Essential Fatty Acids In Psychiatric Disorders

精神疾病中的必需脂肪酸

基本信息

批准号：
8148172
负责人：
Joseph Hibbeln
金额：
$ 38.5万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Increasing rates of suicide among military personnel are of great concern to the Department of Defense. We evaluated the serum fatty acid status from n=800 Military suicide deaths and n=800 matched controls. We found that that all US Military personnel studied had low levels of docosahexaenoic acid and with in this narrow range, the lowest levels were associated with a75% increase risk of suicide death. We are proposing to evaluate if restoring adequate omega-3 fatty acid nutritional status can reduce or prevent neuropsychiatric harm among military personnel. In Oct 2010, we organized an international workshop entitled "Nutritional Armor for the Warfighter: Can Omega-3 Fatty Acids Enhance Resilience, Wellness and Optimize Performance". In conjunction with this conference we modeled fatty acid intake of a typical US Garrison diet and modeled enhancement of the omega-3 content of this diet to deliver our estimations of adequate daily intakes of long chain omega-3 fats. The conclusions of this workshop has reached the US Army Surgeon general and the Chairman of the Joint Chiefs of Staff who have directed further evaluation of this issue. Dietary intakes that meet criteria for Recommended Daily Intakes (RDAs) have been calculated from two sources of data: cross-national data sets and the ALSPAC cohort study. Dose response relationships were derived comparing greater intake of seafood and lower prevalence rates of four psychiatric disorders and lower mortality rates of eight major causes. These publications are the only calculations of DRI's for long chain omega-3 fatty acids that utilize the Institute of Medicine statistical methodologies. Chronic excessive alcohol consumption depletes brain stores of omega-3 fatty acids which are necessary for optimal neural function. In our ongoing clinical trial of aggressive alcoholics, we determine if treatment with 2.8 g/d of omega-3 fatty acids will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotonergic function as well as other neurotransmitters associate with impulsivity and alcohol use 3) reduce measures of craving 4) reduce risk of relapse. This protocol is active and has enrolled 96 subjects with 100% tracking of data. Preliminary results indicate that anger is reduced by 33% (p<0.0008) in 12 weeks. An unexpected finding was the substantial reduction of heavy drinking days among recovering alcoholics. Those compliant with the protocol in the active group drank 3.2 days/90 while those compliant in the placebo group drank 17 days/ 90. This indicates that treatment with omega-3 fatty acids may have an effect size of 8.4. In comparison the effect size of Naltrexone, also used for relapse prevention , has an effect size of 0.2. These findings complement a placebo controlled clinical trial conducted with collaboration with Laure-Budens Branchey, M.D., among polysubstance dependent subjects where omega-3 fatty acids reduced anger scores by 50% over 4 months. We have collaborated with Marc Schuckit, M.D and Jean Golding, Ph.D. in designing a study to prospectively capture initial drinking behavior of these children as they enter adolescence. If this is identified