脑源性神经营养因子与双相障碍及药物治疗急性躁狂疗效的研究

【作者】 叶尘宇；

【导师】 王立伟； 施慎逊； 禹顺英；

【作者基本信息】 复旦大学 ， 精神病与精神卫生学， 2009， 博士

【摘要】 [目的]:了解脑源性神经营养因子(BDNF)血清浓度、单核苷酸基因多态性(SNP)rs6265和rs11030101和双相障碍的关联;了解BDNF血清浓度、SNP rs6265和rs11030101基因型与药物治疗急性躁狂疗效的关系。[方法]:1.收集2008年6月至2008年12月在上海市精神卫生中心和其它区精神卫生中心门诊或住院患者的双相障碍患者,诊断标准为《美国精神疾病诊断和统计手册-第四版》(DSM-Ⅳ)。知情同意后抽取血样测试BDNF血清浓度和BDNF SNPsrs6265和rs11030101的基因型,同时进行一般资料的收集和杨氏躁狂量表(YMRS)、汉密尔顿抑郁量表(HAMD)、临床大体评定量表(CGI)的评定。比较BDNF血清浓度和BDNF SNPs rs6265和rs11030101的基因型与双相障碍之间的关系。2.对于符合躁狂发作诊断并且知情同意的患者进行为期四周的药物治疗,药物的种类和剂量不限,但规定必须在一周内滴定到治疗剂量。在基线、治疗1周、2周、3周、4周时评定YMRS、CGI和不良反应量表(TESS),并在治疗4周时再次抽取血样,测定BDNF血清浓度,比较BDNF血清浓度和BDNF SNPs rs6265和rs11030101的基因型与药物治疗的关系。3.搜索所有的中国人群为研究对象的关于双相障碍和BDNFrs6265多态性的研究,进行荟萃分析。[结果]:第一部分:共有228名双相患者入组本研究,其中男性107名(46.7%),平均年龄38.28±14.03岁,均为汉族人。有家族史的60人(26.3%),双相Ⅰ型200例(87.7%),平均病程为为138.15±134.9月,中位发病年龄23.62岁。多数患者(86.84%)既往12个月内使用2种或2种以上的精神科药物。目前用药中,使用最多的药物为非典型抗精神病药物(62.28%)和丙戊酸盐(53.95%),87.72%的患者使用2种或2种以上的精神科药物。有85名患者处于躁狂发作期,14名处于抑郁发作期,129名为缓解期。所有患者的平均BDNF血清浓度为18.75±8.98 ng/ml,正常对照组的浓度为23.72±5.60 ng/ml,两组的差异有统计学意义,P＜0.001。躁狂组、抑郁组和缓解期组的平均BDNF血清浓度分别为20.64±8.49 ng/ml,17.55±8.45 ng/ml,17.66±9.20 ng/ml,与正常对照相比差别均有统计学意义,所有P=0.001。不论是全体讨论还是分组分析,BDNF血清浓度与性别、年龄、疾病的分型、家族史、发病年龄、疾病严重程度和耐受性各组之间都无显著性差异。但在全体病例组分析和缓解期组均发现既往治疗效果为恶化的血清浓度最高,效果明显的反而最低,差别有统计学意义,P=0.003和P=0.015。不同基因型之间比较,全体患者SNPrs6265的G/G和A/A型之间的血清浓度差异有统计学意义,P=0.036,躁狂组和缓解组之间的差异无统计学意义。基因型分析结果显示rs6265和rs11030101基因型、等位基因和联合基因型与双相障碍的年龄、性别、分型、家族史、既往治疗效果、耐受性均无显著性差异。第二部分:共有58名患者入组药物治疗急性躁狂的研究,共43名完成研究。统计结果显示:平均年龄38.43±14.65,男性26名(44.8%),平均病程为138.28±116.23月。用末次观测值结转法推测缺省值后,基线、治疗1,2,3,4周后的YMRS评分逐渐下降,差别有统计学意义,P＜0.001。各周之间两两比较都有统计学差异。比较治疗1,2,3,4周后的CGI的疾病严重程度和病情改善程度,各周之间的差异均有统计学意义,P＜0.001。剔除脱落患者后,治疗前后的血清浓度分别为,19.74±7.94ng/ml和24.68±10.78 ng/ml,两组之间的差异有统计学意义,P=0.001。血清浓度的改变程度和症状的改善无关联。根据治疗的疗效比较rs6265和rs11030101各组基因型和等位基因型,发现治疗有效的患者的rs6265的G等位基因明显较高,与正常对照相比,差异有统计学意义。研究中出现的不良反应较少,程度较轻微,均无需处理。最常见的不良反应为嗜睡,出现的比率为8.62%。第三部分:共搜索出3篇文献是针对中国人群样本的比较rs6265基因多态性和双相障碍的关系,加上本研究共4篇。各项研究之间无明显异质性。统计结果显示共有627名患者和920名正常对照,G等位基因的比例和正常对照相比,差异无统计学意义。2项比较早发型躁狂的研究荟萃分析后发现,早发型躁狂的ra6265的G等位基因的比例和正常对照之间的差异无统计学意义。[结论]:1.双相障碍患者的BDNF的血清浓度不论是在缓解期、抑郁发作期还是在躁狂发作期都低于正常对照,且差别有统计学意义;2.未发现BDNF血清浓度与症状的严重程度相关;3.rs6265基因型可能与BDNF血清浓度有关;4.药物治疗急性躁狂后,BDNF血清浓度明显上升,BDNF血清浓度可能是躁狂症状的一个状态指标;5.rs6265的G等位基因可能与治疗的疗效有关;6.针对中国人群的研究中,rs6265基因多态性未发现与双相障碍相关。更多还原

