利培酮对首发精神分裂症患者脑源性营养因子的影响

费小聪, 陈海支, 杨胜良, 钱敏才, 沈鑫华, 崔力军, 雷礼磊, 宋宝华, 支胜利, 李建华

浙江省湖州市第三人民医院精神科,湖州 313000

FEI Xiaocong^,, CHEN Haizhi^,, YANG Shengliang, QIAN Mincai, SHEN Xinhua, CUI Lijun, LEI Lilei, SONG Baohua, ZHI Shengli, LI Jianhua

Department of Psychiatry, the Third People's Hospital of Huzhou City,Zhejiang Province, Huzhou 313000, China

通信作者陈海支(1972-),男,湖北十堰人,主任医师,主要研究方向:精神分裂症。E-mail:chenhz2007@sina.com。

作者简介费小聪(1980-),男,浙江湖州人,主治医师,学士,主要研究方向:精神分裂症基础与临床。E-mail:13362258313@189.cn。

基金资助: 湖州市科技局公益性技术应用研究(一般)(2014GY21)

中图分类号: R971.41 文献标识码: B 文章编号: 1004-0781(2017)10-1158-03

摘要:

目的观察利培酮对首发精神分裂症患者血清脑源性营养因子(BDNF)的影响。方法治疗组90例首发精神分裂症患者,给予利培酮治疗16周,利培酮剂量为(3.79±0.88) mg·d^-1。在治疗前,治疗第2,8,16周末检测血清BDNF,治疗前及治疗第16周末用阳性与阴性症状量表(PANSS)评定患者精神分裂症症状严重程度。同时测定90名健康对照组血液BDNF浓度。结果对照组BDNF为(22.867±6.051) ng·mL^-1;治疗组治疗前及治疗2,8,16周末血清BDNF水平分别为(14.256±4.096),(13.078±3.462),(18.001±5.753),(21.089±6.692) ng·mL^-1,治疗组治疗前明显低于对照组,差异有统计学意义(P<0.01)。治疗组治疗后BDNF水平出现先降后升现象,与治疗前比较差异有统计学意义(P<0.05或P<0.01)。治疗组治疗16周末,BDNF水平与对照组比较,差异无统计学意义(P>0.05)。治疗组治疗后患者PANSS 量表总分及各分量表分下降,差异有统计学意义(P<0.01)。治疗16周末PANSS量表减分率与血清BDNF浓度变化率正相关( r=0.499,P=0.001)。治疗16周末血清BDNF浓度变化率与16周末利培酮剂量无相关性( r=0.103,P=0.335)。结论首发精神分裂症患者存在BDNF异常,利培酮治疗能够获得改善。

关键词: 利培酮 ; 精神分裂症 ; 脑源性神经营养因子

Abstract:

Objective To observe the effect of risperidone on serum brain derived neurotrophic factor (BDNF) in first-episode schizophrenic patients. Methods In the treatment group, 90 first-episode schizophrenics were treated with risperidone for 16 weeks, and the dose of risperidone was (3.79±0.88) mg·d^-1. Serum BDNF levels were measured before treatment, at 2, 8, and 16 weeks after treatment. The severity of schizophrenia symptoms was assessed by the positive and negative symptom scale (PANSS) before and after sixteen weeks of treatment. Serum BDNF concentrations were measured in 90 healthy controls. Results BDNF in the control group was (22.867±6.051) ng·mL^-1. The serum BDNF levels before treatment and at the end of week 2, 8, 16 after the treatment in the treatment group were (14.256±4.096), (13.078±3.462), (18.001±5.753), (21.089±6.692) ng·mL^-1, and the serum BDNF level was significantly lower in the treatment group than that in the control group (P<0.01). After the treatment, the level of BDNF in the treatment group decreased at first and then increased, compared with that before treatment, the difference was significantly (P<0.05 or P<0.01). The level of BDNF in the treatment group at the end of week 16 was not significantly different from that of the control group (P>0.05). After treatment, the total score of PANSS scale and its subscales decreased, the difference was significantly (P<0.01). At the end of week 16, the PANSS subscale reduction rate was positively correlated to the serum BDNF concentration change (r=0.499, P=0.001). The change rate of serum BDNF concentration at the end of week 16 was not correlated with the dose of risperidone (r=0.103, P=0.335). Conclusion BDNF is abnormal in the first episode of schizophrenia, which can be improved by risperidone treatment.

