藥物引發急性肌張力異常或巴金森氏症之精神分裂症病患對Risperidone及Olanzapine的隨機分配對照研究

背景:第一代抗精神病藥物常會產生錐體外路徑副作用（EPS），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，而且也沒有華人的轉換研究。本研究以隨機分配有對照組的研究，來比較risperidone以及olanzapine這兩種第二代抗精神病藥物，對於無法耐受第一代抗精神病藥物所產生錐體外路徑副作用中的急性肌張力異常或巴金森氏症，轉換後其發生急性肌張力異常或巴金森氏症且需使用抗膽鹼藥物來加以治療的比例是否有所差別。另外收集risperidone及 olanzapine在不同時間點的平均劑量變化，來作為擬定此類病患的起始劑量、加藥速度及維持劑量的參考。方法: 本研究是由行政院衛生署桃園療養院在民國八十九年七月至九十二年五月期間收案。對象是符合DSM-IV schizophrenia的精神分裂症診斷標準，並且發生符合DSM-IV neuroleptic-induced acute dystonia or parkinsonism診斷標準的副作用，且其嚴重度達到global impression of dystonia or parkinsonism of ESRS (extrapyramidal syndrome rating scale)的中度以上所有個案。並符合以下條件：女性必須同意試驗期間避孕；年齡18-65歲；個案或法定代理人同意參加研究且簽署同意書。排除條件為個案目前有DSM-IV其他第一軸的診斷；個案目前有主要系統性身體疾病，或需併用相關治療藥物，而無法配合研究藥物之治療及評估；個案目前有相關神經學疾病而影響錐體外路徑副作用評估；個案一年內除香煙及咖啡外，有其它物質濫用或依賴的診斷。共收案70人，以隨機分配的方式分派到risperidone或olanzapine，兩組各35人。個案研究期間最長為八週，因此研究結束時間為九十二年七月。本研究為任意劑量評分者單盲的研究，risperidone的平均起始劑量為1.8 mg/d，之後逐漸增加到研究結束的平均劑量為3.5 mg/d，olanzapine的平均起始劑量為7.7 mg/d，之後逐漸增加到研究結束的平均劑量為11.7 mg/d。主要的研究變項包括發生顯著acute dystonia或parkinsonism副作用而需使用抗膽鹼藥物的比例，ESRS評量表以測量錐體外路徑副作用的嚴重度，BPRS(brief psychiatric rating scale)以及CGI-S(clinical global impression-severity)評量表以評估精神症狀的嚴重度。以Chi-square 或Fisher’s exact test來比較兩組使用抗膽鹼藥物的比例及其他binominal data是否有統計上的差異；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 method以及Cox regression來加以分析；以independent t-test來比較兩組間之研究起始與研究結束連續性變項的改變程度是否有統計上的差異；精神症狀評量表重複測量的資料將以mixed model for repeated measurement處理。結果:使用研究藥物後發生顯著acute dystonia或parkinsonism副作用而需使用抗膽鹼藥物，risperidone組顯著高於olanzapine組（OR=5.17, 95%CI=1.49-17.88, p=0.013）；以存活資料來分析，發生事件的機率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）。分析精神症狀的改善幅度，兩組並無統計顯著差異。結論:本研究結果支持以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科學證據做為優先選擇之參考的論點一致。

關鍵字

抗精神病藥物；精神分裂症；錐體外路徑副作用

並列摘要

Background: First genergation antipsychotics frequently induced extrapyramidal side effects（EPS）. Second generation antipsychotics were the choices for EPS intolerant schizophrenic patients. But which one of second generation antipsychotic was the better choice did not have definitive results. There was no such shifting study in Chinese populations. We wish to establish local data to help clinical decision in such patients by a well designed randomized controlled trial. We used risperidone and olanzapine in schizophrenic patients with acute dystonia or parkinsonism side effects and copmared the incidence of needing concomitat anticholinergic drugs. We also collected the average dose in different assessment periods of risperidone and olanzapine to establish the dosing strategy guidelines for EPS intolerant schizophrenic patients. Materials and Methods: We collected patients at Taoyuan Mental Hospital since July 2000 to May 2003. The target populations of this study were patients met the schizophrenia criteria of DSM-IV. Patients also needed to meet the research criteria of neuroleptic-induced acute dystonia or parkinsonism research criteria of DSM-IV and greater than moderate severity of global impression of dystonia or parkinsonism of extrapyramidal syndrome rating scale（ESRS）. The inclusion criteria were（1）Female patients need to use reliable methods to prevent preganacy（2）Age between 18-65 y/o（3）Patients or legal responsible person agree to attend study and sign inform consent. The exclusion criteria were（1）Have other axis I diagnosis of DSM-IV（2）Have major systemic disease and influence to assessment or the use of study medications（3）Have neurological disease and influence to assessment of EPS（4）Have substance abuse or dependence in recent 1 year except tobacco or coffee. The total numbers of pateints were 70 and random assignment to risperidone or olanzapine. This study ended at July 2003 due to the study period was 8 weeks. This is a flexible dose, rater-blinded, randomized, controlled trial. The average dose of risperidone and olanzapine from baseline to study end point were 1.8 to 3.5 mg/d and 7.7 to 11.7 mg/d respectively. The primary outcome was to compare the incidence of concomitant anticholinergics to manage acute dystonia or parkinsonism in these 2 groups. The secondary outcomes were to comapre the results of rating scales in these 2 groups. The severity of EPS was assessed by ESRS. The severity of psychotic symptoms was assessed by BPRS (brief psychiatric rating scale) and CGI-S (clinical global impression-severity). The statistical methods included Chi-square or Fisher’s exact test for binominal data, Kaplan-Meier method or Cox regression for survival data, independent or paired t-test for continous variables, mixed model for repeated measures. Results: Risperidone had significant higher incidence to use anticholinergics to manage acute dystonia or parkinsonism（OR=5.17, 95%CI=1.49-17.88, p=0.013）. Risperidone also had significant higher incidence to use anticholinergics to manage acute dystonia or parkinsonism if consider time and censor cases（log-rank test: p=0.0023; hazard ratio: 4.60, 95% CI: 1.70-11.52）. There was no significant difference in change of psychotic symptoms. Conclusion: The results of our study favor olanzapine as better choice for schizophrenic patients with acute dystonia or parkinsonism side effects. This result was compatible with the suggestion of Maudsley prescription guideline of United Kingdom as some second generation antipsychotics as priority choice for EPS sensitive populations.

並列關鍵字

antipsychotic ； schizophrenia ； extrapyramidal side effects

參考文獻

1. Chouinard G, Johns B, Remington G, et al.: A Canadian multi-center placebo-controlled study of fixed dose of risperidone and haloperidol in the treatment of chronic schizophrenia. J Clin Psychopharmacol 1993; 13:25-40

3. Peuskens P: Risperidone in the treatment of patients with chronic schizophrenia. Br J Psychiatry 1995; 166: 712-26

4. Beasley CM, Tollefson GD, Tran PV, et al.: Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14: 111-23

5. Beasley CM, Hamilton SH, Crawford AM, et al.: Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997; 7: 125-37

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藥物引發急性肌張力異常或巴金森氏症之精神分裂症病患對Risperidone及Olanzapine的隨機分配對照研究

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