修回日期: 2024-08-03
接受日期: 2024-08-14
在线出版日期: 2024-08-28
在临床上精神心理障碍与消化系统疾病的共病愈发常见, 二者既存在共同的发病机制, 同时也互为因果, 其中当以抑郁症研究最为广泛. 脑肠轴是中枢神经系统和肠神经系统之间双向信息交流通路, 该通路的提出解释了许多消化系统疾病与精神心理障碍共病的原因, 同时也为消化系统疾病的诊治提供了新的可能. 其中, 一些研究已经证实了抗抑郁药物在改善消化系统疾病症状方面的治疗潜力.
核心提要: 在脑肠轴的双向作用下, 精神心理障碍与消化系统疾病共病愈发常见, 其中以抑郁症与消化系统疾病共病研究最为广泛. 本文就抗抑郁药物在消化系统常见病中应用的研究进行总结和述评, 旨在为消化系统疾病的诊治提供新的思路及策略.
引文著录: 李熳. 基于脑肠轴探讨抗抑郁药物对消化系统疾病的治疗策略. 世界华人消化杂志 2024; 32(8): 556-560
Revised: August 3, 2024
Accepted: August 14, 2024
Published online: August 28, 2024
Co-morbidity between psychiatric disorders and digestive disorders is becoming more and more common in clinical practice. They have common pathogenesis as well as mutual causation, among which depression is the most widely studied. The brain-gut axis is a bi-directional information exchange pathway between the central nervous system and the enteric nervous system, which has been proposed to explain the mechanisms of co-morbidity between many digestive disorders and psychosomatic disorders. Meanwhile, it also provides new possibilities for the diagnosis and treatment of digestive disorders. Several studies have demonstrated the therapeutic potential of antidepressants in improving the symptoms of digestive disorders.
- Citation: Li M. Exploring antidepressant-based therapeutic strategy for digestive disorders based on brain-gut axis. Shijie Huaren Xiaohua Zazhi 2024; 32(8): 556-560
- URL: https://www.wjgnet.com/1009-3079/full/v32/i8/556.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v32.i8.556
抗抑郁药目前也被称之为"神经调节剂", 在胃肠道疾病中的应用越来越被医生和患者所接受. 临床上抗抑郁药主要分为五大类, 包括三环类抗抑郁药(tricyclic antidepressants, TCAs)、选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitors, SSRIs)、选择性5-羟色胺和去甲肾上腺素再摄取抑制剂(serotonin and norepinephrine reuptake inhibitors, SNRIs)、去甲肾上腺素和特异性5-羟色胺再摄取抑制剂及非典型抗抑郁药. 据报道, 临床抗抑郁药的使用频率急剧增加, 并呈逐年上升的趋势[1]. 在英国的一项研究中, 超过三分之二的抗抑郁药属于超说明书用药. 其中, 当以在消化系统疾病中的应用最为广泛[2].
脑肠轴是一个复杂的双向通信系统, 它连接了中枢神经系统与肠道, 通过神经递质、激素和免疫介质等信号分子, 实现两者之间的信息交流, 这一系统对于维持肠道功能稳态、调节情绪状态以及应对外界应激等具有重要作用[3]. 近年来的研究表明[4], 抗抑郁药物能够增加肠道内5-羟色胺(5-hydroxytryptamine, 5-HT)等神经递质的含量, 从而改善肠道的蠕动、分泌和感觉功能; 其次, 部分抗抑郁药物能够减轻肠道炎症反应, 改善肠道屏障功能[5]; 第三, 抗抑郁药物还能够通过影响肠道菌群的组成和代谢, 进一步发挥改善肠道功能的作用[6], 可见抗抑郁药物在治疗消化系统疾病中的机制主要基于其在脑肠轴中的调节作用. 有观点认为[7], 抗抑郁药作为中枢神经系统调节剂, 在治疗胃肠道疾病中的作用甚至超过了对精神疾病的作用. 临床上目前应用抗抑郁药治疗的消化道疾病主要有功能性胃肠病(functional gastrointestinal disorders, FGIDs)、胃食管反流病(gastroesophageal reflux disease, GERD)、消化道溃疡(peptic ulcer, PU)及炎症性肠病(inflammatory bowel disease, IBD)等.
FGIDs是一组以胃肠道功能紊乱为主要特征的疾病, 主要包括功能性消化不良与肠易激综合征(irritable bowel syndrome, IBS). FGIDs的病理生理学具有异质性, 涉及脑肠轴功能失调、肠道菌群紊乱、内脏高敏性、胃肠道运动异常及胃肠道粘膜免疫功能障碍等相关机制[8]. 研究表明, 全球范围内约有40%人口受到FGIDs的影响, 然而由于疾病的异质性、高度复发性等特点, 对于FGIDs的治疗仍然存在很大的挑战. 研究表明[9], FGIDs合并精神心理障碍比例约为42%-61%, 而多数人精神心理障碍的起病先于或同时于肠道症状的发生. 2016年罗马Ⅳ将其更名为肠-脑相互作用障碍, 强调了脑肠轴作为双向关系基础的重要性, 同时也揭示了精神类药物在消化系统疾病中的治疗潜力[10]. 目前临床上主要有三类抗抑郁药用于治疗功能性胃肠病, 即TCAs、SSRIs和SNRIs[11].
