IJPN International Journal of Psychiatry and Neurology 2166-5788 Scientific Research Publishing 10.12677/IJPN.2023.123005 IJPN-70466 IJPN20230300000_34764926.pdf 医药卫生 多巴胺受体基因多态性与抗躁狂治疗的进展 Dopamine Receptor Gene Polymorphisms and Therapy Advances for Antimanic 陶 何健 2 1 金 卫东 3 1 孙 峰俐 3 1 浙江省精神卫生中心浙江省立同德医院精神卫生科，浙江 杭州 浙江中医药大学第二临床医学院，浙江 杭州 null 07 08 2023 12 03 42 48 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

双相障碍(Bipolar Disorder, BD)是情感高涨与低落相互交替发作的一种精神疾病。BD的相关家系调查和双生子寄养子研究表明，其遗传率高达60%~85%，但其遗传学并不很清楚，也不符合孟德尔遗传定律。国内外均已经展开了一些BD相关基因遗传多态性研究，来寻找攻克这一疾病的突破口。研究较多之一的是多巴胺受体基因，根据BD多巴胺机制的理论假设认为双相躁狂发作与多巴胺功能亢进有关，反之则产生抑郁症状，从而形成循环性的特点。相关文献和研究不多，促使我们进行这方面的研究和探讨。本综述将探讨多巴胺受体基因多态性与抗躁狂治疗进展。 Bipolar disorder (BD) is a mental illness that alternates between emotional highs and lows. BD’s related family survey and twin foster study showed that its heritability was as high as 60%~85%, but its genetics was not very clear and did not conform to Gregor Mendel’s genetic law. Both domestically and internationally, some genetic polymorphisms of BD-related genes have been studied to find a breakthrough in overcoming this disease. One of the most studied is the Dopamine receptor gene. According to the theoretical hypothesis of BD dopamine mechanism, it is believed that bipolar manic episode is related to dopamine hyperfunction, and on the contrary, it will produce depressive symptoms, thus forming a cyclical feature. The lack of relevant literature and research has prompted us to conduct research and exploration in this area. This review will explore the Dopa-mine receptor gene polymorphism and the progress of anti-manic treatment.

 双相障碍，多巴胺受体，基因位点疗效，Bipolar Disorder Dopamine Receptor Gene Locus Therapy Efficacy 关键词

双相障碍，多巴胺受体，基因位点疗效

 Dopamine Receptor Gene Polymorphisms and Therapy Advances for Antimanic<sup> </sup>

Hejian Tao1, Weidong Jin2, Fengli Sun2*

1The 2nd Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou Zhejiang

2Department of Psychiatry, Tongde Hospital of Zhejiang Province, Zhejiang Province Mental Health Center, Hangzhou Zhejiang

Received: Jul. 4th, 2023; accepted: Aug. 4th, 2023; published: Aug. 14th, 2023

 ABSTRACT

Bipolar disorder (BD) is a mental illness that alternates between emotional highs and lows. BD’s related family survey and twin foster study showed that its heritability was as high as 60%~85%, but its genetics was not very clear and did not conform to Gregor Mendel’s genetic law. Both domestically and internationally, some genetic polymorphisms of BD-related genes have been studied to find a breakthrough in overcoming this disease. One of the most studied is the Dopamine receptor gene. According to the theoretical hypothesis of BD dopamine mechanism, it is believed that bipolar manic episode is related to dopamine hyperfunction, and on the contrary, it will produce depressive symptoms, thus forming a cyclical feature. The lack of relevant literature and research has prompted us to conduct research and exploration in this area. This review will explore the Dopamine receptor gene polymorphism and the progress of anti-manic treatment.

Keywords:Bipolar Disorder, Dopamine Receptor, Gene Locus Therapy Efficacy

Copyright © 2023 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 前言

世界卫生组织有关全球疾病总负担(GBD)的统计显示，BD从1990年的306万增加到2017年的453万，根据残疾调整生命年(DALYs)衡量，它在精神和药物使用障碍的疾病负担中排名第六 [ 1 ] ，DALY从1990年的602万增加到2017年的929万 [ 2 ] ，全球范围内BD的发病率在持续增加，1998年双相障碍的患病率0.5% (95% CI: 0.27~0.79)，2004年为1.0% (95% CI: 0.61~1.31)，2008年为1.5% (95% CI: 1.05~1.91) [ 3 ] ，2015年为2.63%，其中I型双相障碍1.06% (95% CI: 0.81~1.31) II型双相障碍1.57% (95% CI: 1.15~1.99) [ 4 ] 。目前，双相障碍终身患病率已经接近6% [ 5 ] 。现代治疗最终能使50%的患者完全恢复，但仍有少数患者残留轻度情感症状，社会功能也未能完全恢复至病前水平 [ 6 ] 。

