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目录 contents

    摘要

    精神疾病危害严重,其发病机制复杂难解,临床治疗效果不一,且存在明显的个体差异. 近期精准医学研究发现精神药物作用于脑神经的生化过程受到遗传多态性的影响. 本文从五羟色胺能、去甲肾上腺素能和多巴胺能三大系统入手,系统综述精神药理影像遗传学的相关研究进展,深入探讨精神药理的神经作用机制以及药物-基因-脑之间的交互作用. 我们发现:SLC6A4、BDNF、FKBP5、COMT和多巴胺相关受体等基因多态性与多种精神疾病的发生发展及其治疗效果具有一定的相关性,可能成为相关精神疾病诊断的候选基因. 杏仁核、海马、眶额叶、扣带回和前额叶等皮层与皮层下脑结构可能是不同神经递质相关的基因多态性影响精神药物生化作用过程的关键靶点脑区. 在建立精神药物-基因-脑影像-行为的因果链中,仍然存在很多相互矛盾的结果和一定的局限性. 因此,开展同质性强的临床试验、研究表观遗传作用等可以作为未来的研究发展趋势.

    Abstract

    Although the harm of mental illness is serious, its pathogenesis remains unclear, clinical treatment is not effective, and there are obvious individual differences. Recent precision medical research has discovered the role of gene polymorphism in the individualized treatment of drugs. Based on the three major systems of serotonin, norepinephrine and dopaminergic, this article systematically reviewed the research progress of psychiatric pharmacogenomics and imaging pharmacogenomics studies, and explored in depth the mechanism of action of the brain, the mechanism of drug action, and gene-drug-brain interactions. We found that genetic polymorphisms such as SLC6A4, BDNF, FKBP5, COMT, and dopamine-related receptors were found to correlate with the occurrence of multiple mental disorders and the efficacy of antidepressant treatment, and consequently may be candidates for the diagnosis of related mental disorders. The cortical and subcortical brain regions including the amygdala, the hippocampus, the orbitofrontal cortex, the anterior cingulate cortex and the prefrontal lobe may be the key targets of the effect of different neurotransmitter gene polymorphisms on the biochemical process of psychotropic drugs. These related important brain areas may become biological markers for the diagnosis and treatment of related mental disorders. However, in the establishment of psychotropic drug-gene-neuroimaging-behavior causal chain, there are still many contradictory results and limitations. Therefore, the studies on homogenous clinical trials and epigenetic effects can be recommended as future research trends.

    随着精神疾病的流行,精神健康已经成为了世界范围内所关注的重点健康问题之一. 常见的精神障碍包括精神分裂症(schizophrenia)、重性抑郁障碍(major depression disease,MDD)、焦虑症(anxiety)、物质依赖症(substance dependence)等. 精神类疾病通常会造成个体功能和能力受限,甚至可能导致残疾和自[1],给患者、家属及社会带来沉重的负担. 2017年世界卫生组织(WHO)发布的最新数据表明,抑郁症等精神障碍已经成为人类致残的首要原因,是导致全球疾病负担的一个重大因[2]. 因此,精神疾病俨然成为了世界范围内公共卫生的重大议题之一,急需有效的方法对其进行治疗与预防.

    然而,精神疾病作为一种慢性病,在科学研究和临床实践上仍存在着许多难点. 精神疾病的临床症状表现多样,致病因素复杂,病理机制不清;临床诊断依赖经验,缺乏客观的诊断标准;用药方案无客观依据,疗效不一,导致治疗效果差;复发率高,存在较多难治性精神疾病的解决方法缺乏的现象. 因此,在临床诊断上,研究者希望找到客观的生物学标记物用于诊断精神类疾病,从而更加高效和准确地判断精神疾病的发生,甚至在临床症状表现之前利用客观的生物学标记物进行早期诊断与早期治疗,及时地进行二级预[3]. 同时,个体之间存在的差异使个体化治疗成为必然,只有在个体基础上依据客观事实来设计精准治疗的方案,才能实现药物疗效最大化.

    针对以上一系列问题,研究者从基因、行为和脑等多层次探讨精神疾病的发生发展规律,试图寻找精神疾病诊断和治疗的客观标记物,对精神疾病的发生发展进程进行深入探究,并且为精神疾病的个体化精准治疗提供理论基础和客观证据. 其中,药理遗传学是精神疾病精准治疗的重要内容和途径. 药理遗传学是药理学和遗传学相结合的研究,通过分析个体的基因多态性来反映其服用药物后的效[4]. 通过研究先天性与获得性的基因多态性和表观遗传的修饰度与药物代谢学和药物动力学的相关性,使药物治疗能够达到个体化的目标. 在精神疾病的治疗上,精神药理遗传学的研究在一定程度上揭示了临床治疗时相同症状的人群在使用相同药物后效果不一的原因在于患者携带的重要基因具有不同的单核苷酸多态性(single nucleotide polymorphism,SNP). 其中,一些重要基因的不同基因型与药物疗效之间显示出显著的相关性. 然而,精神药理基因组学仍难以解释精神药物对不同基因或相同基因不同多态性类型的神经药理作用机制.

