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: 10622580
• 负责人: TIFFANY CHEING HO
• 金额: $ 67.48万
• 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/10622580
• 关键词: 17 year old; Address; Adolescent; Age; Amygdaloid structure; Anterior; Antidepressive Agents; Behavioral; Blood specimen; Brain; Cardiovascular Diseases; Chronic; Clinical; Clinical assessments; Cluster Analysis; Data; Development; Disease remission; Evaluation; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutamates; Goals; Heterogeneity; Hippocampus; Immune; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Life Stress; Longitudinal Studies; MRI Scans; Magnetic Resonance Spectroscopy; Maintenance; Measures; Mediating; Mediator; Mental Depression; Mental Health; Mentored Research Scientist Development Award; Moods; Outcome; Peripheral; Pharmaceutical Preparations; Prediction of Response to Therapy; Prefrontal Cortex; Prevalence; Production; Psychosocial Stress; Public Health; Role; Scanning; Selective Serotonin Reuptake Inhibitor; Severities; Stimulus; Stress; Stress Tests; Stressful Event; Subgroup; Suicide; Symptoms; Testing; Therapeutic; Time; Trier Social Stress Test; Vulnerable Populations; Work; behavioral response; child depression; cingulate cortex; cortico-limbic circuits; cytokine; depressive symptoms; design; experience; high risk; improved; machine learning method; multimodal neuroimaging; neural; neurobiological mechanism; novel; open label; peer; physical conditioning; preclinical study; prospective; response; social; social stress; social stressor; therapeutically effective; treatment effect; treatment optimization; treatment planning; treatment risk; treatment-resistant depression

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.

摘要 尽管抑郁症的流行和公共卫生的重要性，高达40%的抑郁症青少年做 对一线抗抑郁药没有反应（即，5-羟色胺选择性再摄取抑制剂（SSRIs）。青少年 治疗无反应（TNR）是在高风险的身体和精神健康问题相关的 抑郁症治疗无效，包括心血管疾病和自杀。因此，识别 青少年TNR的神经生物学机制是优化治疗的关键一步 为那些对一线治疗没有反应的人制定计划。在这种情况下，持续的威胁社会压力， 如通过对应激刺激的升高的炎症特征所测量的，已经显示出驱动发病， 青少年抑郁症的维持与TNR有关。的机制 然而，炎症升高对抑郁青少年大脑的影响尚不清楚。解决这些 在我们的知识的差距，我们将测试我们的中心假设，过量的谷氨酸（Glu）在抑郁症相关的 皮质边缘回路-包括前扣带皮层，腹内侧前额叶皮层，杏仁核， 在抑郁症青少年中，外周炎症和TNR之间的关键中介。 具体来说，我们将对160名未经药物治疗的寻求治疗的抑郁症患者进行一项为期18个月的前瞻性研究。 青少年（14-18岁）在7特斯拉下使用最先进的多模态神经成像数据。在时间1（之前 SSRI治疗）和时间2（开放标签12周SSRI试验后），我们将评估外周指标， 经过充分验证的青少年前后皮质边缘回路中的促炎细胞因子和谷氨酸盐- 特里尔社会压力测试（Trier Social Stress Test，TSST）我们还将使用一个经过充分验证的功能磁共振成像任务， 对消极同伴评价的行为和神经反应，这是青少年社会威胁的一种突出形式。在 时间1，我们将测试TSST是否诱导皮质边缘回路中炎症和谷氨酸的增加， 抑郁的青少年在时间2，我们将使用机器学习方法来识别多个 TNR水平的预测因素，基于对社会持续威胁的行为、炎症和神经指标， 我们还将测试皮质边缘回路中的谷氨酸是否介导基线水平与 炎症和TNR水平。最后，我们将继续临床评估抑郁症症状，并收集 关于社会压力源的信息（例如，背景、严重程度、持续时间），时间点2后每3个月一次，持续15个月 (i.e.,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 青少年抑郁轨迹的基础上（例如，持续性抑郁、逐渐缓解等），以及 识别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状态的影响和治疗的任何变化（以及其他相关因素，包括 压力性生活事件）。这项工作的结果将激励未来的研究测试替代疗法， 抑郁的青少年有患难治性抑郁症的风险。