Risk for Adolescent Depression: Stress, Cognitive Vulnerability, & Inflammation

描述(申请人提供)：抑郁症状和诊断率在15-18岁之间显著上升。尽管具有科学和公共卫生意义，但导致青少年抑郁症激增的机制尚不完全清楚。认知脆弱-应激模型对我们理解青春期抑郁症发病率的增加做出了重要贡献；然而，这些模型没有充分解释一些躯体症状，也没有纳入认知脆弱引起抑郁的生物应激机制。另一项关于抑郁症免疫相关性的令人兴奋的研究强调了促炎途径的作用；然而，只有一些抑郁的人表现出炎症。这个项目提供了一种新颖而引人注目的整合认知脆弱性-压力框架和应用于青春期的抑郁症的促炎模型。当分开考虑时，这项研究有可能解决两种模型面临的困惑和局限性。这些发现可能有助于解释抑郁症状的全部范围，并确定认知脆弱的人特别可能表现出细胞因子失调的迹象和对应激事件的反应增加。此外，众所周知，儿童早期的逆境既会导致认知脆弱性的发展，也会导致促炎偏见的发展。主要目标是确定炎症状态与认知脆弱性、压力和童年逆境相结合所起的作用，这些因素是青少年抑郁症上升的基础。一项为期4年的多波前瞻性研究将对300名青少年进行现有的、具有良好特征的社区样本，其中包括数量相似的男性和女性、高加索人和非裔美国人，这些青少年刚刚达到抑郁症急剧上升的关键年龄。我们将每年抽血评估促炎症和调节性细胞因子(由7种细胞因子组成的多细胞因子阵列)和C反应蛋白(CRP)，同时每6个月进行一次生活压力、抑郁和焦虑症状的持续评估。每年将获得认知缺陷、抑郁和焦虑的诊断，以及这一独特的城市青少年队列中童年逆境的历史。我们还将检测白细胞介素6(IL-6)对急性应激源(Trier社会压力测试)的反应，以确定个体差异如何在 认知反应转化为IL-6释放的增加。这个项目填补了一门重要的知识 关于青春期免疫的正常发育及其在青春期抑郁症急剧上升中的作用的差距。它可能导致针对抑郁症的新干预措施，目标是认知影响细胞因子对压力的反应，以及通过药物操作细胞因子来解决疲劳、快感丧失和戒断等症状。

DESCRIPTION (provided by applicant): Rates of depressive symptoms and diagnoses rise markedly between ages 15-18. Despite the scientific and public health significance, the mechanisms responsible for the adolescent surge in depression are not fully understood. Cognitive vulnerability - stress models have contributed importantly to our understanding of the increased incidence of depression in adolescence; however, these models do not adequately explain some of the somatic symptoms or incorporate biological stress mechanisms through which cognitive vulnerability evokes depression. A separate exciting body of research on immune correlates of depression has highlighted the role of proinflammatory pathways; yet, only some depressed individuals exhibit inflammation. This project provides a novel and compelling integration of the cognitive vulnerability - stress framework and the proinflammatory model of depression as applied to adolescence. The research has the potential to solve puzzles and limitations faced by both models when considered separately. The findings may help to account for the full spectrum of depressive symptoms and identify cognitively vulnerable individuals as especially likely to evince signs of cytokine dysregulation and increased reactivity to stressful events. Moreover, it is known that early childhood adversity contributes to both the development of cognitive vulnerability and a proinflammatory bias. The primary goal is to determine the role of inflammatory states in combination with cognitive vulnerabilities, stress, and childhood adversity as contributors that underlie the rise in adolescent depression. A multiwave, 4-year prospective study will be conducted with an existing, well-characterized community sample of 300 adolescents, including similar numbers of males and females and Caucasians and African-Americans, just reaching the critical age when the dramatic rise in depression begins. We will conduct yearly blood draws to assess proinflammatory and regulatory cytokines (a multicytokine array of 7 cytokines) and C-reactive protein (CRP), in parallel with ongoing assessments of life stress and depression and anxiety symptoms every 6 months. Cognitive vulnerabilities and depression and anxiety diagnoses will be obtained yearly, along with a history of childhood adversity in this unique cohort of urban adolescents. We also will examine interleukin-6 (IL- 6) reactivity to an acute stressor (Trier Social Stress Test) to determine how individual variation in cognitive reactivity translates into increased IL-6 release. This project fills a crucial knowledge gap about normal development of immunity in adolescence and its role in the dramatic rise in adolescent depression. It may lead to novel interventions for depression that target cognitive influences on cytokine responses to stress, as well as pharmacological manipulations of cytokines to address symptoms such as fatigue, anhedonia, and withdrawal.