Department of Biomedical Sciences and Biotechnology, Genetic and Biology Section, University of Brescia, Brescia, Italy.
Neuropsychopharmacology. 2013 Feb;38(3):377-85. doi: 10.1038/npp.2012.191. Epub 2012 Sep 19.
To improve the 'personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants ('predictors'), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment ('targets'). In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-α), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels of IL-1β (+33%), MIF (+48%), and TNF-α (+39%). Antidepressants reduced the levels of IL-1β (-6%) and MIF (-24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (-9%) and of FKBP5 (-11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)-that is, response was associated with changes in genes that did not predict, at the baseline, the response. Our findings indicate a dissociation between 'predictors' and 'targets' of antidepressant responders. Indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect.
为了改善抑郁症治疗的“个体化医学”方法，我们需要确定生物标志物，这些标志物在开始治疗前评估，可以预测抗抑郁药的未来反应（“预测因子”），以及抗抑郁药靶向并在治疗过程中纵向变化的生物标志物（“靶点”）。在这项研究中，我们测试了健康对照组（n=34）和抑郁症患者（n=74）白细胞 mRNA 表达水平，这些患者属于糖皮质激素受体（GR）功能（FKBP-4、FKBP-5 和 GR）、炎症（白细胞介素（IL）-1α、IL-1β、IL-4、IL-6、IL-7、IL-8、IL-10、巨噬细胞抑制因子（MIF）和肿瘤坏死因子（TNF）-α）和神经可塑性（脑源性神经营养因子（BDNF）、p11 和 VGF），这些患者在接受依西酞普兰或去甲替林治疗 8 周之前和之后。无反应者的 IL-1β（+33%）、MIF（+48%）和 TNF-α（+39%）的基线 mRNA 水平更高。抗抑郁药降低了 IL-1β（-6%）和 MIF（-24%）的水平，并增加了 GR（+5%）和 p11（+8%）的水平，但这些变化与治疗反应无关。相比之下，成功的抗抑郁反应与 IL-6（-9%）和 FKBP5（-11%）水平的降低以及 BDNF（+48%）和 VGF（+20%）水平的升高有关，即反应与基线时不能预测反应的基因的变化有关。我们的研究结果表明，抗抑郁药反应者的“预测因子”和“靶点”之间存在分离。事实上，虽然促炎细胞因子水平较高预示着未来对抗抑郁药无反应，但与抗抑郁药反应相关的炎症变化并不总是反映在所有细胞因子上。相比之下，需要调节 GR 复合物和神经可塑性才能观察到治疗性抗抑郁作用。
