The Role of Omega-3 Fatty Acids in Adolescent Depression

描述(申请人提供)：目标是通过质子磁共振波谱成像(1H MRSI)获得omega-3脂肪酸(FA)对青少年MDD中发现异常的神经化学物质总脑胆碱(Tcho)、总肌酸(TCR)和3-氨基丁酸(GABA)区域浓度影响的初步数据。Omega-3FA的安慰剂对照试验将解决这一目标。基本原理。该建议基于相关发现：1)MDD出现在青春期；2)其病理生理涉及额纹状体结构异常，涉及神经胶质细胞和神经元的死亡和萎缩；3)omega-3 FA在神经胶质和神经元功能中发挥关键作用，对神经细胞膜的动态结构至关重要，在MDD具有良好的治疗作用；4)omega-3FA对脑功能的影响可以通过1H MRSI进行评估。假设是：在患有MDD的青少年中，1)与安慰剂相比，omega-3FA将导致纹状体(尾状核和壳核)和前扣带回(ACC)Tcho、Tcr的浓度显著降低，而ACC中的GABA浓度更高；2)omega-3FA和安慰剂的改善将与纹状体和ACC Tcho和Tcr的减少以及ACC GABA浓度的增加有关。探索性地，我们将检验与安慰剂相比，omega-3FA的改善是否与纹状体和ACC Tcho和TCR的下降以及ACC GABA浓度的增加更密切相关。方法：研究方法。受试者。根据力量分析，24名医学上健康的、未服用抗抑郁药物的青少年，年龄12-18岁，患有MDD至少8周，CDRS-R的严重程度评分为40分，首次MDD发病12年。MDD诊断将用K-SADS-PL建立。研究治疗方法。用omega-3FA(联合EPA/DHA，比例2：1)或匹配的安慰剂进行10周的双盲随机治疗。起始剂量为1.2g/d，每两周灵活滴定一次，最大剂量为3.6g/d。每个剂量的两周将通知每个剂量的临床反应。研究前和研究结束时的评估包括诊断、MDD严重程度(CDRS-R)和红细胞中的omega-3FA。每周将获得临床总体改善、不良事件/生命体征、自杀意念和食物摄入量清单。神经成像将包括在10周试验之前和结束时在高(3T)磁场下获得的高空间分辨率的多体素1H MRS，重点放在纹状体和ACC上。青少年MDD是一个主要的公共卫生问题，与发病率和死亡率有关。这项拟议的研究代表了先进的神经影像研究和对患有MDD的青少年进行的严格的临床试验的结合。它试图为旨在加强我们对CAM的作用机制的理解的翻译方法奠定基础，并最终可能导致对青少年MDD的新颖和有效的治疗。 公共卫生相关性：这项工作旨在为旨在加强我们对补充和替代药物(CAM)(如omega-3脂肪酸(FA))的作用机制的理解的翻译方法奠定基础。这项研究考察了omega-3FA对患有严重抑郁障碍(MDD)的青少年大脑化学物质的影响，MDD是一个主要的公共卫生问题。为潜在重要的CAM如omega-3FA奠定科学基础将加速将它们适当地纳入MDD等特定疾病的标准医疗实践(床边到社区转换)。

DESCRIPTION (provided by applicant): The goal is to obtain preliminary data on omega-3 fatty acids (FA) effects on regional concentrations of total brain choline (tCho), total creatine (tCr) and 3-aminobutyric acid (GABA) - neurochemicals found to be abnormal in adolescent MDD, with proton magnetic resonance spectroscopic imaging (1H MRSI). A placebo-controlled trial of omega-3FA will address this goal. Rationale. The proposal rests on related findings that: 1) MDD emerges in adolescence; 2) its pathophysiology involves abnormalities in fronto-striatal structures involving death and atrophy of glia and neurons; 3) omega-3 FA play a crucial role in glial and neuronal function, are critical to the dynamic structures of neuronal membranes, and have promising therapeutic properties in MDD; 4) omega-3FA effects on brain function can be assessed by 1H MRSI. Hypotheses are: in adolescents with MDD, 1) Compared to placebo, omega-3FA will lead to significantly lower concentrations of striatal (caudate and putamen) and anterior cingulate cortex (ACC) tCho, tCr, and greater GABA concentrations in the ACC; 2) improvement with omega-3FA and placebo will be associated with decreases in striatal and ACC tCho and tCr, and increases in ACC GABA concentrations. Exploratorily, we will examine whether improvement with omega-3FA is more strongly associated with declines in striatal and ACC tCho and tCr, and increases in ACC GABA concentrations, than improvement with placebo. Methods. Subjects. Based on power analyses, 24 medically healthy, antidepressant-naive adolescents, ages 12-18, with MDD for at least 8 weeks and a severity score of >40 on the CDRS-R, and first MDD onset > 12 years. MDD Diagnosis will be established with the K-SADS-PL. Study Treatments. 10 weeks of double-blind randomized treatment with omega-3FA (combined EPA/DHA, ratio 2:1) or matching placebo. Dose will be initiated at 1.2g/d, titrated flexibly every 2 weeks to 3.6g/d, maximum. Two weeks at each dose will inform clinical response at each dose. Assessments before and at study end include diagnosis, MDD severity (CDRS-R), and omega-3FA in red blood cells. Clinical global improvement, adverse events/vital signs, suicidal ideation, and food intake checklist will be obtained weekly. Neuroimaging will include multi-voxel 1H MRS acquired at high (3T) magnetic field with high spatial resolution, focusing on the striatum and the ACC, before and at the end of the 10 week trial. Adolescent MDD is a major public health concern, associated with morbidity and mortality. The proposed study represents the integration of advanced neuroimaging research and a rigorous clinical trial in adolescents with MDD. It seeks to lay the groundwork for translational approaches aimed at enhancing our understanding of the mechanisms of action of CAM's, and eventually may lead to novel and effective treatments for adolescent MDD. PUBLIC HEALTH RELAVANCE: This work seeks to lay the groundwork for translational approaches aimed at enhancing our understanding of the mechanisms of action of complementary and alternative medicines (CAM's) such as omega-3 fatty acids (FA). This study examines the effects of omega-3FA on brain chemicals in adolescents with major depressive disorder (MDD), a major public health concern. Laying the scientific groundwork for potentially important CAM's such as omega-3FA will accelerate their appropriate incorporation into standard medical practice (bedside to community translation) in specific disorders such as MDD.