Improving Therapeutic Options for Hypoxia-related Depression with an Animal Model

通过动物模型改善缺氧相关抑郁症的治疗选择

• 批准号: 9519716
• 负责人: PERRY FRANKLIN RENSHAW
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519716
• 关键词: 5-Hydroxytryptophan; Address; Adult; Altitude; Animal Model; Antidepressive Agents; Area; Asthma; Behavior; Bioenergetics; Brain; Brain region; Bypass; Cerebrum; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Cigarette Smoker; Clinical; Communities; Corpus striatum structure; Creatine; Data; Depression and Suicide; Diagnosis; Diet; Disease; Drops; Etiology; Exhibits; Exposure to; Face; Feeling suicidal; Female; Fluoxetine; Future; Gender; General Population; Goals; Health; Health Status; Health behavior; Housing; Human; Hypoxia; Intervention; Link; Longevity; Major Depressive Disorder; Measures; Mental Depression; Mental Health; Metabolism; Modeling; Motor; Oxygen; Partial Pressure; Population; Post-Traumatic Stress Disorders; Prevalence; Prevention Research; Prosencephalon; Rattus; Reporting; Research Priority; Risk; Risk Behaviors; Saline; Sea; Selective Serotonin Reuptake Inhibitor; Serotonin; Smoking; Sucrose; Suicide prevention; Swimming; System; Testing; Therapeutic; Traumatic Brain Injury; Treatment outcome; Veterans; Woman; Women' s Health; aged; base; combat; comorbid depression; disability; effective therapy; efficacy testing; experience; field study; high risk; improved; interest; male; monoamine; neurochemistry; noradrenergic; novel; novel therapeutics; preference; programs; public health relevance; receptor; reducing suicide; response; standard of care; suicidal risk; suicide rate; treatment effect; treatment-resistant depression; young woman

 DESCRIPTION (provided by applicant): The recent escalation in suicide rates amongst veterans is of urgent concern, likely reflecting high rates of both major depression (MDD) and treatment-resistant depression (TRD). Higher rates of MDD and suicide are linked to living at altitude as well as with chronic hypoxic disorders (COPD, asthma, smoking), implying that chronic hypoxia intensifies MDD status, increases the prevalence of TRD and elevates suicide risk. Using a novel translational animal model for hypoxia-related depression, we plan to test the efficacy of current standard of care (SOC) antidepressants (AD) in chronic hypoxia, and also to explore alternative therapeutic options for MDD in chronic hypoxia, with a special focus on women. This proposal thus meets 3 out of 8 priority research areas of interest to the BLR&D program: Suicide Prevention, Women's Health and Risky Behaviors (Smoking). People residing at altitude or those with hypoxic disorders (COPD, asthma, smoking) are exposed to chronic hypoxia. In animal models, hypobaric hypoxia (the low oxygen levels experienced at altitude) lowers brain serotonin levels, and low brain serotonin can reduce the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed ADs and the ADs of choice for the veteran population. Using a novel animal model, we find that after a week of housing at altitude (4500, 10,000 or 20,000ft), female rats show significantly more depression-like behavior (DLB) in the FST vs. at sea level, with motor behavior in the open field test (OFT) unchanged. Future studies will analyze DLB in rats with the FST and the sucrose preference test and further will evaluate locomotor effects of treatments with the OFT. In our model, hypobaric hypoxia also lowers brain striatal serotonin and forebrain total creatine (a brain bioenergetic marker) in rats, and reduces efficacy of the SSRI fluoxetine (Prozac(r)) in the FST. A similar drop in forebrain creatine levels is also seen in people residing at altitude (4500 ft) vs. at sea level. Our overarching hypothesis therefore is that chronic hypoxia may cause neurochemical deficits in people, leading to increased rates of MDD and TRD, and higher suicide risk, implying the need for therapeutic options specific to MDD in chronic hypoxia. We thus plan to initially test for efficacy of SOC ADs from serotoninergic and noradrenergic classes in hypobaric hypoxia, towards optimizing SOC AD use in veterans with chronic hypoxia. We then plan to test dietary augmentation with 5-hydroxytryptophan (5HTP, to enhance brain serotonin levels), creatine (to enhance brain bioenergetics), and a combination of 5HTP+creatine, each ±SSRI treatment, as options to reduce MDD and improve SSRI efficacy in TRD in veterans in chronic hypoxia. Data from these studies are expected to serve to significantly reduce suicide risk in the veteran population. A chronic disease, depression is particularly prevalent amongst veterans: with elevated MDD rates in combat-returned veterans, high depression comorbidity, and significantly higher suicide rates than the general public. Female veterans are even more severely impacted by depression: 27% of women at the VA are treated for MDD, and women veterans report significantly higher depression comorbidity and MDD-based disability status than male veterans. Suicidal ideation amongst veterans is highly linked to female gender and MDD diagnosis. Suicide rates in veterans aged 18-29 have increased from 45 to 57 per 100,000 between 2005 and 2007, significantly higher than the general US population at 12.4 per 100,000. Also, 20% of those treated at the VHA have COPD and 40% of young veterans are cigarette smokers, and these and other veterans dealing with chronic hypoxic conditions are at increased risk for MDD, TRD and suicide. Of 23 million US veterans, over 2 million in the VA system are female veterans, almost 2 million veterans live in the high altitude Rocky Mountain states, and a significant portion suffer from chronic hypoxic conditions such as COPD, asthma and smoking. Therefore, strategies to improve AD efficacy in both hypoxia-related depression and other forms of TRD are likely to have a significant impact on mental health status and longevity in the veteran community.

