A prospective,multicentre, open-label study of aripiprazole in the management of patients with schizophrenia in psychiatric practice in Europe: Broad Effectiveness Trial with Aripiprazole in Europe (EU-BETA)

ABSTRACT

Objective: To examine the effectiveness of aripiprazole in schizophrenia in a naturalistic setting in 14 European countries.

Methods: This multicentre, open-label study of aripiprazole evaluated outpatients with schizophrenia for whom a medication switch was clinically reasonable or antipsychotic initiation was required. Patients (n = 833) were randomized in a 4:1 ratio to aripiprazole (recommended starting dose 15?mg/day, permitted adjustment 10–30?mg/day) (n = 680) or another antipsychotic (safety control [SC] group) (n = 153) for 8 weeks. The control group received an antipsychotic different to their recent pre-study medication. The primary effectiveness measure was the Clinical Global Impression – Improvement (CGI – I) score of aripiprazole-treated patients at Week 8 (last observation carried forward [LOCF]). Patients’ and caregivers’ medication preference was assessed using the Preference of Medication (POM) questionnaire. The Investigator Assessment Questionnaire (IAQ) was used to record investigators’ assessments of their patients’ responses to the study antipsychotic. Adverse events (AEs) were recorded.

Results: At endpoint (Week 8, LOCF), the mean CGI – I score of 3.16 (95% confidence interval, [CI]: 3.04, 3.28) demonstrated the effectiveness of aripiprazole. At endpoint, 43% of aripiprazole-treated patients showed a response (CGI – I score = 1/2). Aripiprazole was rated as slightly or much better than previous antipsychotic at endpoint by 68% of patients and 65% of caregivers. The mean CGI – I score (Week 8, LOCF) for the SC group was 3.37 (95% CI: 3.14, 3.60). No major differences in the occurrence of AEs were noted between aripiprazole- and SC-treated patients.

Limitations: As this is an open-label design, there may have been a bias. Secondly, the study was not powered to show differences between treatment groups and no statistical comparisons were planned. Thirdly, 8 weeks is too short to evaluate long-term effectiveness.

Conclusions: Aripiprazole was effective, well tolerated and well accepted by patients and caregivers in this naturalistic study.     

抗精神病药物对女性精神病患者血清催乳素的影响研究

目的分析几种抗精神病药物对女性精神病患者血清催乳素的影响。方法将164例女性精神分裂症患者随机分成4组,每组各41例。分别进行阿立哌唑、利培酮、奥氮平以及舒必利治疗,均治疗9周,并将所有患者治疗后的血清催乳素水平与治疗前相比较。结果患者经过四种药物治疗后精神状况均明显好转,但作为女性患者来讲,有些药物对于患者的催乳素水平有一定的影响。相比之下,用阿立哌唑治疗的患者不良反应较轻,催乳素前后变化最小。结论利培酮、阿立哌唑、奥氮平、舒必利对女性精神病的治疗,均有很好的效果。但相比之下,用阿立哌唑治疗的患者的催乳素水平变化不明显。阿立哌唑对于女性精神病患者的催乳素影响较轻,建议将其广泛应用于医学领域。     

Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole

Abstract

1.?We investigated how deficiencies in P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) affect the pharmacokinetics of atypical antipsychotics aripiprazole and its active metabolite (dehydroaripiprazole) using normal Friend leukemia virus strain B (FVB) mice, BCRP knockout (Bcrp[?/?]) mice, and P-gp and BCRP triple knockout (Mdr1a/1b[?/?]Bcrp[?/?]) mice.

2.?While plasma concentrations of aripiprazole and dehydroaripiprazole after oral administration were slightly higher in both Bcrp(?/?) and Mdr1a/1b(?/?)/Bcrp(?/?) mice than in normal FVB mice, the difference was not marked. The increase in absolute bioavailability (F) compared with normal mice (approximately 1.3-fold increase) was comparable between Bcrp(?/?) and Mdr1a/1b(?/?)/Bcrp(?/?) mice. This finding suggests that BCRP may be involved in the intestinal absorption of aripiprazole in mice, albeit with minimal contribution to absorption at best.