    随着影像学技术和方法的不断发展与创新,人们因此可以寻找精神疾病患者脑区的客观生物学标记物,进而不断地探索精神疾病患者异常的神经基础及其发生发展机制,以及临床药物对患者神经生化反应的作用机制,从而孕育了精神药理影像遗传学这一新兴学科. 精神药理影像遗传学的方法旨在通过寻找有效的生物学标记将基因的突变与药物治疗的疗效联系起来,建立基因突变与大脑当中特定脑区的生物学改变之间的因果关系. 该方法综合运用基因检测、磁共振检查和临床精神心理测查等方法,在对受试者进行一段时间的随访后分析数据,从而找到药物、基因、脑区和行为之间的关联,为精神类药物的临床应用和个体化治疗提供一定的循证依[5]. 在影像学当中,结构性磁共振成像(sMRI)主要用于测量脑区体积、密度、厚度等形态学特征;功能性磁共振成像(fMRI)研究的是受试者在完成特定任务时大脑血流量的分布情况,常用于脑区功能定位研究;弥散张量成像(DTI)用于测量神经纤维束的走向与粗细等结构连接特征;正电子发射型计算机断层显像(PET)和单光子发射计算机断层成像(SPECT)用于检测大脑中特定化学物质的代谢. 这些脑影像数据采集和分析技术的发展,有助于更加直观地通过大脑的变化来理解和探索精神疾病的发病机制及相应治疗的病理生理机制,从而更好地制定出个性化的医疗方案.

    目前,精神疾病的药理机制及其用药范围主要集中在大脑中的单胺类神经递质,包括五羟色胺、去甲肾上腺素与多巴胺这三大神经递质系统. 每个系统对大脑均有特定的作用机制,并且在整个神经环路中相互影响、相互作用. 精神药理影像遗传学的研究表明,这三大系统中所涉及的重要候选基因和重要脑区在揭示精神疾病的神经生物学机制上有重要的理论意义,在诊断和治疗中也具有重要的临床应用价值. 因此,本文通过系统综述的方法从三大神经递质系统当中的基因上分类、梳理总结了以往研究药理影像遗传学在精神疾病中相关联的研究,旨在归纳总结精神疾病在治疗过程中,基于医学影像的生物学标记改变的检测和基因对临床疗效的预测规律. 我们致力于建立一条完整的因果链:相关候选基因多态性的差异引起特定脑区的生物学效应,导致不同个体对药物的反应产生差异性,而这些基因多态导致的神经生物化学反应的差异可能是临床精神药物治疗效果不一的根本原因. 通过这条因果链的不断完善,我们对于人体大脑改变引起精神疾病发生发展的病理机制会有更深入的理解,同时在临床应用上能够更加有针对性地对患者进行治疗,为精准治疗提供基础,从而使治疗更加有效,降低精神疾病带来的巨大的社会成本.

  • 1 五羟色胺(5-HT)能系统

    1

    五羟色胺 (5-HT, serotonin) 是一种内源性的传导神经信号的化学活性物质,主要存在于延脑中线旁的中缝核群、丘脑及丘脑下部、杏仁核、壳核和海马等脑区. 5-羟色胺释放到突触或神经元之间的间隙,并在相对较宽的间隙扩散,以激活位于相邻神经元的树突、细胞体和突触前末端的5-HT受体. 5-HT受体与5-羟色胺的传导均受到相关基因的调控. 例如,5-羟色胺神经递质在与5-HT1A和5-HT2A受体结合后,能够作用于神经组织,减少抑郁症、焦虑症和精神分裂症等精神疾病的发生,与5-HT4、5-HT6、5-HT7受体结合后,可以改善抗抑郁药的作[6]. 5-羟色胺的传导及与5-HT受体结合在其分布的脑区内可以发现与精神疾病相关的血流量的功能改变及脑区体积和形态的结构改变密切相关, 并在情感、动机、认知、睡眠和痛觉等各种调节过程中起着关键性作[7].

    5-羟色胺在大脑中的传导比较广泛,其主要通过在杏仁核、前额叶和前扣带回等脑区的再摄取调控情绪,并且与杏仁核-前额叶的情绪调控反馈有较强的相关[8,9]. 5-羟色胺已经被证明对参与情绪加工的边缘及前额区域相关的大脑回路的激活产生影[10,11],而血清素系统的遗传变异可能构成上述精神疾病发生的易感因[12]. 在精神疾病的研究中,五羟色胺能系统中的某些重要基因多态性被发现与抗抑郁药物药理、脑区影像学的改变与行为的转变相关,并且不同基因型人群的指标之间存在显著差异.

    5-羟色胺系统涉及精神疾病的基因包括五羟色胺转运体(5-HT transporter, 5-HTT/serotonin transporter, SERT)、神经肽Y(NPY)、白介素1β(IL-1β)、糖原合酶激酶3-β(GSK3-β)等基因,其中五羟色胺转运体是目前在诊断与治疗中最具有参考价值的基因多态类型,在精神药理影像遗传学中的研究也是最为深入的.

