Pharmacogenetics of the Antidepressant Response in Geriatric Major Depression

描述（由申请人提供）：一些患者对抗抑郁药反应良好，而另一些患者则不然。抗抑郁反应患者之间差异的生物学基础知之甚少。药物遗传学寻求可以预测药物治疗结果的DNA标记。我们的DNA和临床数据来自一项前瞻性、双盲、随机药物遗传学研究，研究对象为246名65岁及以上认知功能完整的重度抑郁症患者，他们接受米氮平或帕罗西汀治疗24周。该数据集对于药物遗传学特别有价值，因为帕罗西汀和米氮平的作用相反，并且因为老年患者非常容易发生药物不良事件。迄今为止的分析揭示了编码肾上腺素能和肾上腺素能受体和再摄取转运蛋白的基因中的重要预测因子。我们现在建议使用这种独特的DNA和临床资源来确定抗抑郁药疗效和副作用的其他新的遗传标记。我们将集中在两个相互作用的系统，神经营养因子和HPA轴。神经营养因子及其受体和相关的信号转导效应子在抗抑郁药的治疗作用中起重要作用。我们将瞄准BDNF系统，它受到抗抑郁药的强烈调节。HPA轴的失调可能是抑郁症发病的关键，使HPA轴功能正常化具有治疗价值。将检查参与皮质类固醇调节和作用的基因，皮质类固醇可能加重抑郁症，并被米氮平下调。将对24例受试者的发现样本中的选定基因进行编码区和调控区重测序。将选择通过重测序鉴定的SNP，用于对其潜在功能意义进行进一步的基于研究的生物信息学评估，并将在所有246份样本中进行基因分型。推断的单倍型以及未定相的双倍型将被用作预测因子，具有用于多重测试的适当对照。此外，将根据Perlegen数据库中经验证的SNP的连锁不平衡数据，采用间接候选基因方法。主要结局指标将是情绪变化（HDRS-17，CDS）、不良事件的严重程度、治疗中止的频率和认知变化。关键协变量（如依从性、给药和血浆药物水平）将纳入分析。还将检测基因组对照。这项工作将提供一个有针对性的药物遗传学分析，在老年患者的两个相互关联的生物系统出现在抗抑郁药治疗的重要性。重度抑郁症是一种在老年人中普遍存在的精神疾病。许多患者对抗抑郁药物治疗有抵抗力。一种识别可能从抗抑郁治疗中获益的患者的方法将减少患者的痛苦并节省医疗费用。

DESCRIPTION (provided by applicant): Some patients respond well to antidepressants, whereas others do not. The biological basis for differences among patients in antidepressant response is poorly understood. Pharmacogenetics seeks DNA markers that can predict medication treatment outcomes. We have DNA and clinical data from a prospective, double-blind, randomized pharmacogenetic study of 246 cognitively intact patients 65 years of age and older with major depression who were treated with either mirtazapine or paroxetine for 24 weeks. This dataset is particularly valuable for pharmacogenetics because of the contrasting actions of paroxetine and mirtazapine, and because older patients are highly vulnerable to medication adverse events. Analysis thus far has revealed significant predictors in genes encoding serotonergic and adrenergic receptors and reuptake transporters. We now propose to use this unique DNA and clinical resource to identify additional novel genetic markers for antidepressant efficacy and side effects. We will focus on two interacting systems, neurotrophins and the HPA axis. Neurotrophins, their receptors, and related signal transduction effectors are important in the therapeutic effects of antidepressants. We will target the BDNF system, which is strongly modulated by antidepressants. HPA axis dysregulation is likely to be key in the etiology of depression, and normalizing HPA axis function has therapeutic value. Genes involved in the regulation and actions of corticosteroids, which may exacerbate depression and are downregulated by mirtazapine, will be examined. Resequencing of coding and regulatory regions will be performed for selected genes in a discovery sample of 24 subjects. SNPs identified by resequencing will be chosen for further study based bioinformatic assessment of their potential functional significance, and genotyping will be performed in all 246 samples. Inferred haplotypes as well as unphased diplotypes will be used as predictors, with appropriate controls for multiple testing. In addition, an indirect candidate gene approach will be utilized based on linkage disequilibrium data from validated SNPs in the Perlegen database. The primary outcome measures will be change in mood (HDRS-17, CDS), the severity of adverse events, the frequency of treatment discontinuations, and cognitive changes. Key covariates such as compliance, dosing, and plasma drug levels will be included in the analyses. Genomic controls will also be tested. This work will provide a targeted pharmacogenetic analysis in geriatric patients of two interrelated biological systems emerging as important in antidepressant therapeutics. Major depression is a prevalent psychiatric disorder among the elderly. Many patients are resistant to antidepressant medication treatment. A method for identifying patients likely to benefit from antidepressant treatment would decrease patient distress and save health care dollars.