研究背景
憂鬱症(Major depressive disorder, MDD)是老年常見的精神疾病，造成失能也伴隨著相對高的死亡風險；給予抗憂鬱藥物治療後，仍有高達三分之一以上的患者，無法有效改善疾病，這群病人為罹患難治型憂鬱症(treatment-resistant depression, TRD)。根據過去的研究指出，抗精神病藥物 (antipsychotics)可作為難治型憂鬱症的加成治療且有效地改善憂鬱症狀；然而抗精神病藥物卻與老年族群死亡風險增加具有關聯性。因此，本研究旨在分析老年族群難治型憂鬱症之抗精神藥品處方型態與病人臨床特性，比較使用不同抗精神病藥物加成治療後之住院率與全因死亡風險，以建立國人老年族群藥物安全性數據。
研究方法
本研究使用2001-2013年全民健保資料庫進行觀察性回溯性世代研究 (retrospective cohort study)。研究對象為2004年至2012年間，55歲以上診斷為難治型憂鬱症，並接受口服抗精神病藥物治療之病患。難治型憂鬱症之定義為過去三年內至少接受兩種以上抗憂鬱劑治療，且新使用抗精神病藥物治療，藥品須連續使用超過14天或接受兩筆以上處方治療，並排除其他可能的適應症如失智症、雙極性情感疾病、阿茲海默症及巴金森氏症等之病患。分析研究族群抗精神病藥物處方型態與病患臨床特性，及全因死亡和精神科住院之發生率，再以比例風險模型比較不同抗精神病藥物之安全性和有效性之相對風險。

研究結果
本研究共納入47,838人，平均年齡為67.8歲 (SD=9.4)，女性佔62.9%，多數病患者使用的抗精神病藥物為quetiapine (33.1%)、其次為sulpiride(23.9%)及risperidone (8.1%)。用藥死亡風險方面，與quetiapine組相比，haloperidol [adjusted hazard ratio (aHR) 1.34; 95%CI 1.14-1.58]及risperidone (aHR 1.51; 95%CI 1.31-1.75)有較高的死亡風險，反之sulpiride (aHR 0.77; 95%CI 0.62-0.94)及trifluoperazine (aHR 0.48; 95%CI 0.34-0.68)有較低的死亡風險，而aripiprazole (aHR 0.64; 95%CI 0.40-1.01)則有較低死亡風險傾向；在有效性評估中，與quetiapine組相比，病患使用risperidone (aHR 1.65, 95%CI 1.38-1.97)有較高精神科住院風險，較低風險則有sulpiride (aHR 0.57; 95%CI 0.47-0.69)、haloperidol (aHR 0.64; 95%CI 0.47-0.87)、trifluoperazine (aHR 0.15; 95%CI 0.07-0.32)及chlorpromazine (aHR 0.55; 95%CI 0.39-0.77)。
研究結論
根據研究結果發現，老年難治型憂鬱症病患應避免使用risperidone，因其安全性疑慮且效果不佳之情況；而使用haloperidol時則應謹慎評估，因死亡風險高但對於控制精神相關症狀療效顯著。在臨床實務中，醫師根據實證研究結果，可能會考慮使用aripiprazole，本研究中也顯示與quetiapine相比，有相對較好的安全性。此外，本研究也發現第一代抗精神病藥物中sulpiride與trifluoperazine似乎具有較好的療效及安全；未來可進一步評估是否使用sulpiride和trifluoperazine可作為TRD患者的抗精神病藥物替代選擇。

Antipsychotic augmentation has been proven to pose favorable effects in patients with treatment-resistant depression (TRD). However, it raised a great concern of increased mortality risk in elderly patients receiving antipsychotics. The study aimed to compare the safety and effectiveness between antipsychotics. We analyzed the Taiwan National Health Insurance Research Database from 2001-2013 and identified patients with major depressive disorder aged 55 years and older, newly added on oral antipsychotics. We performed intention-to-treat analysis and followed patients from antipsychotic initiations to one year or until the occurrence of events, including all-cause mortality and psychiatric hospitalization. We performed multivariate Cox proportional hazard model to compare the risks of events between antipsychotics. We identified a cohort of 45,231 patients with mean age of 67.8 (±9.4) years and 63% were female. Most patients receiving quetiapine (33.1%), sulpiride (23.9%) and risperidone (8.1%). Compared with the quetiapine users, we found that risperidone [Adjusted hazard ratio (aHR) 1.51; 95%CI 1.31-1.75)] and haloperidol (aHR 1.34; 95% CI 1.14-1.58) users had a higher risk of mortality, sulpiride (aHR 0.77; 95% CI 0.62-0.94), trifluoperazine (aHR 0.48; 95%CI 0.34-0.68) and aripiprazole (aHR 0.64; 95% CI 0.40-1.01) had a lower risk of mortality. The risk of psychiatric hospitalization were high in risperidone (aHR 1.65, 95% CI 1.38-1.97) and lower in sulpiride (aHR 0.57; 95% CI 0.47-0.69) and trifluoperazine (aHR 0.15; 95% CI 0.07-0.32), comparing with quetiapine users. We suggest to avoid using risperidone in elderly patients with TRD to prevent unintended outcome. The findings indicated clinicians may consider to use aripiprazole because it posed comparable effectiveness but with better safety profile comparing with to quetiapine. The study provides strong grounds for future investigations to evaluate using sulpiride and trifluoperazine as good alternative antipsychotics in patients with TRD.

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