將精神分裂症病人由其他抗精神病藥物轉換至Aripiprazole：以隨機分派、不加盲方式比較快速與緩慢兩種不同換藥策略

Abstract

背景：近年來，第二代抗精神分裂症藥物有顯著的發展，然而，其主要副作用包括失眠、代謝症候群、泌乳激素過高與心電圖上呈現QTc波延遲。安立復（aripiprazole）是第一個具有部份多巴胺D2受器促進功能的抗精神病藥物，被認為能夠減少上述副作用的發生，且血清素5HT1A部分促進與血清素5HT2A拮抗能力亦使得安立復能夠改善精神分裂症患者的負性症狀與認知功能障礙。當病人有意願從目前藥物轉換成其他藥物時，逐漸減少舊藥並增加新藥被認為較能夠避免症狀復發並減少副作用發生，此外，CYP2D6及CYP3A4基因表現型的差異亦影響安立復之藥物動力學，使得個體間服藥後之反應有所差異。 主旨：探討不同換藥速率間，藥物反應與安全性之差異，並決定適合運用於臨床之換藥策略。 方法：本研究為一區段隨機分派、不加盲、平行設計、為期八週之第四期臨床試驗，於2007年七月至2009年七月從三家醫院篩選出合適的精神分裂症患者，並將他們隨機分派至快速或慢速換藥組。藥物反應評估工具包含了正性與負性症狀評估量表與臨床整體評估表；安全性評估工具則包含了辛普森-安格斯評量表、靜坐困難評估表與異常不自主動作量表；此外，亦抽血測量病人之代謝功能、藥物濃度以及CYP2D6與CYP3A4基因型。 結果：進入試驗的79位病人中，52位完成本試驗，快速換藥組與慢速換藥組在基本資料與舊藥方面皆具有可比較性。兩組間在研究結束後，負性症狀皆有顯著改善，且錐體外症候群、代謝症候群、心電圖與泌乳激素濃度皆不惡化，其中，幾乎所有病人之泌乳激素皆降至正常範圍。測量研究開始第14天所抽取的血液發現，安立復之血中藥物濃度已達穩定，第56天之血中濃度並無顯著差異；所測得的CYP2D6與CYP3A4基因型中，帶有CYP2D6*10變異之患者相較於不帶有CYP2D6*10變異之患者，具有較低的血中安立復濃度。 結論：本研究提供了換藥過程中豐富的治療經驗，並監測了完整的代謝指數之變化，整體而言，經由八週的換藥治療，無論是快速或慢速換藥組，都能獲得藥效與安全性之改善，且兩組間藥物反應與安全性無顯著差異。

Background: The development of atypical antipsychotics has markedly improved the treatment of schizophrenia; however, somnolence, metabolic syndrome, hyperprolactinemia and QTc prolongation are their main adverse events. Aripiprazole, the first D2 partial agonist effect antipsychotics, is proposed to reduce such adverse events. Furthermore, the 5HT1A partial agonist and 5HT2A antagonist effect may improve negative and cognitive symptoms. When patients are willing to switch from other antipsychotics to aripiprazole, “cross-tapering” are considered during the switching period. It may reduce the worsening psychosis and unpleasant side effects. Besides, the individual phenotype of CYP2D6 and CYP3A4 may influence the pharmacokinetics of aripiprazole. Objectives: To evaluate the efficacy and safety in different switching strategies and determine which strategy is more appropriate to implement in clinical practice. Methods: This was a block randomization, open-label, parallel assignment, phase IV and 8-week study conducted at 3 hospitals in Taiwan between September 2007 to July 2009. Patients with a primary DSM-IV diagnosis of schizophrenia and schizoaffective disorder were randomly assigned to either fast-switch or slow-switch group. Efficacy measurements included Positive and Negative Symptom Scales and Clinical Global Impressions. Safety measurements included Simpson-Angus Scale, Barnes Akathisia Rating Scale and abnormal Involuntary Movement Scale. Patients were also taken blood samples for the measurement of metabolic profile, drug concentration, and cytochrome P450 CYP2D6 and CYP3A4 genotypes. Results: In a total of 79 patients, 52 (66%) completed the 8-week trial. The fast switching group (n = 29) and the slow switching group (n = 23) were comparable in the demographic features and previous medications. PANSS negative score was significantly improved in both groups over the 8 weeks of treatment (both p < .05), Meanwhile, extrapyramidal symptom, metabolic profile, electrocardiogram and the prolactin level were maintained or somewhat improved as well. The prolactin level in almost all patients returned to normal range by the endpoint. After switching to aripiprazole from other antipsychotics, the symptoms of extrapyramidal symptoms did not increase. The serum concentrations of aripiprazole reached a stable level at day14, and did not significantly change at day 56 for both groups. After grouping by different CYP2D6 and CYP3A4 genotypes for all the subjects, only the CYP2D6*10 variant was associated with a lower serum concentration of aripiprazole as compared with those without the variant. Conclusions: This study provided empirical clinical experience in the treatment of switching patients to aripiprazole from other antipsychotics. Compared with the slow switching strategy, the fast switching strategy has similar efficacy and safety in the 8-week treatment of patients with schizophrenia.