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

描述（申请人提供）：我们建议在NIH资助的大规模随机试验中评估维生素D3（1600 IU/天）和Omega-3脂肪酸（二十碳五烯酸[EPA]+二十二碳六烯酸[DHA]，1 g/天）补充剂对老年抑郁症和抑郁症状风险的影响，维生素D和Omega-3 TriaL（VITAL，1 U01 CA 138962）。VITAL是一项2x2析因RCT，旨在评估维生素D3和海洋omega-3脂肪酸补充剂在20，000名美国老年男性和女性中对心血管疾病和癌症的一级预防的有效性。我们将讨论两个主要目标。首先，我们将测试维生素D或omega-3补充剂是否会降低试验中所有参与者的抑郁事件和复发率。抑郁症病例将使用问卷调查和来自医疗保险和医疗补助服务中心数据库的精神病学访视、诊断和药物治疗的额外数据进行识别。其次，我们将测试在5年的研究期间，维生素D或omega-3补充剂是否会在重复测量中产生更好的连续情绪评分。此外，我们将讨论三个次要目标。首先，在1,000名高危参与者的子研究中，定义为具有已知的晚年抑郁症风险因素（选择性预防）或具有亚综合征抑郁症状（指示性预防）的人，我们将测试药物是否有效降低抑郁症的风险，并随着时间的推移降低抑郁症评分。该子研究的受试者将在美国的四个临床和转化科学中心（CTSC）研究中心（波士顿、芝加哥、旧金山弗朗西斯科和休斯顿）招募，并将在基线和2年随访时接受精神病学访谈（访视将与季节匹配，以避免维生素D的季节性偏倚）。其次，我们将讨论非洲裔美国人的种族是否会改变维生素D补充剂对整个VITAL队列中抑郁风险和情绪评分的影响（非洲裔美国人受维生素D不足的影响不成比例）。第三，在巢式病例对照设计中，我们将评估维生素D和ω-3脂肪酸的基线血浆水平是否与抑郁症风险相关，以及它们是否改变治疗效果。我们还将能够探索药物的累加和/或协同效应，以及年龄，性别，基线营养水平，基线医疗合并症，纬度和体力活动的影响。总之，该提案提出了一种高效和创新的策略，以同时评估维生素D和ω-3脂肪酸补充剂对老年抑郁症的普遍性、选择性和指示性预防的功效，以及提供可能影响这种益处的相关生理参数的表征。我们申请资金用于抑郁症病例确定、精神病评估以及嵌套病例对照样本中随机化前维生素D和脂肪酸血液水平的测定。为了检验我们的假设并完成随机化前的精神病学评估，这项辅助研究与母试验VITAL的入组期平行进行是非常重要和具有时间敏感性的，计划于2010年开始。 公共卫生相关性：生物和观察证据支持维生素D和海洋欧米茄-3脂肪酸对精神健康的潜在益处。然而，目前尚不清楚使用这些补充剂是否可以预防晚年抑郁症的发作，或者可以显着减少晚年的抑郁症状。这项拟议研究的结果是在美国60岁及以上成年人中进行的一项大型临床试验，将澄清维生素D和/或omega-3脂肪酸补充剂是否会降低晚年抑郁症和抑郁症状的风险，并将提供适用于抑郁症一级和二级预防的公共卫生和临床指南的重要数据。

DESCRIPTION (provided by applicant): We propose to evaluate the effects of vitamin D3 (1600 IU/day) and omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1g/day) supplements on risk of late-life depression and depressive symptoms in the setting of an NIH-funded large-scale randomized trial, the VITamin D and OmegA-3 TriaL (VITAL, 1 U01 CA 138962). VITAL is a 2x2 factorial RCT designed to evaluate the efficacy of vitamin D3 and marine omega-3 fatty acid supplements in the primary prevention of cardiovascular disease and cancer among 20,000 older U.S. men and women. We will address two primary aims. First, we will test whether vitamin D or omega-3 supplementation reduces incident and recurrent depression rates among all participants in the trial. Cases of depression will be identified using questionnaires and additional data on psychiatric visits, diagnoses, and medications from the Centers for Medicare and Medicaid Services database. Second, we will test whether vitamin D or omega-3 supplementation yields better continuous mood scores on repeated measures over the 5-year study period. In addition, we will address three secondary aims. First, in a substudy of 1,000 high-risk participants, defined as persons with known risk factors for late-life depression (selective prevention) or with subsyndromal depressive symptoms (indicated prevention), we will test whether the agents are effective at reducing risk of depression and at yielding lower depression scores over time. Participants in this substudy will be recruited at four Clinical and Translational Science Center (CTSC) sites across the U.S. (Boston, Chicago, San Francisco, and Houston), and will undergo a psychiatric interview at baseline and at 2 years of follow-up (visits will be matched for season, to avoid seasonal bias for vitamin D). Second, we will address whether African-American race modifies effects of vitamin D supplementation on depression risk and on mood scores in the entire VITAL cohort (African-Americans are disproportionately affected by vitamin D insufficiency). Third, in a nested case-control design, we will assess whether baseline plasma levels of vitamin D and omega-3 fatty acids are related to depression risk, and whether they modify treatment effects. We will also be able to explore additive and/or synergistic effects of the agents, as well as effect modification by age, gender, baseline nutrient levels, baseline medical comorbidity, latitude, and physical activity. In summary, this proposal presents a highly efficient and innovative strategy to evaluate simultaneously the efficacy of vitamin D and omega-3 fatty acid supplementation for universal, selective and indicated prevention of late-life depression, as well as to provide characterization of relevant physiologic parameters that may influence this benefit. We request funds for depression case ascertainment, psychiatric assessments, and assays of pre-randomization blood levels of vitamin D and fatty acids in a nested case-control sample. In order to test our hypotheses and to complete pre- randomization psychiatric assessments, it is critically important and time-sensitive that this ancillary study be undertaken in parallel to the enrollment period for the parent VITAL trial, which is scheduled to begin in 2010. PUBLIC HEALTH RELEVANCE: Biologic and observational evidence supports potential mental health benefits of both vitamin D and marine omega-3 fatty acids. However, it remains unclear whether the use of these supplements can prevent onset of late-life depression or can significantly reduce depressive symptoms in late-life. Findings from this proposed study, conducted within a large clinical trial among U.S. adults aged 60 years and above, will clarify whether vitamin D and/or omega-3 fatty acid supplementation reduces risk of late-life depression and depressive symptoms, and will provide important data that will be applicable to public health and clinical guidelines for both primary and secondary prevention of depression.