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

摘要重度抑郁障碍(MDD)是精神病学中异质性最强的疾病之一。 对于大多数患者来说，治疗是不够的，可能是因为它们没有针对个人的亚型。 提高我们对MDD亚型的理解将使我们能够(1)识别针对亚型的治疗- 特定的病理生理学和(2)确定MDD患者的哪个亚组对这些反应最好 治疗，从而改善抗抑郁药物的效果。在神经炎性亚型中，MDD可能通过 慢性神经炎。位于线粒体膜外膜的转运蛋白(TSPO)。 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，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的神经炎性亚型TSPO，通过 研究发现，与健康人相比，MDD患者前额叶皮质(PFC)的PET-1平均升高了30% 个人。此外，我们有来自反复社会失败应激小鼠模型的初步数据，表明 抑郁、无弹性患者的PFC、TSPO和其他神经炎标志物升高 这种表型可以通过消除表达TSPO的神经胶质细胞而逆转！为了达到同样的效果 在人类身上，可以使用塞来昔布等脑穿透性抗炎药物。塞来昔布有 MDD中的抗抑郁效应；然而，观察到的效应大小变化很大，可能反映了 MDD的生物异质性。我们假设像塞来昔布这样的抗炎治疗将是 对于神经炎性MDD亚型的患者最有效，抗抑郁药的作用机制 行动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检验这些假说。 在啮齿动物身上。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 在石溪医学(PI：PARSY)通过招募已经接受治疗的参与者进行表演 塞来昔布(8周，400 mg/d)。将有53名MDD参与者参加，其中42人预计将完成研究 治疗前后分别进行TSPO PET检查。我们假设较高的PFC TSPO(AS 治疗前进行正电子发射计算机断层扫描)将与对塞来昔布的较好反应相关，此外， 在调整协变量后，PFC TSPO的减少将与抑郁的改善相关。在一个 在啮齿动物中进行的平行研究中，我们假设PFC、TSPO和其他中枢神经系统炎症标志物在我们重复的 抑郁的社会失败应激小鼠模型将通过microPET测量升高，定量 蛋白质/mRNA水平分析和反应性小胶质细胞形态，与野生型小鼠相比。此外， 我们假设塞来昔布治疗后升高的PFC、TSPO和其他神经炎性标志物将会减少 治疗。如果老鼠和人类的研究不一致，这表明TSPO PET提供了一种临床- 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 是神经炎性MDD亚型的标志，也是治疗的靶点。

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.