NEURO-GENETIC MARKERS OF SOCIAL ANXIETY DISORDER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。拟议研究的目标是研究社交焦虑症(SAD)的神经生物学和治疗。尽管有足够的剂量和持续时间，大约一半的SAD患者对一线选择性5-羟色胺再摄取抑制剂(SSRI)治疗无效，但对其治疗效果的神经生理学机制知之甚少。越来越多的证据表明，杏仁核对社会威胁的反应性和血清素转运蛋白基因(5-HTTLPR)的功能多态性是SSRI治疗反应的潜在生物标志物。本研究旨在通过脑功能磁共振成像(FMRI)和药物遗传学的应用，阐明SAD药物治疗反应的神经遗传学基础。在舍曲林开放标签临床试验的背景下，本研究建议对80名全身性SAD患者和80名匹配的健康对照组进行治疗前和治疗后杏仁核对恶劣/负面面孔/社会刺激的功能磁共振成像和5-HTTLPR的DNA基因分型，以检查这些神经遗传标记与治疗反应之间的关系。关于5-HTTLPR，我们请求CRC支持的假设是：假设1：与S/S基因携带者相比，长等位基因纯合子(L/L)的SAD患者对舍曲林的抗焦虑反应更强。假设2：5-HTTLPR的基因变异将预测治疗反应，因此与L/L基因相比，S/S基因将与治疗无反应的可能性更高相关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the proposed research is to study the neurobiology and treatment of social anxiety disorder (SAD). Although approximately half of patients with SAD fail to respond to first-line selective serotonin reuptake inhibitor (SSRI) treatment despite adequate dose and duration, little is known about the neurophysiological mechanisms underlying treatment efficacy. Converging evidence suggests that amygdala reactivity to social threat and a functional polymorphism on the sertonin transporter gene (5-HTTLPR) are potential biomarkers of SSRI treatment response. The proposed research focuses on elucidating the neuro-genetic basis of pharmacologic treatment response in SAD through the application of brain functional magnetic resonance imaging (fMRI) and pharmacogenetics. In the context of an open-label clinical trial of sertraline, this study proposes to perform pre- and post-treatment fMRI of amygdala reactivity to harsh/negative face/social stimuli and pre-treatment DNA genotyping of the 5-HTTLPR in 80 patients with generalized SAD and 80 matched healthy controls in order to examine the relationship between these neuro-genetic markers and treatment response. Our hypotheses regarding the 5-HTTLPR, for which we request CRC support are: Hypothesis 1: SAD patients with the homozygous long allele genotype (L/L) will have greater anti-anxiety response to sertraline, compared to those with the S/S genotype. Hypothesis 2: Genotypic variation of the 5-HTTLPR will predict response to treatment, such that the S/S genotype will be associated with a higher likelihood of non-response to treatment, relative to the L/L genotype.