Irwin Michael R, Boyle Chloe C, Cho Joshua H, Piber Dominique, Breen Elizabeth C, Sadeghi Nina, Castillo Daisy, Smith Michael, Eisenberger Naomi I, Olmstead Richard
Department of Psychiatry and Biobehavioral Sciences, Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Department of Psychiatry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
Brain Behav Immun Health. 2023 Feb 3;28:100601. doi: 10.1016/j.bbih.2023.100601. eCollection 2023 Mar.
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 selective depression prevention strategies are needed. Insomnia predicts depression recurrence and is a modifiable target to prevent incident and recurrent depression in older adults. 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. Sleep disturbance activates inflammatory signaling and primes immune responses to subsequent inflammatory challenge. In turn, inflammatory challenge induces depressive symptoms, which correlate with activation of brain regions implicated in depression. This study hypothesizes that insomnia serves as a vulnerability factor for inflammation-related depression; older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. To test this hypothesis, this protocol paper describes a placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (n = 160; 60-80 y) with insomnia vs. comparison controls without insomnia. The aims of this study are to examine differences in depressive symptoms, measures of negative affective responding, and measures of positive affective responding as a function of insomnia and inflammatory challenge. If the hypotheses are confirmed, older adults with two "hits", insomnia and inflammatory activation, 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.
抑郁症是老年人中最常见的疾病之一，具有很高的发病和死亡风险。由于老年人口的不断增加、晚年抑郁症的巨大负担以及目前抗抑郁药在老年人中的疗效有限，因此需要能够转化为选择性抑郁症预防策略的生物学上合理的模型。失眠可预测抑郁症复发，是预防老年人新发和复发性抑郁症的一个可改变的目标。然而，尚不清楚失眠是如何转化为抑郁症的生物学和情感风险的，这对于确定药物干预的分子靶点以及改进针对情感反应以提高疗效的失眠治疗方法至关重要。睡眠障碍会激活炎症信号，并使机体对随后的炎症刺激产生免疫反应。反过来，炎症刺激会诱发抑郁症状，这与抑郁症相关脑区的激活有关。本研究假设失眠是炎症相关性抑郁症的一个易患因素；与无失眠的老年人相比，有失眠的老年人对炎症刺激会表现出更强的炎症反应和情感反应。为了验证这一假设，本方案文件描述了一项针对有失眠的老年人（n = 160；60 - 80岁）与无失眠的对照者进行的低剂量内毒素安慰剂对照、随机、双盲研究。本研究的目的是检验作为失眠和炎症刺激函数的抑郁症状、负面情感反应指标和正面情感反应指标的差异。如果假设得到证实，同时有失眠和炎症激活这两个“因素”的老年人将代表一个高危群体，应优先进行监测，并使用针对失眠或炎症的治疗方法来预防抑郁症。此外，本研究将为基于机制的治疗方法的开发提供信息，这些治疗方法除了针对睡眠行为外，还针对情感反应，并且可能还会与减少炎症的努力相结合，以优化抑郁症预防的疗效。
