细胞色素P450酶1A2和2C19基因多态性与难治性抑郁症的关联分析

目的探讨细胞色素P450酶(cytochromeP450enzymes,CYP)1A2、2C19基因多态性与难治性抑郁症的关联。方法应用聚合酶链反应(PCR)扩增技术及限制性片段长度多态性(RFLP)测定79例难治性抑郁症患者及107名正常对照者CYP1A2C163A、CYP2C19G681A基因多态性。结果两组间基因型及等位基因分布差异无显著性(χ2=3.605,P>0.05;χ2=3.154,P>0.05)。难治性抑郁症患者对照组间基因型及等位基因分布差异无显著性(χ2=0.853,P>0.05;χ2=0.568,P>0.05)。79名患者中46名接受氟西汀合并小剂量利培酮(0.5～2.0mg/d)治疗,将其分为治疗有效组和无效组,两组间CYP1A2C163A(χ2=0.785,P>0.05;χ2=7.142,P>0.05)CYP2C19G681A(χ2=3.008,P>0.05;χ2=2.722,P>0.05)基因型及等位基因分布差异均无显著性。根据CYP2C19G681A基因多态性将患者分为无突变组(G/G型)和突变组(G/A型和A/A型),两组患者CYP1A2C163A基因型及等位基因分布差异无显著性(χ2=0.252,P>0.05;χ2=0.682,P>0.05)。结论CYP1A2C163A和CYP2C19G681A基因多态性与难治性抑郁症无显著关联,不是影响利培酮对氟西汀增效作用的主要因素。     

难治性精神分裂症与细胞色素P4502D6基因多态性相关性研究

目的 探测难治性精神分裂症与细胞色素P4502D6基因多态性关系。方法 用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术分析92例难治性精神分裂症患者的CYP2D6基因多态性,并以92例正常人作为对照。结果 在难治性精神分裂症组和对照组中,等位基因C、T及基因型T/T的差异具有非常显著性和显著性（P=0.002;P=0.002;P=0.014）。结论 本组样本中CYP2D6C188T基因多态性与难治性精神分裂症关联。提示CYP2D6C188T突变可能是难治性精神分裂症发病因素之一,本组中国汉族人中22号染色体长臂（22q13.1）可能存在难治性精神分裂症易感性基因。     

细胞色素P450 2D6酶基因多态性与氟西汀临床效应的相关性研究

目的：研究中国人P450 2D6酶（CYP2D6）基因多态性与氟西汀临床效应之间的关系。方法：用氟西汀对108例抑郁患者（抑郁症89例，精神分裂症后抑郁7例，分裂情感性精神病抑郁型4例，强迫性神经症2例，焦虑性神经症1例，抑郁性神经症4例，分裂样精神病（伴抑郁症状）1例）进行治疗， 和汉密尔顿抑郁量表（HAMD）和治疗中需处理的副反应症状量表（TESS）评定疗效和副反应，用聚合酶链反应－限制性片段长度多态性分析法（PCR－RFLP）分析患者CYP2D6基因型。结果：（1）PCR－RFLP分析表明，在108例抑郁患者中，CYP2D6基因型为wt/wt者26例，wt/Ch者55例，Ch/Ch者26例，wt/A者1例，未发现B等位基因。CYP2D6等位基因频率分别为CYP2D6wt(50%),CYP2D6Ch(49.5%),CYP2DY6A(0.5).(2）入组时，不同基因型的患者之间HAMD基础评分的差异无显著性（P＞0．05）。经氟西汀治疗后4周和8周后，不同CYP2D6基因型患者的HAMD量表评分比治疗前 降低，差异均有非常显著性（P＝0．000）；8周后减分率达80％左右，TESS评分较低。在不同基因型的患者之间，治疗后的HAMD评分、HAMD减分率及TESS评分的差异均无显著性（P＞0．05）。患者治疗前后的HAMD评分及HAMD减分率、TEWW评分等与CYP2D6基因型及CYP2D6突变等位基因数目的相关关系均无显著性（P＞0．05）。结论：未发现中国人CYP2D6基因多态性与氟西汀临床效应之间的关联。     

