VITAL-DEP Depression Endpoint Prevention in the VITamin D and OmegA-3 TriaL

 描述(申请人提供)：VITAL-DEP(维生素D和omega-3试验中的抑郁症终点预防)是一项正在进行的大规模2x2因素随机试验，其中包括维生素D(维生素D3[胆钙化醇]2000IU/d)和omega-3脂肪酸(EPA和DHA，比例为1：1,1000 mg/d)，用于预防晚年抑郁和促进对情绪的长期好处。在第一个资助期间(9/29/10-06/30/15)，我们完成了对近19,000名成功随机分组的男性和女性的抑郁症结果的基线和早期随访，这些男性和女性年龄在50岁以上(平均年龄=65岁)，他们有资格发生或复发晚年抑郁症；近70%的参与者提供了随机前血液样本进行营养生化分析。此外，在临床和翻译科学中心(CTSC)部分，对1,000多人进行了详细的表型评估，这些人接受了面对面的结构化精神病学诊断访谈，接受了神经心理测试，并提供了情绪、幸福感以及社交和日常功能的维度测量数据。最后，VITAL-DEP的另一个具有里程碑意义的方面是其丰富的种族和民族多样性：超过25%的参与者来自少数族裔和/或民族背景，包括19%的非裔美国人。事实上，我们的第一个资助期旨在强调非洲裔美国人中维生素D反应的潜在差异，因为这一群体中25(OH)D水平低的风险很高。然而，最新的证据表明，可生物利用的维生素D与种族/民族差异最相关。在这份为期5年的续展提案中，我们对第一阶段取得的成就--组建一个独特的试验队列--进行了扩展，并重点介绍了这一随机对照试验设计所提供的前所未有的科学机会。我们的主要目标是：1)扩展对情绪的跟踪，以高统计能力检查维生素D和海洋omega-3脂肪酸对所有19,000名参与者的长期(长达7年)抑郁结果的影响；2)高强度检查生化营养素水平维生素D和omega-3脂肪酸对抑郁结果的影响以及与基线生化水平的治疗相互作用。次级目标侧重于我们的特定试验设计独特地准备解决的两个关键主题：1)长期治疗效果中的种族/民族差异；2)在这个不同的队列中，维生素D和鱼油对情绪影响的机制、调节和调节因素。具体地说，在2000名参与者的子集中，我们将检查可生物利用的维生素D与抑郁症的关系，并关注结果的种族差异。此外，在整个符合条件的CTSC队列中，我们将获得随机前后的血清脑源性神经营养因子和目标血浆代谢物水平，以检查与维生素D和鱼油治疗的情绪反应有关的生物学途径，并测试生物标记物的变化是否解释治疗效果的变化。因此，这项建议不仅将确保全面、明确地测试维生素D和鱼油对晚年情绪的益处，还将为涉及不同样本的具体机制提供信息。

 DESCRIPTION (provided by applicant): VITAL-DEP (Depression Endpoint Prevention in the VITamin D and OmegA-3 TriaL) is an ongoing, large- scale, 2x2 factorial randomized trial of vitamin D (vitamin D3 [cholecalciferol] 2000 IU/d) and omega-3 fatty acids (EPA and DHA, in 1:1 ratio, 1000 mg/d) for the prevention of late-life depression and promotion of long- term benefits for mood. In the first funding period (9/29/10-06/30/15), we completed baseline and early follow- up of depression outcomes among nearly 19,000 successfully randomized men and women, aged 50+ years (mean age=65y), who were eligible for incidence or recurrence of late-life depression; nearly 70% of participants have provided pre-randomization blood samples for nutrient biochemical assays. Furthermore, in the Clinical and Translational Science Center (CTSC) component, detailed phenotypic assessments were conducted among a subset of over 1,000 individuals who received in-person structured psychiatric diagnostic interviews, underwent neuropsychological testing, and provided data on dimensional measures of mood, well- being, and social and daily functioning. Finally, another landmark aspect of VITAL-DEP is its substantial racial and ethnic diversity: over 25% of participants are from minority racial and/or ethnic backgrounds, including 19% who are African American. Indeed, our first funding period aims emphasized potential differences in vitamin D response among African Americans, given high risk of low 25(OH)D in this group. However, late- breaking evidence indicates that bioavailable vitamin D is of greatest relevance to race/ethnic differences. In this 5-year renewal proposal, we expand upon what has been achieved in the first period - assembly of a unique trial cohort - and focus on the unprecedented scientific opportunities afforded by this RCT design. Our Primary Aims are: 1) to extend follow-up of mood to examine with high statistical power the long-term (up to 7 years) effects of vitamin D and marine omega-3 fatty acids on depression outcomes among all ~19,000 participants; 2) to examine with high power the impact of biochemical nutrients levels of vitamin D and omega- 3 fatty acids on depression outcomes as well as treatment interaction with baseline biochemical levels. Secondary Aims focus on two critical themes that our particular trial design is uniquely poised to address: 1) racial/ethnic differences in long-term treatment effects; 2) mechanisms, mediators and moderators of mood effects of vitamin D and fish oil in this diverse cohort. Specifically, in a sub-set of 2,000 participants, we will examine relations of bioavailable vitamin D to depression, with attention to race differences in outcomes. Further, among the entire eligible CTSC cohort, we will obtain pre- and post-randomization serum brain- derived neurotrophic factor and targeted plasma metabolite levels to examine biological paths involved in mood responses to vitamin D and fish oil treatment and to test whether biomarker change explains variation in treatment effects. Thus, this proposal not only will ensure comprehensive, definitive testing of the benefits of vitamin D and fish oil for late-life mood but also will inform specific mechanisms involved in a diverse sample.