Antidepressent Response and Gene Expression

抑郁症估计每年花费650亿美元，而任何给定的抗抑郁治疗（ADT）仅在大约一半的病例中有效。尽管ADT明显需要改进，但在了解反应机制方面只取得了一些进展。最近的证据表明，抗抑郁反应（ADR）可能依赖于5-羟色胺转运体（SERT）基因序列中的多态性启动子区域。这种多态性（5-HTTLPR）对几种细胞因子和激酶信号的敏感性不同。 试点基因芯片数据现在已经显示，这些相同的细胞因子和激酶信号中的一些在慢性抗抑郁药治疗（ADT）的外周中发生变化。该开发项目将使最初的临床基础设施能够开发必要的实验室和临床程序，以测试研究外周基因表达作为抗抑郁治疗（ADT）功能的可行性和应用。 该实验将使用Affyphase HG-U 133 A基因芯片微阵列检测25名抑郁症患者在用s-西酞普兰治疗8周之前和之后以及10名抑郁症患者在用安慰剂治疗8周之前和之后的淋巴细胞中的基因表达模式。这些受试者的RNA将以分开的样本采集，并以分开的两份样本分析ADT与安慰剂的效应。我们预计，调节SERT螯合的基因，在5 HTTLPR具有差异作用的转录因子，以及一组共调节基因，包括具有5 HTTLPR 44碱基对多态性的共有序列的基因，可能与ADT一起表达。将对表达SERT的淋巴细胞进行SERT转运动力学表征，这与ADT不同。这将评估该方法在未来资助提案中的实用性，以分析这些患者的基因表达，并最终研究100名抑郁症患者的ADR表型和100名年龄，性别和种族匹配的对照。

DESCRIPTION (provided by applicant): Depression is estimated to cost 65 billion dollars yearly, whereas any given antidepressant treatment (ADT) is only effective in approximately half of all cases. Despite the obvious need for improvement of ADT, only some progress has been made in understanding the mechanisms of response. Recent evidence has revealed that antidepressant response (ADR) may be dependent upon a polymorphic promoter region in the serotonin transporter (SERT) gene sequence. This polymorphism (5-HTTLPR) is differentially sensitive to several cytokine and kinase signals. Pilot gene chip data has now shown that some of these same cytokine and kinase signals change in the periphery with chronic antidepressant treatment (ADT). This developmental project will enable the initial clinical infrastructure to develop the necessary laboratory and clinical procedures to test the feasibility and application of studying gene expression in the periphery as a function of antidepressant treatment (ADT). The experiment will examine gene expression patterns in lymphocytes using Affymetrix HG-U 133A GeneChip microarrays in 25 depressed patients before and after 8 weeks treatment with s-citalopram, and 10 depressed patients before and after 8 weeks treatment with placebo. RNA from these subjects will be collected in split sample and analyzed for ADT vs. placebo effects in split duplicate. We anticipate that genes that regulate SERT sequestration, transcription factors with differential action at the 5HTTLPR, and sets of co-regulated genes, including those with consensus sequences to the 5HTTLPR 44 base pair polymorphism may be expressed with ADT. Lymphocytes, which express SERT, will be characterized for SERT transport kinetics, which differ with ADT. This will assess the utility of the approach for a future funding proposal to analyze gene expression in those patients, and ultimately study 100 depressed patients phenotyped for ADR and 100 age, sex, and race matched controls.