  • 1.1 5-HTT精神药理影像遗传学研究进展

    1.1

    当前5-羟色胺转运体基因连锁多态性区域(serotonin-transporter-linked polymorphic region, 5-HTTLRP)与药物相关的神经影像学研究已经比较成熟,许多研究采用了fMRI方法,监测受试者完成任务时大脑相关脑区的血流量改变,在对照组与实验组之间进行对比后找到相对应的特定脑区,寻找潜在的生物学标记. Outhred[13]在36名健康高加索女性服用西酞普兰(20 mg)或安慰剂后进行了磁共振扫描,期间要求被试判断恐惧、快乐和中性等面孔表情. 该研究发现西酞普兰在L/L携带者对恐惧表情的感知过程中增加了左侧杏仁核的活动,在快乐表情的感知过程中减少了左侧杏仁核的活动,而对S/S携带者的脑部活动无明显影响. Ma[14]采用类似的实验设计对46名健康的中国男性进行研究,得到了相似的主要结果,但部分结果也有所差异:Outhred等发现的L/L携带者在唤醒图片(包括恐惧与快乐)影响下杏仁核区域活动增强,而Ma等的实验中仅有恐惧表情影响下双侧杏仁核及脑岛区域的活动性增强. 这显示出西酞普兰作用范围的差别在于非特异性的唤醒类情绪和特异性的仅对恐惧情绪有所反应,并且在脑区范围上也有所差异. 除此之外,Outhred等的研究发现:与唤醒性刺激的效果相比,L/L携带者在非唤醒性的中性刺激时,其左侧杏仁核的反应有所增加,而Ma等的研究中没有发现面对中性刺激时脑区活动的改变. 这些研究结果说明,5-HTTLPR在积极情绪中的神经反应中相比负面情绪而言扮演的角色可能没那么重要. 而且由于抑郁症患者往往把快乐的表情认为是中性的,表明其大脑对负面情绪的存在认知偏向,因而在服用西酞普兰药物后受试者表现出仅对恐惧面容显著增强脑部活动的结果. 当然,造成上述不一致结果的原因还可能是研究对象的人种差异、性别差异和给药量的差异.

    与上述治疗效果相似的结果同样表现在疼痛研究上:L/L基因型在药物作用下疼痛缓解的效果更加明显. Ma[15]在50名中国健康男性一过性服用西酞普兰后,发现5-HTTLPR基因型调节西酞普兰对丘脑、小脑、前脑岛、中脑皮层和额下皮质的疼痛相关脑区的反应. 具体来说,西酞普兰显著降低了L/L基因型受试者疼痛相关的脑区反应,而S/S纯合子对此无显著反应. 此外,5-HTTLPR基因型与疼痛相关脑区活动之间的相互作用是西酞普兰诱导的疼痛减少报告的良好预测指标.

    在研究脑区激活的同时,还有研究开始探索脑区之间的连通性与精神类疾病治疗的相关性. 有研究表明,西酞普兰可能是通过增强负性功能连接性而影响药效的:Outhred[16]对36名健康高加索女性一过性服用西酞普兰后,发现随着L等位基因的数量增加,左侧杏仁核与右侧额下回的负性连接性也显著增加. 具体来说,S等位基因与左侧杏仁核-右侧额下回连接在情绪失调时的活动调节作用相关,而L等位基因与左侧杏仁核-右侧额下回连接在情绪调节改善时的活动相关.

    药物对个体具有特异性的治疗反应,该差异不仅表现在基因型的差别上,同时也存在药物与脑区之间的相互作用. Ramasubbu[17]对57名抑郁症患者分别使用喹硫平XR和西酞普兰治疗,结果发现杏仁核激活的降低可能是有效反映S/L基因型患者在奎硫平XR治疗中临床反应的生物学标记. 相比之下,用西酞普兰治疗的S/L患者则在第1周显示出扣带回和右前额活动的下降,但在第8周显示左前额叶活动的增加. 除此之外,用西酞普兰治疗的L/L纯合子在第1周时,杏仁核反应表现为下降,而前扣带皮层(ACC)活动增加,在第8周时出现杏仁核和ACC的共同激活. 西酞普兰和奎硫平XR对5-HTTLPR基因型的S / L携带者作用的大脑反应的差异,可能反映了基因型和药理作用在情感核心脑区反应过程中的相互作用关系.

    有大量重复的实验数据表明,受试者服用选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitor, SSRI)后,L/L基因型个体的杏仁核脑区的血流量与携带有S基因的个体相比显著增高,同时治疗的结果也呈现出显著改善的情况,说明杏仁核的生物学改变可能具有作为生物学指示标志的意义. 因此,5-HTTLRP作为一个非常重要的候选基因,其作用的机理和对脑区的影响都需要进一步深入地研究.

  • 1.2 NPY等其他基因精神药理影像遗传学研究进展

    1.2

    在5-HT系统当中还有其他可能的候选基因的多态性被发现与精神疾病药物的疗效相关,其在脑区也主要表达在杏仁核. 神经肽Y(NPY)由人体中定位于染色体7p15.3的神经肽Y基因(NPY)编码,是一种含有36个氨基酸的蛋白质,参与中枢和外周神经系统的各种生理和内稳态过程. Eaton[18]研究发现,神经肽Y(NPY)基因的变异与异常食欲、昼夜节律、应激和焦虑相关. 其中SNP位点rs16147 的C等位基因携带者与TT纯合子相比,在35例MDD患者的样本中发现在2周的抗抑郁药治疗后反应较慢,并且没有达到改善的效果,同时在面对恐惧表情时对双侧杏仁核有较强的激活作[19]. 以上研究表明NPY可能是潜在的抑郁症诊断和治疗的候选基因,C等位基因的携带者在负性情绪的刺激下会引起更强的情绪抑制作用.

    白介素1β(IL-1β)由人体内染色体2q14.1上的白介素1β基因(IL1β)编码,被认为是通过调节HPA轴和促肾上腺皮质激素和皮质醇的分泌,共同增加而导致MDD发生及抗抑郁药反应差异的物[20]. 在32例MDD患者的样本中,rs16944和rs1143643的A等位基因纯合子被发现与无缓解反应相关,并且与杏仁核活动的减少和ACC活动的增加有[21]. 因此,可以假设IL-1β的A等位基因的数量与治愈率下降呈正相关,而且其影响机制除了杏仁核的改变与其他5-HT系统中的发现相一致以外,还提出了前扣带回的激活可能与治愈率的降低有关的假设.

