研究背景：
1.抗憂鬱藥的不良反應：
抗憂鬱藥被廣泛用於治療重度憂鬱症（major depressive disorder），雙極性疾病（bipolar disorder），焦慮症，情感障礙（affective disorder），或減輕神經性疼痛。但在抗憂鬱藥產生良好的療效的同時也會帶來許多副作用，最常見包括嗜睡、噁心、口乾、便秘、體重增加，和性功能障礙。近年來，一些發生率低但嚴重的藥物不良反應，如中風與腸胃道出血，也被提出討論。
2.中風與抗憂鬱藥的研究：
2014年一項meta-analysis研究報告顯示，使用SSRI的病人，其缺血性中風（OR, 1.48; 95％CI, 1.08-2.02; I2 = 83.9％）和出血性中風（OR, 1.32; 95％CI, 1.02-1.71; I2 = 74.9％）的風險都會增加。但此項meta-analysis所納入的文章都非隨機對照研究，且文章之間的異質性（heterogeneity）很高。而自2014年後除了一項世代研究發現使用SSRI的病人其中風的比例較高（p <0.01）之外；其他研究則顯示使用抗憂鬱藥並不會顯著增加中風風險。因此，究竟使用抗憂鬱藥是否與中風風險相關，至今仍存在著爭議。
3.先前研究的干擾因子與限制：
過去的研究皆為世代研究或病例對照研究等非隨機觀察性研究中，如何處理干擾因子（confounding factors）一直是重要的議題。由於過去大多數研究是比較暴露組與非暴露組的風險，使得兩組之間年齡、心血管疾病、糖尿病、中風病史、使用抗凝血劑，與吸煙和飲酒等的分佈也可能不同。這些問題都會造成研究結果的偏差。另外，超過半數的研究納入的是抗憂鬱藥的現行使用者（prevalent users），如果風險隨時間變化，可能會引起嚴重的偏差。另外也有超過三分之一的研究並未將曾經發生過中風的病人排除，也會導致這些研究所感興趣的結果「中風」的發生可能會受先前中風的影響。
4.年齡重要嗎？
大多數病人初次使用抗憂鬱藥都是在輕年或中年時期，但過去只有少數研究曾討論不同年齡的抗憂鬱藥使用者的中風風險，而在這之中，多數研究都將受試者限制在患有重度憂鬱症的病人，或者僅針對使用SSRI的病人進行分析。在研究設計中限制了病人使用抗憂鬱藥的適應症或使用的抗憂鬱藥品種類，會導致這些研究存在著外推性（generalizability）的問題。再者，某些研究並未將使用抗憂鬱藥之前曾經中風的病人從研究中排除，使得這些研究的結果可能被高估。至今，年齡對於抗憂鬱藥使用和中風風險關係的影響仍未知，由於預期年輕人在中風後會比老年人有更長的存活時間，所以長期照護會形成醫療保健系統和照護人員（通常是家人）的巨大負擔，因此我們需要進一步的研究設計來闡明不同年齡的抗憂鬱藥使用者的中風風險。
5.使用抗憂鬱藥後多久會發生中風？
使用抗憂鬱藥後，通常需要至少4週才能達到治療效果。然而，值得注意的是，藥物不良反應可能會在開始治療後的短時間內出現。過去只有一項研究報告指出，使用SSRI後中風的病人，約20％是發生在初始治療後的6個月內。先前的研究發現，病人在接受抗憂鬱藥治療後1至3週內，體內的血小板功能以及腦血流量會明顯的降低；然而對於使用抗憂鬱藥後多快會發生中風仍然未知。
6.自我控制病例系列（self-controlled case-series, SCCS）研究設計：
SCCS研究只納入有發生事件的病人，並針對病人個體內（within individual）藥品暴露與非暴露期間進行風險的比較，提供了另一種流行病學方法來評估暴露與結果之間的關聯。由於是病人的自我比較，因此不會隨著時間推移而變動的潛在干擾因子，例如遺傳因子、性別、生活習慣、居住地、社會經濟地位、潛在疾病的嚴重性，甚至無法測量的干擾因子都可以被移除。
7.傾向分數配對（propensity score matching, PSM）世代研究設計：
傾向評分（propensity score）的概念是透過每個病人的可觀察變項來衡量特定個體接受治療的機率。PSM研究設計的主要目的是平衡治療組和未治療組中的干擾因子，因此可以更準確地估算治療效果。

研究目的：
首先我們使用臺灣全民健康保險研究資料庫（National Health Insurance Database, NHID）進行了SCCS研究，以評估抗憂鬱藥使用與中風風險之間的關聯，然後進行了PSM世代研究，以驗證我們在SCCS研究中的發現。在此研究中，我們還描述了在不同年齡層和暴露時間下，抗憂鬱藥與中風風險之間的關係。

