Pharmacogenetics of the Antidepressant Response in Geriatric Major Depression

描述(申请人提供)：一些患者对抗抑郁药物反应良好，而另一些患者反应不佳。抗抑郁药反应不同的患者之间的生物学基础尚不清楚。药物遗传学寻找可以预测药物治疗结果的DNA标记物。我们有一项前瞻性、双盲、随机药物遗传学研究的DNA和临床数据，研究对象是246名认知正常的65岁及以上重度抑郁症患者，他们接受了米氮平或帕罗西汀24周的治疗。这一数据集对药物遗传学特别有价值，因为帕罗西汀和米氮平的作用截然不同，而且老年患者非常容易受到药物不良事件的影响。到目前为止，分析已经揭示了编码5-羟色胺能和肾上腺素能受体以及再摄取转运体的基因的重要预测因素。我们现在建议使用这一独特的DNA和临床资源来识别其他新的抗抑郁疗效和副作用的遗传标记。我们将关注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分子在抗抑郁药物的治疗效果中起着重要作用。我们将以BDNF系统为目标，该系统受到抗抑郁药物的强烈调节。HPA轴功能失调可能是抑郁症发病的关键，HPA轴功能正常化具有治疗价值。涉及皮质类固醇调节和作用的基因将被研究，皮质类固醇可能加剧抑郁，并被米氮平下调。在24名受试者的发现样本中，将对选定的基因进行编码和调控区域的重新测序。通过重新测序确定的SNPs将被选择用于基于生物信息学的进一步研究，以评估其潜在的功能意义，并将在所有246个样本中进行基因分型。推断的单倍型和非相双倍型将被用作预测因子，并对多项测试进行适当的对照。此外，还将根据Perlegen数据库中经过验证的SNPs的连锁不平衡数据，采用间接候选基因方法。主要的结果测量将是情绪的变化(HDRS-17，CDS)、不良事件的严重性、停止治疗的频率和认知变化。关键的协变量，如依从性、剂量和血浆药物水平将包括在分析中。基因组对照也将接受测试。这项工作将在老年患者中对两个相互关联的生物系统进行有针对性的药物遗传学分析，这些系统在抗抑郁治疗中发挥着重要作用。重度抑郁症是老年人普遍存在的一种精神障碍。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受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.