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

摘要 尽管抑郁症的流行率和公共卫生意义重大，但高达40%的抑郁症青少年患有抑郁症 对一线抗抑郁药(即5-羟色胺选择性再摄取抑制剂[SSRIs])不起作用。青少年患有 治疗无反应(TNR)是与以下相关的身心健康困难的高危人群 治疗抑郁症效果不佳，包括心血管疾病和自杀。因此，标识 青少年TNR的神经生物学机制是优化治疗的关键一步 为那些对一线治疗无效的人制定的计划。在这方面，对社会压力源的持续威胁， 通过对应激性刺激升高的炎症反应来衡量，已被证明推动了发病和 青少年中抑郁的维持，并与TNR有关。它们的作用机制 然而，炎症升高对抑郁青少年大脑的影响尚不清楚。要解决这些问题 在我们的知识缺口中，我们将检验我们的中心假设，即过量的谷氨酸(Glu)与抑郁症有关 皮质边缘环路--包括前扣带回皮质、腹内侧前额叶皮质、杏仁核和 海马体-是抑郁青少年外周炎症和TNR之间的关键中介。 具体地说，我们将对160名寻求治疗的抑郁症患者进行为期18个月的前瞻性研究 青少年(14-18岁)在7特斯拉使用最先进的多模式神经成像数据。在时间%1(在 SSRI治疗)和时间2(在为期12周的开放标签SSRI试验之后)，我们将评估 在一名经过充分验证的青少年前后皮质边缘环路中的促炎细胞因子和谷氨酸 特里尔社会压力测试(TSST)的版本。我们还将使用经过充分验证的fMRI任务来探测 对负面同伴评价的行为和神经反应，这是青少年的一种突出的社会威胁形式。在… 时间1，我们将测试TSST是否诱导大鼠皮质边缘环炎症和谷氨酸增加 患有抑郁症的未服用药物的青少年。在第二时间，我们将使用机器学习方法来识别多个 基于对社会持续威胁的行为、炎症和神经指标的TNR水平预测因子 应激；我们还将测试皮质边缘环路中的谷氨酸是否介导基线之间的联系 炎症和TNR水平。最后，我们将继续对抑郁症状进行临床评估并收集 在时间2之后的15个月中，每3个月提供关于社会压力来源(例如，背景、严重程度、持续时间)的信息 (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 基于抑郁轨迹的青少年(例如，持续性抑郁、逐渐缓解等)，以及 确定这些亚组的预测因素和其他相关的临床结果(例如，缓解状态)，同时 考虑到TNR状况的影响和治疗方面的任何变化(以及其他相关因素，包括 有压力的生活事件)。这项工作的结果将激励未来测试替代疗法的研究 抑郁的青少年有患难治性抑郁症的风险。

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.