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

项目概述：通过本次指导患者导向研究职业发展奖（K23），候选人的长期目标是熟练掌握神经生物学和社交焦虑障碍（SAD）治疗的研究。尽管大约一半的SAD患者对一线选择性血清素再摄取抑制剂（SSRI）治疗没有反应，尽管有足够的剂量和持续时间，但对治疗效果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。拟开展的研究培训和项目重点是通过应用脑功能磁共振成像（fMRI）和药物遗传学来阐明SAD药物治疗反应的神经遗传学基础。为了实现这一目标，候选人将利用他在情绪脑成像方面的强大背景，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。在一项开放标签的头孢曲林临床试验的背景下，本研究拟对80名广发性SAD患者和40名匹配的健康对照者进行治疗前和治疗后的杏仁核反应性fMRI和治疗前5- HTTLPR的DNA基因分型，以研究这些神经遗传标记物与治疗反应之间的关系。通过本研究项目和培训计划的实施，候选人将获得足够的知识和技能，成为社交焦虑障碍领域独立的临床转化神经科学研究者，并进一步了解基因在神经生理学和焦虑障碍治疗方面的作用。相关性：社交焦虑症是一种非常普遍、致残且难以治疗的慢性精神疾病。本研究的主要目标是确定治疗反应性的神经生物学标记，以便为患者节省昂贵和漫长的药物试验，这些药物不太可能有效，并指导治疗朝着更有可能成功的模式发展。

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.