早期关于精神障碍与多巴胺受体基因的研究多针对精神分裂症、双相障碍，其中多数研究结论认为多巴胺受体基因的突变与精神分裂症密切相关，却不是BD的主要决定因素，这些结果大多来源于病例对照设计研究，容易受到群体分层的影响，并且检测遗传关联的功效较低。近10年来随着精神病学研究的发展，关于其遗传位点多态性与BD发病关联的报道增加，大量研究表明非典型抗精神病药联合心境稳定剂的疗效药明显优于单独使用心境稳定剂，许多靶向多巴胺能神经传递的药物被用于“辅助”治疗BD、帕金森病等精神疾病。因此，从这两个系统的已知受体上寻找BD的候选基因具有广阔的前景。

 2. 疾病概念

双相障碍(BD)是一种慢性、严重的精神疾病，以狂躁、轻度躁狂和抑郁情绪发作为特征，发病通常在青春期至20岁中期 [ 7 ] [ 8 ] ，躁狂可以混合方式存在，也可单独存在，躁狂一般分为双相I型、双相II型、混合型、快速循环型等，冲动攻击行为和自杀自伤、暴力行为等是双相障碍显著症状。BD生物病因学研究主要包括遗传学、神经内分泌、脑成像、神经递质、免疫系统等诸多方面。特别是神经递质的功能异常最为重要，并形成了BD的神经递质假说，在临床上也得到了一定的验证 [ 8 ] 。

 3. 多巴胺受体

多巴胺受体可分为D1样受体(DRD1和DRD5)和DII样受体(DRD2、DRD3和DRD4)两大类。D1主要定位于突触后膜，D2主要定位于基底神经节，D3、D4、D5主要定位于皮质区和边缘区 [ 9 ] 。多巴胺功能亢进假说是解释BD病因机制的主要生化机制之一。多数典型抗精神病药能与多巴胺受体以很高的亲和力结合并能改善BD患者的阳性症状。临床上BD的治疗是临床工作上的一个难题，用于治疗BD的药物对中枢多巴胺活性有显著影响，如，锂降低多巴胺循环周转并且可能通过DRD1来改变对多巴胺能药物的敏感性 [ 10 ] ，BD治疗上存在许多的差异，这种差异可能也和多巴胺基因多态性相关。

3.1. DRD1

基因全长约1.7 kb，定位于5q35号染色体 [ 11 ] ，具有7个跨膜结构域，在视束、尾壳核、脑皮层、伏隔核和杏仁核都有表达 [ 12 ] 。DRD1是一个无内含子的基因，在5'非翻译区有116个碱基对 [ 13 ] [ 14 ] 。许多依赖于D2类多巴胺受体活动的急性行为效应需要同时激活D1类受体，D1类和D2类受体的强交互作用和协同效应会影响神经反应，这种交互作用已被强调为临床重要性，我们可以认为D1多巴胺受体单独和/或与D2多巴胺能受体在BD中的存在作用。在BD患者检测到最多的D1基因序列多态性有：-800T/C (rs265981)、-48A/G (rs4532)及1403T/C (rs686) [ 15 ] [ 16 ] [ 17 ] ，这些关联研究的结果并不完全一致。研究发现 [ 18 ] 等人的某岛人群中170名双相I型中研究得出双相I型患者与DRD1单核苷酸多态性(800T/C、1403T/C)呈正相关，最常见的单倍型是800C/48G/1403T (C-G-T)。Dmitrzak-Weglarz [ 19 ] 等报道特别是BDII型(尤其是女性患者)其48A/G基因型G/G和等位基因G更是显著性增高，推测BD更多通过母亲(非父亲)遗传给后代。王英成的研究结果提示DRD1的rs5326多态性与双相障碍I型执行功能损害有关 [ 20 ] 。目前对于DRD1多态性与BD药物治疗疗效关联较少，其rs4532 (48A/G，由DdeI酶切位点识别)被许多研究证实其可能和双相躁狂临床疗效相关，特别是在改善阴性和阳性这种方面 [ 21 ] 。

