Essential Fatty Acids In Psychiatric Disorders

精神疾病中的必需脂肪酸

• 批准号: 7146649
• 负责人: JOSEPH R. HIBBELN
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7146649
• 关键词: aggression; alcoholism /alcohol abuse; behavior test; behavioral /social science research tag; chemoprevention; child behavior disorders; child psychology; clinical depression; clinical trials; conduct disorder; developmental nutrition; diet therapy; dietary lipid; essential fatty acids; human subject; human therapy evaluation; mental disorder chemotherapy; mental health epidemiology; mother /embryo /fetus nutrition; nutrition related tag; omega 3 fatty acid; pathogenic diet; patient oriented research; seafood; simvastatin; suicide; unsaturated fatty acids

This project examines whether inadequate dietary intake of omega-3 essential fatty acids increases the risk for pathological traits and behaviors associated with alcoholism, specifically depression, aggression and suicide. Randomized placebo-controlled clinical intervention trials continue to be conducted in adult populations of aggressive alcoholics, women with depression during pregnancy and suicide attempters. These studies have been stimulated by the discovery that there are large differences in the prevalence of several psychiatric disorders amongst populations with high or low measurese of seafood consumption, which was further verified by examinations of omega-3 fatty acid tissue concentrations in epidemiological studies. Furthermore, it has been found that nutritional inadequacies during early development may leave residual neuropsychiatric deficits which contribute to an increased predisposition toward psychiatric disorders in adulthood. Developmental outcome studies are discussed below. In our ongoing clinical trial of aggressive alcoholics, the key questions are to assess if treatment with 2.8 g/d of omega-3 fatty acids will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotonergic function, and 3) improve cardiovascular measures thought to be associated with depressive and violent behaviors. This protocol is active and has enrolled 47 subjects with 100% tracking of data. Preliminary results indicate that anger is reduced by 33% (p<0.0008) and that there is a trend towards reduction in number of relapse days (55%, p= ns). Completion of the study is estimated for autumn 2007. In collaboration with Garth Bissette, PhD, we determined that low plasma DHA levels predict elevated levels of corticotrophin releasing hormone in the CSF of perpetrators of domestic violence. This finding, now in press, may lead to down regulation of the HPA axis through dietary changes. This proposition is currently being tested in our placebo-controlled, intervention trial of aggressive alcoholics. In collaboration with Laure-Budens Branchey, M.D., we published that low plasma levels of DHA and AA predicted relapse among cocaine and alcohol dependent subjects over the course of two years. Preliminary results of a placebo controlled clinical trial with Dr. Branchey indicates that anger scores are reduced by 50% over 4 months. In a collaborative trial among subjects admitted to an emergency room with deliberate self harm, we found that 2 g/d of omega-3 fatty acids reduced future suicidal thinking, anger and depression scores while improving positive outlooks to life. 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=20 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). In clear dose-response relationships, deficient intakes were associated with nearly a doubling of the risk of depressive symptoms (EPDS >12) at 32 weeks gestation (p<1.4 X 10-17) and 18 weeks gestation and at both 8 weeks and 8 months postpartum. Findings were robust after rigorous examination of potential confounding factors. Deficient intake of omega-3 essential fatty acids during early development may also have adverse residual effects on the behaviors of children. In collaboration with the ALSPAC study, we found that deficient intake of omega-3 fatty acids during pregnancy were related to a doubling of the risk of adverse behavioral disorders among children at both 3.5 and 7 years of age. A dose response relationship predicted such parameters as increased risk of conduct disorders: fighting, lying, stealing, disobedience, which are well recognized risk factors for future sociopathic and criminal behaviors. 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. These data can be evaluated to determine if inadequate intake during pregnancy or early childhood is a risk factor for future substance abuse. If this is identified as a risk factor, prevention studies can be planned. A significant finding was that compliance with the FDA and EPA advisory for women to limit seafood consumption during pregnancy, to avoid methyl-mercury, inadvertently creates harm in the specific developmental domains in which protection was intended. The ALSAPC study was examined by either compliance or exceeding intake described by the advisory. These finding are currently being prepared for publication. In a prior cross-national analysis we found higher rates of homicide mortality were correlated to lower rates of seafood consumption. In order to further refine this finding we utilized the observation that the omega-6 fatty acids from seed oils compete for space in the tissues with omega-3 fatty acids, which are rich in seafood. We found that from 1950 to 2000, the increasing rates of homicide mortality were closely correlated with increasing availability omega-6 fatty acids in the food supply, in the USA, the United Kingdom, Australia and Canada. This association is also consistent with observational and interventional data for violence and hostility published by other investigators. In collaboration with Dr. Carlos Iribarren, we examined the dietary intake of omega-3 fatty acids and behavioral correlates among the 4,000 subjects in the CARDIA trial. Lower intake of DHA and other omega-3 fatty acids predicted a doubling of the risk of reporting clinically significant measures of hostility. In an intervention trial conducted in collaboration with Dr. Muldoon at the University of Pittsburgh, subjects with hypercholesterolemia were given either Simvistatin, (a cholesterol lowering drug) or a placebo for 8 weeks. We quantified changes in mood, cognition and plasma concentrations of essential fatty acids. Treatment with Simvistatin lowered total fatty acid concentrations, but spared DHA and AA. The relationship between the sparing of these essential fatty acids and improvements or decrements in mood and cognition are still under examination.

