抑郁症是一种危害全球人类生活质量的精神疾病,具有高患病率、高疾病负担、高致残率等特点[1-2]。WHO统计数据显示,全球约3.22亿人口受抑郁症困扰,患病率高达4.4%,我国抑郁症患病率约为4.2%[3]。尽管目前已经有多种治疗抑郁症的药物,但仍有将近1/3的患者对抗抑郁药物或心理治疗无效[2],此类抑郁症被称为难治性抑郁症(treatment-resistant depression,TRD)[4]。随着炎症与抑郁症之间关联研究的深入,TRD的神经炎症机制备受学者们的关注[5]。本文对TRD发病机制的最新研究进展进行综述,重点阐述炎症在TRD发生机制中的作用,以期为TRD的诊断及治疗提供新思路。
1 TRD概述在抑郁症的治疗中,研究者们一致认为需要多种药物或治疗方法才能见效,并且患者在出院后需要继续干预[2]。如果患者在接受至少2个推荐的足疗程抗抑郁治疗后病情仍未缓解,即被诊断为TRD[6-7]。慢性、反复病程导致TRD患者常伴有其他躯体疾病,极大地降低了患者的生活质量,并带来高额的疾病经济负担[8]。目前,临床上对于抑郁症状“缓解”尚无明确定义,TRD的诊断标准仍存在争议[9]。一篇系统综述回顾了155项TRD研究的临床诊断标准,其中一半的研究将其定义为2种及以上抗抑郁药物治疗无效,但是各研究在用药类别、治疗时程和病程方面存在较大差异[10]。多项临床研究显示,抑郁症患者中TRD占30%~40%[11-12],如此高比例的耐药性可能是抑郁症患者内在生物学特性与环境异质性造成的结果[13]。导致TRD的生物学因素主要有神经递质紊乱、神经营养因子不足[14]和炎症失调[5]等。在心理社会学方面,共病焦虑障碍和惊恐障碍、抑郁特征、C型人格障碍、早期创伤等是TRD的危险因素[14-15]。
2 TRD与炎症的关系研究表明,炎症既能维护机体稳态,也能对机体组织器官造成严重损伤[16]。早期研究显示,抑郁症患者的白细胞计数高于普通健康人群[17],现在越来越多的证据表明炎症因子失调可能在抑郁症的病理机制中发挥重要作用。中枢炎症系统的过度激活可干扰抑郁症相关的各种病理生理过程,如神经营养支持、氧化应激、神经发生和细胞凋亡等[18]。研究显示重度抑郁症患者存在炎症因子失调,主要包括IL-6、TNF-α、TNF-β、γ-干扰素和CRP等[19-21]; 但有研究表明,CRP与抑郁症的关联可能仅局限于有特定症状的抑郁症人群[22]。据此有研究者认为炎症因子激活是抗抑郁药物产生耐药性的机制之一。Carvalho等[23]的临床研究表明,当炎症系统过度活跃时抑郁症患者服用抗抑郁药后的症状缓解率下降。动物实验研究也表明,小鼠脑内IL-6的过表达导致其对氟西汀产生耐药性[24]。同时,抗炎药物对TRD患者具有一定的抗抑郁效果,如在高敏CRP和TNF-α基线值升高的TRD患者中,TNF-α拮抗剂英夫利西单抗可明显缓解患者的症状,同时降低患者的血清高敏CRP水平[25]。以上这些结果提示炎症与TRD存在一定的联系。高炎症状态对抗抑郁药物应答率的影响已经成为目前研究的方向之一,有研究者提出炎症细胞因子水平升高可预测TRD,可能是TRD的预测因子[26],这表明炎症可能会诱发不受单胺能神经系统调节影响的、单独的情绪通路,并在TRD的发生机制中具有一定作用。
3 炎症在TRD发病中的作用机制目前对炎症在TRD发病中作用机制的研究有以下几个方向。
3.1 小胶质细胞小胶质细胞的过度激活被认为是在炎症细胞因子水平升高时介导情绪症状的潜在因素[27]。TNF-β和IL-1β是先天性免疫系统中一部分小胶质细胞的有效激活剂[28]。小胶质细胞的过度激活可能引起神经回路过度修剪、神经可塑性下降,最终导致神经回路功能下降及认知和情绪调节在功能水平上的受损[28-30]。小胶质细胞的激活会导致谷氨酸代谢紊乱,从而改变谷氨酸水平并激活谷氨酸受体,这也是TRD发生机制的一部分[31]。氯胺酮作为新兴的快速抗抑郁药物,在TRD患者中具有良好疗效[32]。研究表明,氯胺酮及其2种活性代谢物可以在小胶质细胞中通过信号转导及转录激活因子3调控Ⅰ型干扰素信号通路,这可能是氯胺酮发挥抗抑郁作用的机制之一[33]。另外,氯胺酮通过调节位于谷氨酸受体下游的哺乳动物雷帕霉素靶蛋白信号通路改善神经发生和可塑性,从而在TRD治疗中发挥作用[34]。其中机制的解释仍然有待深入研究,阐明TRD患者持续性炎症的作用和其介导氯胺酮抗抑郁作用的关键机制将可能促进新治疗策略的发展。
