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

项目总结/摘要 高度炎症是与抗抑郁药物反应较差相关的生物学特征。 快感缺失，代表了奖励系统功能障碍的一个方面，是抑郁症的常见症状，也是 预示着治疗效果不佳。最近的文献表明，这些变量（一个生物学变量，另一个 行为）是有联系的。然而，没有研究同时解决这两个维度是否 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的动态纵向变化。 电休克治疗（ECT）和氯胺酮都引起了强大的和快速的抗抑郁反应的患者 患有严重且难以治疗的抑郁症因此，这些治疗方式是测试动态的理想选择。 炎症，奖励的行为结构和治疗结果之间的联系在一个相对较短的时间内， 时间框架。此外，与炎症预测抗抑郁药物治疗的不良结果相反， 我们的初步数据显示，较高的基线炎症（以白细胞介素[IL]-6为指标） ECT治疗反应（n=29，p=0.01）。此外，氯胺酮也被认为是更有效的 对于伴有高度炎症的抑郁症患者，一些初步的临床结果支持这一假设。然而，在这方面， 数据稀少，炎症评估有限，至少有一项氯胺酮研究未能复制 较早的结果。值得注意的是，奖励缺陷尚未被正式评估为ECT反应的预测因子， 氯胺酮我们有独特的机会利用一项大型资助的U 01研究，“治疗的干扰 通过速效疗法治疗耐药抑郁症连接体”（PI Narr，U 01 MH 110008，09/16-05/20），以研究 炎症、奖励过程和治疗结果之间的关系，在ECT内和ECT之间， 氯胺酮炎症和对奖赏过程的全面评估都没有在 家长补助因此，本提案的目标是独特的，与U 01的目标不重叠。这里我们 建议全面捕获炎症的垂直整合评估，包括全身性 水平，上游细胞生产，转录因子激活，并评估奖励动机 并通过行为任务和自我报告来奖励反应。我们的中心假设是炎症会 与奖励缺陷有关，并将影响治疗结果。治疗反应差异的确定 基于相关的临床表型和炎症特征将是突破性的， 针对炎症升高的抑郁症患者的有效个性化治疗策略。K23 综合培训和研究计划的目的是准备候选人成为临床翻译 抑郁症研究者，在心理神经免疫学，奖励过程和研究的专业知识， 在这个界面上进行干预，以改善这种高度流行的疾病的个性化治疗策略。

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.