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

抑郁症是老年人最常见的疾病之一，具有显著的发病风险， mortality.由于老年人口的迅速增长，老年抑郁症的巨大负担， 以及目前抗抑郁药在老年人中的有限疗效， 预防抑郁症的努力是必要的。抑郁症复发的预测，是一个可修改的 预防抑郁症的目标。然而，目前还不知道失眠是如何转化为生物和情感的， 抑郁风险，这对于确定药物干预的分子靶点至关重要， 以改善失眠症的治疗，目标是情感反应，以提高疗效。本研究将使用 炎症激发（即，内毒素）以探测急性炎症和抑郁反应（原发性 结果）在老年人中作为失眠的函数。老年人失眠表现为慢性炎症; 睡眠障碍也激活炎症信号;慢性炎症引发急性炎症 反应;慢性炎症以及急性炎症反应，预测抑郁症超过以下 最后，内毒素诱导急性炎症沿着抑郁症状， 证据表明“两次命中”（即，睡眠障碍和炎症激发）与夸大的 抑郁症的增加，尤其是女性。在这项安慰剂对照、随机、双盲研究中， 患有失眠症的老年人（60-80岁;按性别分层）（n=80）中的低剂量内毒素与无内毒素的比较 失眠（n=80），我们假设患有失眠的老年人会表现出更高的炎症反应， 与无失眠者相比，对炎症刺激的情感反应。我们的目标是：1）检查 抑郁症状的差异和作为失眠功能的负面情绪反应的测量， 炎症挑战; 2）检查积极情绪反应的测量值差异，作为 失眠和炎症激发;和3）检查实验诱导的炎症在 与抑郁症状的关系以及作为功能的消极和积极情感反应的测量 失眠如果这些假设得到证实，患有失眠和炎症这两种疾病的老年人， 代表一个高风险群体，优先进行监测和抑郁症预防工作， 针对失眠或炎症的治疗。此外，这项研究将为发展 基于机制的治疗，除了睡眠行为外，还针对影响反应， 再加上努力减少炎症，以优化预防抑郁症的功效。

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.