiple classes of antidepressant drugs is the transcription factor CREB (cyclic adenosine monophosphate response element binding protein). CREB is upregulated by chronic antidepressant treatment, and increasing CREB levels in rodent models results in antidepressant-like behaviors. Furthermore, postmortem studies indicate that CREB levels are increased in subjects taking antidepressants at the time of death. However, not all antidepressants increase CREB levels and/or activity, and reducing CREB levels in some brain regions also results in antidepressant-like behaviors. This review attempts to consolidate the information relevant to the structure and function of the CREB protein and describe how this relates to the mechanism of antidepressant drugs. Animal models in which CREB function is enhanced, by overexpression of the protein, or reduced, by expression of mutant forms of the protein or through gene deletion experiments, are summarized in terms of identifying a role for CREB in behavioral responses in depression tests that were originally designed to evaluate antidepressant efficacy. Human postmortem and genetic studies that implicate CREB in depression and antidepressant efficacy are also discussed.
重度抑郁症是一个全球性的严重临床问题，女性终生患病风险为10%-30%，男性为7%-15%。世界卫生组织将重度抑郁症列为疾病负担之首，随着该疾病患病率的上升，预计未来十年这一负担还会增加。自20世纪50年代末以来，已有多种针对单胺系统的抗抑郁药物可用于缓解重度抑郁症的症状。尽管这些抗抑郁药物被广泛使用，但它们起效延迟，且副作用多样。因此，进一步阐明其作用背后的生物学机制对于开发新的、更有效的治疗方法至关重要。一种可能成为多类抗抑郁药物作用汇聚点的蛋白质是转录因子CREB（环磷腺苷反应元件结合蛋白）。CREB在慢性抗抑郁治疗后上调，在啮齿动物模型中提高CREB水平会产生类似抗抑郁的行为。此外，死后研究表明，在死亡时服用抗抑郁药物的受试者中CREB水平会升高。然而，并非所有抗抑郁药物都会增加CREB水平和/或活性，在某些脑区降低CREB水平也会产生类似抗抑郁的行为。本综述试图整合与CREB蛋白结构和功能相关的信息，并描述其与抗抑郁药物作用机制的关系。通过蛋白质过表达增强CREB功能，或通过蛋白质突变形式的表达或基因缺失实验降低CREB功能建立的动物模型，根据在最初设计用于评估抗抑郁疗效的抑郁症测试中确定CREB在行为反应中的作用进行了总结。还讨论了涉及CREB与抑郁症及抗抑郁疗效关系的人类死后研究和遗传学研究。
