Peripheral Biomarkers in Major Depression

项目摘要/摘要 个性化医疗将需要使用能够预测疾病状态和个人治疗反应的歧视性测试。严重抑郁障碍(MDD)是一种异质性疾病，在发达国家是导致残疾的主要原因，也是自杀导致过早死亡的主要原因。然而，旨在描述MDD的病理特征的研究大多集中在中枢机制上，只是偶尔被转化为假设，可以在临床环境中使用容易获得的人类受试者的外周血液样本进行测试(例如，神经内分泌测试的结果不大)。聚焦于相关大脑区域的转录组变化，我们现在已经确定了与人类死后大脑和不可预测的慢性轻度应激(UCMS)抑郁啮齿动物模型中的抑郁状态相关的基因表达变化，并且这种变化可以被抗抑郁药(AD)逆转。MDD这种保守的生物特征的存在表明MDD与持久的分子病理有关，在更容易处理的疾病动物模型中进行的平行研究可以支持对复杂的人类数据的分析，以确定保守的和状态依赖的疾病相关变化。我们如何将这些发现转化为潜在的临床工具？ 识别与疾病状态和治疗反应共同变化的外周生物标记物是制定MDD生物学(除了症状)定义的主要目标。研究表明，血液转录本在很大程度上平行于中心轮廓，可以提供关于特定受试者参数的有价值的信息，包括神经精神障碍。因此，基于我们之前在大脑中的发现，我们假设MDD相关的血液变化将表现为保守的基因变化，对于这一点，UCMS啮齿动物模型将提供一条独立的验证路线和一种评估AD治疗的混杂效应的手段，共同促进MDD和相关基因转录变化作为推测的外周疾病生物标志物的识别。为了优化我们的成功概率，我们将评估接受西酞普兰治疗和心理治疗(以增强AD依从性)的MDD和共生焦虑患者。将评估患者(n=40)和对照组(n=20)在AD治疗前后血液转录组的变化(目标1)，以调查外周基因变化跟踪疾病状态和治疗反应/无反应的可能性。在UCMS暴露的小鼠和AD治疗的小鼠中进行的平行研究将帮助我们区分候选生物标记物和混淆的AD对人类受试者的影响，并将开始评估变化的脑血液保护(目标2)。后续研究将评估已确定的生物标志物的敏感性和疾病特异性，扩大对缓解时间框架的反应的发现，并将导致对疾病状态、风险因素和治疗反应的生物学预测，这将在未来的更大临床队列研究中进行测试。

Project Summary / Abstract Personalized medicine will require the use of discriminative tests that are predictive of disease state and individual treatment response. Major depressive disorder (MDD) is a heterogeneous illness that is the leading cause of disability in developed countries and a major cause of premature death due to suicide. Research aimed at characterizing the pathology of MDD however, has mostly focused on central mechanisms and has only occasionally been translated into hypotheses that can be tested in clinical settings using readily available peripheral blood samples from human subjects (and with modest results for neuroendocrine tests for instance). Focusing on altered transcriptome in relevant brain areas, we have now identified gene expression changes that are associated with ¿depressed¿ states in both the human postmortem brain and the unpredictable chronic mild stress (UCMS) rodent model of depression, and that are reversed by antidepressant (AD) treatments in mice. The presence of this conserved ¿biosignature of MDD¿ demonstrates that MDD is associated with persistent molecular pathologies, and that a parallel study in a more tractable animal model of the illness can support the analysis of the complex human data in identifying conserved and state-dependent disease-related changes. How can we translate these findings into a potential clinical tool? The identification of peripheral biomarkers co-varying with disease states and treatment response is a primary goal in developing a biological (in addition to symptomatic) definition of MDD. Studies showed that blood transcriptomes largely parallel central profiles and can provide valuable information on subject-specific parameters, including for neuropsychiatric disorders. Hence, based on our prior findings in the brain, we hypothesize that MDD-related blood changes will manifest as conserved gene changes, for which the UCMS rodent model will provide an independent line of validation and a means to assess confounding effects of AD treatments, together facilitating the identification of MDD- and relevant gene transcript changes as putative peripheral disease biomarkers. To optimize our probability of success, we will assess patients with MDD and co-occurring anxiety receiving citalopram treatment and psychotherapy (to augment AD compliance). Blood transcriptome changes will be assessed in patients (n=40) before and after AD treatment and in control subjects (n=20) (Aim 1) to investigate the potential of peripheral gene changes to track disease state and treatment response/non-response. Parallel studies in UCMS-exposed and AD-treated mice will help us distinguish candidate biomarkers from confounding AD effects in human subjects, and will begin assessing brain-blood conservation of changes (Aim 2). Follow-up studies will assess the sensitivity and disease specificity of the identified biomarkers, extend findings from the response to the remission timeframe, and will lead to biological predictions about disease state, risk factors and treatment responses, which will be tested in future studies in larger clinical cohorts.