as a risk factor, prevention studies can be planned. A low level of response (LR), or low sensitivity, to alcohol as established by alcohol challenges has been shown to predict future heavier drinking, alcohol-related problems and alcohol use disorders. We evaluated the ability of SRE scores as determined at age 12 to predict heavier drinking and alcohol-related problems 2 years later in a sample from the United Kingdom, the Avon Longitudinal Study of Parents and Children (ALSPAC). The subjects were 156 boys (54.5%) and girls from t who had reported consuming one or more standard drinks by age 12 and who were followed up 2 years later. Results: The age 12 SRE scores correlated with the number of drinks per week, maximum drinks and the number of alcohol problems both at baseline and at age 14 follow-ups. In these evaluations, a larger number of drinks required for effects on the SRE (i.e. a lower LR per drink consumed) related to heavier intake and alcohol-related difficulties. Simultaneous entry multiple regression analyses revealed that the age 12 SRE score maintained a significant relationship with age 14 higher number of drinks per week and the number of alcohol problems even when the age 12 values for alcohol intake and problems were used as covariates. These data can be evaluated to determine if inadequate intakes of omega-3 fatty acids during pregnancy or early childhood is a risk factor for future substance abuse. In collaboration with Barbara Gracious, MD, we evaluated a randomized placebo controlled trial of flax oil among children with bipolar disorder. We found that when plasma levels of eicosapentaenoic acid rose, the children had substantially fewer severe psychiatric symptoms. These data indicate that supporting the omega-3 status of theses children can substantially complement pharmacological therapies. Mothers can become depleted of omega-3 essential fatty acids during pregnancy when their dietary intake is inadequate. Dietary deficiencies may increase the risk of depressive symptoms for the mothers. Preliminary data is available from an open trial of omega-3 fatty acids among women with depression during pregnancy currently being conducted in collaboration with Marlene Freeman, MD at the University of Arizona. Depressive symptoms were reduced an average of 43.5 % during 8 weeks of treatment. These findings are significant as they offer a treatment for depression during pregnancy that is not only non-toxic, but has additional health benefits to pregnant women and their babies. These findings are being followed up with a randomized, controlled trial which has enrolled n=60 subjects. The results of these interventional trials were predicted from data from an epidemiological study of the dietary intake of omega-3 fatty acids during pregnancy among nearly 14,500 women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). Findings were robust after rigorous examination of potential confounding factors. In a prior publication we found that the 2004 FDA and EPA advisory for women to limit seafood consumption during pregnancy inadvertently creates neurodevelopmental harm to the children. The children of mothers who ate seafood below the limit advised had greater risks of peer problems, poor prosocial behaviors and low verbal IQ and poorer performance