研究方法：
研究1 – SCCS研究
1.設計與設置：
此SCCS研究使用臺灣NHID，從2010年7月1日至2015年6月30日納入初次使用抗憂鬱藥治療的病人（≥18歲），且有因首次中風而住院的病人。
2.抗憂鬱藥與中風的定義：
初次使用抗憂鬱藥的定義為在NHID中有ATC代碼N06A之抗憂鬱藥處方記錄的病人，並排除在初次服用抗憂鬱藥前36個月內有使用抗憂鬱藥的病人。我們透過住院病人資料庫（inpatient database）中的主要或次要診斷為ICD-9-CM 430-434來確認病人發生中風事件，並排除首次中風前36個月內曾經有中風診斷的病人，和首次中風前30天內診斷為腦損傷的病人（ICD-9-CM：800-804，850-854）。
3.暴露和風險期：
風險期（risk period）定義為抗憂鬱藥治療開始到結束或改藥的期間，而基線期（baseline period）則為未接受抗憂鬱藥治療的時間。我們將研究的主要觀察期設置為自初次接受抗憂鬱藥治療之日起的180天內。
4.統計分析：
使用條件Poisson回歸計算發病率比率（Incidence rate ratios, IRRs），以估計相較於基線期，病人在風險期發生第一次中風的風險。計算結果以95%的置信區間表示。
5.分層分析：
此SCCS研究會針對中風類型，性別，抗憂鬱藥類別，病人是否患有重度憂鬱症、失智症、或精神分裂進行分層分析。此外，我們也將病人分為三個年齡層進行分析，包括（1）18~44歲、（2）45~64歲和（3）≥65歲。最後，我們把風險期分為五個暴露期風險區間進行分析，包括（1）1~7天、（2）8~14天、（3）15~28天、（4）29~90天，和（5）91~180天。

研究2 – PSM世代研究：
1.設計與設置：
此研究與SCCS研究同樣使用了臺灣NHID，納入從2010年7月1日至2015年6月30日，初次使用抗憂鬱藥的病人（≥18歲）。首次開立抗憂鬱藥處方的日期則定義為指標日期（index date）。
2.抗憂鬱藥與中風的定義：
初次使用抗憂鬱藥的病人和中風的定義就如同SCCS研究中的定義。在此PSM世代研究中，我們排除指標日期前36個月內診斷為中風的病人，以及首次中風前30天內診斷為腦損傷的病人（ICD-9-CM：800-804，850-854）。本研究的觀察期（observation period）設定為從指標日期起算的180天時間內，且將在研究的觀察期內換用其他抗抑鬱藥、停用抗憂鬱藥、死亡，或中風的患者列為設限（censor）。
3.統計分析：
使用Cox比例風險回歸（Cox proportional hazards regression）模型分析抗憂鬱藥使用與中風風險之間的關係。此分析採用雙尾（two-sided）統計檢定，在0.05的顯著性水準下進行，統計結果以95%的置信區間呈現。
4.分層分析：
分層分析以及年齡層分析的變項與分組皆與SCCS研究相同。此外，此研究也採用SCCS研究對風險期的時間區分，將抗憂鬱藥的暴露時間分成五個暴露期風險區間，使用二項式廣義估計方程式（binomial generalized estimating equation）進行分析。

研究結果：
在SCCS研究中共納入了53,510名初次使用抗憂鬱藥的病人。其中超過一半（56.26%）是男性，平均年齡為69歲。我們發現在初次使用抗憂鬱藥後的180天內中風風險會增加（IRRs, 1.18; 95% CI, 1.13-1.23），並且此風險在初次用藥後的7天內最高（IRRs, 3.91; 95% CI, 2.60-5.88）。在PSM世代研究中，納入了1,072,922名初次使用抗憂鬱藥的病人和1,072,922名匹配的未使用抗憂鬱藥者。在初次使用抗憂鬱藥的病人中，年輕人佔37.25%，成年人佔38.53%，老年人佔24.23%。我們發現使用抗憂鬱藥的中風風險是未使用者的3.01倍（95% CI, 2.79-3.24）。另外，初次使用抗憂鬱藥的年輕病人，其中風風險比未使用者高3.68倍（95% CI, 2.56-5.29），而在成年人中則是3.08倍（95% CI, 2.65-3.58），然後在老年人是2.42倍（95% CI, 2.22-2.63）。在年輕人中與使用TCA相關的中風風險最高（HR, 4.14; 95％CI, 2.39-7.15）。 在成年人（HR, 4.14; 95％CI, 2.24-7.67）和老年人（HR, 2.90; 95％CI, 1.89-4.47）中，則是與使用SNRI相關的中風風險最高。而在暴露時間方面，與SCCS的結果相似，為初次使用抗憂鬱藥治療後7天內中風風險最高（OR, 3.91; 95% CI, 2.60-5.88）。

