ESSENTIAL FATTY ACIDS IN PSYCHIATRIC DISORDERS

精神疾病中的必需脂肪酸

• 批准号: 6413409
• 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/6413409
• 关键词: Macaca mulatta; arachidonate; baby food; depression; developmental nutrition; dietary supplements; essential fatty acids; nutrition disorders; nutrition related tag; omega 3 fatty acid; schizophrenia; seafood; violence

The central question addressed in our studies is 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. Some essential fatty acids, in particular docosahexaenoic acid (DHA), are selectively concentrated in the brain, but these nutrients are ultimately available only from dietary sources e.g. seafood, which is rich in this omega-3 fatty acid. Our projects have examined these questions from several perspectives: population comparisons in epidemiological studies, clinical interventional studies in adults with psychiatric disorders, and observational studies of the relationship of essential fatty acids status to the function of key neurotransmitter systems, which may help to elucidate mechanism of action. In addition to the status of adults, nutritional inadequacies both in early development may also contribute to an increased predisposition toward psychiatric disorders or abnormal behaviors. Thus, we have also conducted two developmental outcome studies. 1) a four decade follow-up study examined the maternal essential fatty acid status at time of birth and the lifetime risk of developing schizophrenia. 2) An intervention study which examined the effects of supplementing infant formulas with DHA and arachidonic acid (AA) on the short and long term consequences to neurological development among rhesus monkeys. The cross-national ecological studies which have compared the rates of seafood consumption to prevalence rates of psychiatric disorders indicate that there may be a specific relationship to prevalence rates of affective and impulsive disorders, but not to schizophrenia. In a prior study we reported that seafood consumption predicted lower prevalence rates of major depression (r = -0.84, p< 0.0005) over a nearly 60-fold range across countries. Consistent with this report we found that bipolar spectrum disorders (manic depressive disorders) have a well defined relationship to seafood consumption with an apparent threshold of approximately 75 lbs/person/y. We conducted each of these studies using data from the gold standard of psychiatric epidemiological studies, the Epidemiological Catchment Area Study. Two studies within countries yielded similar results. 1) We studied a population of 1,767 subjects within Northern Finland and found that subjects who consumed fish twice a week or more were at lower risk of reporting depressive symptoms (odds ratio 0.63) and suicidal thinking (odds ratio 0.57), compared to infrequent fish consumers. The subjects who consumed vegetable oils were more than twice as likely to report being depressed compared to those with no consumption. This is significant because vegetable oils are high in omega-6 fatty acids which compete with the effects of omega-3 fatty acids. 2) We again found similar results among a community sample of 200 elderly subjects that represented 80% of the elderly people in two counties in Iowa. Low plasma concentrations of plasma DHA alone significantly predicted more severe sleep complaints and reports of anxiety and predicted depression among women.A series of three studies done by our group has indicated that there is no relationship between essential fatty acid status and schizophrenia. 