Transl Psychiatry︱网状荟萃分析：抗精神病药物所致高泌乳素血症的药物治疗策略
抗精神病药物所致的高泌乳素血症（Hyperprolactinemia，HPRL）是抗精神药物常见的副反应，与结节漏斗多巴胺能通路中多巴胺受体被阻断有关。HPRL会导致闭经、泌乳、性功能障碍等不良结局。部分临床指南建议只有当HPRL出现不良结局时再进行干预[1]。泌乳素是一种多效性激素，分泌到循环中，作用于多个组织，参与免疫、生殖、代谢等多种生理功能[2]。病理性HPRL会导致体重增加、瘦素不敏感、胰岛素抵抗、骨质疏松等远期不良结局，甚至会增加乳腺癌的风险，因此在临床中，无症状HPRL也应该加以关注[3-5]。
目前在临床上改善抗精神药物所致HPRL主要以药物干预为主，主要有以下六种干预策略：1）联用阿立哌唑[6-8]；2）换用另一种抗精神病药物（阿立哌唑、氯氮平、喹硫平等）[9-17]；3）联用多巴胺激动剂（卡麦角林、溴隐亭等）[18-20]；4）联用二甲双胍[21]；5）牡丹甘草合剂[22-26]；6）大剂量维生素B6[27]。而这些策略最重要的副反应是精神病性症状的恶化，在换用另一种抗精神病药物和联用多巴胺激动剂这两种策略中最为突出。既往也有一些荟萃分析讨论了阿立哌唑、牡丹甘草合剂、二甲双胍、多巴胺激动剂对HPRL的改善效果，但仍不够全面[28-34]。因此，有必要探索上述6种干预策略之间有效性和安全性的差异。
单臂试验荟萃分析用于比较干预策略治疗前后的疗效，随机对照试验荟萃分析用于比较干预策略与安慰剂之间的疗效差异，网状荟萃分析用于比较不同干预策略之间的疗效差异，最后综合得出结论。
二、单臂试验荟萃分析
结果显示，相较于对照组，联用阿立哌唑策略可以有效的降低抗精神病药物所致的泌乳素升高（MD = - 68.84 ng/ml, 95% CI = -85.65 to -52.04 ng/ml）（图2）。换用另一种抗精神病药物和牡丹甘草合剂这两种策略由于纳入研究数量少以及研究异质性高，未达到显著性水平。
4.1 六种治疗策略的有效性比较
结果显示，与安慰剂相比，联用阿立哌唑（MD = -60.21 ng/ml, 95% CI = -78.36 to -41.89 ng/ml）、换用另一种抗精神病药物（MD = -38.23 ng/ml, 95% CI = -68.76 to -8.04ng/ml）和大剂量维生素B6（MD = -91.98 ng/ml, 95% CI = -159.55 to -25.78ng/ml）这三种策略具有显著降低泌乳素水平的作用。
结果显示，与安慰剂相比，联用阿立哌唑（5mg亚组：MD = -61.21 ng/ml, 95% CI = -80.23 to -42.33 ng/ml；10mg亚组：MD = -55.97 ng/ml, 95% CI = -78.66 to -33.14 ng/ml；>10mg亚组：MD = -62.21 ng/ml, 95% CI = -80.23 to -42.33 ng/ml）、换用另一种抗精神病药物-缓慢减药滴定加药亚组（MD = -44.53 ng/ml, 95% CI = -81.76 to -7.98 ng/ml) ，牡丹甘草合剂（MD = -27.84 ng/ml, 95% CI = -55.23 to -0.29 ng/ml）和大剂量维生素B6（MD = -87.35 ng/ml, 95% CI = -148.31 to -26.15 ng/ml）具有显著降低泌乳素水平的作用。其中联用阿立哌唑较牡丹甘草合剂的效果更好（5mg亚组：MD = -33.53 ng/ml, 95% CI = -63.83 to -2.80 ng/ml；>10mg亚组：MD = -34.13 ng/ml, 95% CI = -68.23 to -0.68 ng/ml）（图3）。
最后，作者评估了6种干预策略的安全性，共纳入15项研究和844例受试者。结果表明，与安慰剂相比，联用10mg以上的阿立哌唑（OR=2.2，95% CI = 1.2-4.3）副作用的发生率更高。
综上所述抗精神病药物所致的高泌乳素血症（HPRL）可采用联用阿立哌唑、换用另一种抗精神病药物、牡丹甘草合剂和大剂量维生素B6这四种策略来进行干预。当基线泌乳素水平低于50ng/ml时，患者不需要进行干预；当基线泌乳素水平高于50ng/ml时，联用阿立哌唑、换用另一种抗精神病药物和大剂量维生素B6均可以显著降低泌乳素水平；当基线泌乳素水平高于100ng/ml时，只有联用5mg阿立哌唑具有显著降低泌乳素水平的作用。但由于部分干预策略纳入的研究数目少，结果缺乏代表性，临床选择时应该谨慎。未来还需要高质量的随机对照试验来对上述结果进行验证。
（照片提供自：岳伟华实验室）
作者简介（上下滑动阅读）
岳伟华，医学博士，研究员，教授，博士生导师，北京大学第六医院(精神卫生研究所)副院(所)长，国家精神心理疾病临床医学研究中心副主任。国家杰出青年科学基金及优秀青年科学基金获得者，北京大学博雅特聘教授，北京McGovern研究所研究员，北京脑科学与类脑研究中心“合作研究员”。陆续获得国家自然科学基金(青年/面上/优青/杰青)、国家重点研发计划(慢病专项)、国家863计划专题课题、国家973计划子课题、“十二五”科技计划项目子课题、北京市自然科学基金等资助。以通讯或第一作者发表论文100余篇，代表性学术论著发表在Nature Genetics (2011, 2019), Molecular Psychiatry (2017), Lancet Psychiatry (2018), Cell Discovery (2021), Schizophrenia Bulletin (2022)， Translational Psychiatry (2022) 等杂志。
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