细胞色素P4502D6及多巴胺D2受体基因多态性与利培酮疗效的关联

目的 探讨细胞色素P450 2D6(cytochromes P450 2D6,CYP2D6)基因多态性、多巴胺D2受体(dopamine D2 receptor,DRD2)基因多态性与利培酮疗效的相关性.方法 对199例首发精神分裂症患者给予利培酮治疗8周,治疗前后采用阳性和阴性症状量表(Positive and Negative Syndrome Scale,PANSS)评定疗效,同时收集198例正常对照进行病例-对照分析.采用聚合酶链反应序列特异性引物扩增技术检测CYP2D6/C188T、DRD2 TaqIA基因型,分析二者与利培酮临床效应的相关性.结果 病例组和对照组CYP2D6/C 188T的基因型和等位基因频率相比,差异有统计学意义(CC:40.7％ vs.21.2％,CT:25.6％ vs.45.5％,TT:33.7％vs.33.3％,P＜0.05;C:53.5％ vs.43.9％,T:46.5％ vs.56.1％,P＜0.05),病例组和对照组DRD2 TaqIA的基因型和等位基因频率相比,差异有统计学意义(A1A1:29.1％ vs.35.9％,A1A2:37.7％ vs.47.5％,A2A2:33.2％ vs.16.6％,P＜0.05; A1:48.0％ vs.59.6％,A2:52.0％ vs.40.4％,P＜0.05);CYP2D6/C 188T与DRD2TaqIA的交互作用对PANSS减分率的影响没有统计学意义(F=0.735,P＞0.05);CYP2D6/C188T,DRD2TaqIA与性别的交互作用对PANSS减分率的影响具有统计学意义(F=3.214,P＜0.05).结论 CYP2D6基因C188T多态性和DRD2基因TaqIA多态性不是影响精神分裂症患者利培酮临床疗效的易感因素,但是在协变量性别的作用下,上述基因多态性的交互作用可能影响利培酮的疗效.     

氟西汀合并小剂量利培酮治疗难治性抑郁症的疗效及安全性分析

目的　探讨小剂量利培酮对氟西汀治疗难治性抑郁症的辅助效果及安全性。方法将101例难治性抑郁症患者随机分为2组: (1)氟西汀合并利培酮组(以下简称合并利培酮组):在氟西汀(20mg/d)治疗的同时合并应用利培酮(0 5 ~2 0mg/d)。共入组51例,其中男26例,女25例;平均年龄(42±13)岁。实际完成试验者49例。( 2 )氟西汀组:单用氟西汀( 20mg/d)治疗。共入组50例,其中男24例,女26例;平均年龄(41±12)岁。实际完成试验者46例。两组持续治疗观察期均为4周。于入组前、入组后第1, 2, 4周末分别应用汉密尔顿抑郁量表(HAMD, 17项)、汉密尔顿焦虑量表(HAMA)及副反应量表进行评定。结果　(1)治疗第2, 4周末, 两组间HAMD、HAMA总分及减分率的差异有统计学意义(P<0 05或P<0 01 )。( 2 )合并利培酮组的总有效率为67%,痊愈和显效占51%。氟西汀组的总有效率为26%,痊愈和显效占18%。两组间的差异有统计学意义(P<0 05)。(3)合并利培酮组患者中27例出现不良反应,占53%;氟西汀组为21例,占40%,两组患者的副反应均较轻微。结论　氟西汀合并小剂量利培酮治疗难治性抑郁症的疗效优于单用氟西汀,安全性较好,是临床治疗中可选用的方法之一。     

利培酮治疗与细胞色素P4502D6/C188T酶基因多态性的关联分析

目的　研究利培酮临床效应的个体差异与其代谢酶细胞色素P4 5 0 2D6 (cytochromeP4 5 02D6 ,CYP2D6 )酶基因多态性的相关性。方法　对 88例符合CCMD 3精神分裂症诊断标准的患者和 96例健康对照者作病例 -对照分析。精神分裂症患者给予利培酮治疗 8周 ,用阳性和阴性症状量表 (posi tiveandnegativesymptomscale ,PANSS)评分评价利培酮疗效。采用聚合酶链反应扩增及限制性片段长度多态性 (PCR RFLP)技术对CYP2D6exonⅠ的C188T位点突变进行检测 ,分析利培酮临床效应与其主要代谢酶CYP2D6 /C188T酶基因多态性的相关性。结果　中国上海地区人群的CYP2D6 /C188T突变率(弱代谢型 )为 36 .3% ,病例组和正常对照组间基因型频率总体分布比较无显著差异 (χ2 =1.15 ,df=2 ,P >0 .0 5 ) ,两组间的等位基因频率之间比较也无显著性差异 (χ2 =0 .78,df=1,P >0 .0 5 )。进行性别及有否家族史分组后分析 ,亦无差异存在 ,且CYP2D6 /C188T突变与利培酮临床效应之间并无相关性 (χ2 =1.12 ,df=2 ;χ2 =0 .0 3,df=1,P >0 .0 5 )。结论　未发现中国人CYP2D6 /C188T多态性与利培酮临床效应的个体差异有相关性。     