研究表明[12]抗抑郁药物不仅可以通过改善焦虑抑郁等心境障碍间接缓解FGIDs患者消化道症状, 而且可以直接通过影响自主神经系统[13], 调节脑肠肽分泌及相关脑区活化状态, 从而影响胃肠道功能. 5-HT是一种经典的脑肠肽, 机体95% 5-HT受体分布在胃肠道, SSRIs则主要通过提高突触间隙5-HT浓度, 通过介导快相及慢相神经递质的释放, 加速肠道蠕动来缓解患者腹胀及便秘的症状[14]. TCAs因为其抗胆碱作用, 更适用于以腹泻症状为主的患者, 其次TCAs具有较强的镇静作用, 由此可用于FGIDs合并焦虑抑郁等心理障碍患者[15]. 有研究表明[16], 在应用抗抑郁药物治疗FGIDs后, 症状的改善可能与相关脑区的活化相关. 其中, 三环类抗抑郁药阿米替林可降低IBS患者应激状态下前扣带回皮层和左后顶叶皮质与痛觉相关的激活. 而对氟西汀有较强反应的患者还存在脑干、纹状体、前岛叶和海马等皮质下、边缘系统功能变化.
以上研究表明, 抗抑郁药物在改善FGIDs患者焦虑抑郁等精神心理障碍的同时[17], 可以缓解腹痛、腹泻、腹胀、便秘等消化系统症状[18], 并且已被证实通过影响相关脑区的活化及神经内分泌水平促进疾病转归. 目前的临床及基础研究并未发现抗抑郁药物在FGIDs中严重的不良反应, 尽管如此, 仍需要大规模多中心研究评估药物有效性及追踪患者后续疾病转归情况.
GERD是指胃内容物反流入食管、口咽或呼吸道, 产生影响到个人生活质量的棘手症状或损害或并发症[19]. GERD依据有无食管糜烂分类; 有GERD症状、无内镜下食管糜烂的称为非糜烂性食管炎; 而具有GERD症状、同时有食管糜烂的称为糜烂性食管炎, 亦称为反流性食管炎[20]. 目前针对GERD症状的治疗主要有质子泵抑制剂(proton-pump inhibitor, PPI)、促动力药、粘膜保护剂、H2受体阻滞剂等. 然而, 有约1/3的GERD患者使用规范的标准剂量PPI治疗仍得不到满意的疗效, 称为难治性胃食管反流病(refractory gastroesophageal reflux disease, rGERD)[21]. rGERD的致病机制很复杂, 食管内脏感觉过敏是其中的一个重要因素. 有研究认为[22], 精神心理障碍可通过脑肠轴参与食道内脏高敏感性形成.
目前临床上常用于GERD的抗抑郁药物有TCAs、SSRIs以及新型抗抑郁药(氟哌噻吨美利曲辛). 研究初期抗抑郁药物在GERD中的使用局限于通过改善焦虑抑郁状态减轻GERD的临床症状[23]. 后续有研究发现, 抗抑郁药对于不伴焦虑或抑郁的GERD患者疗效优于安慰剂, 而对伴焦虑和或抑郁的GERD患者疗效与安慰剂相当[24]. 由此可以推断抗抑郁药物可能存在独立于心理缓解作用的其他机制改善GERD患者症状. 通过进一步研究发现, 抗抑郁药作为神经调节剂可以通过增加脊髓以上及脊髓水平的突触间隙去甲肾上腺素、5-HT来加强痛觉传输的下行抑制通路[25], 从而降低食管内脏敏感性[26].
Ostovaneh等[27]研究人员对比了氟西汀与安慰剂或PPI治疗GERD 6周的疗效, 结果表明治疗后GERD患者烧心症状缓解天数所占比例明显高于安慰剂组和PPI治疗组. 进一步通过食管PH亚组分析, 在PH-阴性亚组中, 氟西汀组烧心完全缓解天数分别优于安慰剂组及PPI治疗组(P<0.001), 而在PH阳性亚组中, 差异无统计学意义(P = 0.379). Limsrivilai等[28]对比了抗抑郁药物与安慰剂在改善症状方面的治疗潜力, 发现抗抑郁药物总有效率优于安慰剂, 尤其在缓解烧心症状方面. 总之, GERD是一种慢性疾病, 需要长程治疗, 然而长期应用抑酸剂同样会引起胃肠功能紊乱. 因此抗抑郁药物能否与常规治疗结合缩短治疗周期, 改善预后可能是未来新的研究方向.
