Neurochemical Effects of Omega-3 Fatty Acids in Adolescents at Risk for Mania

描述(由申请人提供)：与普通人群相比，患有双相情感障碍的父母的青少年后代，特别是那些有明显抑郁症状的人，患躁狂症的风险更高，根据定义，双相I型障碍的风险更高。然而，通常用于治疗抑郁症状的药物可能会加速躁狂或轻躁的发作。因此，对父母为双相的青少年抑郁症状潜在治疗的有效性、安全性和耐受性进行评估的研究是必要的，并可能导致早期干预，并最终预防早期躁狂和低躁狂发作的策略。临床前和临床证据表明，omega-3脂肪酸缺乏可能是发展为双相情感障碍的一个可预防的危险因素。事实上，初步安慰剂对照试验的结果表明，补充omega-3脂肪酸可以降低患有情绪障碍的年轻人和成年人的情绪症状严重程度。此外，尸检研究显示，年轻双相情感障碍患者的前额叶皮质存在显著的omega-3脂肪酸缺陷。最近的神经成像研究表明，双相情感障碍的症状可能源于前缘网络内的功能障碍，包括腹外侧额叶和前扣带回皮质。具体地说，质子磁共振波谱(1HMRS)研究显示，患有双相情感障碍的青少年和患有双相情感障碍的高危青少年表现出过量的谷氨酸和肌醇，N-乙酰天冬氨酸水平下降，这表明高代谢可能是大脑前缘区域紊乱的原因。这些神经化学变化可能是治疗效果的有用生物标志物。考虑到这些考虑，这项研究的目标是：1)收集有关omega-3脂肪酸补充剂治疗患有活动期抑郁症状和患躁狂症的高风险青少年(即他们的父母患有躁狂症，且符合DSM-IV-TR标准)的疗效、安全性和耐受性的试验性数据，2)使用1H MRS(即额叶前部神经化学)和红细胞(RBC)omega-3脂肪酸水平，以研究具有躁狂症高风险青少年对omega-3脂肪酸治疗反应的潜在介质。为了实现这些目标，总共60名青少年(年龄12-21岁)将被随机分配到omega-3脂肪酸或安慰剂治疗12周，这些青少年有活跃的抑郁症状，并有患躁狂症的重要风险因素。这一应用的目的与NIMH R34赠款机制的目标是一致的：“对新的或适应的干预措施进行试点测试”，以及“开发新的干预措施，以针对通过神经科学研究确定的精神病理学或病因的特定风险因素”。此外，拟议的研究将利用NIMH支持的干预开发和应用研究中心(CIDAR)赠款的基础设施；辛辛那提大学双相情感障碍成像和治疗研究中心(BITREC，P50MH077138)。公共卫生相关性：迫切需要循证治疗患有双相情感障碍高危青少年的情绪障碍。这项建议将把新的神经成像技术与安慰剂对照的双结合治疗试验相结合，以检查长期补充omega-3脂肪酸对双相情感障碍高危青少年的神经生理学和治疗效果，作为建立早期干预和预防策略的第一步。

DESCRIPTION (provided by applicant): Adolescent offspring of parents with bipolar disorder, particularly those with prominent depressive symptoms, have an elevated risk of developing mania, and by definition bipolar I disorder, compared with the general population. However, medications that are commonly used to treat depressive symptoms may accelerate the onset of mania or hypomania. Therefore, studies evaluating the efficacy, safety, and tolerability of potential treatments for depressive symptoms in adolescents with a bipolar parent are necessary, and may lead to early intervention, and ultimately prevention, strategies for incipient manic and hypomanic episodes. Preclinical and clinical evidence suggests that omega-3 fatty acid deficiency may represent a preventable risk factor for developing bipolar disorder. Indeed, findings from preliminary placebo-controlled trials indicate that omega-3 fatty acid supplementation reduces mood symptom severity in youth and adults with mood disorders. Additionally, postmortem studies reveal significant omega-3 fatty acid deficits in the prefrontal cortex of young bipolar patients. Recent neuroimaging studies indicate that symptoms of bipolar disorder may arise from dysfunction within the anterior limbic network, which includes the ventrolateral prefrontal and anterior cingulate cortices. Specifically, proton magnetic resonance spectroscopy (1H MRS) studies reveal that adolescents with and at high risk for developing bipolar disorder exhibit excessive glutamate and myo-inositol and decreased N- acetyl aspartate levels, suggesting that hypermetabolism may underlie the disruption in anterior limbic brain regions. These neurochemical changes may be useful biomarkers of treatment effects. With these considerations in mind, the goals of this study are: 1) To collect pilot data regarding the efficacy, safety, and tolerability of omega-3 fatty acid supplementation for the treatment of adolescents with active depressive symptoms and a high risk for developing mania (i.e. they have a bipolar parent and meet DSM-IV-TR criteria for major depressive disorder), and 2) To use 1H MRS (i.e. prefrontal neurochemistry) and red blood cell (RBC) omega-3 fatty acid levels to examine potential mediators of treatment response to omega-3 fatty acids in adolescents with a high risk for mania. To accomplish these aims, a total of 60 adolescents (ages 12-21 years) with active depressive symptoms and significant risk factors for developing mania will be randomized to treatment with omega-3 fatty acids or placebo for 12 weeks. The aims of this application are consistent with those of the NIMH R34 grant mechanism; "pilot testing of new or adapted interventions" and "development of novel interventions to target specific risk factors for psychopathology or etiologic factors identified through neuroscience research". Additionally, the proposed study will capitalize on the infrastructure of the NIMH supported Center for Interventions Development and Applied Research (CIDAR) grant; the University of Cincinnati Bipolar Disorder Imaging and Treatment Research Center (BITREC, P50MH077138). Public Health Relevance: Evidence-based treatments are urgently needed for mood disorders in youth at high risk for developing bipolar disorder. This proposal will combine novel neuroimaging techniques with a placebo-controlled double-bind treatment trial in order to examine the neurophysiologic and therapeutic effects of chronic omega-3 fatty acid supplementation in adolescents at high risk for developing bipolar disorder, as an initial step to establish early intervention and prevention strategies.