细胞色素P4502D6遗传多态性与氟西汀对肝功能的影响

目的：了解细胞色素P4502D6酶（CYP2D6）遗传多态性与氟西汀对肝功能指标的影响之间有无相关。方法：采用PCR－RFLP方法分析88例患者CYP2D6基因型,用氟西汀治疗8周,并测定患者治疗前后肝功能各项指标。结果：治疗后患者肝功能指标普遍升高,但大致仍在正常范围内,未发现CYP2D6遗传多态性与氟西汀导致的肝功能指标升高有显著性相关关系。结论：氟西汀对肝功能的影响可能与多种因素有关。     

小剂量奥氮平联合氟西汀治疗难治性抑郁症的随机对照研究

目的 评价小剂量奥氮平联合氟西汀治疗难治性抑郁症的临床效果.方法 64例难治性抑郁症患者随机分为研究组和对照组,每组32例,研究组患者给予氟西汀合并小剂量奥氮平治疗,对照组患者给予氟西汀单药治疗,两组疗程均为8周.治疗前及治疗后第1、2、4、8周末应用汉密尔顿抑郁量表(HAMD)进行评分并评价疗效,应用治疗中需处理的不良反应症状量表(TESS)及实验室检查评定治疗安全性.结果 治疗后第2周末起,两组患者HAMD评分均显著下降,与治疗前比较差异有统计学意义(P＜0.05),研究组治疗后第1、2、4、8周末HAMD评分显著低于对照组,差异有统计学意义(P＜0.05).研究组临床有效率为46.88％,对照组有效率为21.88％,两组临床有效率比较,差异有统计学意义(P＜0.01).两组患者均无明显不良反应,不良反应发生率无统计学意义(P＞0.05).结论 小剂量奥氮平联合氟西汀治疗难治性抑郁症具有较好的临床疗效.     

氟西汀合并奥氮平治疗难治性抑郁症对照研究

目的探讨小剂量奥氮平合并氟西汀治疗难治性抑郁症的疗效和不良反应。方法将74例难治性抑郁症患者随机分为2组,研究组在氟西汀(20mg/d)治疗的同时合并应用奥氮平(5~10mg/d);对照组仅用氟西汀(20mg/d)治疗,两组作4周的持续治疗观察,于入组前及入组后第1、2、4周末分别用汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)及副反应量表进行评定。结果两组在治疗后第2、4周末,HAMD、HAMA总分及减分率的差异有统计学意义,两组间有效率的差异也有统计学意义。研究组和对照组分别有48.5%和38.9%出现不良反应,差异无统计学意义。结论小剂量奥氮平在难治性抑郁症的治疗中有增效作用,优于单用氟西汀,且安全性较好,在临床上可以作为治疗难治性抑郁症的一个备选方案。     

氟西汀合并奥氮平治疗难治性抑郁症的双盲对照研究

目的本研究探讨氟西汀合并奥氮平治疗难治性抑郁症的安全性和疗效。方法采用双盲对照研究,将52例诊断为难治性抑郁症的患者随机分为两组,一组采用氟西汀治疗,一组采用氟西汀合并奥氮平治疗,分别在治疗后第2、4、6、8周末,评定汉密顿抑郁量表(HAMD)和临床总体印象量表(CGI),同时采用Asberg抗抑郁剂副反应量表评定两组的药物副反应。结果氟西汀联合奥氮平治疗难治性抑郁症的疗效要明显优于单一应用氟西汀治疗(P<0.05),药物副反应两组间无明显差异(P>0.05)。结论氟西汀联合奥氮平治疗难治性抑郁症的疗效要明显优于单一应用氟西汀治疗(P<0.05),药物副反应两组间无明显差异(P>0.05)。     

Cytochrome P-450 2D6*10 C188T polymorphism is associated with antipsychotic-induced persistent tardive dyskinesia in Chinese schizophrenic patients

