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

描述（由申请人提供）：父母患有双相情感障碍的青少年后代，特别是那些有明显抑郁症状的父母，与一般人群相比，患躁狂症的风险更高，根据定义，双相情感障碍I。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狂的发作。因此，有必要研究评估父母有双相情感障碍的青少年抑郁症状的潜在治疗方法的有效性、安全性和耐受性，并可能导致早期干预，最终预防早期躁狂和轻躁发作的策略。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脂肪酸可以减轻青少年和成人情绪障碍患者情绪症状的严重程度。此外，死后研究显示，年轻双相患者的前额皮质存在显著的omega-3脂肪酸缺陷。最近的神经影像学研究表明，双相情感障碍的症状可能是由前边缘网络功能障碍引起的，包括腹外侧前额叶和前扣带皮层。具体来说，质子磁共振波谱（1H MRS）研究显示，患有双相情感障碍和患双相情感障碍高风险的青少年表现出谷氨酸和肌醇过量以及N-乙酰天冬氨酸水平降低，这表明高代谢可能是大脑前边缘区域破坏的基础。这些神经化学变化可能是治疗效果的有用生物标志物。考虑到这些因素，本研究的目标是：1)收集关于补充omega-3脂肪酸治疗具有活动性抑郁症状和发展为躁狂症高风险的青少年（即父母有双相情感障碍且符合DSM-IV-TR重度抑郁症标准）的有效性、安全性和耐受性的试点数据；2)利用1H MRS（即前额叶神经化学）和红细胞（RBC） omega-3脂肪酸水平检测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，总共有60名青少年（12-21岁）有活跃的抑郁症状和发展为躁狂的显著危险因素，将随机接受omega-3脂肪酸或安慰剂治疗12周。本申请的目的与NIMH R34拨款机制一致；“新的或适应的干预措施的试点测试”和“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或病因因素的特定风险因素”。此外，拟议的研究将利用NIMH支持的干预发展和应用研究中心（CIDAR）资助的基础设施；辛辛那提大学双相情感障碍成像与治疗研究中心（BITREC, P50MH077138）。公共卫生相关性：在发展为双相情感障碍的高风险青年中，迫切需要循证治疗。本研究将新型神经影像学技术与安慰剂对照双相结合治疗试验相结合，以检验慢性omega-3脂肪酸补充剂对双相情感障碍高风险青少年的神经生理和治疗效果，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.