【Abstract】 [Objective] To investigate the relationship between serum concentration of the brain-derived neurotrophic factor (BDNF) , single nucleotide polymorphisms (SNP) and bipolar disorder. To study the relationship between serum concentration of BDNF, SNP and the effect of acute mania with drug treatment.[Methods] 1. Patients meet the diagnostic criteria of bipolar disorder in Diagnostic and Statistical Manual for mental disorder-IV in Shanghai Mental Health Center and other mental health center from July to December in 2008 were included with informed consent. Blood sample were got to test the serum concentration of BDNF and the genotype of rs6265 and rs11030101 and the assessment of Young Mania Rating Scale, Hamilton Depression Rating Scale and Clinical Global Impression were collected at the same time. The BDNF concentration and the genotype of rs6265 and rs11030101 were compared to the clinical characters of bipolar disorder.2. Those meet the criteria of acute mania were treated for 4 weeks with drugs which were not strictly defined but titrated to full treatment dosage in a week. YMRS, CGI and Treatment Emergent Symptoms Scale (Tess) were assessed in the base line, the first, second, third and forth week in the treatment. The BDNF concentration and genotype of rs6265 and rs11030101 were compared to the clinical characters of bipolar disorder.3. All the studies of the relationship between BDNF polymorphisms and bipolar disorder with Chinese samples were included and analysized with mate-analysis.[Results]Part I: Two hundred and twenty eight bipolar disorder patients were included with 107 males, 60 with family history and 200 divided into type I. The average age was 38.28±14.03 years old and the average course were 138.15±134.9 months. The median onset age was 23.62 years old. 86.84% patients used two or more drugs in the latest 12 months. At the baseline, 87.72% patients used two or more drugs and the most used drug were antipsychotic drugs(62.28%) and valproate(53.95%). All among the patients, 85 were in acute mania and 14 were in depression with the other 129 were in euthymic phase.The average concentration of BDNF were 18.75±8.98 ng/ml and were significantly lower than the normal control ( 23.72±5.60 ng/ml), p<0.001. The average BDNF concentration of mania group, depression group and euthymic group were respectively 20.64±8.49 ng/ml, 17.55±8.45 ng/ml and 17.66±9.20 ng/ml, with statistically lower than the normal control.The average BDNF concentration has no relationship with gender, age, type, family history, onset age, severity and the tolerance of drug treatment. However, in the all patients group and euthymic group, the average BDNF concentration of deterioration group in the global improvement was the highest while that of obviously group was the lowest. The difference has statistical meaning, P=0.003 and P=0.015. The average BDNF concentration between rs6265 G/G and A/A genotype were significantly different, P=0.036.The genotype and allele of rs6265 and rs11030101 has no relationship with age, gender, type, family history, treatment effect and tolerance in bipolar disorder.Part 2: Fifty-eight patients were included in this study and 43 finished it. 26 patients were male. The average age was 38.43±14.65 years old and the average course was 138.28±116.23 months. The YMRS scores were lower step by step at the base line, 1, 2, 3, 4 weeks after treatment. The difference has statistical meaning, P<0.001. The distribution of severity and change degree of CGI were significantly changed at the base line, 1, 2, 3 , 4 weeks after treatment, P<0.001. The BDNF concentration were significantly increased after 4-week-treatment(19.74±7.94ng/ml and 24.68±10.78 ng/ml), P=0.001. The change of BDNF concentration has no relationship with the change of symptoms. Compared to the normal control, the G allele of rs6265 were significantly higher than other allele in the response group. The adverse events were rare and need not any treatment. The most common adverse event was 8.62%.Part 3: Three articles were found and it was 4 studies with our investigate included. There were 627 bipolar patients and 920 normal controls. There was no significant difference between two groups in the genotype of rs6265. And there was no significant difference between early onset bipolar disorder and normal controls.[Conclusions]1. The BDNF concentration was significantly lower than normal controls, whether it was in mania, depression or euthymic phase.2. There was no relationship between the change of BDNF concentration and the change of symptoms. 3. The genotype of rs6265 maybe related to the BDNF concentration.4. The BDNF concentration increased significantly after 4 weeks drugs treatment. The BDNF concentration maybe is a marker of mania symptoms.更多还原