3.?In contrast, the brain-to-plasma concentration ratio (K_p,brain) for aripiprazole and dehydroaripiprazole after oral administration was significantly higher in Mdr1a/1b(?/?)/Bcrp(?/?) mice than in normal mice, whereas Bcrp(?/?) mice exhibited K_p,brain values similar to those in normal mice. In addition, the K_p,brain values in Mdr1a/1b(?/?)/Bcrp(?/?) mice were not drastically different from those previously reported in Mdr1a/1b(?/?) mice, suggesting that brain penetration of aripiprazole and dehydroaripiprazole can be affected by P-gp, but with little synergistic effect of BCRP.     

阿立哌唑联合米氮平治疗精神分裂症阴性症状的疗效观察

目的观察阿立哌唑联合米氮平治疗精神分裂症阴性症状的疗效。方法选取2011年9月—2012年12月我院收治的66例精神分裂症阴性症状患者。按照治疗方式的不同,将66例患者随机分为两组,每组各33例。对照组采用阿立哌唑联合舍曲林治疗;观察组采用阿立哌唑联合米氮平治疗。比较两组治疗前后临床指标变化情况以及疗效。结果两组疗效比较差异有统计学意义（P〈0.05）;观察组患者治疗后的指标变化情况优于对照组,差异有统计学意义（P〈0.05）。结论阿立哌唑联合米氮平治疗精神分裂症阴性症状疗效显著,安全性高,值得临床推广。     

阿立哌唑联合氯氮平治疗难治性精神分裂症的疗效观察

目的探讨阿立哌唑联合氯氮平治疗难治性精神分裂症的疗效及安全性。方法对40例单用氯氮平治疗效果差的难治性精神分裂症患者给予阿立哌唑联合氯氮平治疗8周,运用日常生活能力量表（ADL）、社会功能缺陷筛选量表（SDSS）、阳性与阴性症状量表（PANSS）及副反应量表（TESS）在治疗前和治疗后2、4、8周进行评估。结果治疗后2周末起,PANSS各项评分与治疗前比较有明显降低,差异有统计学意义（P〈0.05）;治疗后4周末起,日常生活能力有明显提高,不良反应明显减少,差异有统计学意义（P〈0.01）;治疗后8周末,社会功能缺陷有明显改善,差异有统计学意义（P〈0.01）。结论阿立哌唑联合氯氮平治疗难治性精神分裂症能有效改善阳性症状和阴性症状,有利于社会功能的恢复,安全性较好。     

首发精神分裂症患者阿立哌唑血药浓度与临床应用的关系

目的探讨首发精神分裂症患者体内阿立哌唑血药浓度与临床应用的关系。方法采用高效液相色谱（HPLC）的方法测定60例首发精神分裂症患者体内阿立哌唑的血浆药物浓度,并用阳性与阴性症状量表（PANSS）评定疗效,治疗副反应量表（TESS）评定不良反应．并对血药浓度与疗效评分进行相关性分析。结合受试者特征曲线（ROC曲线）推测阿立哌唑最佳血药浓度。结果阿立哌唑血药浓度与药物剂量、PANSS减分率及TESS分值呈正相关。最低有效血药浓度为364μg／L,发生不良反应的血药浓度阈值为550μg/L。血药浓度在364—550μg／L的范围内疗效较好,副反应较轻。结论阿立哌唑治疗精神分裂症的最佳血药浓度为364—550μg／L．血药浓度和临床疗效存在一定的相关性。     

