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，具有极大的发病风险和 死亡率。由于老年人口的迅速增长，晚年抑郁症的巨大负担， 以及目前抗抑郁药物在老年人中的有限疗效，生物学上看似合理的模型将 转化为预防抑郁症的努力是必要的。失眠预示着抑郁症的复发，而且是一种可修改的 抑郁症预防的目标。然而，目前还不知道失眠是如何转化为生理的和情感的。 抑郁症的风险，这对于确定药物干预的分子靶点至关重要，以及 用于精炼针对情感反应的失眠治疗，以提高疗效。这项研究将使用 探索急性炎症和抑郁反应的炎性挑战(即内毒素)(主要 结果)在老年人中作为失眠的一种功能。失眠的老年人表现为慢性炎症； 睡眠障碍也会激活炎症信号；慢性炎症引发急性炎症 反应；慢性炎症，以及急性炎症反应，预示以下方面的抑郁 最后，内毒素引起急性炎症和抑郁症状，初步的 有证据表明“两次打击”(即睡眠障碍和炎症挑战)与夸张有关 抑郁症的增加，尤其是在女性。在这项安慰剂对照、随机、双盲研究中 患有失眠的老年人(60-80岁；按性别分层)(n=80)的低剂量内毒素与没有失眠的对照 失眠(n=80)，我们假设失眠的老年人会表现出高度的炎症性--和 与不失眠的人相比，对炎症性挑战的情感反应。我们的目标是：1)检查 抑郁症状和负性情绪反应作为失眠和抑郁反应的功能的差异 炎症性挑战；2)检查作为以下函数的积极情绪反应测量的差异 失眠和炎症挑战；以及3)检查在实验诱导的炎症中的差异 抑郁症状与消极情绪反应和积极情绪反应的关系 失眠。如果这些假设得到证实，失眠和发炎这两种情况下的老年人会 代表要优先进行监测和抑郁症预防工作的高危群体 针对失眠或炎症的治疗。此外，这项研究将为 除了睡眠行为外，针对影响反应的基于机制的治疗，也可能 配合消炎的努力，以优化抑郁症预防效果。

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.