Risk and protective factors for SGA-induced metabolic syndrome in bipolar youth

双相青少年 SGA 诱发代谢综合征的危险因素和保护因素

基本信息

批准号：
9277452
负责人：
ROBERT K. MCNAMARA
金额：
$ 34.37万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277452
关键词：
17 year old Acute Adolescence Adolescent Adult Age Anabolism Antipsychotic Agents Attenuated Bipolar Disorder Bipolar I Body mass index Cardiovascular Diseases Cardiovascular system Cell membrane Child Childhood Clinical Data Dietary Supplementation Disease Double-Blind Method Enrollment Enzymes Erythrocytes Exhibits Future General Population Generations Health Hypertriglyceridemia Insulin Resistance Intervention Trial Laboratories Lead Liver Manic Mediating Mental disorders Metabolic Metabolic syndrome Morbidity - disease rate Obesity Omega-3 Fatty Acids Outcome Patients Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Populations at Risk Premature Mortality Prevalence Prevention strategy Primary Prevention Prospective Studies Public Health Randomized Rattus Relapse Research Research Design Research Infrastructure Risk Risk Factors Safety Seroquel Stearoyl-CoA Desaturase Suicide attempt Supplementation Symptoms Testing Triglycerides United States Universities Weight Gain Youth adolescent patient attributable mortality bipolar patients cardiometabolic risk cardiovascular risk factor improved metabolic rate modifiable risk mortality novel open label pediatric patients pre-clinical programs prospective protective effect psychosocial public health relevance quetiapine surveillance study treatment duration

项目摘要

DESCRIPTION (provided by applicant): The initial onset of mania, and by definition bipolar I disorder, most frequently occurs during childhood and adolescence. Bipolar disorder is associated with significant psychosocial morbidity as well as increased rates of obesity, metabolic syndrome, and associated cardiovascular risk factors, and outcomes data indicate excess premature mortality attributable in part to cardiometabolic-related disorders. Although second generation antipsychotic (SGA) medications are efficacious for the treatment of acute mania in bipolar youth, they frequently lead to excessive weight gain and obesity and precipitate and/or exacerbate cardiometabolic risk factors including elevated triglyceride levels. This is a significant concern because SGA-induced cardiometabolic symptoms and weight gain increase risk of treatment discontinuation and relapse, more frequent suicide attempts, and poses substantial long-term health risks in adulthood. There is therefore an urgent and unmet public health need to identify modifiable risk and protective factors for SGA-induced cardiometabolic symptoms and weight gain in pediatric and adolescent bipolar patients to guide ameliorative and preventative strategies. Emerging translational evidence suggests that long-chain omega-3 (LCn-3) fatty acid deficiency exhibited by first-episode adolescent manic patients may represent a modifiable risk factor for SGA-induced cardiometabolic symptoms and weight gain. Recent evidence also suggests that stearoyl-CoA desaturase, a lipogenic enzyme implicated in hypertriglyceridemia, insulin resistance, and obesity, may mediate the detrimental effects of SGA medications as well as the beneficial effects of LCn-3 fatty acids. We believe that extant evidence and our preliminary data supports the hypothesis that low LCn-3 fatty acid status is a modifiable risk factor for SGA-induced weight gain and cardiometabolic risk in pediatric and adolescent bipolar patients. Moreover, we hypothesize that SGA-induced weight gain and cardiometabolic risk are mediated through elevations in stearoyl-CoA desaturase activity, and that increasing LCn-3 fatty acids status through dietary supplementation will attenuate the progression of cardiometabolic symptoms and weight gain by reducing stearoyl-CoA desaturase activity. To evaluate these hypotheses, we propose a two-phase study design to first prospectively evaluate LCn-3 fatty acid status as a risk factor for the emergence of SGA-induced weight gain and cardiometabolic symptoms in first-episode bipolar youth (Phase I), and a 24-week randomized placebo-controlled double-blind LCn-3 fatty acid intervention trial to determine whether increasing LCn-3 fatty acid status can attenuate the progression of cardiometabolic symptoms and weight gain in SGA-treated patients (Phase II). It is anticipated that the data generated by this study will provide novel prospective evidence that low LCn-3 fatty acid status is a modifiable risk factor for SGA-induced adverse cardiometabolic effects and weight gain in adolescent bipolar patients in support of future large-scale primary prevention studies.

描述（由申请人提供）：躁狂症的初始发作，以及定义上的双相情感障碍，最常见于儿童和青春期。躁郁症与明显的社会心理发病率以及肥胖，代谢综合征和相关心血管危险因素的增加有关，结果数据表明，部分归因于心脏代谢相关疾病的过度死亡率。尽管第二代抗精神病药（SGA）药物有效地治疗了双极年轻人的急性躁狂症，但它们经常导致体重增加，肥胖和沉淀和/或加剧心脏代谢危险因素，包括甘油三甘油三酸酯水平升高。这是一个重要的问题，因为SGA诱导的心脏代谢症状和体重增加会增加治疗中断和复发的风险，更频繁地自杀尝试，并在成年期间构成了实质性的长期健康风险。因此，迫切需要公共卫生需要确定可改变的风险和保护性因素，用于SGA诱导的心脏代谢症状以及小儿和青少年双极患者的体重增加，以指导改善和预防性策略。新兴的翻译证据表明，第一期青春期躁狂患者表现出的长链omega-3（LCN-3）脂肪酸缺乏症可能是SGA诱导的心脏代谢症状和体重增加的可修改风险因素。最近的证据还表明，与高甘油三酯血症，胰岛素抵抗和肥胖有关的脂源性酶（一种脂肪生成酶）可能介导SGA药物的有害作用以及LCN-3脂肪酸的有益作用。我们认为，现有的证据和我们的初步数据支持了以下假设：低LCN-3脂肪酸状况是SGA诱导的小儿和青少年双极患者体重增加和心脏代谢风险的可修改风险因素。此外，我们假设SGA诱导的体重增加和心脏代谢风险是通过stearoyl-CoA去饱和酶活性的升高来介导的，并且通过补充饮食中的补充而增加LCN-3脂肪酸状况会减少心脏代谢症状和体重的进展，从而减少stearoyl-CoA desaturasy desaturasy desaturase活性。为了评估这些假设，我们提出了两阶段的研究设计，以先前瞻性评估LCN-3脂肪酸状态，作为在第一期双极年轻人（I期I）中SGA诱导的体重增加和心脏代谢症状的出现的危险因素，以及24周的24周随机安慰剂型LCN-lc-3-lc-3-lcn-ftilenty frity lccn-fity firtity frity lcity rcition-lc-3酸是否会增加酸度酸酸的酸度，以确定酸度酸酸是否会增加酸度酸度酸酸酸性酸度酸是否可以确定。减轻SGA治疗患者的心脏代谢症状和体重增加的进展（II期）。预计这项研究产生的数据将提供新的前瞻性证据，表明低LCN-3脂肪酸状态是SGA诱导的不良心脏代谢效应和青少年双极患者体重增加的可修改风险因素，以支持未来的大规模初级预防研究。