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  • 學位論文

精神分裂症患者由第一代轉換為第二代抗精神病藥物隨機分配有對照組之研究:針對療效、短期錐體外路徑副作用以及長期錐體外路徑副作用之系列研究

Randomized Controlled Series Studies of Shifting First Generation Antipsychotics to Second Generation Antipsychotics for the Schizophrenic Patients: Focus on Efficacy, Short-Term Extrapyramidal Side Effects and Long-Term Extrapyramidal Side Effects

指導教授 : 賴美淑
共同指導教授 : 胡海國(Hai-Gwo Hwu)

摘要


背景:第一代抗精神病藥物對於精神分裂症的治療常會產生療效不佳、短期錐體外路徑副作用,如急性肌張力異常和巴金森氏症,以及長期錐體外路徑副作用,如遲發性運動障礙,臨床上常會使用第二代抗精神病藥物來加以取代,但是要轉換為何種第二代抗精神病藥物,過去的研究或是各國的治療指引結論不一。本系列研究比較risperidone以及olanzapine這兩種第二代抗精神病藥物,對於使用第一代抗精神病藥物後所產生的三種問題,轉換為不同第二代藥物後這三種問題的改善程度是否有所差別。 方法: 這三個研究分別依照各自的納入以及排除條件收案。三個研究都是評分者單盲、彈性劑量、隨機分配的研究。在第一線第一代抗精神病藥物療效不佳方面,個案隨機分派到第一代抗精神病藥物組、risperidone組或olanzapine組,研究期間最長為8週,主要的研究變項為PANSS總分的變化。在肌張力異常和巴金森氏症副作用研究方面,個案隨機分派到risperidone組或olanzapine組,研究期間最長為8週,主要的研究變項為研究期間發生顯著肌張力異常或巴金森氏症副作用而需使用抗膽鹼藥物的比例。在遲發性運動障礙研究方面,個案隨機分派到risperidone組或olanzapine組,研究期間最長為24週,主要的研究變項為AIMS總分的變化。 以chi-square 或Fisher’s exact test來比較組間類別變項是否有統計上的差異;在肌張力異常和巴金森氏症副作用的研究中,若考慮使用抗膽鹼藥物發生的時間以及存活的狀態,則以Kaplan-Meier 方法以及Cox回歸模型來加以分析;以獨立t檢定或變異數分析來比較組間之研究起始點與研究結束點連續變項的改變程度是否有統計上的差異,以配對t檢定來比較組內之研究起始點與研究結束連續性變項的改變程度是否有統計上的差異,但若連續性變項的資料並不符合常態分佈或相同變異數的假設,將以Wilcoxon signed ranks test做組內的比較,以Mann-Whitney U test 或 Kruskal-Wallis test做組間的比較;重複測量的資料將以混合模型做重複測量的處理。 結果: 在第一線第一代抗精神病藥物療效不佳方面,第一代藥物組、risperidone組以及olanzapine組在PANSS總分的減少程度並未達統計上的顯著意義(-14.9±16.6, -12.7±14.3, -14.8±13.7; p=0.890);第一代藥物組有較高的錐體外路徑副作用,而第二代藥物有較高體重增加的情形。在肌張力異常和巴金森氏症副作用研究方面,使用研究藥物後發生顯著肌張力異常或巴金森氏症副作用而需使用抗膽鹼藥物的比例,risperidone組顯著高於olanzapine組(14/35 vs. 4/35, OR=5.17, 95% CI=1.49-17.88, p=0.013);以存活資料來分析,發生事件的危險率risperidone組仍顯著高於olanzapine組(Log-rank test: p=0.0023; hazard ratio: 4.60, 95% CI: 1.70-11.52)。在遲發性運動障礙研究方面,risperidone組以及olanzapine組在AIMS總分的減少程度並未達統計上的顯著意義(-7.4 ± 6.9, -6.2 ± 8.0; p=0.548)。 討論: 在第一線第一代抗精神病藥物療效不佳方面,第二代抗精神病藥物的療效並未優於第一代抗精神病藥物,只在副作用的種類上有所差別。在肌張力異常和巴金森氏症副作用研究方面,結果支持以olanzapine來作為此類病患的優先選擇,與英國的Maudsley prescription guideline建議使用第二代抗精神病藥物於此類病患仍應有先後選擇的論點一致。在遲發性運動障礙研究方面,結果不支持以olanzapine來作為此類病患的優先選擇,與英國Maudsley prescription guideline建議不把risperidone列入遲發性運動障礙治療的選擇不同。

並列摘要


Background: FGAs had treatment-resistant, short-term EPS and long-term TD problems in schizophrenia treatment. SGAs were the choices for these problems. But which one of the SGA is the better choice does not have definitive conclusions. There were no related randomized controlled shifting studies. We compare the efficacy of two SGAs, risperidone and olanzapine, in schizophrenic patients with above three clinical problems. Materials and Methods: Patients were recruited as the inclusion and exclusion criteria of these three studies. These three studies are all flexible-dose, rater-blind, randomized controlled trial. In treatment-resistant to only one line of FGA study, subjects were randomly assigned to another FGA, risperidone or olanzapine group and study duration was 8 weeks. The primary endpoint of this study is the change of PANSS total score. In dystonia and parkinsonism study, subjects were randomly assigned to risperidone or olanzapine group and study duration was 8 weeks. The primary endpoint of this study is the proportion of subjects that need anticholinergic medications to treat clinical significant dystonia or parkinsonism. In TD study, subjects were randomly assigned to risperidone or olanzapine group and study duration was 24 weeks. The primary endpoint of this study is the change of AIMS total score. The statistical methods included chi-square or Fisher’s exact test for binominal data, Kaplan-Meier method or Cox regression model for survival analysis, independent, paired t-test and ANOVA for continuous variables, linear mixed model for repeated measurements. If continuous variables did not fit normal distribution and equal variance assumption, Mann-Whitney U test, Wilcoxon signed ranks test or Kruskal-Wallis test would be used. Results: In treatment-resistant to only one line of FGA study, there were no significant differences among the three groups in PANSS total score changes (FGA: -14.9±16.6, risperidone: -12.7±14.3, olanzapine: -14.8±13.7; p=0.890). Worsened EPS and higher proportion of subjects needed to use anti-EPS drugs in the FGA group. SGA group was associated with significant body weight gain. In dystonia and parkinsonism study, patients taking risperidone had significantly higher incidence of using anticholinergic drugs to manage dystonia or parkinsonism during the study (14/35 vs. 4/35, OR=5.17, 95% CI=1.49-17.88, p=0.013). If we used survival analysis to deal with the event time of anticholinergic drug use and censored cases, risperidone still had a higher hazard ratio (Log-rank test: p=0.0023; hazard ratio: 4.60, 95% CI: 1.70-11.52). In TD study, there were no significant differences among risperidone and olanzapine groups in AIMS total score changes (-7.4 ± 6.9, -6.2 ± 8.0; p=0.548). Discussion: In treatment-resistant to only one line of FGA study, FGA demonstrated similar efficacy of psychotic symptom reductions as risperidone or olanzapine. The findings suggest that side effect profiles might be taken into considerations for choosing the next antipsychotic drug. In dystonia and parkinsonism study, the results of this study favor olanzapine as a better choice in schizophrenic patients with intolerant EPS. This result is compatible with Maudsley prescription guideline suggests olanzapine as the first line medication and risperidone as second line medication. In TD study, the results of this study do not favor olanzapine as a better choice in schizophrenic patients with TD. This result is not compatible with Maudsley prescription guideline which suggests olanzapine as the first line medication and risperidone does not take into consideration in schizophrenic patients with TD.

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