PU泛指胃肠道粘膜被损伤性因素侵蚀而形成深达粘膜下层的粘膜破损, 可发生于食管、胃、十二指肠以及胃空肠吻合口. 近年来越来越多研究证明PU是生物和心理因素共同作用的结果. 焦虑抑郁等精神障碍可通过影响神经内分泌调节, 使迷走神经异常兴奋, 肾上腺皮质激素分泌增加, 从而增加胃酸、胃蛋白酶的分泌并抑制胃粘液等保护因素的分泌, 最终导致溃疡病的发生, 并增加溃疡病复发概率. 一项Meta分析提示[29], PU患者传统治疗联合抗抑郁治疗可提高PU愈合率. 目前临床上多采用SSRIs及SNRIs对PU进行干预治疗.
SSRIs和SNRIs均可通过提高胃肠道局部释放的5-HT水平, 降低胃液和胃蛋白酶的过度分泌, 改善PU的症状并能降低复发率. 西酞普兰作为SSRIs中的代表药物已被证实可以通过增加前列腺素的分泌、促进一氧化氮的合成及增加黏液的分泌来加强粘膜屏障保护作用, 同时通过减少自由基生成、降低脂质过氧化物作用减少侵袭因素来改善PU症状[30]. 研究表明[31]度洛西汀可以通过减少应激诱导的促肾上腺皮质激素释放激素和促肾上腺皮质激素含量, 从而下调HPA轴活性; 同时也可通过减少粘膜细胞凋亡及炎症细胞募集从而减弱胃肠道局部炎症免疫反应. Spina等[32]人发现氟伏沙明能通过抑制细胞色素P450酶活性, 减少活性氧生成, 从而减少对胃黏膜的氧化损伤.
IBD是肠道慢性非特异性免疫炎症性疾病, 包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crohn,s disease, CD). 目前为止, IBD病因和发病机制尚不明确, 可能与环境因素、遗传因素、免疫因素及心理因素密切相关. 研究发现[33], IBD患者的抑郁率高达21%-26%. 另一项研究表明[34], 抑郁症患者与普通人群相比更容易发展成UC或者CD. 这说明抑郁症可能与IBD之间存在相互作用关系. Duan等[35]发现合并抑郁症状的IBD患者出现类固醇耐药性和IBD相关不良预后的风险较高. 由此推断, 在IBD患者中应用抗抑郁药物辅助治疗不仅可以预防疾病进展及相关情绪心理障碍的发生, 而且可能提高IBD合并抑郁患者常规用药的有效性.
抗抑郁药作为补充替代疗法在IBD患者中被证实可通过缓解肠道炎症及调节肠道菌群等关键作用机制改善患者症状, 阻止疾病进一步恶化. 西方国家有10%-30%的患者使用抗抑郁药物治疗IBD[36]. Fritsch等[37]发现使用TCAs和SSRIs均可改善IBD相关IBS症状, 使用TCAs或SSRIs治疗, 约55%患者将在腹痛及睡眠方面受益, 而安慰剂组约为35%; TCAs改善了约60%患者的腹痛症状, 安慰剂组为30%. 研究证实[38], IBD活动期有70%的患者会出现腹部疼痛, 这种情况下的腹痛多考虑与炎症活动性密切相关. 抗抑郁药已被证实具有抗炎作用, 可降低外周血中白细胞介素-6、白细胞介素-10以及肿瘤坏死因子-α等炎症因子的水平[39], 而动物实验则证明抗抑郁药可抑制NLRP3/caspase-1炎症途径的激活[40]. 结合以上研究结果分析, 抗抑郁药物可通过抑制炎症反应, 降低内脏高敏性, 从而改善患者腹痛症状. 有研究报告[41,42]抗抑郁药物可通过调节肠道微生物, 影响菌群代谢产物水平的改变, 以脑肠轴为媒介调节机体神经内分泌水平, 维持肠道正常微环境, 从而改善患者症状.
抗抑郁药物不仅在上述良性消化系统疾病中的应用广泛, 据报道[43], 抗抑郁药可能还具有抗癌作用, 而这种抗癌作用与多种信号通路和微环境的改变有关. 其机制包括细胞凋亡、抗增殖作用、线粒体介导的氧化应激、DNA损伤、改变免疫反应和炎症状况以及通过抑制癌细胞的多药耐药性发挥作用. 抗抑郁药在抗肿瘤中与靶向药物的协同作用受到了广泛的关注. 同样在治疗精神心理障碍合并器质性疾病方面, 抗抑郁药物也显示出巨大的潜力.
从脑肠轴的角度深入研究抗抑郁药物的作用机制, 将为今后抗抑郁药物在消化系统疾病治疗中的应用带来更大的前景. 然而, 在不同临床实验中, 抗抑郁药物的相关不良反应仍不可忽视. 同时, 抗抑郁药物与其他常规治疗药物的联合使用、剂量及效果评估、个体药物耐受差异、针对不同疾病药物应用的特异性等问题仍亟待解决.
学科分类: 胃肠病学和肝病学
手稿来源地: 天津市
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