研究結論：
成人使用抗憂鬱藥會增加中風的風險，年齡越輕，風險越高。在年輕人中建議避免選擇TCA做為首選藥物，至於在成年人和老年人則建議避免選擇SNRI做為首選藥物。另外，須注意初次接受抗憂鬱藥的一周內，發生中風的風險最高。本研究的結果在SCCS研究和傾向得分匹配世代研究中得到了一致的結論，為臨床治療的病人安全性提供了寶貴而重要的信息。

BACKGROUND:
1.Adverse reaction of antidepressant:
Antidepressants are widely used to ameliorate major depressive disorder (MDD), bipolar disorder, anxiety, affective disorder, and even relieve neuropathic pain. However, the antidepressants can also bring many unpleasant side effects while patients are getting well control of their diseases. The most common side effects include drowsiness, nausea, dry mouth, constipation, weight gain, and sexual dysfunction. However, some other adverse reactions with lower incidence but higher severity, such as stroke and gastrointestinal bleeding has been reported recently.
2.Previous studies of the stroke and antidepressant:
One meta-analysis study in 2014 reported that serotonin reuptake inhibitors (SSRI) users had higher risks in both ischemic stroke (OR, 1.48; 95 % CI, 1.08 to 2.02; I2=83.9%) and hemorrhagic stroke (OR, 1.32; 95 % CI, 1.02 to 1.71; I2=74.9%). However, the studies included in the meta-analyses were not randomized control studies, and likely to bias the analysis due to heterogeneity. Since 2014, except for one cohort study that reported SSRI users had a significantly (p<0.01) higher stroke rate (6.7%) than nonusers (2.8%), other articles found that the risk of stroke was not associated with antidepressant use. Whether the stroke risk is associated with use of antidepressants remains controversial.
3.Confounding factors in previous study:
Because the previous research was all non-random observational studies and compared exposures with non-exposures, the differences in age distribution, cardiovascular disease, diabetes, previous stroke, anticoagulant use, smoking and alcohol drinking were deemed inherited between the two groups. These confounding factors would bias the research results. In addition, more than half of the studies included prevalent users of antidepressants, which could introduce substantial bias if risk varied with time. More than one third of the studies did not exclude patients who had stroke history, and the events of interested in these studies (stroke) may be affected by previous stroke.
4.Does age matter?
Most patients initially used antidepressant are at young to middle-age, but few studies discussed the stroke risk for antidepressants users at different ages. Previous studies only enrolled participants with MDD or those who used SSRI, which did not reflect a broader spectrum of clinical indications and various choices of antidepressants and would lead to a poor generalizability. Besides, studies included patients who had stroke prior to antidepressant use would likely overestimate the stroke risk from recurrent episodes. Due to the longer life expectancy of young patients after stroke, long-term care will become a heavy burden for the health care system and the caregivers. Further study is needed to clarify the stroke risk of antidepressant users at different ages.
5.How soon does stroke occur after using of antidepressants?
Treatment with antidepressants usually takes at least 4 weeks to achieve therapeutic effect. It is worth noting that patients may experience adverse reactions within a short period after initial treatment. Only one study found that about 20% of strokes among SSRI users occurred within 6 months after initial treatment. On the other hand, previous studies reported that antidepressants decreased platelet function and cerebrovascular blood flow within 1 to 3 weeks after treatment. Therefore, how soon a stroke will occur after antidepressants use needs further investigation.
6.The self-controlled case-series (SCCS) study design:
The SCCS study is a case-only design which makes comparisons within individual of patients who experience both the event and the exposure, and provides an alternative epidemiological approach to assess the association between an exposure and an outcome. Since the comparison is between different experiences in the same patient, potential confounders that are fixed over time, such as genetic disposition, gender, location, socioeconomic status, individual frailty, severity of underlying disease, and even extend to undetected confounders, can be eliminated.
7.The propensity score matching (PSM) cohort study design:
The concept of a propensity score is to measure the probability of a particular individual receiving treatment through the patient's own observable variables. The main purpose of the PSM is to balance the confounding variables in the treated group and the untreated group, so the treatment effectiveness can be estimated more accurately.

OBJECTIVES:
We first conducted a SCCS study using Taiwan National Health Insurance Database (NHID) to assess the association between antidepressant use and stroke risk, and employed a PSM cohort study to verify our findings in the SCCS study. We also delineated the association between antidepressants and stroke risk at different age groups and exposure time.