    在神经发育上有着重要作用的蛋白质的调控基因多态性,在患者服用精神类药物后也会对脑区结构或功能改变和药物疗效造成一定的影响. 在大脑神经纤维发育过程中,糖原合酶激酶3-β(GSK3-β)作为Wnt /β-连锁蛋白通路的基本成分,能够影响大脑脑区之间的连接,参与细胞行为、细胞黏附、细胞极性、神经元极性和可塑性的调[22]. GSK3-β基因在人体中位于染色体3q13.33,其中rs334558 G等位基因被发现可能对双相障碍起一定的保护作[23]. Benedetti[24]在伴有重大抑郁发作双相障碍的70名患者使用锂进行长期治疗后,发现GSK3-β启动子rs334558的不活跃C等位基因与白质纤维束微结构上轴突扩散的增加相关,并认为GSK3-β的抑制作用和锂的应用可以抵消双相障碍对白质结构的负面影响,有利于大脑功能的完整性与胼胝体、额叶、顶叶和颞枕联合脑区之间的连接.

  • 2 去甲肾上腺素(NE)系统

    2

    去甲肾上腺素(norepinephrine,NE)是一种重要的单胺类神经递质,其在脑内分布集中在脑桥及延髓,其中在蓝斑核分布最为密集. 有3束投射纤维由蓝斑核向前脑方向发出,分别是中央被盖束、中央灰质背纵束和复测被盖-内侧前脑束. 其中,纤维束上行支配同侧大脑皮层、边缘系统和海马及杏仁核等核团,蓝斑核下行纤维束投射到延髓和脊髓,作为神经递质作用于附近的交感神经节,并且还能通过肾上腺直接释放到血流[25].

    大脑中的去甲肾上腺素广泛作用于各个脑区,其功能常常体现在调控觉醒和应激反射[26],其中蓝斑的活性水平与警惕性和反应速度密切相[27]. 蓝斑释放的去甲肾上腺素以多种方式影响大脑功能. 它增强了感官输入的处理,增强了注意力,增强了长期记忆和工作记忆的形成和恢复,并通过改变前额叶皮层和其他区域的活动模式,增强了大脑对输入的反应能[28],因此与注意力缺陷障碍等疾病有所关联. 除此之外,有靶向定位于NE系统的药物可产生抗焦虑的效果,用于治疗焦虑和抑郁的患[29]. 总而言之,去甲肾上腺素在大脑的情绪调节中起重要作用,并涉及多种精神类疾病,包括焦虑症、抑郁症和注意力缺陷障碍等,对研究精神疾病有重要作用.

    该系统涉及的基因包括脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)、FK506结合蛋白(FK506 binding protein 51, FKBP5)和烟碱型乙酰胆碱受体(nAChR)等基因,其中BDNF是已知与抗抑郁药物有明显关联的基因,因而具有作为精神疾病候选基因的重要研究价值.

  • 2.1 BDNF精神药理影像遗传学研究进展

    2.1

    BDNF在神经元存活、分化和突触可塑性方面具有关键作用. 基于神经营养因子抑郁症假说,BDNF被认为在心理障碍的病理生理以及在抗抑郁治疗反应中起重要作[30]. 较早的神经影像学研究发现BDNF的Met等位基因与健康受试者的海马体积的减少相关,并且可能是影响海马功能障碍相关的疾病发生发展的易感因[31].

    在BDNF相关的药物基因组学研究中,Yan[32]对18个BDNF rs6526多态性与精神疾病相关的独立临床队列研究进行了meta分析,其总体样本量包括1 695名患者. 该研究结果表明Met等位基因与抗抑郁药物治疗疗效呈正相关,Met等位基因携带者与Val / Val纯合子相比具有显著的缓解率. 因此,BDNF与精神药理和神经影像中生物学改变之间的关系是理解抑郁症等精神疾病病理机制的关键.

    为了探究BDNF基因-药物-影像之间的相关性,Alexopoulos[33]研究发现携带BDNF Met的抑郁症患者在治疗12周后,比BDNF Val/Val 纯合子更有可能获得缓解;Val/Val纯合子脑区中胼胝体、左上冠状核、右下纵束的微结构异常均与较低的缓解率有关. 该研究发现BDNF基因型与治疗效果之间有较强的相关性,但在脑区活动与治疗效果之间没有明显的相关性. 之后,有研究发现了BDNF Met携带者中存在有脑区活动与治疗效果之间的关联:Cardoner[34]在37名MDD患者中发现,携带有Met66的患者中左海马体灰质体积有明显的减少,而右眶额皮层体积的增加,与此同时发现右眶额皮层的体积与在Met66携带者中缓解的天数呈负相关;在Val66纯合子中发现左海马体积和缓解天数之间存在显著负相关. 因此,海马脑区可能是潜在的生物学标记[34,35].

