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）： 退伍军人最近自杀率的升级令人担忧，这可能反映出严重抑郁症（MDD）和耐治疗抑郁症（TRD）的高率。较高的MDD和自杀率与生活在高度以及慢性低氧疾病之间有关 （COPD，哮喘，吸烟），这意味着慢性缺氧增强了MDD状态，增加了TRD的患病率并提高了自杀风险。我们计划使用一种与缺氧相关抑郁症的新型动物模型，我们计划测试当前护理标准（SOC）抗抑郁药（AD）在慢性缺氧中的有效性，并探索MDD在慢性缺氧中的替代治疗选择，并特别关注女性。 BLR＆D计划感兴趣的8个优先研究领域中有3个：预防自杀，妇女健康和危险行为（吸烟）。居住在海拔高度或缺氧疾病（COPD，哮喘，吸烟）的人患有慢性缺氧。在动物模型中，低碱性缺氧（高氧气水平低）降低了脑血清素水平，而低脑血清素可以降低选择性5-羟色胺再摄取抑制剂（SSRIS）的效率，最常见的规定的广告，是资深人群的选择广告。使用新型的动物模型，我们发现，在海拔一周的住房（4500、10,000或20,000英尺）之后，雌性大鼠在FST与海平面的抑郁症状行为（DLB）明显更多，在开放式测试（OFT）中，运动行为不变。未来的研究将通过FST和蔗糖偏好测试分析大鼠的DLB，并进一步评估与OFT治疗的运动作用。在我们的模型中，低碱性缺氧还降低了大鼠的脑纹状体5-羟色胺和前脑总创造（脑生物能标记），并降低了FST中SSRI氟西汀（Prozac（r））的有效性。在 居住在海拔高度（4500英尺）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定义，从而导致MDD和TRD的发生率提高，并且自杀风险较高，这意味着需要在慢性缺氧中对MDD特定的治疗选择。因此，我们计划最初测试低刺激性缺氧中5-羟色胺能和去甲肾上腺素能类别的SOC AD效率，以优化患有慢性缺氧退伍军人的SOC AD使用。然后，我们计划使用5-羟基trypophan（5HTP，以提高脑血清素水平），创建（增强脑生物能力）和5HTP+肌酸的组合，每种±SSRI治疗，以降低MDD和SSRI的效率，以提高TrdD indd indd indd indd indd indd consronicaia效率。这些研究的数据有望大大降低退伍军人人口的自杀风险。在退伍军人中，一种慢性疾病，抑郁症尤为普遍：战斗退伍军人的MDD率升高，抑郁症的高度合并症高，自杀率明显高于公众。女性退伍军人甚至受到抑郁症的严重影响：VA的27％的女性接受了MDD治疗，而妇女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。退伍军人中的自杀念头与女性性别和MDD诊断高度联系。在2005年至2007年之间，18-29岁退伍军人的自杀率从每100,000人的45人增加到57，显着高于美国普通人口，为每100,000人12.4。同样，在VHA治疗的患者中有20％患有COPD，40％的年轻退伍军人是吸烟者，而处理慢性低氧条件的这些退伍军人和其他退伍军人患MDD，TRD和自杀的风险增加。在VA系统中，超过200万的美国退伍军人是女性退伍军人，近200万退伍军人居住在落基山脉的高海拔地区，很大一部分患有COPD，哮喘和吸烟等慢性低氧状况。因此，提高与缺氧相关抑郁症和其他形式的TRD的AD效率的策略可能会对资深社区的心理健康状况和寿命产生重大影响。