Essential Fatty Acids In Psychiatric Disorders

精神疾病中的必需脂肪酸

• 批准号: 6535860
• 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/6535860
• 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

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. During the time period covered by this report, 14 manuscripts have been prepared and submitted for publication. In addition, a double blind placebo controlled clinical trial was planned and approved in April 2001. In this protocol, entitled Polyunsaturated Fatty Acids and the Neurochemistry of Cardiovascular and Motor Reactivity, aggressive subjects will be given either 3.8 gm/d of EPA and DHA or a placebo. The key questions of the protocol are to assess if this treatment will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotinergic function 3) improve cardiovascular measures thought to be associated with depressive and violent behaviors. Both before and after receiving the omega-3 fatty acids or the placebo, subjects will undergo the following evaluations: 1) Laboratory defined measures of aggressive behavior, 2) A lumbar puncture for evaluation of cerebrospinal fluid, 3) measures of heart rate variability. Subjects are actively being recruited for screening evaluations for this protocol. Our projects have examined the question of the role of omega-3 fatty acids in psychiatric disorders 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. 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 the time of birth and the lifetime risk of developing schizophrenia. 2) An intervention study that 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 that 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 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/yr. Below this level of national average consumption, the prevalence rates of bipolar disorder rise precipitously from 0.04% in Taiwan (81.6 lbs/person/y) to 6.5% in Germany (27.6 lbs/person/y) a nearly 60-fold difference in prevalence. We conducted each of these studies using data from a gold standard of psychiatric epidemiological studies, the Epidemiological Catchment Area Study. Two studies within countries yielded similar results. 1) In collaboration with Antti Tanskanen, M.D., Ph.D., we studied a population of 1,767 subjects within Northern Finland. We 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 that 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 as well as depression among women. A series of four studies done by our group have 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 in patients consuming supplements of 3 g/d of EPA relative 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. 4) We found that smoking markedly lowered erythrocyte fatty acid DHA concentrations. This is significant because eight prior reports that schizophrenics who smoked had lower RBC, DHA concentrations, but they did not control for the numbers of smokers in the schizophrenic and control populations. 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 or to biochemical abnormalities associated with schizophrenia. Three of our recent 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 were correlated to lower rates of seafood consumption across 26 countries in a cross-national analysis. 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. Infant formula studies The cross-national correlational relationships do not indicate if an increased predisposition towards impulsive and depressive behaviors occurs only in adulthood, or is 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. 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. This study is ongoing.

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。在本报告所述期间，已编写并提交了14份手稿供出版。此外，计划于2001年4月批准了一项双盲安慰剂对照临床试验。在这个名为“多不饱和脂肪酸与心血管和运动反应性的神经化学”的方案中，侵袭性受试者将给予3.8 gm/d的EPA和DHA或安慰剂。该方案的关键问题是评估这种治疗是否会减少1)攻击行为，2)改善血清素能功能的神经化学指标，3)改善被认为与抑郁和暴力行为相关的心血管指标。在接受omega-3脂肪酸或安慰剂之前和之后，受试者将接受以下评估：1)实验室定义的攻击行为测量，2)腰椎穿刺评估脑脊液，3)心率变异性测量。本方案正在积极招募受试者进行筛选评估。我们的项目从几个角度研究了omega-3脂肪酸在精神疾病中的作用：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。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年的随访研究检查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，研究了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之间的关系，表明海产品消费量与情感和冲动障碍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，食用海鲜可以预测各国抑郁症的患病率降低近60倍。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。低于这个全国平均消费水平，双相情感障碍的患病率从台湾的0.04%（81.6磅/人/年）急剧上升到德国的6.5%（27.6磅/人/年），患病率相差近60倍。我们使用精神病学流行病学研究的黄金标准，即流行病学集水区研究的数据进行这些研究。两项国内研究也得出了类似的结果。1)与Antti Tanskanen医学博士合作，我们研究了芬兰北部1767名受试者。我们发现，与不经常吃鱼的人相比，每周吃两次或两次以上鱼的人报告抑郁症状（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，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、焦虑和抑郁报告。我们小组进行的一系列四项研究表明，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）。与服用矿物油3克/天相比，服用3克/天EPA补充剂4个月的患者没有发现临床改善。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。4)吸烟显著降低红细胞脂肪酸DHA浓度。这是很重要的，因为之前有8份报告称，吸烟的精神分裂症患者红细胞和DHA浓度较低，但他们没有控制精神分裂症患者和对照组人群中吸烟者的数量。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或与精神分裂症相关的生化异常无关。我们最近的三项研究表明，omega-3脂肪酸摄入不足可能会增加自杀和他杀的死亡风险。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，单独服用低浓度的omega-3脂肪酸二十碳五烯酸（EPA）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个国家的一项跨国分析中，较高的杀人死亡率与较低的海鲜消费量相关。与其他行为结果相比，杀人死亡的诊断受跨国文化差异的影响较小。这些数据也与其他调查人员发表的关于暴力和敌意的观察和干预数据一致。婴儿配方奶粉研究跨国相关关系并没有表明冲动和抑郁行为倾向的增加是否只发生在成年期，还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，恒河猴婴儿在出生时与母亲分开，并在托儿所中抚养，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缺乏DHA和AA。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。这项研究正在进行中。