Biomarkers of fast acting therapies in major depression

描述（由申请人提供）：重度抑郁症（MDD）是一种严重的复发性疾病，是导致残疾的主要原因。虽然有治疗方法，但通常需要几周到几个月的时间才能发挥作用，有些人只有部分反应或根本没有反应。因此，为了在临床环境中指导更有效、更快速和个性化的治疗策略，有必要确定预测快速治疗反应的生物标志物。为了推进这一领域的发现，该K24提案包括指导，职业发展和研究目标，这些目标建立在我们nih资助的R01 （MH092301）的目标之上，该R01专注于使用先进的神经成像方法来检测MDD治疗相关的大脑可塑性的不同方面。电惊厥治疗（ECT）是目前治疗重度重度抑郁症最有效的急性治疗方法，它直接作用于中枢神经系统，被用作R01治疗方式。由于生物标志物的组合可以更好地表征治疗反应的机制和预测因素，作为我们R01的最新补充，我们也在检查外周淋巴细胞基因表达，以更全面地解决ECT快速治疗反应的生物学基础。NMDA受体拮抗剂氯胺酮在数小时内产生临床反应，最近成为一种新的治疗抑郁症的药物，其反应率仅与ECT相当。为了更好地了解速效疗法背后的生物学过程，并确认涉及谷氨酸能途径的基础科学发现，候选人的K24研究计划是确定氯胺酮治疗反应的成像和基因表达标记。为了针对重叠的快速反应机制，我们将利用R01项目的数据，比较氯胺酮和ECT反应的候选标记物。应用于氯胺酮患者亚样本的新型成像方法将为探索定位于背侧和/或腹侧额边缘网络的治疗相关神经可塑性提供进一步的机会。为了使候选人能够更好地设计和领导临床研究，结合跨学科的方法来调查和比较快速抗抑郁作用的机制，候选人的职业发展计划是在基因组学领域和抗抑郁药物治疗的药理学基础上发展知识和/或新技能，以及磨练现有的神经影像学技能。根据候选人在成像和临床神经科学方面的专业知识，指导计划将为学员提供临床成像应用方面的理论和实践培训，指导学员针对重度抑郁症和潜在的其他精神疾病的治疗机制进行纵向调查，以及成功将成像方法纳入面向患者的研究（POR）计划的技能，这将导致未来的独立资助。候选人的研究和职业发展目标与我们资助的R01是互补和独特的，将为培训提供丰富的基础，同时在关键领域进一步推进POR。

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a serious and recurrent illness and a leading cause of disability. Though treatments are available, these often take weeks to months to exert their effect, and some people only respond partially or do not respond at all. To guide more effective, faster acting and personalized treatment strategies in the clinical setting, there is thus an important need to identify biological markers predictive of rapid therapeutic response. To advance discovery in this area, this K24 proposal includes mentorship, career development and research aims that build onto the goals of our NIH-funded R01 (MH092301), which is focused on using advanced neuroimaging methods to detect different aspects of treatment-related brain plasticity in MDD. Electroconvulsive therapy (ECT), which is currently the most effective acute treatment for severe MDD and which involves direct action on the central nervous system, is used as the R01 treatment modality. Since a combination of biological markers may better characterize the mechanisms and predictors of treatment response, as a recent adjunct to our R01, we are also examining peripheral lymphocyte gene expression to more comprehensively address the biological bases of rapid therapeutic response to ECT. Producing a clinical response within hours, the NMDA receptor antagonist, ketamine, has recently emerged as a novel pharmacologic agent for depression treatment with a response rate comparable only to ECT. To obtain a greater understanding of the biological processes underlying fast-acting therapies and to confirm basic science findings implicating glutamatergic pathways, the candidate's K24 Research Plan is to identify imaging and gene expression markers of therapeutic response to ketamine treatment. To target overlapping rapid response mechanisms, by leveraging data from our R01 project, candidate markers of response to ketamine and ECT will be compared. Novel imaging methods applied in a subsample of ketamine patients will provide further opportunity to explore treatment-related neuroplasticity localized to dorsal and/or ventral fronto-limbic networks. To allow the candidate to better design and lead clinical studies incorporating interdisciplinary approaches to investigate and compare mechanisms of rapid antidepressant action, the candidate's Career Development Plan is to develop knowledge and/or new skills in the field of genomics and in the pharmacological basis of antidepressant treatments for MDD as well as also hone existing skills in neuroimaging. In line with the candidate's area of expertise in imaging and clinical neuroscience, the Mentoring Plan will provide theoretical and hands-on training to mentees in clinical imaging applications directed towards the longitudinal investigation of treatment mechanisms in MDD and potentially in other psychiatric conditions, and the skills to successfully incorporate imaging methods into patient-oriented research (POR) programs that will lead to future independent funding. The candidate's research and career development aims, which are both complementary and unique to our funded R01, will provide a rich basis for training while furthering POR in a critical area.