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

 描述（由申请人提供）：重度抑郁症（MDD）是普遍的，衰弱的，对个人和社会都是昂贵的。这种异质性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， 患者，因此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低至33%并不奇怪。这些事实表明，我们应该重新概念化我们的方法来治疗MDD。我们需要通过识别对特定抗抑郁治疗有反应的患者的更同质的队列来实现个体化的MDD治疗策略。ω-3多不饱和脂肪酸（n-3 PUFA）是许多医学和精神疾病的治疗研究的焦点。可以解释在各种综合征中的治疗益处的一个基本原理是观察到增加n-3 PUFA水平使类二十烷酸的产生从花生四烯酸、促炎级联转移到抗炎代谢物的产生。因此，将炎症作为疾病组成部分的个体可能会从n-3 PUFA干预中受益。尽管在MDD受试者中进行的研究表明，n-3 PUFA可能是传统抗抑郁药物的有益辅助治疗，但大多数单药治疗试验发现，在MDD受试者的异质性样本中，n-3 PUFA的效应量最多也就很小。我们之前R-01的工作确定了一组对n-3 PUFA二十碳五烯酸（EPA）特别敏感的MDD受试者：具有多种生物标志物表明高度炎症的MDD受试者。与高炎症标志物存在相关的一个临床特征是肥胖（BMI >30）。事实上，48%的肥胖MDD受试者（正常体重组为11%）的基线高敏C反应蛋白（hs-CRP）水平> 3 mg/l，这是定义高度炎症的公认临界点。所有高hs-CRP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。本申请的总体目标是通过进行确定性临床试验来扩展我们先前的发现：我们提出了一项150名受试者、两个地点、8周的双盲随机试验，研究1000 mg/天富含EPA的PUFA单药治疗与安慰剂相比在患有MDD、肥胖和hs-CRP基线水平> 3 mg/l的受试者中的疗效。我们将检验1个主要有效性假设、2个中介假设和2个探索性假设。成功完成这项R-01将产生重大的公共卫生后果：（1）我们将确定一组可能对相对良性的天然产品治疗有反应的MDD患者;（2）我们将首次测试负责n-3脂肪酸抗抑郁作用的一种潜在机制;（3）在精神病学领域推进个性化医疗的理念。

 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.