Essential Fatty Acids In Psychiatric Disorders

精神疾病中的必需脂肪酸

• 批准号: 6680132
• 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/6680132
• 关键词: Macaca mulatta; aggression; arachidonate; baby food; behavior test; clinical trials; depression; developmental nutrition; dietary supplements; essential fatty acids; heart rate; homicide; human subject; lumbar puncture; mental health epidemiology; neurochemistry; nutrition; nutrition disorders; nutrition related tag; omega 3 fatty acid; patient oriented research; schizophrenia; seafood; violence

This project examines the question of whether a low nutritional status of essential fatty acids increases the predisposition to psychiatric disorders including depression and schizophrenia or to pathological behaviors such as homicide and suicide from several perspectives. Clinical interventional trials are currently being conducted in adult populations among aggressive alcoholics, women with depression during pregnancy and schizophrenics. These studies have, in part, been designed after discovering large differences in the prevalence rates of several psychiatric disorders when comparing populations with high or low measure of seafood consumption and omega-3 fatty acid tissue concentrations in epidemiological studies. The residual effects of these nutritional inadequacies in early development may also contribute to an increased predisposition toward psychiatric disorders. Three developmental outcome studies are discussed below. 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. 1) A cross-national comparison of 23 countries indicated that low consumption of seafood strongly predicted a 50-fold increased risk for postpartum depression. Low concentrations of DHA in mothers' breast milk were also associated with a similar increase in risk. 2) The dietary intake of omega-3 fatty acids during pregnancy was examined among nearly 14,000 women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). In clear dose response relationships deficient intakes was 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. 3) Two intervention trials, of omega-3 fatty acids among women with depression during pregnancy and in the postpartum, are being currently conducted in collaboration with Marlene Freeman, MD at the University of Arizona. Deficient intake of omega-3 essential fatty acids during early development may also have adverse residual effects on the behaviors of children. 1) 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, similar to the increased risk of postpartum depression, 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. These data are still being evaluated to determine the contribution of other variables such as socioeconomic status. 2) In an animal model we have documented long-term adverse residual effects of infant formulas, which are deficient in DHA and another essential fatty acid, arachidonic acid. Supplementing the formulas of infant rhesus monkeys with DHA and AA produced improvements in motor and visual development in as little as 5 days. After 6 months, all these animals received diets rich in these nutrients to restore their body stores. Despite up to 3.5 years of nutritional repletion these animals had residual deficits in the ability to regulate their autonomic nervous system as measured by differences in heart rate variability. A poor capacity to regulate autonomic nervous system reactivity, and measures of low heart rate variability, have been reported to predict future sociopathy. 3) In order to determine if these findings are applicable to human populations we are following up children, who are now 10 years old who had been fed either standard infant formulas or formulas supplemented with DHA and AA as part of a controlled intervention trial. This study in being conducted in collaboration with Dr. Peter Willats at the University of Dundee, Scotland, who has been funded for the study with an Independent Investigators Award from NARSAD, the National Association for Research in Schizophrenia and Depression. Earlier studies conducted by our group had indicated that low plasma concentrations of omega-3 fatty acids predicted low concentrations of cerebrospinal fluid 5-HIAA, a marker of serotonin concentrations in the brain. Since low concentrations of 5-HIAA have been linked to impulsive violence and homicide, we have examined the role of omega-3 intake as a mediating risk factor for aggression and violence. 1) In a cross-national analysis across 26 countries, we found higher rates of homicide mortality were correlated to lower rates of seafood consumption. The diagnosis of death due to homicide is subject to fewer cross-national cultural differences than are other behavioral outcomes. These data also are consistent with observational and interventional data for violence and hostility published by other investigators. 2) 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. We found that among all categories of subjects, white men, white women, black men and black women, lower intake of DHA and other omega-3 fatty acids predicted a doubling of the risk of reporting clinically significant measures of hostility. These findings were robust after evaluation of confounding factors. 3) In an interventional 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. 4) In an interventional trial conducted in collaboration with Jay Kaplan at Bowman Grey University, adult Rhesus monkeys were fed each of four different diets for 6 months. Initial analyses indicate that there is a dose-dependent increase in aggression closely related to lower concentrations of the omega-3 fatty acids eicosapentaenoic acid and DHA as measured in plasma. 5) An interventional trial in collaboration with a Fulbright scholar has received a high priority for funding as an R0-1 grant. A randomized trial of omega-3 fatty acids to reduce aggression among Thai school children will be conducted. The key questions our ongoing clinical trial are to assess if treatment of aggressive alcoholics with 2.8 g/d of omega-3 fatty acids will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotonergic function 3) improve cardiovascular measures thought to be associated with depressive and violent behaviors.

