抑郁症早期起效预测稳定临床痊愈的生物学标记物研究

Diagnostic guideline of depression has suggested that change of medicine treatment should be considered after 4-6 antidepressant treatment. Some recent studies have found early improvement has highly predictive effect on treatment outcome (i.e. stable remission) of depression, with highly sensitivity of more than 90%, while with low specificity, which was proved that 50%-75% of patients with early improvement failed to get stable remission. In order to improve the specificity of early improvement, we will utilize functional MRI (fMRI) scan to measure the pattern of brain functional activity and measure brain derived neurotrophic factor (BDNF) and cytokine concentration in plasma in the first 2 weeks of treatment. Specifically, data of each biomarker (i.e. pattern of brain activity revealed by fMRI, BDNF and cytokine concentration in plasma) will be collected and compared at baseline and after 2 week treatment between patients with early improvement and those without. Furthermore, data of those biomarkers will be compared between patients with stable remission and those without stable remission, which will be assessed by 12-week following-up. Thus, the current study will be more likely to seek out some biomarkers which are specific to predict stable remission based on early improvement. In addition, the current study will aim to testify predictive effect of biomarkers on stable remission in depression, which is not similar as previous studies. Thus, the current study has great effects to guide clinical treatment of depression directly.

治疗指南建议，抗抑郁药治疗4-6周才考虑是否改变用药策略。近期研究发现，早期起效对治疗结局有很高的预测价值，其对稳定临床痊愈的预测灵敏度高（>90%），但特异性较低，有50-75%的早期起效者继续原治疗方案不能获得临床稳定痊愈。为了提高早期起效预测作用的特异性，我们将采用功能磁共振成像（fMRI）测量治疗早期（两周）的脑活动模式，同时检测外周血浆脑源性神经因子（BDNF）、细胞因子浓度。具体内容包括：（1）比较基线、治疗2周时早期起效与非早期起效患者的各生物学指标的差异；（2）比较早期起效患者中稳定痊愈者与非稳定痊愈者（通过12周持续治疗的跟踪评估）的各生物学指标的差异。该项目有望鉴定出若干个早期起效获得稳定痊愈患者的特异性生物学标记。与以往研究不同的是，本项目专注于考察治疗早期生物学标志对抑郁症稳定痊愈的预测价值，对抑郁症临床实践具有直接的指导意义。

抑郁症急性期的治疗目标是临床治愈，但只有1/3的患者在急性期达到这个目标。如何及早地预测抗抑郁药治疗是否会达到临床治愈，以便及早进行治疗方案的调整，对提高治愈率非常重要。早期起效（2周内汉密尔顿抑郁量表（HAMD）减分率≥20%）可以预测临床治愈，但进一步的分析发现，HAMD对稳定临床治愈的预测率只有25%；因此，寻找预测稳定临床治愈的评价方法非常重要。一些研究认为，功能磁共振（fMRI）和细胞因子可以评价抑郁症治疗效果，但不清楚是否可以评价早期起效。为阐明早期起效对抑郁症患者稳定临床治愈的预测作用，我们采用fMRI联合细胞因子检测，对24例符合美国精神疾病诊断统计手册第4 版(DSM-IV ) 抑郁发作诊断标准的首发抑郁症患者治疗前后的变化进行评估，比较早期起效与非早期起效患者fMRI和肿瘤坏死因子（TNF)、白介素（IL）-6/18的浓度变化；对其中15例患者通过12周持续治疗的跟踪观察，比较早期起效患者中稳定临床治愈者与非稳定临床治愈者间的差异。结果发现：1）左侧颞中回、舌回和角回脑区功能连接强度与HAMD-17得分变化率呈负相关；2）早期起效组的临床治愈率（60%）明显高于非早期起效组（17%）。结论：抑郁患者治疗2周后，左侧颞中回、舌回和角回的的功能连接越强，2周后其HAMD-17量表得分降低率越高；左侧颞中回、舌回和角回的的功能连接增强与临床治疗效果相关；早期起效患者获得更高的临床治愈率。