1) Across 14 countries, there was no significant relationship between prevalence rates of schizophrenia and seafood consumption using Epidemiological Catchment Area data. 2) These cross-national data are consistent with the results of a double-blind, placebo-controlled multi-center trial we conducted among 74 chronic schizophrenics (In collaboration with the Stanley Foundation). No clinical improvements were found comparing consuming supplements of 3 g/d of EPA to 3 g/d of mineral oil, for 4 months. 3) We examined the essential fatty acid composition of maternal plasma drawn on the day of birth comparing 51 control mothers to mothers of 27 children that developed psychosis over the next four decades. In contrast to the predicted hypothesis, the mothers of children who developed psychosis were not deficient in any essential fatty acid. In summary, these data suggest that there could be a specific relationship of seafood consumption and omega-3 status to prevalence rates of affective and impulsive disorders, but not to the prevalence of schizophrenia. Three studies indicate that inadequate omega-3 fatty acid consumption may contribute to an increased risk of mortality from suicide and homicide. 1) Across 31 countries, greater seafood consumption predicts a lower risk of death due to suicide. 2) Among suicide attempters, low concentrations of the omega-3 fatty acid, eicosapentaenoic acid (EPA), alone were robustly correlated with greater psychopathology scores. 3) Finally, in a cross-national analysis, higher homicide mortality rates correlated with lower rates of seafood consumption across 26 countries in a cross-national analysis (r= - 0.63, p< 0.0005).One of the most well replicated findings in biological psychiatry is that suicide is associated with low concentrations of a marker of central serotonin concentrations called CSF 5-HIAA. Regulating central serotonin concentrations is also the cornerstone of pharmacological therapy for major depression. Thus we predicted, and found, that low plasma concentrations of omega-3 fatty acids predicted low concentrations of CSF 5-HIAA in healthy control subjects and late onset alcoholics, higher concentrations of plasma DHA predicted higher concentrations of CSF 5-HIAA. We also replicated this finding among 104 adult rhesus monkeys finding again that higher concentrations of the omega-3 fatty acids in plasma predicted higher concentrations of CSF 5-HIAA. Among these animals, higher EPA and DHA concentrations in plasma also predicted more functional dominance behaviors. These findings also suggest that omega-3 fatty acids may modulate impulsive behaviors through regulation of the serotonergic nervous system. The basic mechanisms by which essential fatty acid status might regulate serotonergic function merits further exploration.We have begun to examine if these disorders are, in part, a long-term consequence of a nutritional deficiency during early development. In prior experiments, it has been established that separating rhesus infants from their mothers at birth and raising them in a nursery imparts a lifetime predisposition toward abnormal and aggressive behaviors. We noted that while in the nursery the infants