Key words: Risperidone ; Schizophrenia ; Brain derived neurotrophic factor

脑源性神经营养因子(brain derived neurotrophic factor,BDNF)可能参与精神分裂症病理生理过程^[1]。有研究显示,精神分裂症患者BDNF水平低于正常人^[2-4]。目前仅少数第2代抗精神病药在人体获得证明具有增加BDNF的作用,主要是氯氮平和奥氮平及喹硫平^[3,5-7],利培酮并无明确结果。因此,2015年1—12月,笔者观察利培酮对精神病患者BDNF的影响,报道如下。

1 资料与方法

1.1 临床资料

治疗组样本来源于湖州市第三人民医院精神科住院及门诊患者。入组标准:符合《疾病和有关健康问题的国际统计分类》第10次修订本(International Statistical Classification of Diseases and Related Health Problems 10^th Revision,ICD-10)中诊断标准的首发精神分裂症患者,年龄18~55岁,且2位主治及以上精神科医师诊断一致;患者基线阳性和阴性症状量表(positive and negative syndrome scale,PANSS)总分≥60分;入组前未接受过抗精神病药治疗或未接受过电休克治疗;获得本人或家属、监护人、法定代理人的书面知情同意。排除标准:合并脑器质性精神障碍、情感性精神障碍等其他精神障碍者;患严重躯体疾病或可能干扰评估的疾病,有明确的肥胖、饮食障碍、糖尿病、高血压和心脏病史及家族史;过去1年内有药物滥用或药物依赖史者;入选前使用过抗精神病药物、抗抑郁症药、情绪稳定药、抗癫痫药及妊娠或哺乳期妇女。退出标准:①治疗过程中出现严重并发症;②严重药物不良反应;③使用或者需要使用研究方案中禁止使用的药物;④患者的法定监护人撤除知情同意书;⑤研究者考虑患者的病情而认为应该退出研究。对照组为我院健康体检者,入组标准:年龄18~55岁;既往无精神疾病史;签署知情同意书。排除标准:严重躯体疾病;乙醇或药物依赖者;精神病阳性家族史;妊娠及哺乳期妇女。本研究通过湖州市第三人民医院伦理委员会批准。治疗组共完成病例90例,男48例,女42例,年龄(29.85±7.62)岁,总病程(7.21±5.91)个月;对照组90例,男46例,女44例,年龄(30.49±8.26)岁,两组间年龄及性别构成比差异均无统计学意义(均P>0.05)。

1.2 方法

1.2.1 研究设计本研究采用病例-对照及治疗前后自身配对研究方法。

1.2.2 药物治疗方法患者常规服用利培酮片(商品名:维思通,杨森制药有限公司生产,批准文号:国药准字J20100136,规格:每片 1 mg),日剂量依病情需要进行调整(2~5 mg),2周内加至治疗剂量,进行为期16周的临床观察。16周末利培酮剂量为(3.79±0.88) mg·d^-1。在治疗过程中根据需要只允许酌情加用氯硝西泮片、普萘洛尔片、苯海索片及护肝药。

1.2.3 指标检测在治疗前及治疗第2,8,16周末检测血清BDNF,血常规、生化、心电图检查。血清BDNF的测定:均于清晨7:00抽取空腹静脉血5 mL,不抗凝,静置后分离血清,取上清液2 mL,置于-70 ℃条件储存备用。采用酶联免疫吸附测定(ELISA)法测定血清BDNF水平,试剂盒为武汉博士德生物工程有限公司提供,批号:EK0305)。BDNF检测严格按照试剂盒操作说明书完成。

1.2.4 量表评定分别在治疗前、治疗第16周末用PANSS量表评定疗效。PANSS评分由两位经过培训的主治医师进行双盲评定,评定者之间的一致性Kappa值=0.82)。

1.2.5 统计学方法采用SPSS19.0版统计软件进行统计分析。计量资料以均数±标准差( $\begin{matrix} \bar{x} \end{matrix}$ ±s)表示,组内治疗前后用单因素方差分析,组间均数比较用独立样本t检验,计数资料用率表示,采用χ²检验。因素间关系研究用相关分析(r),以P<0.05为差异有统计学意义。

2 结果

2.1 血清BDNF水平比较

对照组BDNF为(22.867±6.051)ng·mL^-1;治疗组治疗前及治疗2,8,16周末血清BDNF水平分别为(14.256±4.096),(13.078±3.462),(18.001±5.753),(21.089±6.692)ng·mL^-1,治疗组治疗前明显低于对照组,差异有统计学意义(t=-11.180,P<0.01)。治疗组治疗后BDNF水平出现先降后升现象,与治疗前比较差异有统计学意义(P<0.05或P<0.01)。治疗组治疗16周末,BDNF水平与对照组比较,差异无统计学意义(t=1.869,P>0.05)。