 描述（由申请人提供）： 最近退伍军人自杀率的上升值得迫切关注，这可能反映出重度抑郁症（MDD）和难治性抑郁症（TRD）的高发病率。抑郁症和自杀率较高与生活在高海拔地区以及慢性缺氧性疾病有关 （慢性阻塞性肺病、哮喘、吸烟），这意味着慢性缺氧会加剧MDD状态，增加TRD的患病率并增加自杀风险。我们计划使用一种新型的缺氧相关抑郁症转化动物模型来测试当前护理标准（SOC）抗抑郁药（AD）在慢性缺氧中的疗效，并探索慢性缺氧中MDD的替代治疗方案，特别关注女性。因此，该提案满足了 BLR&D 计划感兴趣的 8 个优先研究领域中的 3 个：自杀预防、妇女健康和危险行为（吸烟）。 居住在高海拔地区的人或患有缺氧性疾病（慢性阻塞性肺病、哮喘、吸烟）的人容易遭受慢性缺氧。在动物模型中，低压缺氧（在高海拔地区经历的低氧水平）会降低大脑血清素水平，而低脑血清素水平会降低选择性血清素再摄取抑制剂（SSRI）的功效，SSRI是最常用的AD药物，也是退伍军人群体的首选AD药物。 使用一种新颖的动物模型，我们发现在海拔（4500、10,000或20,000英尺）饲养一周后，与海平面相比，雌性大鼠在FST中表现出明显更多的抑郁样行为（DLB），而在旷场测试（OFT）中的运动行为没有变化。未来的研究将通过 FST 和蔗糖偏好测试来分析大鼠的 DLB，并进一步评估 OFT 治疗的运动效果。在我们的模型中，低压缺氧还会降低大鼠的脑纹状体血清素和前脑总肌酸（一种脑生物能量标志物），并降低 SSRI 氟西汀 (Prozac(r)) 在 FST 中的功效。前脑肌酸水平也有类似的下降 居住在海拔高度（4500 英尺）的人们与居住在海平面的人们。 因此，我们的总体假设是，慢性缺氧可能会导致人们的神经化学缺陷，导致 MDD 和 TRD 发生率增加，以及更高的自杀风险，这意味着需要针对慢性缺氧的 MDD 的治疗方案。因此，我们计划首先测试 5-羟色胺能和去甲肾上腺素能类 SOC AD 在低压缺氧中的功效，以优化 SOC AD 在患有慢性缺氧的退伍军人中的使用。然后，我们计划测试使用 5-羟色氨酸（5HTP，以增强大脑血清素水平）、肌酸（以增强大脑生物能）和 5HTP+肌酸组合（每种±SSRI 治疗）的饮食增强，作为减少 MDD 和提高 SSRI 对慢性缺氧退伍军人 TRD 疗效的选择。这些研究的数据预计将有助于显着降低退伍军人群体的自杀风险。 抑郁症是一种慢性疾病，在退伍军人中尤为普遍：退伍军人的抑郁症发病率较高，抑郁症合并症较高，自杀率也明显高于普通公众。女性退伍军人受抑郁症的影响更为严重：退伍军人管理局 27% 的女性接受 MDD 治疗，女性退伍军人报告的抑郁症合并症和基于 MDD 的残疾状况明显高于男性退伍军人。退伍军人的自杀意念与女性性别和抑郁症诊断密切相关。 2005 年至 2007 年间，18 至 29 岁退伍军人的自杀率从每 10 万人 45 人上升到 57 人，明显高于美国总人口每 10 万人 12.4 人的自杀率。此外，在 VHA 接受治疗的人中有 20% 患有慢性阻塞性肺病，40% 的年轻退伍军人吸烟，这些人和其他患有慢性缺氧状况的退伍军人患 MDD、TRD 和自杀的风险增加。在 2300 万美国退伍军人中，退伍军人管理局系统中有超过 200 万是女性退伍军人，近 200 万退伍军人生活在高海拔的落基山脉各州，其中很大一部分患有慢性缺氧疾病，如慢性阻塞性肺病、哮喘和吸烟。因此，提高 AD 对缺氧相关抑郁症和其他形式 TRD 的疗效的策略可能会对退伍军人群体的心理健康状况和寿命产生重大影响。