on British nationally administered standardized academic tests. The work was conducted in collaboration with the ALSPAC study and examined nearly 9,000 children. These data have formed the core of an FDA model that reevaluates both the risks and benefits of seafood consumption in pregnancy, issued 15 JAN 2009. Appropriate modeling of risks and benefits of seafood consumption requires large numbers of samples Tissue compositional data of trace metals (MeHg,Se,Pb,Fe and Cd) and essential fatty acids, as well as follow up neuropsychaitric assessments among large numbers of subjects. We have completed evaluation of n=4,090 umbilical cord blood samples n=5,853 & year old blood samples and Our collaborator Robert Jones has completed assays of more than n=5,000 samples from early pregnancy. Analyzes of these data are underway but should substantially inform revision of the current FDA/ EPA advisory.

军事人员自杀率的上升引起了国防部的高度关注。我们评估了 n=800 名军人自杀死亡者和 n=800 名匹配对照者的血清脂肪酸状态。我们发现，所有研究的美国军事人员的二十二碳六烯酸水平都较低，在这个狭窄的范围内，最低水平与自杀死亡风险增加 75% 相关。我们建议评估恢复足够的 omega-3 脂肪酸营养状况是否可以减少或预防军事人员的神经精神伤害。 2010年10月，我们组织了一次题为“战士的营养盔甲：Omega-3脂肪酸能否增强弹性、健康和优化表现”的国际研讨会。结合本次会议，我们模拟了美国驻军典型饮食的脂肪酸摄入量，并模拟了该饮食中 omega-3 含量的增加，以提供我们对长链 omega-3 脂肪每日摄入量的估计。这次研讨会的结论已传达给美国陆军军医长和参谋长联席会议主席，他们指示对此问题进行进一步评估。符合推荐每日摄入量 (RDA) 标准的膳食摄入量是根据两个数据源计算得出的：跨国数据集和 ASPAC 队列研究。通过比较更多的海鲜摄入量和四种精神疾病的较低患病率以及八种主要原因的较低死亡率，得出了剂量反应关系。这些出版物是唯一利用医学研究所统计方法对长链 omega-3 脂肪酸 DRI 进行计算的出版物。长期过量饮酒会消耗脑部储存的 Omega-3 脂肪酸，而 Omega-3 脂肪酸是最佳神经功能所必需的。在我们正在进行的攻击性酗酒者临床试验中，我们确定每天 2.8 克 omega-3 脂肪酸治疗是否会减少 1) 攻击性行为，2) 改善血清素能功能以及与冲动和饮酒相关的其他神经递质的神经化学指标3) 减少渴望的措施 4) 降低复发的风险。该协议已启动，已招募 96 名受试者，并 100% 跟踪数据。初步结果表明，12 周内愤怒减少了 33% (p<0.0008)。一个意想不到的发现是戒酒者的酗酒天数大幅减少。活性治疗组中符合方案的参与者每 90 人喝了 3.2 天，而安慰剂组中符合协议的参与者每 90 人喝了 17 天。这表明使用 omega-3 脂肪酸治疗的效果可能为 8.4。相比之下，同样用于预防复发的纳曲酮的效应大小为 0.2。这些发现补充了与医学博士 Laure-Budens Branchey 合作进行的一项安慰剂对照临床试验，该试验在多物质依赖受试者中进行，其中 omega-3 脂肪酸在 4 个月内将愤怒分数降低了 50%。我们与医学博士 Marc Schuckit 和博士 Jean Golding 合作。设计一项研究，前瞻性地捕捉这些儿童进入青春期时的初始饮酒行为。如果这被确定为风险因素，则可以计划预防研究。通过酒精挑战建立的对酒精的低反应水平（LR）或低敏感性已被证明可以预测未来的酗酒、酒精相关问题和酒精使用障碍。我们在英国雅芳父母和儿童纵向研究 (ALSPAC) 的样本中评估了 12 岁时确定的 SRE 分数预测 2 年后酗酒和酒精相关问题的能力。受试者为来自 t 的 156 名男孩（54.5%）和女孩，他们报告在 12 岁时饮用了一种或多种标准饮料，并在 2 年后进行了随访。结果：12 岁时的 SRE 评分与基线和 14 岁时随访时的每周饮酒次数、最大饮酒量以及酒精问题的数量相关。在这些评估中，需要大量饮酒才能对 SRE 产生影响（即每次饮用饮料的 LR 较低），这与大量摄入和酒精相关的困难有关。同时输入多元回归分析显示，即使将 12 岁时的酒精摄入量和问题值用作协变量，12 岁时的 SRE 评分仍与 14 岁时每周饮酒次数和酒精问题的数量保持显着关系。可以对这些数据进行评估，以确定怀孕期间或幼儿期 omega-3 脂肪酸摄入不足是否是未来药物滥用的危险因素。我们与医学博士 Barbara Gracious 合作，评估了一项针对双相情感障碍儿童的亚麻油随机安慰剂对照试验。我们发现，当血浆二十碳五烯酸水平升高时，儿童的严重精神症状明显减少。这些数据表明，支持这些儿童的 omega-3 状态可以极大地补充药物治疗。当母亲在怀孕期间饮食摄入不足时，Omega-3 必需脂肪酸可能会耗尽。饮食不足可能会增加母亲出现抑郁症状的风险。初步数据来自目前与亚利桑那大学医学博士 Marlene Freeman 合作在怀孕期间患有抑郁症的女性中进行的 omega-3 脂肪酸公开试验。治疗 8 周期间，抑郁症状平均减轻 43.5%。这些发现意义重大，因为它们为怀孕期间的抑郁症提供了一种治疗方法，不仅无毒，而且对孕妇及其婴儿有额外的健康益处。一项随机对照试验对这些发现进行了跟踪，该试验招募了 60 名受试者。这些干预试验的结果是根据参加雅芳父母和儿童纵向研究 (ALSPAC) 的近 14,500 名女性怀孕期间 omega-3 脂肪酸饮食摄入量的流行病学研究数据预测的。经过严格检查潜在的混杂因素后，结果是可靠的。在之前的出版物中，我们发现 2004 年 FDA 和 EPA 针对女性在怀孕期间限制海鲜消费的建议无意中对儿童的神经发育造成了伤害。海鲜摄入量低于建议限度的母亲的孩子，出现同伴问题、亲社会行为不良、语言智商低以及在英国国家标准化学术考试中表现较差的风险更大。这项工作是与 ALSPAC 研究合作进行的，对近 9,000 名儿童进行了检查。这些数据构成了 FDA 模型的核心，该模型于 2009 年 1 月 15 日发布，重新评估怀孕期间食用海鲜的风险和益处。对海鲜消费的风险和益处进行适当的建模需要大量样本、微量金属（甲基汞、硒、铅、铁和镉）和必需脂肪酸的组织成分数据，以及对大量受试者的后续神经精神评估。我们已完成对 n=4,090 份脐带血样本（n=5,853 岁）的评估，我们的合作者 Robert Jones 已完成对超过 n=5,000 份早孕样本的分析。对这些数据的分析正在进行中，但应为当前 FDA/EPA 咨询的修订提供重要信息。