Omega-3 Fatty Acids for MDD with High Inflammation: A Personalized Approach

Omega-3 脂肪酸治疗重度炎症性抑郁症：个性化方法

• 批准号: 8946083
• 负责人: Mark Hyman Rapaport
• 金额: $ 118.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8946083
• 关键词: Adjuvant Therapy; Anhedonia; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Anxiety; Arachidonic Acids; Benign; Biological Factors; Biological Markers; C-reactive protein; Cell membrane; Characteristics; Clinical; Clinical Trials; Data; Desire for food; Disease remission; Double-Blind Method; Early-life trauma; Eicosanoid Production; Eicosapentaenoic Acid; Equipment and supply inventories; Erythrocytes; Face; Fatigue; High Prevalence; Hypochondriasis; Individual; Inflammation; Inflammatory; Interleukin-6; Intervention; Leptin; Literature; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Medical; Mental disorders; N-3 polyunsaturated fatty acid; Obesity; Omega-3 Fatty Acids; Patients; Pharmaceutical Preparations; Placebos; Play; Production; Psychiatry; Public Health; Research; Role; Sampling; Site; Sleep; Societies; Stress; Symptoms; Syndrome; System; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Weight; Work; adiponectin; anakinra; base; cohort; cytokine; depressive symptoms; improved; inflammatory marker; meetings; monoamine; personalized medicine; public health relevance; randomized trial; response; treatment strategy

 DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is prevalent, debilitating, and costly both to individuals and society. One of the challenges with this heterogeneous syndrome is our inability to identify clinically and biologically distinct subsets of patients and so treatment assignment is fairly arbitrary. A second problem we face is that the majority of antidepressant medications share a common mechanism of action: modulation of monoamine systems. Thus, it is not surprising that the overall remission rate to initial therapy can be as low as 33%. These facts suggest that we should reconceptualize our approach to the treatment of MDD. We need to move toward individualized MDD treatment strategies by identifying more homogenous cohorts of patients who are responsive to specific antidepressant therapies. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are a focus of treatment research for many medical and psychiatric disorders. One rationale that could explain therapeutic benefit across a wide array of syndromes is the observation that increasing n-3 PUFA levels shift the production of eicosanoids away from the arachidonic acid, pro-inflammatory, cascade and toward the production of anti-inflammatory metabolites. And so, individuals who manifest inflammation as a component of their illness might benefit from an n-3 PUFA intervention. Although studies in subjects with MDD suggest that n-3 PUFA may be a beneficial adjuvant therapy with traditional antidepressant medications, most monotherapy trials find, at best, a small effect size benefit for n-3 PUFA in heterogeneous samples of subjects with MDD. Work from our previous R-01 identified a homogeneous set of subjects with MDD who were particularly responsive to the n-3 PUFA eicosapentaenoic acid (EPA): subjects with MDD who had multiple biomarkers indicating high inflammation. The one clinical characteristic correlated with the presence of high inflammatory markers was obesity (BMI >30). In fact, 48% of our obese subjects with MDD (vs. 11% in our normal weight group) had baseline levels of high sensitivity C-Reactive Protein (hs-CRP) > 3 mg/l, the accepted cut-point for defining high inflammation. All of the obese subjects with high hs-CRP met criteria for high inflammation on multiple additional markers of inflammation. The overall aim of this application is to extend our previous findings by performing a definitive clinical trial: We propose a 150-subject, two-site, 8-week double-blind randomized trial investigating the efficacy of a 1000 mg/day of EPA-enriched PUFA monotherapy vs. placebo in subjects with MDD, obesity, and baseline levels of hs-CRP > 3 mg/l. We will test 1 primary efficacy hypothesis, 2 mediator hypotheses, and 2 exploratory hypotheses. Successful completion of this R-01 will have significant public health consequences: (1) we will identify a cohort of patients with MDD who are likely to respond to treatment with a relatively benign natural product; (2) we will provide the first test of one potential mechanism responsible for the antidepressant effect of n-3 fatty acids; and (3) we will advance the concept of personalized medicine in the field of psychiatry.

 描述(由申请人提供)：严重抑郁障碍(MDD)很普遍，使人虚弱，对个人和社会都是昂贵的。这种异质综合征的挑战之一是我们无法识别临床和生物学上不同的亚群 因此，患者的治疗分配是相当随意的。我们面临的第二个问题是，大多数抗抑郁药物都有一个共同的作用机制：调节单胺系统。因此，初始治疗的总体缓解率可以低至33%也就不足为奇了。这些事实表明，我们应该重新构思我们治疗MDD的方法。我们需要通过确定更多对特定抗抑郁药物治疗有反应的同质患者队列来转向个性化的MDD治疗策略。Omega-3多不饱和脂肪酸(n-3 PUFA)是许多内科和精神科疾病治疗研究的重点。可以解释多种症状治疗益处的一个基本原理是，观察到n-3多不饱和脂肪酸水平的增加将二十烷基类化合物的产生从花生四烯酸、促炎、级联转移到抗炎代谢物的产生上。因此，将炎症表现为疾病组成部分的个人可能会从n-3多不饱和脂肪酸干预中受益。尽管对MDD患者的研究表明，与传统的抗抑郁药物相比，n-3多不饱和脂肪酸可能是一种有益的辅助治疗方法，但大多数单一疗法试验发现，在MDD患者的不同样本中，n-3 PUFA最多只有很小的效果规模的益处。我们以前R-01的工作确定了一组对n-3多不饱和脂肪酸二十碳五烯酸(EPA)特别敏感的MDD受试者：MDD受试者有多个指示高度炎症的生物标志物。与高炎性标志物的存在相关的一个临床特征是肥胖(BMI&GT；30)。事实上，48%的患有MDD的肥胖受试者(在正常体重组中为11%)有超敏C反应蛋白(hs-CRP)基线水平和GT；3毫克/L，这是公认的定义高度炎症的临界点。所有hs-CRP升高的肥胖受试者在多个额外的炎症标志物上都符合高炎症标准。这项应用的总体目标是通过进行明确的临床试验来扩展我们之前的发现：我们提出了一项150名受试者、两个地点、为期8周的双盲随机试验，调查每天1000毫克EPA强化的多不饱和脂肪酸单一疗法与安慰剂在患有MDD、肥胖和hs-CRP&GT；3 mg/L基线水平的受试者中的疗效。我们将检验1个主要疗效假说、2个中介假说和2个探索性假说。成功完成这项R-01将对公共卫生产生重大影响：(1)我们将确定一组MDD患者，他们可能对使用相对良性的天然产品的治疗有反应；(2)我们将对n-3脂肪酸抗抑郁作用的一个潜在机制进行首次测试；以及(3)我们将在精神病学领域推进个性化药物的概念。