A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.
A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.
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DOI：
10.1001/2013.jamapsychiatry.4
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发表时间：
2013-01
期刊：
影响因子：
25.8
通讯作者：
Miller, Andrew H.
中科院分区：
文献类型：
--
作者：
Raison, Charles L.;Rutherford, Robin E.;Woolwine, Bobbi J.;Shuo, Chen;Schettler, Pamela;Drake, Daniel F.;Haroon, Ebrahim;Miller, Andrew H.
炎症生物标志物增加可预测抗抑郁药无反应，而炎症细胞因子可破坏和规避常规抗抑郁药治疗的作用机制。确定抑制炎性细胞因子肿瘤坏死因子（TNF）-α是否可减轻难治性抑郁症（TRD）患者的抑郁症状，以及基线血浆炎性生物标志物（包括高敏C反应蛋白（hs-CRP）、TNF-α及其可溶性受体）升高是否可预测治疗反应。双盲、安慰剂对照、随机临床试验。埃默里大学门诊输液中心。根据马萨诸塞州总医院分期方法确定，60例接受一致抗抑郁药方案或停药≥4周且中度治疗抵抗的重度抑郁症患者（n=23）的病情稳定门诊患者。在基线和12周试验的第2周和第6周输注TNF-α拮抗剂英夫利昔单抗（5 mg/kg）（n = 30）或安慰剂（n=30）。17-项目汉密尔顿抑郁量表（HAM-D-17）。各治疗组间HAM-D-17评分变化无总体差异，但治疗、时间和基线hs-CRP对数之间存在显著相互作用（p=0.01），基线hs-CRP> 5 mg/L的患者和基线hs-CRP ≤ 5 mg/L的安慰剂治疗患者的HAM-D-17评分变化（基线至第12周）更有利于英夫利昔单抗治疗患者。针对基线hs-CRP> 5 mg/L患者的探索性分析显示，英夫利西单抗组的治疗应答率（治疗期间任何时间点HAM-D-17降低≥50%）为62%（8/13），安慰剂组为33%（3/9）（p=0.19）。与无应答者相比，接受英夫利昔单抗治疗的应答者的TNF-α及其可溶性受体的基线浓度显著更高（p<0.05），与接受安慰剂治疗的应答者相比，接受英夫利昔单抗治疗的应答者从基线至第12周的hs-CRP降幅显著更大（p<0.01）。脱落和不良事件有限，组间无差异。这项概念验证研究表明，TNF-α拮抗作用对TRD没有普遍疗效，但可能改善基线炎症生物标志物高的患者的抑郁症状。ClinicalTrials.gov标识符：NCT 00463580
Increased inflammatory biomarkers predict antidepressant non-response, and inflammatory cytokines can sabotage and circumvent mechanisms of action of conventional antidepressant therapy. To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF)-alpha reduces depressive symptoms in patients with treatment resistant depression (TRD) and whether increased baseline plasma inflammatory biomarkers including high sensitivity c-reactive protein (hs-CRP), TNF-alpha and its soluble receptors predict treatment response. Double-blind, placebo-controlled, randomized clinical trial. Outpatient infusion center, Emory University. Sixty medically-stable outpatients with major depression on a consistent antidepressant regimen or medication-free (n=23) for ≥4 weeks and moderate treatment resistance as determined by the Massachusetts General Hospital Staging method. Three infusions of the TNF-alpha antagonist infliximab (5mg/kg)(n=30) or placebo (n=30) at baseline and weeks 2 and 6 of a 12-week trial. 17-item Hamilton Depression Rating Scale (HAM-D-17). No overall difference in change of HAM-D-17 scores between treatment groups across time was found. However, there was a significant interaction between treatment, time and log baseline hs-CRP (p=0.01), with change in HAM-D-17 scores (Baseline to Week 12) favoring infliximab-treated patients at a baseline hs-CRP>5mg/L and placebo-treated patients at a baseline hs-CRP≤5mg/L. Exploratory analyses focusing on patients with a baseline hs-CRP>5mg/L revealed a treatment response (≥50% reduction in HAM-D-17 at any point during treatment) of 62% (8/13) in the infliximab group versus 33% (3/9) in placebo-treated patients (p=0.19). Baseline concentrations of TNF-alpha and its soluble receptors were significantly higher in infliximab-treated responders versus non-responders (p<0.05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from Baseline to Week 12 compared to placebo-treated responders (p<0.01). Drop-outs and adverse events were limited and did not differ between groups. This proof-of-concept study suggests that TNF-alpha antagonism does not have generalized efficacy in TRD, but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. ClinicalTrials.gov Identifier: NCT00463580
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