    有研究发现转入人BDNF以及携带Met/Met纯合子表型基因的小鼠对糖皮质激素应激激素皮质酮(皮质醇的啮齿动物等价物)具有选择性敏感,使活性依赖性BDNF分泌减少,这引发了恐惧情绪和海马的记忆功能. 由于海马功能失调是一些精神疾病的核心,Notaras[35]认为Met载体中存在糖皮质激素的长期作用,其加强了恐惧的神经回路,并在进入成年期后可能增加对创伤应激障碍的易感性,消极的情绪效价和有关精神病的患病可能性.

    以上的研究说明BDNF Val66Met的多态性可能在MDD患者的治疗中与海马、胼胝体、冠状核等脑区的活动有一定的相关性,为在BDNF神经通路当中找到合适的靶点开发新型精神疾病药物,并为未来寻找生物学标记并应用于临床治疗提供了基础.

  • 2.2 FKBP5等其他基因精神药理影像遗传学研究进展

    2.2

    研究发现FKBP5基因多态性与抑郁症、焦虑症和双相性精神障碍有[36]. 为了更好地解释FKBP5基因多态性在抗抑郁治疗中的作用,以及造成疗效差异性的原因,许多研究者开展了相关神经生物学标记物的研究. 在纳入表观遗传中遗传物质的修饰情况后,目前普遍认为:慢性应激与FKBP5的低甲基化有关. Tozzi[37]通过对受试者的FKBP5内含子7的GR响应区域甲基化和rs1360780等位基因状态的评估发现,在携带rs1360780的T高危等位基因的MDD患者中,FKBP5的低甲基化水平与儿童时期的逆境呈正相关,在所有受试者中,较低的FKBP5内含子甲基化水平与双侧下额叶眶回中灰质浓度降低相关. 这可能表明在携带高危基因的遗传易感个体中,童年创伤可能诱导FKBP5的去甲基化,这与MDD临床症状的相关脑区,也就是下额叶眶回结构和功能改变有关. 该研究说明FKBP5的表观遗传学改变可能是连接遗传和环境因素与抑郁症临床症状相关领域大脑变化相互作用的一个环节. 以上的研究能够说明基因多态性和表观遗传能够影响脑区生物学物质的改变,从而在影像学和抑郁症临床症状变化上得到体现,但是仍需要对抗抑郁药物治疗后疗效进行深入的探究.

    在去甲肾上腺素能系统中,烟碱型乙酰胆碱受体(nAChR)容易受到烟草烟碱来源的尼古丁的影响. nAChRs是通常由α和β亚基组成的五聚体配体门控通道,α-5亚基是辅助亚基,由乙酰胆碱受体(nAChR)α-5亚单位基因(CHRNA5)编码,与其他α和β亚基共同表达,α-5亚基能够增加nAChR的功[38]. Janes[39]对CHRNA5的rs16969968位点研究发现基因型为G/G纯合的女性吸烟者在与记忆和习惯性行为相关的大脑区域(如海马体和背侧纹状体)显示出更大的活性. 因此可以认为,rs16969968的G/G纯合的尼古丁依赖的吸烟者相对于含有A等位基因的吸烟者,他们更容易回忆与吸烟有关的信息,并且习惯性地对烟草线索刺激做出反应. 这一发现可能对个性化的戒烟治疗有启示作用.

  • 3 多巴胺(DA)系统

    3

    多巴胺(dopamine,DA)是脑内十分重要的神经递质,在控制行为和认知功能中具有重要作[40]. DA在CNS的分布相对集中于中脑和下丘脑,主要投射至纹状体、广泛的边缘系统和皮质,在大脑的运动控制、情感思维和神经内分泌方面发挥着重要的生理作[41]. DA有几种不同的传递途径,其中一种在奖励驱动的行为中起主要作用,也就是说奖励能够提高大脑中的多巴胺水平,其中许多成瘾药物能够增加多巴胺释放或提高神经元对多巴胺反应的活性. 此外,通过黑质-纹状体通路中的DA调节可以引起帕金森病与注意缺陷障碍的发生,并发现与精神分裂症、药物依赖与成瘾、抑郁症和双相障碍等精神疾病的发生和发展密切相[42]. 因此,多巴胺作为重要的神经递质系统,在精神类疾病的研究中扮演着重要的角色.

    多巴胺系统涉及的基因包括儿茶酚O-甲基转移酶(catechol-O-methyl transferase,COMT)、多巴胺转运体(DAT)、γ-氨基丁酸A型受体基因(GABRA2)、mu阿片受体1(OPRM1)和大麻素受体1(CNR1)等基因,其中儿茶酚O-甲基转移酶(catechol-O-methyl transferase,COMT)基因编码多巴胺的重要降解酶,在多巴胺系统内起重要作用,并有多个研究揭示该基因与精神类疾病的相关性,因此具有重要的研究价值.

  • 3.1 COMT精神药理影像遗传学研究进展

    3.1

    COMT是儿茶酚胺的代谢酶,也是中枢神经递质多巴胺的重要降解酶之一. 许多研究发现COMT基因多态性与精神分裂症和双相障碍等精神障碍有[43,44]. 神经影像研究也发现COMT的表达量与大脑的脑区活性有一定的关联,在不同的药物作用下导致精神集中和工作记忆的效率有所改变. Mattay[45]发现安非他明在注意缺陷障碍Val / Val基因型携带者中增强了前额叶皮层功能的活性,而且在所有任务难度水平上具有相对较低水平的前额突触多巴胺浓度. 相比之下,低活性Met / Met基因携带者基线条件下前额叶功能较好的受试者在低至中等工作记忆负荷下对皮质激活无影响,但在高工作记忆负荷下导致皮质激活降低.该研究认为在低精神兴奋剂剂量下,患者在任务负荷的各个级别的短期记忆测试中显示出显著的改善,而在较高剂量下,在更困难的任务下则表现显著下降. 而Bertolino[46]在接受奥氮平治疗8周后的精神分裂患者中发现COMT Met等位基因携带者前额叶活动的增加,以及工作记忆能力的明显改善. 这说明前额叶多巴胺分解代谢的基因变异可能影响了奥氮平的药理反应特征. 这些研究结果对精神分裂症和注意缺陷障碍等精神类疾病的治疗有一定的启示.

