Wang Peipei, Zhang Cuizhen, Lv Qinyu, Bao Chenxi, Sun Hong, Ma Guo, Fang Yiru, Yi Zhenghui, Cai Weimin
Department of Clinical Pharmacy, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai, 201203, People's Republic of China.
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wanping Rd, Shanghai, 200030, People's Republic of China.
Eur J Clin Pharmacol. 2018 Aug;74(8):1011-1020. doi: 10.1007/s00228-018-2463-z. Epub 2018 May 10.
The neurotrophin brain-derived neurotrophic factor (BDNF) has been found to be associated with both the pathophysiology of depression and antidepressants response. Gene expression differences were partly mediated by SNP, which might be identified as a predictor of antidepressant response. In the present study, we attempt to identify whether DNA methylation, another factor known to affect gene transcription, might also predict antidepressant response.
A total of 85 depressed Chinese Han patients were followed-up 8 weeks after initiating escitalopram treatment. Treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The bisulfate sequencing was used to assess DNA methylation. Four single nucleotide polymorphisms (SNPs) in the BDNF gene were genotyped using PCR-RFLP or PCR sequencing.
We identified a DNA methylation predictor (P = 0.006-0.036) and a DNA methylation by LES interaction predictor (OR = 1.442 [1.057-1.968], P = 0.021) of general antidepressant treatment response. Lower mean BDNF DNA methylation was associated with impaired antidepressant response. Furthermore, the present data indicated that age, life stress, and SNPs genotype might be likely related to DNA methylation status. Average DNA methylation of BDNF at baseline was significantly lower than that at endpoint after 8 weeks of escitalopram treatment, which was based only on a subset of cases (n = 44).
Our results suggest that BDNF DNA hypomethylation and its interaction with lower LES score might result in impaired antidepressant treatment response. The pharmacoepigenetic study could eventually help in finding epigenetic biomarkers of antidepressant response.
神经营养因子脑源性神经营养因子（BDNF）已被发现与抑郁症的病理生理学及抗抑郁药反应均有关联。基因表达差异部分由单核苷酸多态性（SNP）介导，SNP可能被确定为抗抑郁药反应的预测指标。在本研究中，我们试图确定另一个已知会影响基因转录的因素——DNA甲基化是否也能预测抗抑郁药反应。
共85例中国汉族抑郁症患者在开始艾司西酞普兰治疗8周后进行随访。通过汉密尔顿抑郁量表17项（HAMD - 17）评分的变化评估治疗反应。使用生活事件量表（LES）和儿童期创伤问卷（CTQ）评估既往生活压力。采用亚硫酸氢盐测序法评估DNA甲基化。使用聚合酶链反应 - 限制性片段长度多态性（PCR - RFLP）或PCR测序对BDNF基因中的四个单核苷酸多态性（SNP）进行基因分型。
我们确定了一个DNA甲基化预测指标（P = 0.006 - 0.036）以及一个LES与DNA甲基化的相互作用预测指标（比值比[OR] = 1.442 [1.057 - 1.968]，P = 0.021）用于预测一般抗抑郁治疗反应。较低的BDNF平均DNA甲基化与抗抑郁反应受损相关。此外，目前的数据表明年龄、生活压力和SNP基因型可能与DNA甲基化状态有关。仅基于部分病例（n = 44），艾司西酞普兰治疗8周后，BDNF的基线平均DNA甲基化显著低于终点时的水平。
我们的结果表明，BDNF DNA低甲基化及其与较低LES评分的相互作用可能导致抗抑郁治疗反应受损。药物表观遗传学研究最终可能有助于找到抗抑郁反应的表观遗传生物标志物。