Typical antipsychotic treatment had been postulated to be a risk factor for the susceptibility to tardive dyskinesia (TD). The cytochrome P-450 debrisoquine/sparteine hydroxylase (CYP2D6) metabolizes a majority of antipsychotics and exhibits various phenotypes on enzymatic activities from poor metabolizers to ultrarapid metabolizers. The various phenotypes are encoded by polymorphic genetic variants on the CYP2D6 gene. Although several studies had explored the association between the CYP2D6*10 C188T polymorphism, which encodes the phenotype intermediate metabolizers, and TD in Orientals, the findings were inconclusive. In the present study, we examined the relationship between the CYP2D6*10 C188T polymorphism and the TD occurrence in 216 Chinese schizophrenic patients (113 patients with TD and 103 patients without TD) and explored the correlation between the TD severity assessed by the Abnormal Involuntary Movement Scale (AIMS) and each C188T genotype in the 113 TD patients. Using logistic regression analysis, we found a modest association (p = 0.045) between TD and C188T genotypes. This positive finding was only observed in male patients (p = 0.001), but not in females. Our findings also support the correlation between AIMS scores and C188T polymorphism within the TD group after adjusting for confounding effects with the multiple regression analysis (p = 0.033). We concluded that the CYP2D6*10 C188T polymorphism may be associated with the susceptibility to the occurrence of TD induced by typical antipsychotics, especially in male patients, and may also be correlated with AIMS scores in TD patients.     

5-羟色胺2A、2C受体基因多态性与难治性抑郁症的关联分析

目的：探讨中国汉族人群难治性抑郁症患者5-羟色胺2C（5-HT2C）受体基因与5-HT2A受体基因之间的关联性。方法：应用聚合酶链式反应（PCR）扩增技术及限制性片段长度多态性（RFLP）分别测定77例难治性抑郁症患者及90名正常人5-HT2C受体基因和5-HT2A受体基因的基因型和等位基因。结果：难治性抑郁症组-759野生型频率明显低于对照组。-759野生型／-697野生型频率也显著低于正常;患者组5-HT2A受体基因型杂合子组的-759野生型、-697野生型以及-759野生型／-697野生型均明显高于纯合子组。结论：-759野生型可能与难治性抑郁症的发病存在一定的相关性;5-HT2A受体基因与5-HT2C受体基因相互之间对难治性抑郁症易患性可能存在一定的关系。     

Pharmacogenetics of antidepressant medication intolerance

OBJECTIVE: The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect). METHOD: An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood. RESULTS: Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. CONCLUSIONS: Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.     

Cytochrome P4502D6 (debrisoquine 4-hydroxylase) and Parkinson''s disease in Chinese and Caucasians

Four polymorphic sites (C/T188, C/T2938, G/C4268, G/A1934) in the cytochrome P4502D6 (debrisoquine 4-hydroxylase) gene were investigated for their association with sporadic Parkinson's disease (PD). Three mutant alleles (C/T188, C/T2938 and G/C4268) result in amino acid changes which could alter the substrate specificity or alter its ability to metabolize their substrates; the fourth (G/A1934) causes a loss of enzyme activity. The study was carried out in two ethnically homogenous populations: Chinese (123 PD patients, 124 controls); and Caucasian (95 PD patients, 62 controls). Haplotype status, which took into account amino acid changes at three polymorphic sites, was deduced from genotyping results in order to investigate whether substrate specificity was important rather than loss of enzyme activity. There was no gender difference in the distribution of the alleles in either race. There was, however, significant association among the three polymorphic sites (C/T188, C/T2938, G/C4268) in both ethnic groups. T/T188:C/C2938:C/C4268 is the most common genotype in the Chinese population, in contrast to C/C188:C/T2938:C/G4268 (followed by C/C188:C/C2938:G/G4268) in Caucasians. All 69 of the sub-group of Chinese patients tested were homozygous for the wild-type allele at the G/A1934 polymorphic site. Neither the CYP2D6 allele nor haplotype was associated with PD in either ethnic group.     

难治性精神分裂症与亚甲基四氢叶酸还原酶基因多态性的关联分析

目的:探讨难治性精神分裂症与亚甲基四氢叶酸还原酶(MTHFR)基因C677T和A1298C多态性的关系。方法:应用聚合酶链反应-限制性片断长度多态性方法(PCR-RFLP)检测102名正常对照、138例难治性精神分裂症患者及97例非难治性精神分裂症患者MTHFR基因的C677T和A1298C多态性。结果:患者组与对照组,难治组与非难治组C677T、A1298C基因型分布差异均无统计学意义(C677T,χ2=4.83,P=0.09;χ2=1.90,P=0.39;A1298C,χ2=1.50,P=0.47;χ2=3.90,P=0.14),而患者组C677T的T等位基因频率显著高于正常对照组(P=0.04),难治组A1298C的C等位基因频率显著高于非难治组(P=0.04)。677TT/1298AA、677CT/1298AC复合基因型患病相对风险度比677CC/1298AA型显著提高(OR=4.13,95%CI=1.26～13.58,P=0.02;OR=2.95,95%CI=1.23～7.07,P=0.01),而在难治组和非难治组中,复合基因型差异无统计学意义。结论:MTHFR基因677T等位基因和677TT/1298AA、677CT/1298AC复合基因型是精神分裂症发病危险因素,MTHFR基因1298C等位基因可能是难治性精神分裂症的危险因子之一。     