 3.2. DRD2

定位于染色体11q22-23，至少跨越270千个碱基，主要表达于基底神经节 [ 22 ] 。启动子区和第8外显子外3'端非编码区10 kb处这两个位点被研究的较多，第7外显子(Ser311→Cys311)也有研究。TaqI A1限制性片段长度多态性(RFLP)多态性被记录为A1和A2，A1等位基因携带者的DRD2密度低于纯合子A2等位基因携带者，其与DRD2的密度和功能效应有关，表现出纹状体和偏远区域的葡萄糖代谢减少，这对情绪调节很重要 [ 23 ] [ 24 ] 。Zou等人对3个DRD2基因多态(-141Cins/del、Ser311/Cys311和TaqI A1)进行meta分析，发现DRD2基因-141Cins/del、Ser311/Cys311多态性与心境障碍之间没有关联(P > 0.05)，而TaqI A1多态性与心境障碍相关，A1A1基因型的个体与A2A1和A2A2基因型相比，A1A1患心境障碍的几率更高，携带A1等位基因的个体比不携带者有更高的冲动水平 [ 25 ] 。张明等人同时对精神分裂症、双相障碍与DRD2 (141C Del/lns、Taql A、Ser311Cys)的关联性进行了meta分析，结果提示TaqI-A的T/C多态性和BP发病存在显著关联(P < 0.05)，TaqI-A的TT基因型可能是BP的风险因子而对于精神分裂症是保护因子，Ser311Cys、141C Del/lns与精神分裂症发病相关，与双相障碍无关 [ 26 ] 。在BD的冲动攻击行为方面与DRD2相关研究中，多位研究发现C957T多态性与冲动行为的相关性，携带957C纯合子的个体在急性心理应激下冲动水平增加 [ 27 ] 。在研究精神障碍患者(包括顽固性重度抑郁症、双相谱系障碍、精神分裂症谱系障碍)的基因多态性与吸烟习惯和尼古丁依赖之间的相关性结果中DRD2 rs1800497与没有T等位基因的个体相比，有T等位基因表达的受试者的尼古丁依赖年限显著降低(t = 1.99; P = 0.05) [ 28 ] 。

 3.3. DRD3

位于3q13.3上，在与情绪和行为、新奇寻求、奖励系统和认知相关的大脑中边缘区域有较高水平的表达 [ 29 ] ，早些年提出DRD3与精神分裂症关联性更大，后这一想法逐渐被推翻，DRD3基因可能是双相障碍重要的候选功能基因。DRD3 Ser9Gly多态性(rs6280)是DRD3基因中最常被研究的变体，它会导致Ser-to-Gly的替代，并导致多巴胺结合亲和力的显著增加。大量文献证明DRD3多态性与冲动攻击行为相关。如，Chun Il Park研究关于酒精渴望的强迫症方面，rs6280与酒精所致精神障碍中渴望、冲动和攻击性有显著相关性(P = 0.0061) [ 30 ] 。张沛文研究得出DRD3基因TT-rs3773679 TT基因型的人有最高的攻击风险 [ 27 ] 。Chiaroni等认为DRD3的BalI RFLP可能参与了一种特定的BD内表型，该内表型包括躁狂的临床特征、低发病年龄的开始和急性妄想发作，但有研究结果显示双相患者和对照组之间这种多态性的等位基因分布没有差异(OR = 1.04; P = 0.60) [ 31 ] 。

 3.4. DRD4

由11号染色体上位于11p15.5的基因DRD4编码，主要分布在大脑边缘和前额皮质背外侧，该区域提示DRD4基因在情绪和认知中扮演重要角色。在DRD4第三个外显子48 bp中含功能可变数量的串联重复序列(VNTR)，最常见的版本是2 (2R)，4 (4R)和7 (7R)重复，4R等位基因是最常见的，而2R和7R等位基因频率差异很大，与BD常见症状冲动行为相关，BD冲动行为发生率较精神分裂症高 [ 32 ] 。位于DRD4第一内含子中非编码区的rs752306多态性与被证实与儿童攻击行为存在一定相关性(x2= 5.908, P = 0.05) [ 33 ] 。有研究发现携有DRD2基因C957T多态性的TT基因纯合体与冲动行为相关 [ 34 ] 。近年Buchmann等研究发现携带VNTR等位基因7重复片段的DRD4基因型个体且其母亲产前有应激的，在成年期会出现更多的攻击行为。有研究]结果提示DRD4的rs3758653多态性也与双相障碍I型有关 [ 21 ] 。

