NEURO-GENETIC MARKERS OF SOCIAL ANXIETY DISORDER

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。本研究旨在探讨社交焦虑障碍（SAD）的神经生物学和治疗。尽管约有一半SAD患者对一线选择性5-羟色胺再摄取抑制剂（SSRI）治疗无效，尽管剂量和持续时间足够，但对治疗疗效的神经生理机制知之甚少。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。拟议的研究重点是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。在舍曲林的开放标签临床试验的背景下，本研究建议进行治疗前和治疗后的杏仁核反应性的功能磁共振成像苛刻/负面的脸/社会刺激和治疗前的5-HTTLPR的DNA基因分型的80例患者与广义SAD和80名匹配的健康对照，以检查这些神经遗传标记和治疗反应之间的关系。 我们关于5-HTTLPR的假设，我们要求CRC支持：假设1：与S/S基因型相比，具有纯合长等位基因型（L/L）的SAD患者对舍曲林的抗焦虑反应更强。假设二：5-HTTLPR的基因型变异将预测对治疗的反应，因此S/S基因型与相对于L/L基因型更高的对治疗无反应的可能性相关。

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.