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

• 批准号: 8677887
• 负责人: ROBERT K. MCNAMARA
• 金额: $ 34.47万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677887
• 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; 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; Premature Mortality; Prevalence; 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; cardiovascular risk factor; improved; modifiable risk; mortality; novel; open label; pre-clinical; programs; prospective; protective effect; psychosocial; public health relevance; quetiapine; surveillance study; treatment duration

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）：躁狂症的最初发作，根据定义，I型双相情感障碍，最常发生在儿童期和青春期。双相情感障碍与显着的心理社会发病率以及肥胖、代谢综合征和相关心血管危险因素的发生率增加有关，结果数据表明过早死亡率过高部分归因于心脏代谢相关疾病。尽管第二代抗精神病药 (SGA) 药物对于治疗双相情感障碍青少年的急性躁狂症有效，但它们经常导致体重过度增加和肥胖，并加速和/或加剧心脏代谢危险因素，包括甘油三酯水平升高。这是一个值得关注的重大问题，因为 SGA 引起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、更频繁的自杀企图，并对成年期造成重大的长期健康风险。因此，迫切且未得到满足的公共卫生需求是确定 SGA 引起的儿童和青少年双相情感障碍患者心脏代谢症状和体重增加的可改变风险和保护因素，以指导改善和预防策略。新出现的转化证据表明，首发青少年躁狂症患者表现出的长链 omega-3 (LCn-3) 脂肪酸缺乏可能是 SGA 诱发的心脏代谢症状和体重增加的一个可改变的危险因素。最近的证据还表明，硬脂酰辅酶 A 去饱和酶（一种与高甘油三酯血症、胰岛素抵抗和肥胖有关的脂肪生成酶）可能介导 SGA 药物的有害作用以及 LCn-3 脂肪酸的有益作用。我们相信，现有证据和我们的初步数据支持这样的假设：低 LCn-3 脂肪酸状态是儿童和青少年双相情感障碍患者 SGA 引起的体重增加和心脏代谢风险的一个可改变的危险因素。此外，我们假设 SGA 诱导的体重增加和心脏代谢风险是通过硬脂酰辅酶 A 去饱和酶活性升高介导的，并且通过膳食补充剂增加 LCn-3 脂肪酸状态将通过减少硬脂酰辅酶 A 来减轻心脏代谢症状和体重增加的进展。 CoA 去饱和酶活性。为了评估这些假设，我们提出了一个两阶段的研究设计，首先前瞻性评估 LCn-3 脂肪酸状态作为首发双相情感障碍青少年出现 SGA 引起的体重增加和心脏代谢症状的危险因素（第一阶段），以及一项为期 24 周的随机安慰剂对照双盲 LCn-3 脂肪酸干预试验，以确定增加 LCn-3 脂肪酸状态是否可以减轻心脏代谢症状和体重增加的进展在接受 SGA 治疗的患者中（第二阶段）。预计本研究产生的数据将提供新的前瞻性证据，证明低 LCn-3 脂肪酸状态是 SGA 诱导的青少年双相情感障碍患者不良心脏代谢效应和体重增加的可改变危险因素，以支持未来大规模原发性预防研究。