are fed formulas that are virtually devoid of DHA and AA, which is similar to human formulas in this country. Thus, we compared two groups of infant rhesus monkeys that were removed from their mothers at birth and were raised in a stringently controlled nursery for the first six months. One group received standard infant formula while the other group received formulas supplemented with AA (0.8%) and DHA (0.8%), a composition similar to the milk of rhesus monkey mothers. DHA/AA fed infants had profoundly improved motor development and visual orientation scores in as little as seven days. The heart rate variability, a measure of central nervous system function, remained improved in adolescence up to 3.5 years after the dietary intervention had stopped, indicating an enduring developmental effect. CSF 5-HIAA was decreased in the DHA/AA group, but only during the six months of formula feeding. We cannot determine directly whether the supplementation raised or lowered the brain concentrations of serotonin among these infants. However, the behavioral and physiological improvements noted above, were consistent with improved serotinergic function.

我们的研究中解决的主要问题是，必需脂肪酸的营养状况低下是否会增加对抑郁症和精神分裂症在内的精神疾病的倾向，还是对凶杀和自杀等病理行为的倾向。 一些必需的脂肪酸，尤其是二十二碳六烯酸（DHA），选择性地集中在大脑中，但这些营养素最终仅从饮食来源可用，例如海鲜，富含这种omega-3脂肪酸。 我们的项目从几个角度研究了这些问题：流行病学研究中的人群比较，患有精神疾病的成年人的临床介入研究以及对必需脂肪酸状态与关键神经递质系统功能的关系的观察性研究，这可能有助于阐明行动机制。 除了成年人的地位外，早期发展中的营养不足也可能导致人们对精神疾病或异常行为的倾向增加。 因此，我们还进行了两项发展结果研究。 1）一项四十年的随访研究检查了出生时的母体必需脂肪酸状况以及患有精神分裂症的终生风险。 2）一项干预研究研究了补充婴儿配方素和花生四烯酸（AA）对恒河猴神经系统发育的短期和长期后果的影响。将海鲜消费率与精神疾病的患病率进行了比较的跨国生态研究表明，与情感和冲动性疾病的患病率可能存在特定的关系，但与精神分裂症没有。 在先前的研究中，我们报道说，海鲜消耗预测，大抑郁症的患病率较低（r = -0.84，p <0.0005）在近60倍的范围内。 与这份报告一致，我们发现双极光谱疾病（躁狂抑郁症）与消费量有明确的关系，明显的阈值约为75磅/人/y。 我们使用精神病流行病学研究金标准（流行病学集水区研究的金标准）进行了这些研究。 国家内的两项研究产生了相似的结果。 1）我们研究了芬兰北部北部1,767名受试者的人口，发现每周两次或以上鱼类食用鱼类的受试者的报告抑郁症状的风险较低（几率为0.63）和自杀思维（优势比0.57），与罕见的鱼类消费者相比。 与没有消费的人相比，食用植物油的受试者报告抑郁症的可能性是抑郁症的两倍以上。 这很重要，因为植物油中的omega-6脂肪酸含量很高，这些脂肪酸与omega-3脂肪酸的作用竞争。 2）我们再次发现了200名老年人的社区样本中的类似结果，这些老年受试者占爱荷华州两个县的80％的老年人。 仅血浆DHA的血浆浓度较低会显着预测女性的焦虑和焦虑和预测抑郁症的报道更加严重。我们小组进行的三项研究表明，必需脂肪酸状况与精神分裂症之间没有关系。 1）在14个国家 /地区，使用流行病学集水区数据，精神分裂症和海鲜消费率的流行率之间没有显着关系。 2）这些跨国数据与我们在740种慢性精神分裂症患者中进行的双盲，安慰剂对照的多中心试验的结果一致（与斯坦利基金会合作）。 没有发现将EPA 3 g/d的食用补充剂与3 g/d的矿物油进行比较4个月。 3）我们研究了在出生当天提取的母体血浆的必要脂肪酸组成，将51个对照母亲与未来四十年中患有精神病的27名儿童的母亲进行了比较。 与预测的假设相反，患有精神病的儿童的母亲在任何必需的脂肪酸中都不缺乏。 总而言之，这些数据表明，海鲜消耗和omega-3状态与情感和冲动性疾病的患病率可能存在特定的关系，而不是与精神分裂症的患病率之间的特定关系。三项研究表明，omega-3脂肪酸消耗不足可能导致自杀和杀人罪的死亡率增加。 1）在31个国家 /地区，大型海鲜消费预测自杀导致死亡风险较低。 2）在自杀式意见中，仅欧米茄3脂肪酸，eicosapentaenoic酸（EPA）与更高的心理病理学评分牢固相关。 3）最后，在跨国分析中，在跨国分析中，较高的疫苗死亡率与较低的海鲜消费率相关（r = -0.63，p <0.0005）。生物精神病学中最良好复制的发现之一是自杀是自杀与中央菌素浓度浓度低相关的，称为cssf 5-hiaaa。 调节中央5-羟色胺浓度也是严重抑郁症的药理治疗的基石。 因此，我们预测并发现，低血浆浓度的omega-3脂肪酸可以预测健康对照受试者中CSF​​ 5-HIAA的低浓度和晚期酗酒者，较高浓度的血浆DHA预测CSF 5-HIAA浓度较高。 我们还复制了这一发现，在104只成年恒河猴再次发现，血浆中较高浓度的omega-3脂肪酸预测CSF 5-HIAA浓度较高。 在这些动物中，血浆中较高的EPA和DHA浓度也预测了更多功能优势行为。 这些发现还表明，omega-3脂肪酸可能通过调节血清素能神经系统来调节冲动行为。 基本脂肪酸状况可能调节血清素能功能的基本机制值得进一步探索。我们已经开始检查这些疾病是否在早期发育期间营养缺乏的长期后果。在先前的实验中，已经确定，将恒河猴与母亲分开，并在出生时将其抚养起来，使他们赋予了异常和侵略性行为的终生倾向。 我们注意到，虽然在托儿所中，但婴儿是几乎没有DHA和AA的配方，这与该国的人类公式类似。 因此，我们比较了两组婴儿恒河猴在出生时从母亲身上删除，并在头六个月内在一个严格控制的托儿所中抚养长大。 一组接受了标准婴儿公式，而另一组则接受了补充AA（0.8％）和DHA（0.8％）的配方，这是类似于恒河猴牛奶母亲的组成。 DHA/AA喂养的婴儿在短短七天内就深刻改善了运动发育和视觉取向评分。 心率变异性是中枢神经系统功能的量度，在饮食干预停止后长达3.5年的青春期仍得到改善，表明发育效果持久。 DHA/AA组的CSF 5-HIAA降低了，但仅在配方奶粉的六个月中。 我们无法直接确定这些婴儿中的补充是否增加或降低了5-羟色胺的脑浓度。 但是，上面指出的行为和生理改善与5-羟色胺能功能的改善一致。