Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms

衰老过程中抑郁症的实验模型：失眠、炎症和影响机制

基本信息

批准号：
9925164
负责人：
Michael R Irwin
金额：
$ 55.27万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925164
关键词：
Acute Affect Affective Aging Antidepressive Agents Biological Brain region Chronic Clinical Coupled Cytokine Gene Development Disease Disease remission Dose Double-Blind Method Elderly Emotions Endotoxins Experimental Models Face Feeling Fibrinogen Genetic Polymorphism Immune response Infection Inflammation Inflammatory Inflammatory Response Intervention Ketamine Learning Measures Mental Depression Modeling Molecular Target Monitor Morbidity - disease rate Older Population Patient Self-Report Pharmacology Placebos Preventive Intervention Public Health Randomized Recurrence Rewards Risk Sex Differences Signal Transduction Sleep disturbances Sleeplessness Stress Translating Woman base depressed patient depression model depression prevention depressive symptoms effective intervention emotion regulation geriatric depression high risk population improved men mortality negative affect prevent primary outcome prospective response reward processing sex sleep behavior social

项目摘要

Depression, one of the most common diseases in older adults, carries significant risk for morbidity and mortality. Because of the burgeoning population of older adults, the enormous burden of late-life depression, and the limited efficacy of current antidepressants in older adults, biologically plausible models that translate into depression prevention efforts are needed. Insomnia predicts depression recurrence, and is a modifiable target for depression prevention. Yet, it is not known how insomnia gets converted into biological- and affective risk for depression, which is critical for identification of molecular targets for pharmacologic interventions, and for refinement of insomnia treatments that target affective responding to improve efficacy. This study will use an inflammatory challenge (i.e., endotoxin) to probe acute inflammatory- and depression responses (primary outcome) in older adults as a function of insomnia. Older adults with insomnia show chronic inflammation; sleep disturbance also activates inflammatory signaling; chronic inflammation primes acute inflammatory responses; chronic inflammation, as well as acute inflammatory reactivity, predict depression over the following year; and finally, endotoxin induces acute inflammation along with depressive symptoms, with preliminary evidence that “two-hits” (i.e., sleep disturbance and inflammatory challenge) are associated with exaggerated increases in depression, especially in women. In this placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (60-80 y; stratified by sex) with insomnia (n=80) vs. comparisons without insomnia (n=80), we hypothesize that older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. We aim to: 1) examine differences in depressive symptoms and measures of negative affect responding as a function of insomnia and inflammatory challenge; 2) examine differences in measures of positive affect responding as a function of insomnia and inflammatory challenge; and 3) examine differences in experimentally-induced inflammation in relation to depressive symptoms and measures of negative- and positive affect responding as a function of insomnia. If the hypotheses are confirmed, older adults with two “hits”, insomnia and inflammation, would represent a high risk group to be prioritized for monitoring and for depression prevention efforts using treatments that target insomnia or inflammation. Moreover, this study will inform the development of mechanism-based treatments that target affect responses in addition to sleep behaviors, and which might also be coupled with efforts to reduce inflammation to optimize efficacy of depression prevention.

抑郁症是老年人最常见的疾病之一，具有发病率和死亡。由于老年人迅速迅速的人口，后期抑郁症的巨大伯恩（Burnen）以及老年人当前抗抑郁药的效率有限，在生物学上是合理的模型需要预防抑郁症。失眠预测抑郁症复发，是一种可修改的预防抑郁症的目标。但是，尚不知道失眠是如何转化为生物学和情感的抑郁症的风险，这对于鉴定药物干预措施的分子靶标非常重要，并且用于细化失眠治疗，以靶向情感反应以提高效率。这项研究将使用炎症性挑战（即内毒素）探测急性炎症和抑郁反应（主要结局）在老年人中与失眠有关。失眠的老年人表现出慢性炎症；睡眠障碍还激活炎症信号传导；慢性炎症急性炎症回应；慢性炎症以及急性炎症反应性，预测以下年;最后，内毒素诱导急性炎症以及抑郁症状，初步 “两击”（即睡眠障碍和炎症挑战）与夸张有关的证据抑郁症的增加，尤其是女性。在安慰剂对照，随机，双盲研究中老年人的低剂量内毒素（60-80 y；通过性别分层）失眠（n = 80）与没有的比较失眠（n = 80），我们假设失眠的老年人会显示出炎症性和与没有失眠的炎症挑战相比，情感应对炎症挑战。我们的目标是：1）检查抑郁症状的差异和负面影响的措施与失眠和炎症挑战； 2）检查积极影响响应的测量差异失眠和炎症挑战； 3）检查实验引起的炎症的差异与抑郁症状以及负面影响和积极影响的措施的关系失眠。如果确认假设，则具有两个“命中”，失眠和炎症的老年人，将会代表一个高风险群体，要优先进行监视和预防抑郁症的努力靶向失眠或注射的治疗方法。此外，这项研究将为发展基于机制的治疗方法，除了睡眠行为外影响反应，并且可能还可能与减少感染的努力相结合以优化预防抑郁症的效率。