METHOD:
Study 1 – SCCS design
1.Design and settings:
We conducted a SCCS study using Taiwan NHID and enrolled antidepressant new users (≥18 years) from 1 July 2010 to 30 June 2015, who were hospitalized for first stroke event.
2.Definition of antidepressant and stroke:
Antidepressant new users were identified by a prescription record for antidepressants as ATC code N06A in NHID. Participants were excluded if they had any antidepressants during the 36 months prior to the first antidepressants prescription. Stroke was identified by the primary or secondary diagnosis in the inpatient database as ICD-9-CM 430-434 during the study period. Patients diagnosed with stroke within 36 months and head injuries (ICD-9-CM: 800-804, 850-854) within 30 days before the first stroke were excluded.
3.Exposure and risk period:
The risk period was defined by the calendar days between the start of antidepressant therapy and the end or change of antidepressant therapy, while the baseline period included all unexposed time. We set the main observation period of the study to 180 days from the date of the first antidepressant treatment.
4.Statistical analysis:
Incidence rate ratios (IRRs) were calculated using conditional Poisson regression to estimate the stroke risk during risk periods by compared to baseline periods within each individual. The results were presented as 95% confidence intervals.
5.Subgroup analysis:
Subgroup analyses were performed for stroke types, genders, whether patients had MDD, schizophrenia, and dementia. We divided the patients into three age groups for analysis, including (1) young adults (18~44 years old), (2) adults (45~64 years old), and (3) elderly (≥ 65 years old). We also divided the risk period into five exposure windows in the analysis, including (1) 1~7 days, (2) 8~14 days, (3) 15~28 days, (4) 29~90 days, and (5) 91~180 days.

Study 2 – PSM Cohort design
1.Design and settings:
The study also used Taiwan NHID and enrolled antidepressant new users (≥18 years) from 1 July 2010 to 30 June 2015. The date of first prescription was defined as the index date.
2.Definition of antidepressant and stroke:
Antidepressant new users and stroke were defined as in the SCCS study. Patients diagnosed with stroke within 36 months before the index date and those who diagnosed with head injuries (ICD-9-CM: 800-804, 850-854) within 30 days before the first stroke were excluded. The observation period was set as a 180-day time from the index date, and censored patients who changed to other antidepressants, discontinued exposure, died, and have the outcome of stroke during the observation period.
3.Statistical analysis:
Cox proportional hazards regression models were used to explore the association between antidepressant use and the stroke risk. All statistical tests were two-sided, conducted at the significance level of 0.05, and reported using 95% confidence intervals.
4.Subgroup analysis:
Subgroup and age groups analysis were as in the SCCS study. We also defined the five exposure windows as in the SCCS study for the binomial generalized estimating equation analysis.

RESULT:
In the SCCS study, a total of 53,510 antidepressant new users with stroke were identified. More than half (56.26%) of them were male, and the average age was 69 years old. We found that antidepressants exposure increased the stroke risk (IRRs, 1.18; 95% CI 1.13 to 1.23) within 180 days, and the highest within 7 days after initial antidepressants treatment (IRRs, 3.91; 95% CI, 2.60 to 5.88). In the PSM cohort study, 1,072,922 antidepressants users and 1,072,922-matched nonusers were included. Among antidepressant new users 37.25% were young adults, 38.53% were adults, and 24.23% were elderly. We found the stroke risk was 3.01 times higher (95% CI, 2.79 to 3.24) among antidepressants users than nonusers. Among young adults, the stroke risk was 3.68 times (95% CI, 2.56 to 5.29) higher in antidepressant new users than those nonusers, and 3.08 times (95% CI, 2.65 to 3.58) among adults, then 2.42 times (95% CI, 2.22 to 2.63) among the elderly. The risk of stroke was also highest within 7 days after initial antidepressants treatment (OR, 3.91; 95% CI, 2.60 to 5.88). In addition, we found the TCA was relatively high-risk in young adults (HR, 4.14; 95% CI, 2.39 to 7.15) for initial treatment, while SNRI treatment had highest stroke risk in adults (HR, 4.14; 95% CI, 2.24 to 7.67) and elderly (HR, 2.90; 95% CI, 1.89 to 4.47).

CONCLUSION:
The use of antidepressants in adults increased the risk of stroke, and the younger the age, the higher the risk. The stroke events were most likely to occur within one week after receiving the initial antidepressant treatment. TCA were associated with the highest risk of stroke in young adults, while receiving SNRI were found to be highest risk in adults and elderly. The results of the study were consistent through a SCCS study and a PSM cohort study, which would be robust to inform clinical decision in selecting antidepressants and safety monitoring.

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