    另外,COMT基因多态性的神经影像学研究中发现携带有Val基因型的吸烟者与成瘾呈正向关联. Brody [47]对45名健康吸烟者进行研究发现,COMT Val / Val基因型吸烟者的可用受体(即多巴胺释放的间接测量)与Met携带者相比较低,而且Val/Val基因型吸烟者腹侧尾状核/伏隔核等脑区活动的整体下降较Met携带者有所减少. 在另一项研究中,Wang[48]发现COMT Val / Val基因型受试者与对烟草渴求的区域中存在显著的脑血流量增加. 随后,Loughead [49]进行更深入的研究发现:Val/Val基因型的吸烟者较Met/Met等位基因携带者对禁止摄入尼古丁的耐受力更低,对大脑功能和工作记忆影响更大,在最高工作记忆负荷下工作记忆相关脑区活动的变化最大. 而且,Val / Val等位基因携带者在吸烟时(与禁止摄入状态下相比)进行视觉N-back工作记忆任务表现出显著的更好的行为表现. 该神经机制可能成为增加对尼古丁依赖的易感性和与COMT Val等位基因相关吸烟复发的基础,这提示COMT抑制剂可能作为戒烟援助的药物. 上述研究均说明了基因型差异可能解释了吸烟诱导多巴胺释放的个体差异,Val/Val基因型的人群更倾向于吸烟,这对于不同基因型人群戒烟方式的选择有着一定的指导意义.

  • 3.2 DAT精神药理影像遗传学研究进展

    3.2

    多巴胺转运体(DAT)由SLC6A3基因编码,其主要生理功能在于摄取突触间中的多巴胺,从而终止多巴胺的信号传[50,51]. DAT在涉及注意力加工的神经环路中有着一定的作用. 在注意缺陷障碍儿童使用哌醋甲酯(MPH)治疗的相关神经影像学研究中,Rohde[52] 、Cheon[53] 和Szobot[54]均在携带有DAT1基因的10-重复等位基因纯合子的ADHD患儿内侧额叶和左侧基底节区域中,检测到局部脑血流量比没有该基因型的儿童显著增高,且治疗效果明显降低. 这些研究为ADHD临床治疗的给药提供了方向.

    另外,DAT基因的遗传变异对烟草线索引发的神经和行为反应有影响,目前的研究均表明9-重复等位基因携带者对于吸烟诱惑的渴求更加强烈. Brody[47]发现携带有DAT3VNTR的9-重复等位基因的吸烟者诱导的DA释放(间接测量)更多,而且腹侧尾状核/伏隔核脑区受体与多巴胺结合潜力的下降也有所减少. 与此结果相似的是Franklin[55]的研究结果,该研究显示9-重复等位基因携带者对吸烟(与非吸烟相比)线索刺激的反应在相互连接的双侧纹状体/腹侧苍白球/眶额骨皮质区(VS / VP / OFC)中的活性较10-重复等位基因纯合的吸烟者有更强烈的反应. 之后,Franklin[56]为了测试初步结果的可靠性,在前瞻性队列研究中发现,在VS和腹内侧眶额骨皮质区(mOFC)中,9-重复等位基因的携带者对烟草刺激线索的响应更大. 其中,9-重复载体在VS和mOFC中显示增加的活性,而在10-重复等位基因纯合子中没有观察到增加. 同时,Wetherill[57]的研究也得到了相同结果. 以上的结果均说明香烟渴求的主观报告与DAT基因型依赖性的奖励相关结构(包括杏仁核、脑岛和中央后回)中的活动增加和背外侧前额叶皮层中的活动减少有关. 以上结果表明携带DAT 9-重复等位吸烟者戒烟的难度会更大. 而且不难发现,DAT基因多态性的表达在纹状体和额叶中差异较明显,这些结果为未来物质依赖方面的神经生物学标志物的寻找和确定提供了一定的基础.

  • 3.3 GABRA2等其他基因精神药理影像遗传学研究进展

    3.3

    在多巴胺系统中,还有许多在神经回路的生化反应中起作用的受体,有不少受体在药理影像遗传学的研究中表现出一定的特异性,并且展现出能够为未来的精准医疗提供依据的潜力. 这些候选基因都值得进一步的研究. 其中,γ-氨基丁酸A型受体基因(GABRA2)位于染色体4q12,被认为与酒精依赖有关. Kareken[58]对受试者分别在醉酒和安慰剂对照条件下暴露于偏爱的酒精饮料气味(AO)以及食欲控制气味(ApCO)的香味下进行fMRI检测,结果发现AA纯合子比AG杂合子携带者在与奖励系统相关的内侧额叶皮质区域显示出更明显的激活. 然而,AG受试者在腹侧被盖区具有更明显的激活效应,这是第一个提示GABRA2基因型可能影响大脑对酒精相关信号反应的数据.

