水飛薊對?硫平造成之代謝變異之影響
Metabolic Effects of Quetiapine and the Modulation Role of Silymarin in Schizophrenia Patients
中文摘要
長期使用某些非典型抗精神病藥，譬如：?硫平（quetiapine；QTP）有可能造成體重增加、血 糖調控、肝功能異常等代謝性症候情形。而水飛薊（silymarin；SB）為一般市面上藥局即可購 得之商品，可作為日常肝保健之用，雖有研究顯示，水飛薊可降低胰島素阻抗性（insulin resistance；IR）及肝功能指數，並有改善血糖調控的趨勢，另一臨床研究也顯示 SB 能協同 胰島素控制糖尿病合併有肝硬化病患之血糖；然而，SB 的臨床療效仍受到質疑，且精神分裂症 患者原本的血糖相關數值是否會影響其服用QTP 後生化指數之變化仍待釐清。故本研究欲探討 QTP 對不同血糖原始特性之精神分裂症患者代謝生化指數之影響，以及 SB 對其之調控作用。
接受試驗病患之血樣採檢分為三階段進行，第一階段為服用實驗藥物前（baseline），第二階段 為服用實驗藥物QTP 300 mg/day 達穩定血中濃度時（Qss），以及第三階段為併用 QTP 及 SB 70 mg/day 達穩定血中濃度（QL），或未併用 SB 而持續使用 QTP 之控制組（QC）。研 究對象為臺北縣市兩家私立精神病患康復之家經由精神專科醫師依第四版精神疾患診斷與統計 手冊診斷為精神分裂患者，並尚未使用過QTP 之病患。有效收錄人數有 9 人，其中男性有 5 人，
女性有4 人，男女平均年齡各為 45.6 ± 12.6 及 54.5 ± 5.0 歲，一位為受試前之 fasting plasma glucose（FPG）正常，但在 Qss 時發生高血糖現象（HbA1c = 6.4%；FPG = 126 mg/dL），且 QTP 停藥 2 個半月後亦持續有高血糖現象（三次測量之 FPG > 126 mg/dL），
其餘8 位病患受試前有 4 位（50%）有空腹血糖異常 [impaired fasting plasma glucose
（IFG）； FPG 100～125 mg/dL；n=3]或是 FPG ? 126 mg/dL（n=1）之問題，經病患 特性加以分群分析後顯示，無論血糖相關數值正常與否之精神分裂症病患，服用QTP 2 週後，
體重及身體質量指數方面數值均有增加的趨勢，即使是FPG 正常之組別；無論是何分群方法皆 顯示，血糖相關數值正常之精神分裂症病患服用QTP 2 週後，FPG 數值明顯下降（p = 0.032），
且空腹胰島素值上升，併用SB 可使空腹胰島素下降；血脂方面，QTP 及 SB 對三酸甘油脂並無 顯著影響，然而，血糖相關數值正常之精神分裂症病患服用QTP 2 週，膽固醇、低密度脂肪酸 及高密度脂肪酸皆上升至明顯高於血糖相關數值異常之病患（p < 0.050），且與血糖相關數值 異常之病患相比，併用SB 可使數值明顯降低（p < 0.050），但血糖相關數值原已異常之精神 分裂症病患，在服用QTP 2 週後其三者數值皆有輕微下降的趨勢。由以上結果得知，短期服用 QTP 即需注意病患的體重控制，即使是 FPG 正常之精神分裂症病患，或考慮併服 SB 以降低 IR 的產生，並可考慮常態監測長期（>4 週）服用 QTP 者精神分裂症病患之 FPG 情形；此外，需 監測病患其膽固醇及低密度脂肪酸，即使是短期服用QTP 且 FPG 及 HbA1c 皆正常之精神分裂 症，或考慮併服SB 以改善血脂數值；而若屬 FPG 或 HbA1c 異常之精神分裂症病患，則建議 需監測高密度脂肪酸是否下降至異常範圍值；本研究仍需後續增加受試者人數、試驗時間及藥物 動力學等更進一步的研究，以釐清長期服用QTP 或併用 SB 之結果與作用機制。
英文摘要
Long-term use atypical antipsychotics, such as quetiapine (QTP), may cause weight gain, glucose dysregulation, and hepatic dysfunction. Silymarin (SB) is a
commercially available product in drug stores and may be used as a dietary supplement. Even though silymarin was reported to act coordinately with insulin to control glucose in certain patients and may reduce insulin resistance (IR), its clinical effect on glucose regulation is unclear. And maybe the effects of QTP on patients with different basal fasting plasma glucose (FPG) levels would be different. In order to understand the effects of QTP on serum metabolic parameters in schizophrenia patients with or without glycemic abnormality, patients diagnosed with
schizophrenia were recruited from two long-term care facilities, and their blood samples were taken at baseline and at the end of the titration plus 7-day QTP treatment period (Qss; 300mg once daily). After another 7-day QTP treatments, SB (Legalon?; 70 mg once daily) was then added to drug regimen of patients (n=7) and blood samples were then collected at 7th day (QL) to determine the modulation effects of SB. Patients without taking SB were used as controls (QC; n=2). Among 9 recruited patients, there were 5 men and 4 women (mean age were 45.6 ± 12.6 and 54.5 ± 5.0 years respectively). There was one patient developed diabetes (HbA1c = 6.4%; FPG = 126 mg/dL) at Qss, and his FPG did not return to normal range even QTP was discontinued from his prescription for two and a half months.
Among the other 8 treated patients, four patients (50%) were pre-existing impaired fasting plasma glucose (IFG；FPG 100～125 mg/dL；n=3) or even FPG ? 126 mg/dL (n=1). Patients were grouping with their clinical characteristics to understand the effects of QTP and SB on different groups. Body weight and body mass index increased in both groups at Qss, even for patients with normal basal FPG level.
Moreover, FPG decreased (p = 0.032) and fasting insulin increased in patients with normal basal FPG or HbA1c at Qss, and fasting insulin decreased at QL. There were no differences on triglyceride between groups after using QTP or SB. However, total cholesterol, LDL and HDL of patients with normal basal FPG or HbA1c increased to significantly higher at Qss (p < 0.050), and significantly decreased at QL (p < 0.050) than patients with abnormal basal FPG or HbA1c. While patients with abnormal basal FPG or HbA1c decreased at Qss. In conclusion, body weight assessment is recommended, even for patients with normal basal FPG level. SB may be useful in improving IR. Routine FPG assessment may be necessary for QTP long-term（>4 weeks） users. In addition, total cholesterol and LDL assessment is recommended even for patients with normal basal FPG and HbA1c level after short term uses. SB may be useful in improving lipid controls. While in patients with abnormal basal FPG or HbA1c level, we recommend to monitor HDL in case of its abnormal decreases.
Further studies on large-population and clinical pharmacokinetic analysis are required to clarify long-term effects of QTP and the mechanism of drug interactions.