该项目研究了基本脂肪酸的营养状况低的问题是否会增加包括抑郁症和精神分裂症在内的精神疾病的易感性，还是从多个角度来看的病理行为，例如凶杀和自杀。目前，在侵略性酗酒者，怀孕期间患有抑郁症的妇女和精神分裂症患者中，目前正在临床介入试验。这些研究部分是在比较流行病学研究中具有高或低量度海鲜量消耗和omega-3脂肪酸组织浓度的种群时发现了几种精神疾病的患病率较大的巨大差异。这些营养不足对早期发展的残留影响也可能导致对精神疾病的倾向增加。下面讨论了三项发展结果研究。 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。 1）对23个国家的跨国比较表明，低消费海鲜的消费强烈预测产后抑郁症的风险增加了50倍。母亲的母乳中的低浓度DHA也与风险相似。 2）在接受父母和儿童的Avon纵向研究的近14,000名妇女中，检查了怀孕期间omega-3脂肪酸的饮食摄入量（ALSPAC）。在明确的剂量反应关系中，缺陷摄入量几乎与妊娠32周（p <1.4 x 10 -17）和妊娠18周的抑郁症状风险（EPDS> 12）增加了一倍有关，产后8周和8个月。严格检查潜在的混杂因素后，发现很健壮。 3）目前正在与亚利桑那大学的马里兰州玛琳·弗里曼（Marlene Freeman）合作进行两项对怀孕期间和产后抑郁症女性的omega-3脂肪酸的干预试验。 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。 1）与ALSPAC研究合作，我们发现怀孕期间对omega-3脂肪酸的摄入不足与3.5和7岁儿童不良行为障碍的风险增加了一倍。剂量反应关系类似于产后抑郁症的风险增加，它预测了诸如行为障碍风险增加的参数：战斗，说谎，偷窃，抗命，这是未来社会病和犯罪行为的众所周知的风险因素。仍在评估这些数据，以确定其他变量（例如社会经济状况）的贡献。 2）在动物模型中，我们已经记录了婴儿配方的长期不良残留作用，这些配方不足DHA和另一种必需的脂肪酸蛛网膜酸。补充了带有DHA和AA的婴儿恒河猴的公式，在短短5天内可以改善运动和视觉发育。 6个月后，所有这些动物都接受了富含这些营养的饮食，以恢复其体内储存。尽管有3。5年的营养补充，但这些动物在调节其自主神经系统的能力方面仍存在残留缺陷，如心率变异性的差异所衡量。据报道，调节自主神经系统反应性和低心率变异性措施的能力差可以预测未来的社会病。 3）为了确定这些发现是否适用于人口，我们正在跟随儿童，他们现在已经10岁了，他们被喂养了标准婴儿公式或补充DHA和AA的公式，作为对照干预试验的一部分。这项研究与苏格兰邓迪大学的彼得·威拉斯（Peter Willats）博士合作进行，该研究已获得该研究的资助，并获得了纳尔萨德（Narsad）的独立研究人员奖，即精神分裂症和抑郁症的全国研究协会。 我们小组进行的早期研究表明，低血浆浓度的omega-3脂肪酸预测了低浓度的脑脊液5-HIAA，这是大脑中5-羟色胺浓度的标志物。由于低浓度的5-HIAA与冲动性暴力和凶杀有关，因此我们研究了omega-3摄入量作为侵略和暴力的中介风险因素的作用。 1）在26个国家的跨国分析中，我们发现凶杀死亡率较高与较低的海鲜消费率相关。与其他行为结局相比，杀人造成的死亡的诊断遭受跨国文化差异的影响更少。这些数据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。 2）与卡洛斯·伊里巴伦（Carlos Iribarren）博士合作，我们检查了Cardia试验中4,000名受试者之间的omega-3脂肪酸饮食摄入量和行为相关性。我们发现，在所有类别的受试者，白人，白人妇女，黑人男性和黑人妇女中，DHA和其他omega-3脂肪酸的摄入量较低，预测报告临床上具有重要意义的敌对措施的风险增加了一倍。评估混杂因素后，这些发现非常强大。 3）在与匹兹堡大学的Muldoon博士合作进行的一项介入试验中，对患有高胆固醇血症的受试者进行了Simvistatin（一种降低胆固醇的药物）或安慰剂的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。 4）在与鲍曼·格雷大学（Bowman Gray University）的杰伊·卡普兰（Jay Kaplan）合作进行的一项介入试验中，成人恒河猴每四种饮食中的每种饮食均喂了6个月。初步分析表明，侵略性的剂量依赖性增加与较低浓度的omega-3脂肪酸eicosapentaenoic和DHA浓度较低，如血浆中所测量的。 5）与富布赖特学者合作的一项介入试验因作为R0-1赠款而获得了高度优先级的优先事项。将对omega-3脂肪酸进行随机试验，以减少泰国学童的侵略性。 我们正在进行的临床试验的关键问题是评估用2.8 g/d的omega-3脂肪酸治疗侵略性酗酒者是否会减少1）侵略性行为，2）改善血清素能功能的神经化学测量3）改善被认为与抑郁和剧烈行为相关的心血管措施。