CYP2D6 P34S Polymorphism and Outcomes of Escitalopram Treatment in Koreans with Major Depression

Objective

Cytochrome P450 (CYP) enzymatic activity, which is influenced by CYP genetic polymorphism, is known to affect the inter-individual variation in the efficacy and tolerability of antidepressants in major depressive disorder (MDD). Escitalopram is metabolized by CYP2D6, and recent studies have reported a correlation between clinical outcomes and CYP2D6 genetic polymorphism. The purpose of this study was to determine the relationship between the CYP2D6 P34S polymorphism (C188T, rs1065852) and the efficacy of escitalopram treatment in Korean patients with MDD.

Methods

A total of 94 patients diagnosed with MDD were recruited for the study and their symptoms were evaluated using the 21-item Hamilton Depression Rating scale (HAMD-21). The association between the CYP2D6 P34S polymorphism and the clinical outcomes (remission and response) was investigated after 1, 2, 4, 8, and 12 weeks of escitalopram treatment using multiple logistic regression analysis and χ² test.

Results

The proportion of P allele carriers (PP, PS) in remission status was greater than that of S allele homozygotes (SS) after 8 and 12 weeks of escitalopram treatment. Similarly, P allele carriers exhibited a greater treatment response after 8 and 12 weeks of escitalopram treatment than S allele homozygotes.

Conclusion

Our results suggest that the P allele of the CYP2D6 P34S polymorphism is a favorable factor in escitalopram treatment for MDD, and that the CYP2D6 P34S polymorphism may be a good genetic marker for predicting escitalopram treatment outcomes.     

Frequency of CYP2D6 allelic variants in multiple sclerosis

Recent reports have shown association between CYP2D6 polymorphism and neuronal degenerative diseases such as Parkinson's disease. We investigated the association between this polymorphism and the risk for developing multiple sclerosis (MS). Leucocyte DNA from 118 MS patients and a control group of 200 unrelated healthy individuals was studied for the occurrence of 8 different CYP2D6 allelic variants by using allele-specific PCR amplification, Xba I and EcoR I RFLP analyses. The frequencies for these allelic variants in the MS and control groups were, respectively: CYP2D6wt 75.0% and 79.3%, CYP2D6A 0.4% and 1.3%, CYP2D6B 11.4% and 12.0%, CYP2D6C 4.2% and 2.0%, CYP2D6D 3.0% and 2.3%, CYP2D6L 0.8% and 0.3%, CYP2D6L2 5.1% and 3.0%. The frequencies of subjects with high CYP2D6 activity (those carrying two or more functional genes) were 77.1% and 73.5% in MS and control groups. The frequencies of subjects with absent CYP2D6 activity (those lacking functional genes) were 3.4% and 4.5% in MS and control groups, respectively. These results indicate that mutations at the CYP2D6 gene do not seem to be a factor in determining susceptibility to MS.     

细胞色素P4502D6 基因多态性与帕金森病遗传易感性的关系

目的研究机体解毒系统多态性在帕金森病（ＰＤ）遗传易感性中的作用，以阐明ＰＤ遗传易感性的实质。方法选择ＰＤ病人１００例和年龄、性别基本匹配的正常人１００名，利用聚合酶链反应－限制性片段长度多态等技术检测细胞色素Ｐ４５Ｏ２Ｄ６（ＣＹＰ２Ｄ６）基因的Ａ、Ｂ两种引起酶活性缺乏的突变率和Ｃ１８８→Ｔ、Ｇ４２６８→Ｃ及Ｃ２９３８→Ｔ三种引起酶活性降低的多态性频率。结果结果发现ＰＤ病人ＣＹＰ２Ｄ６基因Ａ、Ｂ突变的频率高于正常对照组，它们的危险度均在２倍以上；而且，ＰＤ病人ＣＹＰ２Ｄ６基因的Ｃ１８８→Ｔ、Ｇ４２６８→Ｃ和Ｃ２９３８→Ｔ的频率也较正常对照组高，尤其是具有Ｃ２９３８→Ｔ等位基因者患ＰＤ的危险度提高了２．５８倍。结论ＰＤ病人ＣＹＰ２Ｄ６酶活性缺乏和降低的基因突变率均高于正常人，提示解毒酶ＣＹＰ２Ｄ６缺陷与ＰＤ发病有一定的关系