Pediatric depression and subsequent cardiac risk factors: a longitudinal study

描述（由申请人提供）：在此修订后的申请中，我们解决了 IRG 的担忧：我们澄清了 3 个科目组的评估数量/类型；提出了进一步的假设，更好地反映了先证者及其同胞的童年档案数据的使用；将 ICAM-1 添加到我们的生物标记中；并回应了其他各种关切。我们的研究重点是抑郁症和冠心病（CHD），它们是全世界面临的巨大公共卫生问题。抑郁不仅可以预测新发冠心病以及现有冠心病患者的发病率和死亡率，而且还与最终冠心病的行为危险因素（例如吸烟、久坐）相关。尽管抑郁症与冠心病之间的联系已得到充分证实，但抑郁症的因果作用仍在争论中，其最具“心脏毒性”的特征尚未得到证实。值得注意的是，尽管抑郁症和冠心病通常起源于成年前，但很少有研究在发育背景下检验它们与行为冠心病危险因素的关系。我们建议评估匈牙利年轻人的 3 个既定样本：a）先证者（n = 325），我们从童年起就对其进行跟踪，他们在平均年龄 9 岁左右首次出现严重抑郁症，b）先证者的从未抑郁的兄弟姐妹（n = 325），c）正常同伴对照（n = 155）。我们最近报道：a）先证者家庭父母的心血管疾病发病率升高，b）到了青春期（平均年龄=17岁），作为先证者预测先证者的行为危险因素发生率增加（例如吸烟、久坐），以及c）行为危险因素的发生率在先证者中最高，在对照组中最低，在先证者的从未抑郁的兄弟姐妹中居中。拟议研究的目标是首次评估传统的生物风险因素（例如 LDL 胆固醇、血压）、行为风险因素以及 CHD 风险的几个标志物：脉搏波速度、白细胞介素 6 和 C 反应蛋白（炎症）、ICAM-1（内皮功能）和代谢综合征。我们的假设涉及冠心病风险标记水平作为受试者群体的函数、青春期行为风险因素在抑郁症和临床前生理结果之间的联系中的作用、压力和风险变量的发展轨迹对先证者同胞生理结果的影响，以及抑郁症最具“心脏毒性”的临床特征。我们对受试者的精神病史、家庭压力事件、父母心血管疾病史、社会人口统计学变量以及冠心病的各种行为风险因素进行了大量档案数据，将得出抑郁症、行为风险因素和冠心病风险早期标志之间正在发展的关系的独特特征。兄弟姐妹设计将通过控制几个基于家庭的变量对健康的不利影响，帮助隔离抑郁症对冠心病早期风险标志物的影响。考虑到抑郁症和冠心病造成的公共卫生负担，他们对年轻人的研究特别有必要，因为冠心病风险的危险因素和/或临床前迹象可能更容易在生命周期的早期而不是后期进行改变。

DESCRIPTION (provided by applicant): In this revised application, we addressed the IRG's concerns: we clarified the number/type of assessments on the 3 subject groups; proposed a further Hypothesis that mirrors better the use of childhood archival data about probands and their sibs; added ICAM-1 to our biological markers; and responded to various other concerns. Our study focuses on depression and coronary heart disease (CHD), which are enormous public health problems across the world. Depression not only predicts new onset CHD, and morbidity, and mortality in those with existing CHD but also is associated with behavioral risk factors (e.g. smoking, being sedentary) for eventual CHD. Although the depression-CHD link is well established, the causal role of depression is still being debated, and its most "cardiotoxic" features are yet to be confirmed. Notably, although both depression and CHD often originate in the pre-adult years, few studies have examined their association with behavioral CHD risk factors in a developmental context. We propose to assess 3 established samples of young adults in Hungary: a) probands (n=325), whom we have followed since childhood, when they had their first episode of major depression around the mean age of 9 years, b) never-depressed siblings of probands (n=325), and c) normal peer controls (n=155). We recently reported that: a) proband families have elevated rates of parental CV disease, b) by adolescence (mean age=17 years), being a proband predicted increased rates of behavioral risk factors for CHD (e.g., smoking, being sedentary), and c) rates of behavioral risk factors were highest among probands, lowest among controls, and intermediate among never depressed siblings of probands. The goal of the proposed study is to assess, for the first time, traditional biological risk factors (e.g., LDL cholesterol, blood pressure), along with behavioral risk factors, and several markers of CHD risk: pulse wave velocity, interleukin-6 and C-reactive protein (inflammation), ICAM-1 (endothelial function), and the metabolic syndrome. Our hypotheses address the levels of CHD risk markers as a function of subject group, the role of behavioral risk factors in adolescence in the link between depression and preclinical physiological outcomes, the impact of developmental trajectories of stress and risk variables on physiological outcomes among probands-sibs, and the most "cardiotoxic" clinical features of depression. Our extensive archival data on subjects' psychiatric history, family stress events, parental history of cardiovascular disease, socio-demographic variables, and various behavioral risk factors for CHD will yield a unique characterization of the unfolding relationships among depression, behavioral risk factors, and early markers of CHD risk. The sibling design will help isolate the contribution of depression to early markers of CHD risk by controlling for the adverse health impact of several family-based variables. Given the public health burden posed by depression and CHD, their study in young adults is particularly warranted, because risk factors and/or preclinical signs of CHD risk may be easier to modify earlier, rather than later, in the lifespan.