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摘要: 迟发性运动障碍(tardive dyskinesia，TD)是与长期服用多巴胺受体阻滞剂相关的一种异常不自主运动，可累及面颈部，引起伸舌、咀嚼、噘嘴、歪颌或转颈，也可累及四肢和躯干，表现为舞蹈样动作。临床上最常见的病因为抗精神病药物(antipsychotic drug，APD)的使用。与TD相关的危险因素包括APD的种类、用药剂量和时间、年龄和性别，遗传因素也发挥一定作用。目前研究较多的TD相关基因为CYP2D6、DRD2、DRD3、HTR2A、HTR2C、VMAT2、MnSOD、HSPG2。TD的发病机制尚不明确，主要有多巴胺受体超敏学说、氧化应激学说和突触可塑性失调学说。临床上治疗TD较为困难，预防至关重要。本文就TD的临床诊治进展进行综述，以进一步加深医务人员对该疾病的认识。
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关键词:
- 迟发性运动障碍 /
- 多巴胺受体阻滞剂 /
- 抗精神病药物 /
- 囊泡单胺转运体2抑制剂
Abstract: Tardive dyskinesia(TD) is a kind of disabling movement disorder characterized by involuntary movements of the face, neck, extremities or trunk that results from long-term use of dopamine receptor blocking agents.The most common reason is the use of antipsychotic drug(APD). Identified risk factors include the type, dose, as well as the duration of APD. Age, sex, genetics also play a role. CYP2D6, DRD2, DRD3, HTR2A, HTR2C, VMAT2, MnSOD, HSPG2 gene may be involved. The pathogenesis is not clear. Three hypotheses are proposed: dopamine receptor super-sensitivity, oxidative stress and maladaptive synaptic plasticity. TD is quite hard to cure, prevention is of vital importance. This article reviews the clinical diagnosis and treatment of TD, so as to further deepen medical staff's understanding of TD.作者贡献：王喜喜负责查阅文献、撰写论文；万新华负责修订、审校论文。利益冲突：所有作者均声明不存在利益冲突 -
表 1 CYP2D6基因与TD相关的变异[23]
基因 核苷酸突变 蛋白质变异 功能 rs16947 2851C＞T R296C 正常(野生型) rs1135840 4181G＞C S486T 正常 rs5030656 2616delAAG K281缺失 下降 rs1065852 100C＞T P34S 下降 rs28371706 1022C＞T T107I 下降 rs28371725 2851C＞T R296C 下降 rs35742686 2550delA 259移码 无 rs3892097 1847G＞A 剪接/169移码 无 rs5030655 1708delT 152移码 无 TD: 迟发性运动障碍 
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表 2 编码多巴胺受体的候选基因作为TD风险预测因子的相关研究[24]
基因 编码蛋白 位置 变异 是否与TD风险相关 样本来源 DRD1 多巴胺D1受体 5q35.2 rs4532(A/G) 是 亚洲 DRD2 多巴胺D2受体 11q23.2 rs6277(C/T) 是 荷兰和比利时 rs6275(C/T) 是 荷兰和比利时 否 - rs1800497(C/T) TaqIA多态性(是) 美国 否 - rs1079597(A/G) TaqIB多态性(是) 美国 rs1799732(141CIns/Del) 是 日本 是 荷兰和比利时 rs1800498(T/C) 否 - rs1801028(C/G) 否 - rs1045280(C/T) 是 中国 DRD3 多巴胺D3受体 3q13.31 rs6280(C/T) 否 中国 rs905568(C/G) 是 美国 rs9817063(T/C) 否 - rs2134655(G/A) - - rs963468(G/A) - - rs324035(C/A) - - rs3773678(C/T) - - rs167771(A/G) - - rs11721264(G/A) - - rs167770(A/G) - - rs9633291(T/G) - - rs1800828(G/C) - - DRD4 多巴胺D4受体 11p15.5 rs3758653(T/C) - - rs1800955(T/C) - - TD: 同表 1；-：缺少相关数据
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表 3 关于TD患者的全基因组关联分析研究[24]
年份(年) 基因 样本来源 2008 SLC6A11，GABRB2，GABRG3 日本 2010 ZNF202 美国 2011 HSPG2 日本 2021 FOXP1 俄罗斯 2021 TNFRSF1B，EPB41L2，CALCOCO1 东亚、欧洲和非洲裔美国人 TD: 同表 1
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VMAT2抑制剂 起始剂量(mg) 最大剂量(mg) 半衰期(h) 给药频率 不良反应 丁苯那嗪(TBZ) 12.5 150 5~7 3次/d 直立性低血压、胃肠运动障碍、鼻塞、抑郁、锥体外系不良反应 氘丁苯那嗪(DBZ) 12 48 9~10 2次/d 头痛、嗜睡、帕金森病 缬苯那嗪(VBZ) 40 80 15~22 1次/d 头痛、嗜睡、静坐不能、口干 VMAT2：囊泡单胺转运体2
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治疗方法(最大日剂量) 作用机制 不良反应 证据级别 典型APD转为非典型APD 低D2受体亲和力 - - 氯硝西泮(4.5 mg) GABA能(GABAA受体) 镇静、共济失调、跌倒风险 B级 金刚烷胺(400 mg) NMDA受体拮抗剂 失眠、便秘、头晕、认知损害 C级 银杏叶提取物(240 mg) 抗氧化剂 - B级 维生素E(1600 IU) 维生素B6(1200 mg) TBZ(150 mg) VMAT2抑制剂 直立性低血压、胃肠运动障碍、鼻塞、抑郁 B级 DBZ(48 mg) 头痛、嗜睡、帕金森病 A级 VBZ(80 mg) 头痛、嗜睡、静坐不能、口干 A级 BTX 阻断神经肌肉接头乙酰胆碱释放 注射部位肌无力 - GPi-DBS 刺激苍白球深部 平衡障碍 C级 TD：同表 1；APD：抗精神病药物；TBZ：丁苯那嗪；DBZ：氘丁苯那嗪；VBZ：缬苯那嗪；BTX：肉毒毒素；GPi-DBS：苍白球内深部脑刺激；-：同表 2；VMAT2:同表 4
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