阿立哌唑与利培酮治疗精神分裂症对照研究的Meta分析

目的:探讨阿立哌唑与利培酮治疗精神分裂症的疗效。方法:用Meta分析对6项阿立哌唑与利培酮治疗精神分裂症对照研究的文章进行再分析,评价其合并效应量大小和综合显著性检验。结果:阿立哌唑治疗前后的自身对照,合并效应量d=-3.12,95%CI为(-4.17,-2.07),综合显著性检验x2=5.83,P<0.01,提示阿立哌唑治疗精神分裂症前后症状学变化有非常显著性差异,效应极强。阿立哌唑与利培酮第2周末和治疗结束后的组间比较,分别为y合并=-1.06,95%CI为(-2.28,0.16)x,2=1.70,P>0.05;d=0.04,95%CI为(-0.11,0.19)x,2=0.52,P>0.05,提示两组疗效相仿,差异无统计学意义。结论:阿立哌唑与利培酮的疗效相仿。     

多巴胺D3受体基因Ser9Gly多态性与阿立哌唑及利培酮治疗效应的关联研究

目的比较阿立哌唑与利培酮治疗女性首发精神分裂症患者的疗效和血浆催乳素水平变化及其与多巴胺D3受体(DRD3)基因Ser9Gly(rs6280)多态性的关联。方法选择完成8周阿立哌唑或利培酮治疗的女性首发精神分裂症患者各60例,于治疗前和治疗8周后分别评测阳性与阴性症状量表(positive and negativesymptom scale,PANSS)。采用放射免疫法检测血浆催乳素水平,DNA测序技术检测DRD3基因Ser9Gly多态性,分析DRD3基因Ser9Gly多态性与两药疗效及血浆催乳素变化的关联。结果治疗8周后,两组PANSS减分率的差异无统计学意义[(59.79±23.48)vs.(63.30±22.66),P>0.05],但利培酮组血浆催乳素的变化值高于阿立哌唑组[(26.92±9.48)vs.(-25.25±8.07),P<0.05]。利培酮组中C等位基因携带者的血浆催乳素的增加明显高于未携带者[(52.48±27.01)ng/mL vs(36.07±17.46),P<0.05];而阿立哌唑组中未见此差异[(-23.27±8.36)vs.TT(-26.05±8.11),P>0.05]。两组8周后PANSS减分率(%)与DRD3基因Ser9Gly的差异均无统计学意义:阿立哌唑组[CC+CT(57.83±19.94)vs.TT(56.84±18.46),P>0.05];利培酮组[CC+CT(53.94±21.08)vs.TT(60.38±19.37),P>0.05]。结论阿立哌唑治疗女性首发精神分裂症疗效与利培酮相当,但引起血浆催乳素水平变化的幅度较小;利培酮引起血浆催乳素水平增加可能与DRD3基因Ser9Gly多态性有关联。     

换用阿立哌唑对慢性精神分裂症患者阴性症状的影响

目的 探讨换用阿立哌唑治疗慢性精神分裂症患者阴性症状的临床疗效和不良反应.方法 对40例服用奋乃静的慢性精神分裂症患者换用阿立哌唑治疗,治疗前与治疗12周时应用阴性症状量表(SANS)和临床疗效总评量表(CGI)评定患者的治疗效果,同时应用不良反应量表(TESS)评定分析不良反应.结果 患者更换阿立哌唑前后SANS总分及各分量表评分的差异有统计学意义(P＜0.01);患者更换阿立哌唑前后CGI病情严重程度总分的差异有统计学意义(P＜0.01);不良反应出现频率降低.结论 阿立哌唑对慢性精神分裂症患者阴性症状治疗效果肯定,可减少部分不良反应.     

阿立哌唑与利培酮治疗精神分裂症患者的疗效及不良反应

目的:观察阿立哌唑、利培酮治疗精神分裂症患者的疗效、不良反应及安全性。方法:将60例符合CCMD-3诊断标准的精神分裂症患者随机分为两组,分别给予患者阿立哌唑、利培酮治疗8周,于治疗前以及治疗2、4和8周采用阳性与阴性症状量表(PANSS)评定患者的疗效,不良反应量表(TESS)评定患者的不良反应。结果:两组患者治疗的疗效相当。利培酮组患者的锥体外系反应、内分泌以及体重增加多于阿立哌唑组。结论:阿立哌唑治疗精神分裂症患者的疗效与利培酮相似,但不良反应更少。