3.2 糖皮质激素炎症细胞因子可刺激活化下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴和抑制负反馈回路,从而导致高糖皮质激素血症。皮质醇水平的升高(内源性或外源性)已经被反复证明会引起情绪症状,被认为是炎症和重性抑郁症另一个潜在的联系[35]。临床研究显示,TRD患者的血清糖皮质激素水平高于同期重性抑郁症患者,提示TRD患者的HPA轴功能紊乱程度更甚[36]。为了进一步探讨糖皮质激素及高炎症激活水平在TRD危险因素方面的介导作用,有学者重点关注童年创伤和TRD之间的机制[15],并发现白天皮质醇水平增高的糖皮质激素抵抗患者儿童期经历的创伤严重程度与抗抑郁药物治疗抵抗相关[37]。此外,HPA轴的激活可导致色氨酸双加氧酶活性增高,从而降解色氨酸和减少5-羟色胺的生成[38]。TRD可能并不是简单的5-羟色胺缺失状态,但是某些因素如5-羟色胺转运体基因缺失、早期的逆境生活和共病双相情感障碍等都与选择性5-羟色胺再摄取抑制剂治疗的耐药性有关[39],相关介导机制可能来源于应激反应导致神经内分泌系统激活后HPA轴功能的紊乱。
3.3 细胞因子细胞因子主要由单核细胞、巨噬细胞及淋巴细胞等免疫细胞合成并分泌,目前已证实中枢神经系统的小胶质细胞和星形胶质细胞等也能释放细胞因子[40]。大量研究结果显示,抗抑郁治疗出现耐药性与血浆细胞因子水平升高相关。Strawbridge等[5]对36例TRD患者在接受专科住院治疗前后进行了纵向调查,比较了TRD患者和非抑郁对照组血浆中的27个炎症因子水平,发现TRD患者的27个炎症因子水平均高于非抑郁对照组,而与未产生耐药性的重性抑郁症患者相比,TRD患者血浆中的IL-6、IL-8、TNF、CRP水平升高且与较差的治疗结果相关,这些细胞因子水平的升高一定程度上与HPA轴激活有关。在基于习得性无助建立的TRD模型小鼠中,TNF-α能够减少血脑屏障连接蛋白的表达,从而在一定程度上降低了血脑屏障的通透性[41]。一篇纳入10项临床研究的系统综述显示,IL-6与CRP/高敏CRP是目前较为公认的与TRD相关的细胞因子[26]。针对快速抗抑郁药氯胺酮的研究支持这一结果,IL-6基线水平可以有效预测TRD对氯胺酮治疗的反应,并且在治疗后IL-6水平也降低[42]。相比重性抑郁症患者,TRD患者外周静脉血CRP水平的升高更显著,与CRP升高相关的其他表型包括童年逆境、特定的抑郁和焦虑症状[43],这一结果与TRD发生的危险因素相匹配[15, 44]。以上这些证据都提示,细胞因子与抑郁症存在着深层的内在联系,但仍需要临床前实验进一步阐明相关机制。
4 小结TRD越来越受到研究者们的重视,但是由于抑郁症治疗“缓解”定义的不明确,TRD的诊断与治疗在各研究体系中存在较大异质性。由于尚无公认可靠的动物模型,TRD发生机制的深入研究存在较大挑战。单胺类药物治疗TRD的有限性也让研究者们开始关注其他的通路。基于大量的临床试验,TRD与炎症之间的关联逐渐受到重视,但是目前研究关注的重心多集中于IL-6、IL-8、TNF、CRP等炎症因子在TRD病理条件下的水平变化,炎症因子的来源、高炎症反应与耐药性之间的介导机制尚未完全阐明。了解炎症在TRD发生中的作用机制将有助于抑郁症治疗药物的研发。
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