A translational study of neuroinflammatory depression: Understanding mechanism and evaluation of a novel pharmacologic intervention

神经炎症抑郁症的转化研究：了解新型药物干预的机制和评估

• 批准号: 10588196
• 负责人: Christine Delorenzo
• 金额: $ 69.97万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588196
• 关键词: Accounting; Affect; Affinity; Aftercare; Anti-Inflammatory Agents; Antidepressive Agents; Astrocytes; Brain; Chronic; Clinical; Clinical Trials; Data; Depressed mood; Disease; Disease remission; Enrollment; Evaluation; Exclusion; Exhibits; Functional disorder; Genetic Polymorphism; Genotype; Health; Heterogeneity; Human; Image; Individual; Inflammatory; Intervention; Major Depressive Disorder; Measures; Medicine; Mental Depression; Messenger RNA; Microglia; Modeling; Molecular; Morphology; Mus; Neuroglia; Outcome; Outer Mitochondrial Membrane; Participant; Pathology; Patient Recruitments; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Positron-Emission Tomography; Prefrontal Cortex; Proteins; Proxy; Psychiatry; Reporting; Rodent; Selective Serotonin Reuptake Inhibitor; Severities; Signal Transduction; Stress; Subgroup; Testing; Text; Treatment outcome; Wild Type Mouse; antidepressant effect; biological heterogeneity; celecoxib; clinically relevant; cohort; density; depression model; depressive symptoms; design; disorder subtype; healthy volunteer; improved; in vivo; inflammatory marker; insight; microPET; mouse model; neuroinflammation; novel; optimal treatments; pharmacologic; prevent; protein expression; response; single episode major depressive disorder; social defeat; targeted treatment; translational study; treatment strategy; volunteer

Major depressive disorder (MDD) is one of the most heterogeneous disorders in psychiatry and first line treatments are inadequate for the majority of patients, likely because they do not target an individual’s subtype. Improving our understanding of MDD subtypes will allow us to (1) identify treatments that target subtype- specific pathophysiology and (2) determine which subgroup of MDD patients will best respond to these treatments, thus improving antidepressant outcomes. In a neuroinflammatory subtype, MDD may manifest via chronic neuroinflammation. The translocator protein (TSPO), located on the outer mitochondrial membrane of microglia and astrocytes, is regarded as a marker of this neuroinflammation and can be measured in vivo by positron emission tomography (PET). In support of a neuroinflammatory subtype of MDD, TSPO, measured by PET, was found to be elevated by 30% on average in the prefrontal cortex (PFC) in MDD relative to healthy individuals. Further, we have preliminary data from a repeated social defeat stress mouse model that shows elevated PFC TSPO and other elevated neuroinflammation markers in a subset of ‘depressed’, non-resilient mice, and that this phenotype is reversed by elimination of TSPO expressing glial cells! To parallel this effect in humans, brain-penetrant anti-inflammatory medications such as celecoxib can be used. Celecoxib has antidepressant effects in MDD; however, the observed effect sizes are highly variable, likely reflecting the biological heterogeneity of MDD. We hypothesize that anti-inflammatory treatments such as celecoxib will be most effective in those with the neuroinflammatory subtype of MDD and that the mechanism of antidepressant action is through a reduction of neuroinflammation. We will test these hypotheses in parallel studies in humans in rodents. For the human aim, we will take advantage of an ongoing study of celecoxib efficacy currently being performed at Stony Brook Medicine (PI: Parsey) by recruiting participants who are already being treated with celecoxib (8 weeks, 400mg/day). 53 MDD participants will be enrolled, with 42 expected to complete the study involving TSPO PET imaging before and after treatment. We hypothesize that higher PFC TSPO (as measured by PET) prior to treatment will be correlated with better response to celecoxib and further, that reductions in PFC TSPO will be correlated to depression improvement after adjusting for covariates. In a parallel study in rodents, we hypothesize that PFC TSPO and other CNS inflammation markers in our repeated social defeat stress mouse model of depression will be elevated as measured by microPET, quantitative protein/mRNA level analysis, and reactive microglial morphology, when compared to wild type mice. Further, we hypothesize that elevated PFC TSPO and other neuroinflammatory markers will be reduced after celecoxib treatment. If mouse and human studies do not agree, this suggests that TSPO PET provides a clinically- relevant proxy of neuroinflammation. However, if our hypotheses are confirmed, this would validate that TSPO is a marker of the neuroinflammatory MDD subtype and a target of treatment.

重度抑郁症（MDD）是精神病学和第一线中最异质的疾病之一 对于大多数患者而言，治疗不足，可能是因为他们不针对个人的亚型。 提高我们对MDD亚型的理解将使我们能够（1）确定针对亚型的治疗方法 特定的病理生理学和（2）确定哪些MDD患者的亚组最能对此做出反应 治疗，从而改善了抗抑郁剂的结局。在神经炎性亚型中，MDD可能通过 慢性神经炎症。转运蛋白（TSPO），位于外部线粒体膜上 小胶质细胞和星形胶质细胞被认为是这种神经炎症的标记，可以通过体内测量 正电子发射断层扫描（PET）。支持MDD的神经炎症亚型TSPO，以 在MDD相对于健康的前额叶皮层（PFC）中，PET平均升高30％ 个人。此外，我们有来自反复的社交失败压力鼠标模型的初步数据 升高的PFC TSPO和其他高架神经炎症标志物在“抑郁”，非弹性的子集中 小鼠，这种表型通过消除TSPO表达神经胶质细胞而逆转！平行这个效果 在人类中，可以使用脑培训抗炎药（例如塞来昔布）。 MDD中的抗抑郁作用；但是，观察到的效应大小是高度变化的，可能反映了 MDD的生物异质性。我们假设抗炎治疗（例如Celecoxib）将是 在MDD的神经炎性亚型和抗抑郁药的机制中最有效 作用是通过减少神经炎症。我们将在人类并行研究中检验这些假设 在啮齿动物中。为了人类的目标，我们将利用目前正在进行的Celecoxib效率的研究 在Stony Brook Medicine（PI：Parsey）上招募已经接受治疗的参与者 塞来昔布（8周，400毫克/天）。将注册53名MDD参与者，预计42名参与者将完成这项研究 治疗前后涉及TSPO PET成像。我们假设较高的PFC TSPO（AS 通过PET测量）在治疗之前将与对Celecoxib的更好反应相关，然后 调整协变量后，PFC TSPO的减少将与抑郁症的改善相关。 在啮齿动物中的平行研究中，我们假设我们重复的PFC TSPO和其他CNS注射标记 社交失败压力小鼠抑郁的模型将通过Micropet测量，定量升高 与野生型小鼠相比，蛋白/mRNA水平分析和反应性小胶质细胞形态。更远， 我们假设PFC ​​TSPO升高和其他神经炎症标志物将在Celecoxib后降低 治疗。如果小鼠和人类研究不同意，这表明TSPO PET在临床上提供了 神经炎症的相关代理。但是，如果我们的假设得到确认，这将证明TSPO 是神经炎症性MDD亚型的标记和治疗靶标。