Neuro-Genetic Markers of SSRI Treatment Response in Social Anxiety Disorder

描述（由申请人提供）：项目摘要：通过这个指导以患者为导向的研究职业发展奖（K23），候选人的长期目标是获得对神经生物学和社交焦虑症（SAD）治疗的研究熟练。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5-羟色胺转运体基因（5-HTTLPR）的功能多态性是SSRI治疗反应的潜在生物标志物。拟议的研究培训和项目的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。为了实现这一目标，候选人将建立在他在情绪脑成像方面的强大背景之上，并获得临床精神药理学，药物遗传学和SAD领域专家的额外指导。此外，候选人将参加正式的课程，并开展与他的研究培训目标密切相关的研究项目。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/负面的面部刺激和治疗前的5- HTTLPR的DNA基因分型的80例患者与广义SAD和40个匹配的健康对照，以检查这些神经遗传标记和治疗反应之间的关系。通过实施本研究项目和培训计划，候选人将获得足够的知识和技能，成为社交焦虑症领域的独立翻译临床神经科学研究者，并推进我们对基因对神经生理学和焦虑症治疗的影响的认识。相关性：社交焦虑障碍是一种高度流行、致残和难以治疗的慢性精神疾病。这项研究的主要目标是确定治疗反应性的神经生物学标志物，以节省患者昂贵和冗长的药物试验，这些药物不太可能有效，并指导治疗走向具有更大成功概率的模式。

DESCRIPTION (provided by applicant): Project Summary: Through this Mentored Patient-Oriented Research Career Development Award (K23), the long-term objective of the candidate is to gain proficiency in research on 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 serotonin transporter gene (5-HTTLPR) are potential biomarkers of SSRI treatment response. The proposed research training and project focus on elucidating the neuro-genetic basis of pharmacologic treatment response in SAD through the application of brain functional magnetic resonance imaging (fMRI) and pharmacogenetics. To accomplish this goal, the candidate will build on his strong background in brain imaging of emotions and gain additional mentoring by experts in the fields of clinical psychopharmacology, pharmacogenetics, and SAD. Furthermore, the candidate will participate in formal coursework and carry out a research project closely aligned with his research training goals. 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 stimuli and pre-treatment DNA genotyping of the 5- HTTLPR in 80 patients with generalized SAD and 40 matched healthy controls in order to examine the relationship between these neuro-genetic markers and treatment response. By implementing this research project and training plan, the candidate will gain sufficient knowledge and skills to become an independent translational clinical neuroscience investigator in the field of social anxiety disorder, and advance our knowledge on the effect of genes on neurophysiology and treatment of anxiety disorders. Relevance: Social anxiety disorder is a highly prevalent, disabling, and difficult-to-treat chronic mental illness. The primary goal of this research is to identify neurobiological markers of treatment responsiveness in order to save patients costly and lengthy trials of medications that are unlikely to be effective and guide treatment towards modalities that have a greater probability of success.