Essential Fatty Acids In Psychiatric Disorders

精神疾病中的必需脂肪酸

基本信息

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
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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。在本报告涵盖的时间段内，已经准备了14项手稿并提交出版。此外，计划并批准了2001年4月的双盲安慰剂对照临床试验。在该方案中，标题为“多不饱和脂肪酸”以及心血管和运动反应性的神经化学，将为EPA和DHA或DHA或安慰剂或安慰剂提供3.8 gm/d。该方案的关键问题是评估这种治疗方法是否会减少1）侵略性行为，2）改善血清素能功能的神经化学度量3）改善被认为与抑郁和暴力行为相关的心血管措施。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措施，2）一种用于评估脑脊液的腰椎穿刺，3）3）心脏率变异性的度量。受试者正在积极招募该协议的评估。我们的项目研究了omega-3脂肪酸在精神疾病中的作用的问题：流行病学研究中的人群比较，具有精神疾病的成年人的临床介入研究，以及观察性脂肪酸状态与关键神经转相系统功能的关系的观察性研究。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）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符和花生四烯酸（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，海鲜消费预测，在整个国家 /地区近60倍的范围内，重度抑郁症的患病率较低。与这份报告一致，我们发现双极光谱疾病（躁狂抑郁症）与海鲜消费有明确的关系，明显的阈值约为75磅/人/人/年。低于这一全国平均消费水平，双相情感障碍的患病率从台湾（81.6磅/人/y）的0.04％急剧上升至德国的6.5％（27.6磅/人/y）的患病率近60倍。我们使用精神病流行病学研究金标准的数据（流行病学集水区研究）进行了这些研究。国家内的两项研究产生了相似的结果。 1）与医学博士Antti Tanskanen合作，我们研究了芬兰北部的1,767名受试者的人口。我们发现，与罕见的鱼类消费者相比，每周两次或更长时间食用鱼的受试者的报告抑郁症状（赔率为0.63）和自杀思维（优势比0.57）的风险较低。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，因为植物油在与omega-3脂肪酸作用的omega-6脂肪酸中含量很高。 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睡眠不足和焦虑和抑郁症的报告。我们小组进行的一系列四项研究表明，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）。相对于3 g/d的矿物油，食用3 g/d的EPA补充剂的患者在4个月内没有发现临床改善。 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。 4）我们发现吸烟显着降低了红细胞脂肪酸DHA浓度。这很重要，因为八个先前的报道称，吸烟的精神分裂症患者的rbc浓度较低，但他们不能控制精神分裂症和控制种群中吸烟者的数量。总而言之，这些数据表明，海鲜消耗和omega-3状态可能存在特定的关系与情感和冲动性疾病的患病率，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。我们最近的三项研究表明，omega-3脂肪酸消耗不足可能导致自杀和杀人剂死亡的风险增加。 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，单独的欧米茄3脂肪酸eicosapentaenoic（EPA）与较高的精神病理学评分牢固相关。 3）最后，在跨国分析中，在跨国分析中，较高的凶杀死亡率与较低的26个国家的海鲜消耗率相关。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。婴儿公式研究跨国相关关系并未表明对冲动性和抑郁行为的倾向增加仅在成年期发生，还是在早期发育过程中营养缺乏的长期后果。在先前的实验中，已经确定将恒河神与母亲分开，并在出生时将其养育在托儿所中，这会赋予异常和侵略性行为的终生倾向。我们注意到，在托儿所中，婴儿是几乎没有DHA和AA的配方。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。这项研究正在进行中。