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.

该项目研究膳食中 omega-3 必需脂肪酸摄入不足是否会增加与酗酒相关的病理特征和行为的风险，特别是抑郁、攻击性和自杀。随机安慰剂对照临床干预试验继续在攻击性酗酒者、怀孕期间患有抑郁症的妇女和自杀未遂者的成人人群中进行。这些研究的发现是，在海鲜消费量高或低的人群中，几种精神疾病的患病率存在​​很大差异，这一点通过流行病学研究中 omega-3 脂肪酸组织浓度的检查得到了进一步证实。此外，研究发现，早期发育期间的营养不足可能会留下残余的神经精神缺陷，从而导致成年后更容易患精神疾病。下面讨论发育结果研究。 在我们正在进行的攻击性酗酒者临床试验中，关键问题是评估每天 2.8 克 omega-3 脂肪酸治疗是否会减少 1) 攻击性行为，2) 改善血清素能功能的神经化学指标，以及 3) 改善被认为与抑郁和暴力行为相关的心血管指标。该协议已启动，已招募 47 名受试者，并 100% 跟踪数据。初步结果表明，愤怒减少了 33%（p<0.0008），并且复发天数有减少的趋势（55%，p=ns）。该研究预计于 2007 年秋季完成。我们与 Garth Bissette 博士合作，确定低血浆 DHA 水平预示着家庭暴力施暴者脑脊液中促肾上腺皮质激素释放激素水平升高。这一发现现已发表，可能会通过饮食改变来下调 HPA 轴。这一主张目前正在我们针对攻击性酗酒者的安慰剂对照干预试验中进行测试。 我们与医学博士 Laure-Budens Branchey 合作，发表了低血浆 DHA 和 AA 水平可预测可卡因和酒精依赖受试者在两年内复发的结果。 Branchey 博士进行的安慰剂对照临床试验的初步结果表明，愤怒评分在 4 个月内降低了 50%。 在对因故意自残而入住急诊室的受试者进行的一项合作试验中，我们发现每天 2 克 omega-3 脂肪酸可以减少未来的自杀想法、愤怒和抑郁评分，同时改善积极的生活观。 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 20 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。在明确的剂量反应关系中，摄入不足与妊娠 32 周 (p<1.4 X 10-17) 和妊娠 18 周以及产后 8 周和 8 个月的抑郁症状 (EPDS >12) 风险增加近一倍相关。经过严格检查潜在的混杂因素后，结果是可靠的。 早期发育过程中 omega-3 必需脂肪酸摄入不足也可能对儿童的行为产生不良影响。与 ALSPAC 合作研究，我们发现怀孕期间 omega-3 脂肪酸摄入不足与 3.5 岁和 7 岁儿童不良行为障碍风险加倍有关。剂量反应关系预测了行为障碍风险增加等参数：打架、撒谎、偷窃、不服从，这些都是公认的未来反社会和犯罪行为的风险因素。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。可以评估这些数据，以确定怀孕期间或幼儿期摄入不足是否是未来药物滥用的危险因素。如果这被确定为风险因素，则可以计划预防研究。 一项重要发现是，遵守 FDA 和 EPA 针对女性在怀孕期间限制海鲜消费以避免甲基汞的建议，会无意中对旨在保护的特定发育领域造成伤害。 ALSAPC 研究通过遵守或超过咨询中描述的摄入量进行了检查。这些发现目前正在准备发表。 在之前的跨国分析中，我们发现较高的凶杀死亡率与较低的海鲜消费率相关。为了进一步完善这一发现，我们利用了以下观察结果：种子油中的 omega-6 脂肪酸与海鲜中富含的 omega-3 脂肪酸竞争组织中的空间。我们发现，从 1950 年到 2000 年，在美国、英国、澳大利亚和加拿大，凶杀案死亡率的上升与食品供应中 omega-6 脂肪酸含量的增加密切相关。这种关联也与其他调查人员发表的暴力和敌意观察和干预数据一致。我们与 Carlos Iribarren 博士合作，检查了 CARDIA 试验中 4,000 名受试者的 omega-3 脂肪酸膳食摄入量及其行为相关性。 DHA 和其他 omega-3 脂肪酸的摄入量较低，预示着报告具有临床意义的敌意措施的风险会加倍。在与匹兹堡大学 Muldoon 博士合作进行的一项干预试验中，高胆固醇血症受试者服用辛维他汀（一种降胆固醇药物）或安慰剂，为期 8 周。我们量化了情绪、认知和血浆必需脂肪酸浓度的变化。辛维他汀治疗降低了总脂肪酸浓度，但不影响 DHA 和 AA。保留这些必需脂肪酸与情绪和认知的改善或降低之间的关系仍在研究中。