该项目研究了omega-3必需脂肪酸的饮食摄入是否不足会增加与酒精中毒相关的病理特征和行为的风险，特别是抑郁症，侵略性和自杀。随机安慰剂对照的临床干预试验继续在成年侵略性酗酒者，怀孕期间患有抑郁症的妇女和自杀时间的成年人群中进行。这些研究已经被发现刺激了这些研究，即在流行病学研究中，欧米茄3脂肪酸组织浓度的检查进一步验证了海鲜消耗量高或低的人群中几种精神疾病的患病率。此外，已经发现，早期发育过程中的营养不足可能会留下残留的神经精神缺陷，这会导致对精神疾病的倾向增加。发展结果研究将在下面讨论。 在我们正在进行的侵略性酗酒者的临床试验中，关键问题是评估2.8 g/d的omega-3脂肪酸的治疗是否会减少1）侵略性行为，2）改善血清素能功能的神经化学测量，以及3）改善心血管措施，被认为与抑郁和剧烈行为相关。该协议是有效的，并且已经招募了47名受试者，并具有100％跟踪数据的受试者。初步结果表明，愤怒降低了33％（p <0.0008），并且有减少复发天数的趋势（55％，p = ns）。该研究的完成估计是2007年秋季的。与Garth Bissette，PhD合作，我们确定低血浆DHA水平可以预测家庭暴力犯罪者CSF中皮质营养素释放激素的水平升高。现在在印刷中，这一发现可能会导致通过饮食变化减少HPA轴的调节。目前，我们正在对我们的安慰剂对照，侵略性酗酒者的干预试验进行了测试。 在与医学博士Laure-Budens Branchey合作的情况下，我们发表了低血浆DHA和AA的水平，预测可卡因和酒精依赖受试者的复发在两年的过程中。安慰剂对照临床试验的初步结果表明，在4个月内，愤怒评分降低了50％。 在接受有意自我伤害的急诊室的受试者之间的合作试验中，我们发现2 g/d的Omega-3脂肪酸减少了未来的自杀思维，愤怒和抑郁得分，同时改善了积极的生活方式。 当母亲饮食摄入不足时，母亲在怀孕期间会耗尽omega-3的必要脂肪酸。饮食不足可能会增加母亲的抑郁症状风险。可以从目前与亚利桑那大学的马里兰州玛琳·弗里曼（Marlene Freeman）合作进行抑郁症的女性的Omega-3脂肪酸的开放试验获得初步数据。在治疗8周期间，抑郁症状平均降低了43.5％。这些发现很重要，因为它们在怀孕期间为抑郁症提供治疗，不仅无毒，而且对孕妇及其婴儿具有额外的健康益处。这些发现正在随机进行随机，对照试验，该试验已招募了n = 20名受试者。这些介入试验的结果是从妊娠期间欧米茄3脂肪酸饮食摄入量摄入的近14,500名妇女的饮食摄入量的流行病学研究中预测的。在明确的剂量反应关系中，缺乏摄入量与32周妊娠（P <1.4 x 10-17）和妊娠18周的抑郁症状风险（EPDS> 12）几乎增加了一倍，并且在产后8周和8个月时。严格检查潜在的混杂因素后，发现很健壮。 早期发育过程中对omega-3必需脂肪酸的摄入不足也可能对儿童行为产生不利的残留影响。通过与ALSPAC研究合作，我们发现怀孕期间omega-3脂肪酸的摄入不足与3.5至7岁儿童不良行为障碍的风险增加一倍。剂量反应关系预测了行为障碍风险增加的参数：战斗，撒谎，偷窃，不服从，这是未来社会病和犯罪行为的公认风险因素。我们已经与Marc Schuckit，M.D和Jean Golding博士合作。在设计一项研究以前瞻性地捕获这些儿童进入青春期的初始饮酒行为时。可以评估这些数据以确定怀孕期间或幼儿期间摄入量不足是滥用药物的危险因素。如果将其确定为危险因素，则可以计划预防研究。 一个重要的发现是，符合FDA和EPA咨询妇女在怀孕期间限制海鲜消耗的咨询，以避免甲基汞，无意中会在预期的特定发育领域造成伤害。通过合规性或超过咨询所描述的摄入量来检查ALSAPC研究。这些发现目前正在准备出版。 在先前的跨国分析中，我们发现凶杀死亡率较高与较低的海鲜消耗率相关。为了进一步完善这一发现，我们利用了这样一种观察结果，即从种子油中的omega-6脂肪酸竞争富含海鲜的omega-3脂肪酸的组织中的空间。我们发现，从1950年到2000年，在美国，英国，澳大利亚和加拿大，凶杀死亡率的增加与欧米茄6脂肪酸的可用性增加密切相关。该关联也与其他研究人员发表的暴力和敌意的观察和介入数据一致。与Carlos Iribarren博士合作，我们研究了CARDIA试验中4,000名受试者的omega-3脂肪酸的饮食摄入量和行为相关性。 DHA和其他Omega-3脂肪酸的摄入量较低，预测报告临床上重要的敌对措施的风险增加了一倍。在与匹兹堡大学的Muldoon博士合作进行的一项干预试验中，患有高胆固醇血症的受试者仿生（一种降低胆固醇的药物）或安慰剂进行了8周。我们量化了必需脂肪酸的情绪，认知和血浆浓度的变化。用近似值的治疗降低了总脂肪酸浓度，但保留了DHA和AA。这些必需脂肪酸的保留与情绪和认知减少之间的关系仍在检查中。