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.

重性抑郁障碍（MDD）是精神科最具异质性的疾病之一， 治疗对大多数患者来说是不够的，可能是因为它们没有针对个体的亚型。 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- 特定的病理生理学和（2）确定MDD患者的哪个亚组将最好地响应这些 治疗，从而改善抗抑郁药的结果。在神经炎症亚型中，MDD可能通过以下方式表现： 慢性神经炎症转运蛋白（TSPO），位于线粒体外膜， 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，并且可以通过以下方法在体内测量： 正电子发射断层扫描（PET）。支持MDD的神经炎性亚型TSPO，通过 与健康人相比，MDD患者前额叶皮层（PFC）的PET平均升高30 个体此外，我们从重复社交失败压力小鼠模型中获得的初步数据显示， PFC TSPO升高和其他神经炎症标志物升高， 小鼠，并且这种表型通过消除表达TSPO的神经胶质细胞而逆转！为了与这种效果相对应， 在人类中，可以使用脑渗透性抗炎药物，例如塞来昔布。塞来昔布 抑郁症的抗抑郁作用;然而，观察到的效应量是高度可变的，可能反映了 MDD的生物学异质性。我们假设，抗炎治疗，如塞来昔布， 对MDD的神经炎症亚型最有效， 作用是通过减少神经炎症。我们将在人类的平行研究中检验这些假设 在啮齿类动物中。为了人类的目的，我们将利用目前正在进行的塞来昔布疗效研究， 在斯托尼布鲁克医学中心（PI：Parsey）通过招募已经接受 塞来昔布（8周，400 mg/天）。将入组53例MDD受试者，预计42例将完成研究 包括治疗前后的TSPO PET成像。我们假设较高的PFC TSPO（作为 通过PET测量）将与对塞来昔布的更好反应相关， 校正协变量后，PFC TSPO的降低与抑郁改善相关。中 在啮齿类动物的平行研究中，我们假设在我们的重复研究中，PFC TSPO和其他CNS炎症标志物 社交失败应激小鼠抑郁模型将升高，如通过microPET测量的，定量 蛋白质/mRNA水平分析和反应性小胶质细胞形态。此外，本发明还 我们假设，塞来昔布治疗后，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提供了一种临床- 神经炎症的相关代表。然而，如果我们的假设得到证实，这将证实TSPO 是神经炎性MDD亚型的标志物和治疗靶点。