    位于染色体4q22.1的α突触核蛋白基因(SNCA)编码了α突触核蛋白. 该蛋白质的低表达有可能在对酒精的依赖中发挥作用,并且与压力相关的饮酒增加有[59]. Wilcox[60]对326名重度饮酒者进行了基因分型,并在血氧水平依赖性(BOLD)应答的功能性磁共振成像过程中进行酒精味觉任务,发现rs2583985位点的AA纯合携带者中的旁扣带回和尾状核和rs1372522位点的GG纯合携带者的旁扣带回中的激活量大小与其他基因型相比有显著性差异. 上述的脑区激活均与酒精依赖严重程度呈正相关,表明SNCA基因型与酒精刺激诱发的相关脑区的BOLD反应程度存在显著的相关性. 这项研究还进一步验证了这种酒精味觉任务能够作为评价酒精依赖严重程度的中间表型.

    mu阿片受体1(OPRM1)由相应的基因(6q25.2)编码,OPRM1的基因多态性可能与酒精和吸烟依赖的发展和治疗有关.在纳曲酮治疗疗效的个体差异的神经影像学研究中,Weerts[61]利用正电子发射断层扫描检测,发现在AG与AA基因组的酒精依赖者中的纳曲酮阻断率均大于90%,其中AG受试者纳曲酮占用率稍高,但是无显著差异. A118G SNP所导致的OPRM1纳曲酮阻滞程度的差异并不能解释纳曲酮疗效的差异. 除此之外,在其他一些吸烟者的神经影像研究中,Wang[48]、Ray[63]和Schacht[64]的数据结果均显示OPRM1 A等位基因纯合的吸烟者在双侧杏仁核、左侧丘脑和左侧前扣带皮层显示出显著高于携带G等位基因吸烟者的mu阿片受体(MOR)水平. 而且在Ray等的研究中可见G等位基因携带者的主观奖励差异程度(脱尼古丁和尼古丁烟草)与右侧杏仁核、尾状核、前扣带回和丘脑的mu阿片受体结合可能性差异显著相关. 因此,尼古丁奖励、戒断和复发的差异性可能由A118G基因多态性所解释,这将有助于阐明MOR在尼古丁成瘾中的作用,并可能带来新疗法的开发.

    大麻素受体1(CNR1)基因(6q15)编码代谢型G蛋白偶联的大麻素(CB1)受体,该受体在谷氨酸能谷氨酸和伽马氨基丁酸能突触中突触前表[65]. 在33例MDD患者中,rs1049353 CNR1的G等位基因被发现与非缓解的临床效应相关,其中双侧杏仁核、壳核和苍白球脑区的活性有所减[66]. 而34名3天戒断常规大麻使用者在大麻线索诱发心理渴求实验任务中的功能性核磁共振成像扫描结果显示:CNR1 rs2023239 G等位基因与A/A基因型携带者相比,在大麻线索诱发条件下,其大脑奖励相关区域,如眶额叶皮层、额下回和前扣带回中具有显著更强的激[62]. 以上的研究表明该受体在各种精神疾病中均有一定的作用,能够为未来的大麻成瘾等精神疾病的精准化治疗提供基础与方向.

  • 4 总结和展望

    4

    本文通过系统综述,将近年来的精神药理影像遗传学研究纳入综述分析,为探究多种精神疾病的发病机制和药物作用机制提供思路,也能够对精神疾病的临床应用提供一定的循证医学证据. 对于抗抑郁反应的个体差异更好的一种理解方式可能是神经影像与药理遗传学的结合,其原因是脑中的结构和功能改变与重要的相关基因多态性、抑郁症的发病机理以及抗抑郁药理反应等生理生化反应紧密相关. 在人体大脑内,五羟色胺能系统、去甲肾上腺素系统和多巴胺系统作为主要的三大神经递质系统涵盖了大多数的神经调节途径,是解开人体大脑作用机制之谜的关键线索.

    以往的MRI研究已经确定了抗抑郁药反应的几种潜在神经影像标记物. 在5-HT的相关研究中已经发现SLC6A4的多态性,在正常人和药物治疗下的抑郁症、焦虑症患者中,L/L基因型均在以杏仁核为主的皮层下脑区和以前额叶为主的皮层脑区及其连接中表现为较强的活性和连通性,并且有着较好的治疗和情绪改善结果. 在NE系统中,BDNF的多态性被发现与以海马为主的皮层下脑区有一定关联,Met等位基因与较小的海马体积以及较好的抑郁、焦虑的治疗效果相关. FKBP5与抑郁症和双相障碍疾病相关,携带rs1360780的T高危等位基因的抑郁症患者中,FKBP5的低甲基化水平与儿童时期的逆境相关,更容易引起焦虑与抑郁的发生,在FKBP5当中还有其他的单核酸多态性位点也发现与精神疾病相关,有待进一步的研究. 在DA系统中,COMT在前额叶与奖励相关回路中表达改变较多,Met等位基因在精神疾病的改善与成瘾戒断上有着更良好的效果,DAT则在奖励相关回路中,DAT的9-重复等位基因对于注意缺陷障碍的治疗效果更优,但是会增大吸烟者戒烟的难度. 以上所提及的基因均在大脑神经递质的传导中起较为重要的作用,而这些基因调控的重点脑区也是调节情绪和精神疾病相关的脑区,因而具有重要的生物学标记物的潜质.

