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是一个紧迫的问题，这可能反映了重性抑郁症（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 (COPD哮喘、吸烟），这意味着慢性缺氧加重了MDD状态，增加了TRD的患病率并提高了自杀风险。我们计划使用一种新的缺氧相关抑郁症的转化动物模型来测试目前标准治疗（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，该提案符合BLR&D计划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（COPD，哮喘，吸烟）的人暴露于慢性缺氧。在动物模型中，低压缺氧（在高海拔地区经历的低氧水平）降低了大脑5-羟色胺水平，低大脑5-羟色胺可以降低选择性5-羟色胺再摄取抑制剂（SSRI）的疗效，SSRI是最常见的处方AD和退伍军人人群的首选AD。 使用一种新的动物模型，我们发现在海拔（4500，10，000或20，000英尺）一周后，雌性大鼠在FST中比在海平面上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。未来的研究将采用FST和蔗糖偏好试验分析大鼠的DLB，并进一步评价OFT治疗的运动效应。在我们的模型中，低压缺氧也降低了大鼠脑纹状体5-羟色胺和前脑总肌酸（一种脑生物能标记物），并降低了SSRI氟西汀（百忧解）在FST中的疗效。前脑肌酸水平也出现类似的下降， 居住在海拔（4500英尺）与海平面的人。 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的发生率增加，自杀风险增加，这意味着需要针对慢性缺氧中MDD的治疗选择。因此，我们计划在低压缺氧中初步测试来自肾上腺素能和去甲肾上腺素能类别的SOC AD的功效，以优化SOC AD在慢性缺氧退伍军人中的使用。然后，我们计划测试5-羟色氨酸（5 HTP，以提高大脑血清素水平），肌酸（以提高大脑生物能量学），以及5 HTP+肌酸的组合，每种±SSRI治疗，作为降低MDD和改善SSRI在慢性缺氧退伍军人TRD中的疗效的选择。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，在退伍军人中特别普遍：退伍军人的MDD率升高，抑郁症合并症高，自杀率明显高于普通大众。女性退伍军人更严重地受到抑郁症的影响：退伍军人管理局27%的女性接受MDD治疗，女性退伍军人报告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。退伍军人中的自杀意念与女性性别和MDD诊断高度相关。2005年至2007年期间，18-29岁退伍军人的自杀率从每10万人45人增加到57人，明显高于美国普通人口的每10万人12.4人。此外，在VHA接受治疗的人中有20%患有COPD，40%的年轻退伍军人是吸烟者，这些人和其他患有慢性缺氧疾病的退伍军人患MDD、TRD和自杀的风险增加。在2300万美国退伍军人中，VA系统中有200多万是女性退伍军人，近200万退伍军人生活在高海拔的落基山脉州，其中很大一部分患有慢性缺氧疾病，如COPD，哮喘和吸烟。因此，改善缺氧相关抑郁症和其他形式TRD的AD疗效的策略可能会对退伍军人社区的心理健康状况和寿命产生重大影响。