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: 9206094
• 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/9206094
• 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; 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令人迫切关注，这可能反映了严重抑郁症(MDD)和难治性抑郁症(TRD)的高比率。更高的MDD和自杀率与居住在高原以及慢性缺氧性疾病有关 (慢性阻塞性肺病、哮喘、吸烟)，意味着慢性缺氧加剧了MDD状态，增加了TRD的患病率，并增加了自杀风险。我们计划使用一种新的低氧相关抑郁的翻译动物模型，测试当前标准护理(SOC)抗抑郁药(AD)在慢性低氧中的疗效，并探索慢性低氧中MDD的替代治疗方案，特别是针对女性。因此，这项建议符合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)。居住在高原或患有缺氧性疾病(慢性阻塞性肺病、哮喘、吸烟)的人暴露在慢性缺氧中。在动物模型中，低压缺氧(在高原经历的低氧水平)会降低大脑5-羟色胺水平，而大脑5-羟色胺水平低会降低选择性5-羟色胺再摄取抑制剂(SSRI)的疗效，选择性5-羟色胺再摄取抑制剂(SSRI)是最常见的处方ADS，也是退伍军人的首选ADS。使用一种新的动物模型，我们发现在海拔(4500英尺、10,000英尺或20,000英尺)居住一周后，雌性大鼠在FST中表现出明显比在海平面上更多的抑郁样行为(DLB)，而在开阔场地测试(OFT)中的运动行为(OFT)没有变化。未来的研究将分析FST和蔗糖偏好试验大鼠的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(一种脑生物能量标志物)，并降低了SSRI氟西汀(Prozac(R))在FST中的疗效。前脑肌酸水平也出现了类似的下降 居住在海拔(4500英尺)与海平面的人。因此，我们的主要假设是，慢性缺氧可能会导致人的神经化学缺陷，导致MDD和TRD的发生率增加，以及更高的自杀风险，这意味着需要针对慢性缺氧中的MDD选择特定的治疗方案。因此，我们计划初步测试5-羟色胺和去甲肾上腺素能类SOC ADS在低压缺氧中的有效性，以优化患有慢性缺氧的退伍军人的SOC AD使用。然后，我们计划测试饮食增加与5-羟色氨酸(5HTP，以提高大脑5-羟色胺水平)，肌酸(以增强脑生物能量学)，以及5HTP+肌酸的组合，每个±SSRI治疗，作为减少MDD和提高SSRI在慢性低氧退伍军人TRD疗效的选项。这些研究的数据有望显著降低退伍军人的自杀风险。抑郁症是一种慢性疾病，在退伍军人中尤其普遍：退伍军人的MDD率较高，抑郁症并存较高，自杀率明显高于普通公众。退伍军人中的女性受抑郁症的影响甚至更严重：退伍军人中27%的女性接受MDD治疗，女性退伍军人报告的抑郁症共患病率和基于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，18岁至29岁退伍军人的自杀率从每10万人中有45人自杀率上升至57人，明显高于美国总人口的每10万人中有12.4人自杀。此外，在VHA接受治疗的人中有20%患有慢性阻塞性肺疾病，40%的年轻退伍军人吸烟，这些退伍军人和其他患有慢性低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，退伍军人系统中有200多万是女性退伍军人，近200万退伍军人生活在高海拔落基山脉州，其中很大一部分人患有慢性阻塞性肺病、哮喘和吸烟等慢性缺氧疾病。因此，在低氧相关性抑郁症和其他形式的TRD中提高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。