权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Depression Response to Fast-Acting Treatments: Inflammation and Reward Mechanisms

抑郁症对速效治疗的反应：炎症和奖励机制

基本信息

批准号：
10237908
负责人：
Jennifer Kruse
金额：
$ 19.76万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237908
关键词：
Address Anhedonia Animals Antidepressive Agents Behavioral Biologic Characteristic Biological Characteristics Clinical Data Dimensions Disease Electroconvulsive Therapy Functional disorder Funding Goals Individual Inflammation Inflammatory Interleukin-6 Intervention Intervention Studies Ketamine Link Literature Mediating Mental Depression Modality Motivation Outcome Pathway interactions Patient Self-Report Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Process Production Property Psychoneuroimmunology Reporting Research Research Personnel Resistance Rewards System Testing Therapeutic Time Training Treatment outcome base behavioral construct career clinical phenotype common symptom connectome depressed patient depressive symptoms design effective therapy improved indexing parent grant personalized medicine predicting response profiles in patients programs public health relevance response transcription factor treatment response treatment strategy treatment-resistant depression

项目摘要

PROJECT SUMMARY/ABSTRACT High inflammation is a biological characteristic associated with poorer response to antidepressant medication. Anhedonia, representing a facet of reward system dysfunction, is a common symptom of depression, and also predicts poor therapeutic response. Recent literature suggests that these variables (one biological, the other behavioral) are linked. However, no research has simultaneously addressed whether both of these dimensional characteristics—higher inflammation and greater reward deficits—impact depression treatment outcome, with consideration of levels at baseline as well as dynamic, longitudinal changes following treatment. Electroconvulsive therapy (ECT) and ketamine both elicit robust and rapid antidepressant response in patients with severe and treatment resistant depression. Thus, these treatment modalities are ideal for testing dynamic links between inflammation, behavioral constructs of reward, and treatment outcomes within a relatively short time frame. Furthermore, contrary to inflammation predicting poor outcome to antidepressant pharmacotherapy, our preliminary data show that higher baseline inflammation (as indexed by interleukin [IL]-6) predicts better treatment response to ECT (n=29, p=0.01). Moreover, ketamine has also been theorized to be more effective for depressed patients with high inflammation, and some initial clinical results support this hypothesis. However, data are sparse, inflammatory assessments are limited, and at least one ketamine study has failed to replicate earlier results. Notably, reward deficits have not been formally evaluated as a predictor of response to ECT nor ketamine. We have the unique opportunity to leverage a large funded U01 study, “Perturbation of the treatment resistant depression connectome by fast-acting therapies” (PI Narr, U01 MH110008, 09/16-05/20) to investigate relationships between inflammation, reward processes, and treatment outcome, within and across ECT and ketamine. Neither inflammation nor a comprehensive assessment of reward processes are examined in the parent grant. The goals of this proposal are thus unique and do not overlap with those of the U01. Here, we propose to comprehensively capture a vertically integrated assessment of inflammation including systemic levels, upstream cellular production, and transcription factor activation, and to evaluate both reward motivation and reward responsiveness via behavioral tasks and self-report. Our central hypothesis is that inflammation will link with deficits in reward, and will impact treatment outcome. Determination of differences in treatment response based upon linked clinical phenotypes and inflammatory profiles would be ground-breaking, informing more effective personalized treatment strategies for depressed patients with elevated inflammation. This K23 integrated training and research program is designed to prepare the candidate to become a clinical translational depression researcher, with expertise in psychoneuroimmunology, reward processes, and the study of interventions at this interface, to improve personalized treatment strategies for this highly prevalent disorder.

项目摘要/摘要高度炎症是一种生物学特征，与抗抑郁药物反应较差有关。快感缺乏是奖赏系统功能障碍的一个方面，是抑郁症的常见症状，也是预示着治疗反应不佳。最近的文献表明，这些变量(一个是生物学的，另一个是行为)是相关联的。然而，还没有研究同时解决这两个维度特征-更高的炎症和更大的奖励赤字-影响抑郁症的治疗结果，考虑基线水平以及治疗后动态的纵向变化。电休克治疗(ECT)和氯胺酮均可引起患者强烈而快速的抗抑郁反应患有严重的难治性抑郁症。因此，这些治疗模式是测试动态的理想选择在相对较短的时间内炎症、奖励的行为结构和治疗结果之间的联系时间框架。此外，与炎症预示着抗抑郁药物治疗效果不佳相反，我们的初步数据显示，更高的基线炎症(以白细胞介素IL-6为指标)预示着更好的结果治疗反应(n=29，p=0.01)。此外，氯胺酮也被理论上认为更有效对于高度炎症的抑郁症患者，一些初步的临床结果支持这一假说。然而，数据稀少，炎症评估有限，至少有一项氯胺酮研究未能复制更早的结果。值得注意的是，奖励不足还没有被正式评估为ECT反应的预测因子，也没有氯胺酮。我们有一个独一无二的机会来利用一项由U01资助的大型研究《治疗的微扰》通过快速治疗抵抗抑郁症连接体“(PiNar，U01 MH110008，09/16-05/20)的研究炎症、奖赏过程和治疗结果之间的关系，在ECT和氯胺酮。无论是炎症还是对奖励过程的全面评估都没有在家长助学金。因此，该提案的目标是独一无二的，不与U01的目标重叠。在这里，我们建议全面获取垂直集成的炎症评估，包括全身性水平、上游细胞生产和转录因子激活，并评估这两种奖励动机并通过行为任务和自我报告来奖励响应性。我们的中心假设是炎症会与奖励不足挂钩，并将影响治疗结果。确定治疗反应的差异基于相关的临床表型和炎症特征将是开创性的，提供更多信息针对炎症升高的抑郁症患者的有效个性化治疗策略。这个K23 综合培训和研究计划旨在为候选人成为临床翻译人员做好准备抑郁症研究人员，在心理神经免疫学、奖赏过程和在这一界面上进行干预，以改进这种高度流行的疾病的个性化治疗策略。