Peripheral Biomarkers in Major Depression

重度抑郁症的外周生物标志物

• 批准号: 8044939
• 负责人: ETIENNE L SIBILLE
• 金额: $ 18.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044939
• 关键词: Animal Model; Antidepressive Agents; Anxiety; Area; Autopsy; Basic Science; Biological; Biological Markers; Blood; Blood specimen; Brain; Cessation of life; Chronic; Citalopram; Clinical; Complex; Depressed mood; Developed Countries; Disease; Disease Progression; Disease remission; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Human; Individual; Lead; Major Depressive Disorder; Medicine; Mental Depression; Mental Health; Molecular; Monitor; Mus; National Institute of Mental Health; Neurosecretory Systems; Pathology; Patients; Peripheral; Probability; Productivity; Psychotherapy; Research; Risk Factors; Rodent Model; Societies; Specificity; Strategic Planning; Stress; Suicide; Testing; Therapeutic Intervention; Transcript; Translating; Validation; base; biosignature; cohort; comparative; disability; follow-up; human data; human subject; molecular pathology; neuropsychiatry; peripheral blood; premature; response; success; tool; treatment response

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.

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，是发达国家致残的主要原因，也是自杀导致过早死亡的主要原因。然而，旨在描述重度抑郁症病理特征的研究主要集中在中心机制上，并且只是偶尔被转化为可以在临床环境中使用人类受试者的外周血样本进行测试的假设（例如，神经内分泌测试的结果一般）。关注相关脑区转录组的改变，我们现在已经确定了人类死后大脑和不可预测的慢性轻度应激（UCMS）啮齿动物抑郁症模型中与“抑郁”状态相关的基因表达变化，并通过抗抑郁药（AD）治疗在小鼠中逆转。这种保守的“MDD生物特征”的存在表明，MDD与持续的分子病理有关，并且在更易于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变的外周生物标志物是开发MDD生物学（除了症状）定义的主要目标。研究表明，血液转录组在很大程度上与中心谱相似，可以提供关于特定主题参数的有价值的信息，包括神经精神疾病。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，为此UCMS啮齿动物模型将提供独立的验证线和评估AD治疗混杂效应的手段，共同促进MDD和相关基因转录物变化作为假定的外周疾病生物标志物的鉴定。为了优化我们成功的可能性，我们将评估重度抑郁症和并发焦虑症患者是否接受西酞普兰治疗和心理治疗（以增加AD的依从性）。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（Aim 1），以研究外周基因变化追踪疾病状态和治疗反应/无反应的潜力。在暴露于ucms和AD处理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的混杂AD效应，并将开始评估脑-血保护变化（目的2）。后续研究将评估已识别生物标志物的敏感性和疾病特异性，将研究结果从反应扩展到缓解时间框架，并将导致有关疾病状态、风险因素和治疗反应的生物学预测，这些将在未来更大的临床队列研究中进行测试。