Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents with Depression: Toward Predictors of Treatment Response and Clinical Course

抑郁症青少年持续威胁的炎症和谷氨酸机制：治疗反应和临床过程的预测因子

• 批准号: 10755122
• 负责人: TIFFANY CHEING HO
• 金额: $ 90.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755122
• 关键词: Inflammatory; Glutamatergic; Mechanisms; Sustained; Threat

ABSTRACT Despite the prevalence and public health significance of depression, up to 40% of depressed adolescents do not respond to first-line antidepressants (i.e., serotonin selective reuptake inhibitors [SSRIs]). Adolescents with treatment non-response (TNR) are at high risk for physical and mental health difficulties associated with ineffectively treated depression, including cardiovascular disease and suicide. Thus, identifying the neurobiological mechanisms that underlie TNR in adolescents is a critical step toward optimizing treatment plans for those who do not respond to first-line treatments. In this context, sustained threat to social stressors, as measured by elevated inflammatory profiles to stressful stimuli, has been shown to drive the onset and maintenance of depression among adolescents and is associated with TNR. The mechanisms by which elevated inflammation impact the brain in depressed adolescents, however, are unclear. To address these gaps in our knowledge, we will test our central hypothesis that excessive glutamate (Glu) in depression-related corticolimbic circuits—including the anterior cingulate cortex, ventromedial prefrontal cortex, amygdala, and hippocampus—is a critical mediator between peripheral inflammation and TNR in depressed adolescents. Specifically, we will conduct a prospective 18-month study of 160 unmedicated treatment-seeking depressed adolescents (ages 14-18) using state-of-the-art multimodal neuroimaging data at 7 Tesla. At Time 1 (prior to SSRI treatment) and Time 2 (after an open-label 12-week SSRI trial), we will assess peripheral measures of pro-inflammatory cytokines and glutamate in corticolimbic circuits before and after a well-validated adolescent- version of the Trier Social Stress Test (TSST). We also will use a well-validated fMRI task designed to probe behavioral and neural responses to negative peer evaluation, a salient form of social threat for adolescents. At Time 1, we will test if TSST induces increases in inflammation and glutamate in corticolimbic circuits in unmedicated adolescents with depression. At Time 2, we will use machine learning methods to identify multi- level predictors of TNR based on behavioral, inflammatory, and neural indicators of sustained threat to social stress; we will also test whether glutamate in corticolimbic circuits mediates the association between baseline levels of inflammation and TNR. Finally, we will continue to clinically assess depression symptoms and collect information on social stressors (e.g., context, severity, duration) every 3 months for 15 months following Time 2 (i.e., from Time 3 to Time 7), which will enable us to use functional clustering analyses to identify subgroups of adolescents on the basis of depression trajectories (e.g., persistent depression, gradual remission, etc), and identify predictors of these subgroups and other related clinical outcomes (e.g., remission status), while accounting for the effects of TNR status and any changes in treatment (and other related factors, including stressful life events). Results from this work will motivate future studies testing alternative therapeutics for depressed adolescents at risk for treatment resistant depression.

抽象的 尽管抑郁症具有普遍性和公共卫生的意义，但多达40％的沮丧青少年确实如此 不对一线抗抑郁药反应（即5-羟色胺选择性再摄取抑制剂[SSRIS]）。青少年 治疗无响应（TNR）面临与身体健康困难相关的高风险 无效治疗的抑郁症，包括心血管疾病和自杀。那，确定 青少年中TNR基础的神经生物学机制是优化治疗的关键步骤 对于那些不回应一线治疗的人的计划。在这种情况下，对社会压力源的持续威胁， 通过通过升高到压力刺激的炎症谱升高的那样，已证明可以驱动发作和 维持青少年的抑郁症，与TNR有关。所在的机制 然而，炎症升高会影响抑郁症的青少年的大脑尚不清楚。解决这些 在我们的知识上，我们将测试我们的中心假设，即与抑郁有关的超过谷氨酸（GLU） 皮质唇侧电路 - 包括前扣带回皮质，腹侧前额叶皮层，杏仁核和 海马 - 是抑郁症的青少年炎症和TNR之间的关键介体。 具体而言，我们将对160个未经医学治疗的抑郁症进行预期的18个月研究 青少年（14-18岁）使用7特斯拉的最先进的多模式神经影像学数据。在时间1（之前 SSRI治疗）和时间2（在开放标签为12周的SSRI试验之后），我们将评估外围测量 在验证的青春期 - Trier社会压力测试（TSST）的版本。我们还将使用旨在证明的验证良好的fMRI任务 行为和神经对负面同伴评估的反应，这是青少年的社会威胁的显着形式。 时间1，我们将测试TSST是否诱导皮质降低的炎症和谷氨酸的升高 抑郁症的未药物青少年。在时间2，我们将使用机器学习方法来确定多个 基于行为，炎症和神经指标的TNR的水平预测因素，对社会的持续威胁 压力;我们还将测试Corticolimbic圆圈中的谷氨酸是否介导基线之间的关联 炎症和TNR的水平。最后，我们将继续在临床上评估抑郁症状并收集 关于社会压力源（例如，上下文，严重性，持续时间）的信息，每3个月15个月后2个月2 （即从时间3到时间7），这将使我们能够使用功能聚类分析来识别 青少年在抑郁轨迹（例如，持续的抑郁症，年级缓解等）的基础上， 确定这些亚组和其他相关临床结果的预测因子（例如，缓解状态），而 考虑TNR状况的影响以及治疗的任何变化（以及其他相关因素，包括 压力性的生活事件）。这项工作的结果将激发未来的研究测试替代疗法 抑郁症的青少年有抗治疗抑郁症的风险。