2.2 治疗前后PANSS 量表评分比较

治疗组治疗16周末PANSS量表总分、阳性症状、阴性症状、一般病理评分均较治疗前下降,差异有统计学意义(P<0.01),见表1。

时间	总分	阳性症状评分
治疗前	85.21±10.32	27.34±6.52
治疗16周末	48.35±9.51	13.21±5.22
t	24.917	16.037
P	0.000	0.000
时间	阴性症状评分	一般病理评分
治疗前	19.74±6.72	38.79±7.53
治疗16周末	12.46±4.91	24.81±6.39
t	8.298	13.429
P	0.000	0.000

表1 治疗组患者治疗前后PANSS 量表评分比较

Tab.1 Comparison of PANSS scores of patients in treatment group before and after treatment 分,x¯±s,n=90

2.3 PANSS量表评分与BDNF浓度变化率相关性

治疗16周末PANSS量表减分率与血清BDNF浓度变化率正相关(r=0.499,P=0.001)。治疗16周末血清BDNF浓度变化率与16周末利培酮剂量无相关性(r=0.103,P=0.335)。

3 讨论

在本研究中,发现精神分裂症患者血液BDNF水平明显低于正常对照群体,说明精神分裂症患者存在BDNF水平下降,与国内外大多数研究结果一致。究其原因:一方面,BDNF与海马皮质神经元、胆碱酯能神经元、黑质多巴胺能神经元及5-羟色胺能神经元的可塑性密切相关^[8],这些神经元在疾病的发生、发展中起重要作用,因此推测,随着疾病发展,BDNF功能也随之下降。另一方面,多巴胺D₁受体(DRD1)与BDNF基因间可能存在基因-基因交互作用,提示精神分裂症患者脑内DRD1结构或功能异常可能与BDNF有关^[9]。

利培酮为临床上常用非典型抗精神病药,大量研究证明,足量治疗可改善患者精神症状。已有研究表明BDNF通过激活酪氨酸激酶受体(TrkB),促进神经元的存活,调节神经元形态、突触可塑性^[10]。而有研究显示利培酮能够上调大鼠左右前额叶皮质、左右颞叶皮质及海马BDNF-TrkB信号通路^[11]。既往研究对利培酮是否具有增强人体BDNF的作用并无明确结果。本研究显示治疗2周末治疗组血清BDNF水平低于治疗前。上述结果表明精神分裂症患者早期已经存在神经损伤及神经营养不足,并且随着病程的发展而持续加重。但本研究在治疗8,16周末发现治疗组血清BDNF水平高于治疗前,且16周末治疗组BDNF水平与对照组比较差异无统计学意义,提示通过利培酮治疗BDNF能够获得改善。这与其他研究有所不同^[12-13],可能与研究的样本、发病年龄、病程长短或抽样的种族等多方面因素有关。

本研究也有一定局限,仅仅检测患者血清中BDNF含量,是否能完全代表中枢神经系统BDNF的含量尚不确定。另外本研究发现治疗16周末PANSS量表减分率与血清BDNF浓度变化率正相关,提示BDNF浓度的变化可能与精神分裂症预后有关,有待进一步研究。

The authors have declared that no competing interests exist.

