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: 10375542
• 负责人: Christine Delorenzo
• 金额: $ 68.91万
• 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/10375542
• 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; 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; Pharmacology; Phenotype; Pilot Projects; Positron-Emission Tomography; Prefrontal Cortex; Proteins; Proxy; Psychiatry; Reporting; Rodent; Selective Serotonin Reuptake Inhibitor; Severities; Signal Transduction; Stress; Subgroup; Testing; Text; Time; 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; 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) 是精神病学和一线疾病中最具异质性的疾病之一 治疗对于大多数患者来说是不够的，可能是因为它们不针对个体的亚型。 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，以及 (2) 确定 MDD 患者的哪个亚组对这些疾病的反应最好 治疗，从而改善抗抑郁效果。在神经炎症亚型中，MDD 可能通过以下方式表现出来： 慢性神经炎症。易位蛋白（TSPO），位于线粒体外膜上 小胶质细胞和星形胶质细胞被认为是这种神经炎症的标志物，可以通过以下方法在体内进行测量 正电子发射断层扫描（PET）。支持 MDD 的神经炎症亚型，TSPO，通过测量 研究发现，与健康人相比，重度抑郁症患者的前额皮质 (PFC) PET 平均升高 30% 个人。此外，我们从重复的社交失败压力小鼠模型中获得了初步数据，表明 在“抑郁”、无弹性的子集中，PFC TSPO 和其他神经炎症标志物升高 小鼠，并且通过消除表达 TSPO 的神经胶质细胞来逆转这种表型！为了平行这个效果 在人类中，可以使用塞来昔布等脑渗透性抗炎药物。塞来昔布有 MDD 的抗抑郁作用；然而，观察到的效应大小变化很大，可能反映了 MDD 的生物学异质性。我们假设塞来昔布等抗炎治疗将 对于患有 MDD 神经炎症亚型的患者最有效，并且抗抑郁药的机制 作用是通过减少神经炎症来实现的。我们将在人类的平行研究中测试这些假设 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塞来昔布功效研究 在 Stony Brook Medicine（PI：Parsey）进行，招募已经接受过治疗的参与者 塞来昔布（8 周，400 毫克/天）。将招募 53 名 MDD 参与者，其中 42 名预计将完成研究 涉及治疗前后的 TSPO PET 成像。我们假设较高的 PFC TSPO（如 治疗前通过 PET 测量）将与塞来昔布的更好反应相关，并且进一步， 调整协变量后，PFC TSPO 的减少将与抑郁症的改善相关。在一个 在啮齿类动物的平行研究中，我们假设 PFC TSPO 和其他中枢神经系统炎症标志物在我们的重复研究中 通过 microPET 定量测量，社交挫败压力小鼠模型的抑郁症会升高 与野生型小鼠相比，蛋白质/mRNA水平分析和反应性小胶质细胞形态。更远， 我们假设塞来昔布后升高的 PFC TSPO 和其他神经炎症标志物将减少 治疗。如果小鼠和人类研究不一致，这表明 TSPO PET 提供了临床- 神经炎症的相关指标。然而，如果我们的假设得到证实，这将验证 TSPO 是神经炎症性 MDD 亚型的标志物和治疗目标。