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.

我们研究的核心问题是，必需脂肪酸的低营养状况是否会增加精神疾病（包括抑郁症和精神分裂症）或病理行为（如杀人和自杀）的易感性。一些必需脂肪酸，特别是二十二碳六烯酸（DHA），选择性地集中在大脑中，但这些营养素最终只能从饮食来源中获得，例如海鲜，其中富含这种omega-3脂肪酸。我们的项目从几个角度来研究这些问题：流行病学研究中的人群比较，成人精神疾病的临床干预研究，以及必需脂肪酸状态与关键神经递质系统功能关系的观察性研究，这可能有助于阐明作用机制。除了成年人的状况外，早期发育中的营养不足也可能导致精神疾病或异常行为的易感性增加。因此，我们也进行了两项发展结果研究。1)一项为期40年的随访研究，研究了母亲出生时的必需脂肪酸状况和患精神分裂症的终生风险。2)一项干预研究，研究在婴儿配方奶粉中添加DHA和花生四烯酸（AA）对恒河猴神经发育的短期和长期影响。跨国生态学研究比较了海产品消费量与精神疾病患病率的关系，表明海产品消费量与情感性和冲动性疾病患病率之间可能存在特定关系，但与精神分裂症无关。在之前的一项研究中，我们报告说，在各国近60倍的范围内，海鲜消费预测较低的重度抑郁症患病率（r = -0.84, p< 0.0005）。与本报告一致，我们发现双相情感障碍（躁狂抑郁症）与海鲜消费有明确的关系，其明显阈值约为75磅/人/年。我们使用来自精神病学流行病学研究的黄金标准，即流行病学流域研究的数据来进行这些研究。两项国内研究也得出了类似的结果。1)我们研究了芬兰北部的1767名受试者，发现与不经常吃鱼的受试者相比，每周吃两次或两次以上鱼的受试者报告抑郁症状（优势比0.63）和自杀念头（优势比0.57）的风险较低。食用植物油的受试者报告抑郁的可能性是不食用植物油的受试者的两倍多。这一点很重要，因为植物油富含omega-6脂肪酸，这与omega-3脂肪酸的作用相竞争。2)我们在爱荷华州两个县的200名老年人的社区样本中再次发现了类似的结果，这些老年人代表了80%的老年人。仅血浆DHA浓度低就能显著预测女性更严重的睡眠抱怨和焦虑报告，并预测抑郁。我们小组进行的一系列三项研究表明，必需脂肪酸状态与精神分裂症之间没有关系。1)在14个国家中，使用流行病学集水区数据，精神分裂症患病率与海鲜消费之间没有显着关系。2)这些跨国数据与我们在74名慢性精神分裂症患者中进行的双盲、安慰剂对照多中心试验的结果一致（与斯坦利基金会合作）。对比服用3克/天的EPA补充剂和服用3克/天的矿物油4个月，没有发现临床改善。3)我们检查了51名对照母亲和27名在接下来的40年里患有精神病的孩子的母亲在出生当天抽取的血浆中必需脂肪酸的组成。与预测的假设相反，患有精神病的孩子的母亲并不缺乏任何必需脂肪酸。总之，这些数据表明，海鲜消费和omega-3水平可能与情感和冲动障碍的患病率存在特定关系，但与精神分裂症的患病率无关。三项研究表明，omega-3脂肪酸摄入不足可能会增加自杀和他杀死亡的风险。1)在31个国家中，更多的海鲜消费预示着更低的自杀死亡风险。2)在自杀未遂者中，低浓度的omega-3脂肪酸，二十碳五烯酸（EPA），单独与较高的精神病理学评分显著相关。3)最后，在一项跨国分析中，在26个国家中，较高的他杀死亡率与较低的海鲜消费量相关（r= - 0.63, p< 0.0005）。在生物精神病学中，最被广泛证实的发现之一是，自杀与一种名为CSF 5-HIAA的中枢血清素浓度标记物的低浓度有关。调节中枢血清素浓度也是重度抑郁症药物治疗的基础。因此，我们预测并发现，在健康对照者和晚发性酗酒者中，低血浆浓度的omega-3脂肪酸预示着低浓度的CSF 5-HIAA，高浓度的血浆DHA预示着高浓度的CSF 5-HIAA。我们还在104只成年恒河猴身上重复了这一发现，再次发现血浆中omega-3脂肪酸浓度越高，脑脊液5-HIAA浓度越高。在这些动物中，血浆中较高的EPA和DHA浓度也预示着更多的功能优势行为。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。必需脂肪酸状态调控血清素功能的基本机制值得进一步探讨。我们已经开始研究这些疾病是否在一定程度上是早期发育期间营养缺乏的长期后果。在先前的实验中，已经确定在出生时将恒河猴婴儿与其母亲分开并在托儿所中抚养他们会使他们终生倾向于异常和攻击行为。我们注意到，在托儿所，婴儿喂养的配方奶粉实际上不含DHA和AA，这与我国的人类配方奶粉相似。因此，我们比较了两组恒河猴婴儿，这两组婴儿在出生时就被从母亲身边带走，并在严格控制的托儿所中饲养了前六个月。一组服用标准婴儿配方奶粉，另一组服用添加了AA（0.8%）和DHA（0.8%）的配方奶粉，这两种成分类似于恒河猴母亲的乳汁。DHA/AA喂养的婴儿在短短7天内就显著改善了运动发育和视觉定向得分。心率变异性是衡量中枢神经系统功能的一项指标，在饮食干预停止后的3.5年里，青少年的心率变异性仍在改善，这表明饮食干预对发育有持久的影响。DHA/AA组脑脊液5-HIAA降低，但仅在配方奶喂养6个月期间。我们不能直接确定补充剂是否提高或降低了这些婴儿大脑中血清素的浓度。然而，上述行为和生理上的改善与血清素能功能的改善是一致的。