参考文献

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[1]	DURANY N,THOME J.Neurotrophic factors and the path-ophysiology of schizophrenic psychoses[J].Eur Psychiatry,2004,19(6):326-337. The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14聽million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders. DOI:10.1016/j.eurpsy.2004.06.020 PMID:15363470 URL [本文引用:1]
[2]	许烨勍,叶尘宇,沈瑜君,等.血清脑源性神经营养因子与精神分裂症症状及认知功能的关系[J].中国神经精神疾病杂志,2011,37(7):425-427. [本文引用:1]
[3]	GRILLO R W,OTTONI G L,et al.LAKE R.Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics[J].J Psychiatr Res,2007,41(1/2):31-35. [本文引用:1]
[4]	RIZOS E N,RONTOS I,LASKOS E,et al.Investigation of serum BDNF levels in drug-naive patients with schizo-phrenia[J].Prog Neuropsychopharmacol Biol Psychiatry,2008,32(5):1308-1311. [本文引用:1]
[5]	刘建君,孙菊水,沈鑫华,等.奎硫平对首发精神分裂症患者脑源性营养因子的影响[J].医药导报,2014,33(9):1185-1187. [本文引用:1]
[6]	RIZOS E N,PAPADOPOULOU A,LASKOS E,et al.Redu-ced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics[J].World J Biol Psychiatry,2010,11(2 Pt 2): 251-255. [本文引用:0]
[7]	GONZALEZ-PINTO A,MOSQUERA F,PALOMINO A,et al.Increase in brain-derived neurotrophic factor in first episode psychotic patients after treatment with atypical antipsychotics[J].Int Clin Psychopharmacol,2010,25(4):241-245. [本文引用:1]
[8]	ANGELUCCI F,BRENE S,MATHE A A,et al.BDNF in schizophrenia depression and corresponding animal models[J].Mol Psychiatry,2005,10(4):345-352. [本文引用:1]
[9]	卢卫红,张晨,易正辉,等.精神分裂症患者脑源性神经营养因子与多巴胺D₁受体基因交互作用研究[J].中华精神科杂志,2013,46(2):94-98. [本文引用:1]
[10]	LU B,MARTINOWICH K.Cell biology of BDNF and its relevance to schizophrenia[J].Novartis Found Symp,2008,11(289):119-135,193-195. [本文引用:1]
[11]	余波,王雪,韦锦学,等.利培酮对大鼠各脑区组织BDNF-TrkB信号通路的影响[J].四川大学学报(医学版),2015,46(4):528-532. [本文引用:1]
[12]	PIRILDAR S,GONUL A S,TANELI F,et al.Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment[J].Prog Neuropsychopharmacol Biol Psychiatry,2004,28(4):709-713. [本文引用:1]
[13]	YOSHIMURA R,HORI H,SUGITA A,et al.Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol(MHPG) levels,but did not alter plasma brain-derived neurotrophic factor(BDNF) levels in schizophrenic patients[J].Prog Neuropsychopharmacol Biol Psychiatry,2007,31(5):1072-1077. [本文引用:1]

Neurotrophic factors and the path-ophysiology of schizophrenic psychoses

2004

... 脑源性神经营养因子(brain derived neurotrophic factor,BDNF)可能参与精神分裂症病理生理过程^[1].有研究显示,精神分裂症患者BDNF水平低于正常人^[2-4].目前仅少数第2代抗精神病药在人体获得证明具有增加BDNF的作用,主要是氯氮平和奥氮平及喹硫平^[3,5-7],利培酮并无明确结果.因此,2015年1—12月,笔者观察利培酮对精神病患者BDNF的影响,报道如下. ...

2011

Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics

2007

Investigation of serum BDNF levels in drug-naive patients with schizo-phrenia

2008

奎硫平对首发精神分裂症患者脑源性营养因子的影响

2014

Redu-ced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics

2010

Increase in brain-derived neurotrophic factor in first episode psychotic patients after treatment with atypical antipsychotics

2010

BDNF in schizophrenia depression and corresponding animal models

2005

... 在本研究中,发现精神分裂症患者血液BDNF水平明显低于正常对照群体,说明精神分裂症患者存在BDNF水平下降,与国内外大多数研究结果一致.究其原因:一方面,BDNF与海马皮质神经元、胆碱酯能神经元、黑质多巴胺能神经元及5-羟色胺能神经元的可塑性密切相关^[8],这些神经元在疾病的发生、发展中起重要作用,因此推测,随着疾病发展,BDNF功能也随之下降.另一方面,多巴胺D₁受体(DRD1)与BDNF基因间可能存在基因-基因交互作用,提示精神分裂症患者脑内DRD1结构或功能异常可能与BDNF有关^[9]. ...

精神分裂症患者脑源性神经营养因子与多巴胺D受体基因交互作用研究

2013

Cell biology of BDNF and its relevance to schizophrenia

2008

... 利培酮为临床上常用非典型抗精神病药,大量研究证明,足量治疗可改善患者精神症状.已有研究表明BDNF通过激活酪氨酸激酶受体(TrkB),促进神经元的存活,调节神经元形态、突触可塑性^[10].而有研究显示利培酮能够上调大鼠左右前额叶皮质、左右颞叶皮质及海马BDNF-TrkB信号通路^[11].既往研究对利培酮是否具有增强人体BDNF的作用并无明确结果.本研究显示治疗2周末治疗组血清BDNF水平低于治疗前.上述结果表明精神分裂症患者早期已经存在神经损伤及神经营养不足,并且随着病程的发展而持续加重.但本研究在治疗8,16周末发现治疗组血清BDNF水平高于治疗前,且16周末治疗组BDNF水平与对照组比较差异无统计学意义,提示通过利培酮治疗BDNF能够获得改善.这与其他研究有所不同^[12-13],可能与研究的样本、发病年龄、病程长短或抽样的种族等多方面因素有关. ...

利培酮对大鼠各脑区组织BDNF-TrkB信号通路的影响

2015

Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment

2004

Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol(MHPG) levels,but did not alter plasma brain-derived neurotrophic factor(BDNF) levels in schizophrenic patients

2007