 3.5. DRD5

它定位于染色体4p15.1-16.1区域，DRD5具有与DRD1相似的基因组结构，两者的整体氨基酸同源性均为50%，染色体4p染色体可能包含一个主要的功能性精神病易感性位点。以芬兰健康人群对比抑郁症患者的研究中显示rs13106539可能与抑郁症相关(P < 0.05) [ 35 ] 。另有对位点rs7655090研究结果提示其与自杀倾向存在相关性(P < 0.05) [ 36 ] 。

 4. 多巴胺受体拮抗剂

这是一类通过阻滞多巴胺功能受体来治疗精神疾病的药物。多巴胺受体拮抗剂被用作治疗急性躁狂发作的有效药物，相反，增加多巴胺活性的药物会引发躁狂。多巴胺受体拮抗剂的主要目的是占据受体改善精神病性症状以及兴奋和行为紊乱。多巴胺过多可能会导致精神病或成瘾习惯，通过抑制该化学物质与任何受体结合来限制该化学物质的过量。这其中与多巴胺不同受体以及受体基因的多态性有关，也是药效学研究的内容。

BD治疗的成功不仅需要稳定急性发作，还需要情绪稳定特性的药物维持长期缓解，包括传统的情绪稳定剂(即锂和抗惊厥药物)和非典型抗精神病药物，考虑到这些药物疗效、安全性等差异，需要制定个性化治疗 [ 37 ] ，特别是针对长期病程患者，随着非典型抗精神病药物诸引进，心境稳定剂和抗精神病药物的组合在治疗BD躁狂发作和分裂情感性疾病方面越来越受欢迎。它们不仅被用于预防BD患者的复发，还被证实可以用于治疗急性躁狂发作。喹硫平、奥氮平、阿塞那平、齐拉西酮、阿立哌唑、利培酮和卡利拉嗪被美国和欧洲的监管机构批准作为治疗躁狂症的单一疗法。第一代抗精神病药易导致锥体外系综合征，Al Hadithy A.F.的研究结果表明，携带编码D2受体的DRD2基因的141C Del等位基因与非携带者相比，接受抗精神病药物治疗的患者发生抗精神病药物诱发的帕金森病(AIP)的风险高9.5倍(P = 0.005)，与第一代抗精神病药相比，非典型抗精神病药被认为是一种进步，相对于疗效方面，他们的安全性得到更多的肯定。虽然在体重增加和代谢综合征(尤其是对于奥氮平等药物)方面影响较大 [ 38 ] 。奥氮平是治疗多种精神障碍(例如精神分裂症或双相情感障碍)的一线药物，在治疗抑郁症和阴性方面与氟哌啶醇和利培酮相似甚至有更好的效果，对一般认知功能改善效果更好，锥体外系效应较小。阿立哌唑在不少双相治疗的指南中以及推荐使用，其与D2、D3、5-HT1A受体有很强的亲和力，对D4以及5-HT2C、5-HT7以及α1肾上腺素、组胺H1受体有中等的亲和力，具有独特的D2、5-HT1A受体的部分激动剂和5-HT2A受体的拮抗剂，阿立哌唑可以延缓躁狂发作的时间并降低了躁狂发作的复发率，并且总体上是安全的，耐受性良好，这也是与多巴胺受体基因多态性在疗效上有密切关系的药物 [ 39 ] 。

无论是哪一种多巴胺受体拮抗剂，其引发的多巴胺阻断效应而引发的生物学反应是与受体的基因多态性相关。同时也有理由推断，不同的多巴胺受体阻断剂所引发的是不同的。至少喹硫平、鲁拉西酮可以被用于双相抑郁的治疗，而大多数的经典和非经典抗精神病药物却都可以用于双相躁狂的治疗。在一定程度上说明，作为多巴胺受体阻断剂的经典和非经典抗精神病药物其药效不仅取决于剂量、药物浓度、药效学相关，也取决于受治个体的生物学特征，其中多巴胺受体多态性就是其中之一，也包括代谢型谷氨酸受体 [ 40 ] 。但对于双相障碍对躁狂药物选择的药效学和基因学研究目前不多，大多两者分别讨论，药物结合基因多态性与双相障碍的关联性研究较少。

 基金项目

1) 浙江省医药卫生科技计划项目(2020KY088)，临床注册号：CHICT2100054696；

2) 浙江省立同德医院高峰学科——精神卫生学(项目编号：2D02022)。

 文章引用

陶何健,金卫东,孙峰俐. 多巴胺受体基因多态性与抗躁狂治疗的进展Dopamine Receptor Gene Polymorphisms and Therapy Advances for Antimanic[J]. 国际神经精神科学杂志, 2023, 12(03): 42-48. https://doi.org/10.12677/IJPN.2023.123005

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