    通过上述的研究可以发现,在综合分析不同疾病、不同的药物治疗后,不同基因型患者的脑区活动存在一定的差异性,这些研究为未来临床治疗上根据患者个体差异当中基因型的区别,以及脑区中生物学标记物的差异而制定精准治疗的临床诊疗方案提供了一定的启示.

    然而,这些研究仍然存在一些局限性.

    首先,大多数的相关研究所纳入的研究对象样本量较小,缺乏多中心同时开展的试验,药物控制和症状测评方法上有出入,数据结果可信度不是很高,结论仅作为临床前实验的初步假设. 而且,不同的研究之间的研究设计与样本特征有差别,同质性较差,很难进行meta分析. 因此,通过本文的系统综述能够较好地总结出精神药理影像遗传学研究的进展,为未来对价值高的基因和药物进行多中心、大样本的临床试验提供思路和方向.

    其次,许多候选基因的治疗反应与基因组关联研究(GWAS)缺乏联系. 在与抗抑郁药反应相关的3个大型GWAS的meta分析(缓解抑郁症的顺序治疗替代方案、基因组治疗抑郁症药物和慕尼黑抑郁药反应)当中,均没有发现基因组意[67]. 而其他大型抗抑郁反应的GWAS研究,如国际SSRI药物遗传学协[68],也没有获得全基因组学意义的结果. 在GWAS研究中,人群混杂因素对分析结果造成较大的影响,从而造成假阴性或假阳性. 同时,环境影响因素和表观遗传因素等均会对GWAS的研究结果造成影响. 因此,为了降低人群混杂对关联结果分析的影响,在进行相关的GWAS研究时应采用控制人群分层、运用统计分析手段降低人群混杂的影响.

    而且,在几乎所有的研究中均缺乏对基因-环境效应和其他混杂因素考虑的限制. 表观遗传受环境和其他混杂因素的影响,使基因在核苷酸序列不发生改变的情况下被修饰,从而改变基因的表达. 表观遗传对染色体和DNA等遗传物质的修饰方法很多:如DNA甲基化(DNA methylation)、基因组印记(genomic imprinting)、母体效应(maternal effects)、休眠转座子激活和RNA编辑(RNA editing)等. 在精神疾病基因的研究中,表观遗传也起到了重要的作用,但迄今为止只进行了少量研究. 主要原因是表观遗传涉及到的影响因素众多,而且基因有可能进行甲基化、乙酰化等基因修饰,测定相对复杂,难以实施. Doclot[69]通过人群和小鼠的实验发现BDNF基因在启动子4(P4)和启动子6(P6)的组蛋白乙酰化与较高的BDNF表达量相关,并且与较好的抗抑郁疗效具有相关性. 因此,在精神药理基因组学的研究和精神疾病的病理生理学研究中,表观遗传学的作用不容忽视. 在未来的相关研究中,应适当进行表观遗传学与影像学相结合的研究,甚至将表观遗传学的测定纳入基因的检测范围内进行深入研究.

    除此之外,最近有研究证实:涉及基因表达调控的微小RNA水平的变化与抗脑区连接性和抗抑郁药物治疗反应的活动有[70]. 然而,应用纵向评估影像表型和反应的研究数量迄今为止非常小. 考虑到CYP2D6在脑中的功能意义以及CYP2D6和其他药物动力学酶对脑中药物浓度的潜在影[71],对药代动力学基因变异和抗抑郁反应的药理影像遗传学研究将是特别有意义的,因为他们将阐明这些可能复杂的酶和转运蛋白变异的影[72]. 然而,到目前为止,还没有研究来验证这些基因的多态性及其影像研究中纵向对抗抑郁药物结果的影响.

    尽管存在这些问题,神经影像中间表型与药理遗传变异分析的结合,有望加深对遗传变异以及未来治疗精神疾病方法的理解,并在临床症状表现严重前利用影像的方法测定早期预测因子,通过识别生物标志物进行有效的治疗选择,这将是开发更加有针对性药物的研究基础. 在这一领域的未来研究,在具有纵向结果测量的抗抑郁治疗的较大样本量患者中,从基因多态性和表观遗传学差异出发,观测脑区表型并结合最终疾病的改善程度进行药物作用效果的判定. 在仪器上,使用更先进的神经影像方法,如高空间分辨率扩散成像或神经元定向扩散和密度成[73]可能有助于更好地描绘与治疗反应相关的神经可塑性的潜在预测因子或标志物. 在推断因果关系过程中,在人群中做相关性研究后,对相关模型动物进行靶向基因处理后进行实验能够增强因果关系的可信度,再回归到人群中进行验证的研究设计可以成为一种较有潜力且适合推荐的研究范式.

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张英哲

机 构:

1. 四川大学华西医院放射科华西磁共振研究中心,成都,610041

2. 四川大学华西公共卫生学院,成都,610041

Affiliation:

1. Huaxi MR Research Center HMRRC,Department of Radiology, West China Hospital of Sichuan University, Chengdu, 610041, China

2. West China School of Public Health, Sichuan University, Chengdu, 610041, China

陈桃林

机 构:四川大学华西医院放射科华西磁共振研究中心,成都,610041

Affiliation:Huaxi MR Research Center HMRRC,Department of Radiology, West China Hospital of Sichuan University, Chengdu, 610041, China

龚启勇

机 构:四川大学华西医院放射科华西磁共振研究中心,成都,610041

Affiliation:Huaxi MR Research Center HMRRC,Department of Radiology, West China Hospital of Sichuan University, Chengdu, 610041, China

image /
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