Establishing Moderators/Biosignatures of Antidepressant Response- Clinical Care

建立抗抑郁药反应的调节因子/生物特征 - 临床护理

• 批准号: 8689305
• 负责人: MADHUKAR H. TRIVEDI
• 金额: $ 14.62万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689305
• 关键词: ABCB1 gene; Adverse effects; Anger; Antidepressive Agents; Behavioral; Biological; Biological Markers; Brain-Derived Neurotrophic Factor; Bupropion; Candidate Disease Gene; Citalopram; Clinical; Clinical Markers; Clinical Trials; Clinical Trials Design; Cognitive Therapy; Complex; Corticotropin; Coupled; DNA Methylation; DRD2 gene; Disease; Disease remission; Early-life trauma; Electroencephalography; Emotions; Employment Status; Environment; Epigenetic Process; Evaluation; Fatigue; Frequencies; Functional Magnetic Resonance Imaging; Gender; Genes; Genetic; Genetic Polymorphism; Goals; HTR2A gene; Hamilton Rating Scale for Depression; Heterogeneity; Hippocampus (Brain); Histone Acetylation; Homozygote; Hydrocortisone; Image; Immune; Individual; Insulin-Like Growth Factor I; Interleukin-6; Lead; Life; Literature; Measures; Mediating; Mediator of activation protein; Melancholic Depression; Mental Depression; Methods; Modeling; Neurobiology; Neurosecretory Systems; Outcome; Patients; Pattern; Performance; Peripheral; Phase; Phenotype; Principal Investigator; Process; Proteomics; Psychotherapy; Qualifying; Randomized; Reaction Time; Recording of previous events; Regulation; Research Personnel; Rest; Scientist; Selection for Treatments; Selective Serotonin Reuptake Inhibitor; Serum; Staging; Symptoms; System; Technology; Time; Trauma; Treatment Step; Treatment outcome; Variant; Vascular Endothelial Growth Factors; base; biosignature; clinical care; comparative effectiveness; cytokine; depressive symptoms; design; effectiveness trial; emotion regulation; epigenetic marker; evidence base; experience; functional status; genome wide association study; improved; indexing; innovation; meetings; neuroimaging; neurotrophic factor; novel; programs; randomized trial; relating to nervous system; response; reward processing; treatment effect; treatment response

DESCRIPTION (provided by applicant): The timely selection of the best treatment for patients with depression is critical to the goal of improving remission rates. Due to the biological heterogeneity and variable symptom presentation of depression, it is unlikely that a single clinical or biological marker can guide treatment selection. Rather, a biosignature developed from a systematic exploration of a group of clinical and biological markers is more likely to be successful. Two types of biosignatures are needed to achieve improved outcomes: 1) biosignatures to maximize the selection of optimal treatment for individual patients at the beginning of treatment (moderators) and 2) biosignatures to identify indicators of eventual outcomes early in treatment (mediators). This approach has great potential to personalize treatment and maximize the number of patients who can be treated to full remission with a given treatment. We propose a comparative effectiveness trial of three mechanistically distinct treatments for MDD (citalopram, bupropion, and cognitive behavioral therapy) in which we will assess a comprehensive array of carefully selected clinical (i.e. anxious depression, early life trauma, & gender) and biological (i.e. genetic, neuroimaging, serum, epigenetic & qEEG) moderators and mediators of outcome. Using innovative statistical approaches the identified moderators and mediators will then be used to develop a differential depression treatment response index (DTRI). The proposed study is a randomized two-stage trial (Stagel:12 wks; Stage2: 12 wks) design with 675 MDD patients (with a history of one adequate trial of an SSRI except citalopram) assigned to one of three treatment conditions (n=225 each). This two stage approach is similar to a Sequential Multiple Assignment Randomized Trial (SMART) design. This application brings together researchers with extensive experience in conducting large clinical trials and experts at the forefront ofthe neurobiology of depression, including: clinical trials (Trivedi, Fava, Schatzberg,Nierenberg, Shelton, Gaynes, Hollon), genetics (Smoller, Binder, McMahan, Perils), neuroimaging (Phillips, Sheline, Etkin, Pizzagalli, Buckner), qEEG (losifescu, Ellenbogen), neurotrophins/cytokines (Duman, Sanacora, Turck, Shelton), clinical predictors (Shelton, Hollon, Trivedi, Fava, Nierenberg, Goodman, Yehuda), neuroendocrine markers (Holsboer, Schatzberg, Shelton, Yehuda), epigenetics (Nestler, Yehuda),and cognitive behavior therapy (Hollon, Manber, Arnow). This team will also be guided by internationally known biomarker scientists (Holsboer, Schatzberg, Krystal, Charney, Goodman), as well as a highly qualified group of biostatisticians (Kraemer, Wisniewski, Schoenfeld).

描述（由申请人提供）：及时选择针对抑郁症患者的最佳治疗方法对于提高缓解率的目标至关重要。由于抑郁症的生物异质性和可变症状表现，单个临床或生物标记物不太可能引导治疗选择。相反，从对一组临床和生物标记的系统探索开发的生物签名更有可能成功。需要两种类型的生物签名来取得改善的结果：1）生物签名，以最大程度地选择治疗开始时为个别患者选择最佳治疗（主持人）和2）生物签名，以鉴定治疗早期最终结果的指标（介体）。这种方法具有个性化治疗并最大化可以通过给定治疗完全缓解的患者数量的巨大潜力。 We propose a comparative effectiveness trial of three mechanistically distinct treatments for MDD (citalopram, bupropion, and cognitive behavioral therapy) in which we will assess a comprehensive array of carefully selected clinical (i.e. anxious depression, early life trauma, & gender) and biological (i.e. genetic, neuroimaging, serum, epigenetic & qEEG) moderators and mediators of outcome.使用创新的统计方法，确定的主持人和调解人将用于开发差异抑郁症治疗反应指数（DTRI）。拟议的研究是一项随机的两阶段试验（Stagel：12 wks; stage 2：12 wks）设计，其675例MDD患者（有一个适当的SSRI试验病史除外，除Citalopram外，还分配给了三种治疗条件之一（N = 225个）。这种两个阶段的方法类似于连续的多个分配随机试验（智能）设计。 This application brings together researchers with extensive experience in conducting large clinical trials and experts at the forefront ofthe neurobiology of depression, including: clinical trials (Trivedi, Fava, Schatzberg,Nierenberg, Shelton, Gaynes, Hollon), genetics (Smoller, Binder, McMahan, Perils), neuroimaging (Phillips, Sheline, Etkin, Pizzagalli, Buckner), qEEG (losifescu, Ellenbogen), neurotrophins/cytokines (Duman, Sanacora, Turck, Shelton), clinical predictors (Shelton, Hollon, Trivedi, Fava, Nierenberg, Goodman, Yehuda), neuroendocrine markers (Holsboer, Schatzberg, Shelton, Yehuda），表观遗传学（Nestler，Yehuda）和认知行为疗法（Hollon，Manber，Arnow）。该团队还将受到国际知名的生物标志物科学家（Holsboer，Schatzberg，Krystal，Charney，Goodman）的指导，以及一个高素质的生物统计学家（Kraemer，W​​isniewski，Schoenfeld）。