Peripheral Biomarkers in Major Depression

描述（由申请人提供）：个性化医疗将需要使用可预测疾病状态和个体治疗反应的判别测试。重度抑郁症（MDD）是一种异质性疾病，是发达国家残疾的主要原因，也是自杀导致过早死亡的主要原因。然而，旨在表征MDD病理学的研究主要集中在中枢机制上，并且仅偶尔被转化为可以在临床环境中使用容易获得的人类受试者外周血样本进行测试的假设（例如，神经内分泌测试的结果不多）。专注于相关脑区的转录组改变，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）抑郁症啮齿动物模型中的“抑郁”状态相关的基因表达变化，并且通过抗抑郁剂（AD）治疗逆转小鼠。这种保守的“MDD生物特征”的存在表明MDD与持续的分子病理学相关，并且在更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进行分析，以识别保守的和状态依赖性的疾病相关变化。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变的外周生物标志物是开发MDD生物学（除症状外）定义的主要目标。研究表明，血液转录组在很大程度上平行的中央配置文件，并可以提供有价值的信息，对受试者的具体参数，包括神经精神疾病。因此，基于我们先前在大脑中的发现，我们假设MDD相关的血液变化将表现为保守的基因变化，对此，UCMS啮齿动物模型将提供独立的验证线和评估AD治疗混杂效应的方法，共同促进MDD和相关基因转录物变化作为推定的外周疾病生物标志物的鉴定。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（以提高AD依从性）的MDD和合并焦虑的患者。将评估AD治疗前后患者（n=40）和对照受试者（n=20）的血液转录组变化（目的1），以研究外周基因变化跟踪疾病状态和治疗应答/无应答的潜力。在UCMS暴露和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志物与人类受试者中混杂的AD效应，并将开始评估脑血保护的变化（目标2）。后续研究将评估所确定的生物标志物的敏感性和疾病特异性，将结果从反应扩展到缓解时间范围，并将导致对疾病状态，风险因素和治疗反应的生物学预测，这将在未来的研究中在更大的临床队列中进行测试。 公共卫生相关性：鉴于严重抑郁症对心理健康和社会生产力的全球负担，以及当前治疗干预的重大局限性，迫切需要开发预测疾病状态和个体治疗反应的区分性测试。将我们的基础科学发现转化为临床环境，并与NIMH战略计划一致，这些研究将调查血液分子生物标志物监测疾病进展轨迹和治疗反应的潜力。与有效的啮齿动物疾病模型的比较分析将协同人类研究，以确定强大的候选生物标志物，控制抗抑郁药物在人类受试者中的作用，并开始研究潜在的机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In view of the global burden of major depression on mental health and on society's productivity, and of the significant limitations of current therapeutic interventions, there is a critical need for developing discriminative tests that are predictive of disease state and individual treatment response. Translating our basic science finding to clinical settings, and consistent with the NIMH Strategic Plan, these studies will investigate the potential of blood molecular biomarkers to monitor the trajectory of disease progression and treatment response. Comparative analyses with a valid rodent model of the illness will synergize the human studies in identifying robust candidate biomarkers, control for antidepressant drug effects in human subjects, and begin investigating potential mechanisms.