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作者：Pam Harrison  
出處：WebMD醫學新聞

　　December 22, 2009 — 根據「Women's Health Initiative (WHI)」研究的新分析，服用三環抗憂鬱藥物(TCA)或選擇性血清素再吸收抑制劑(SSRI)的停經後婦女，各種原因的死亡率風險增加，SSRI使用者的出血性和致命中風風險增加，但是這些的絕對風險還是很低。
　　
　　麻州綜合醫院的Jordan Smoller醫師等人在12月份內科醫學誌(Archives of Internal Medicine)發表的報告中指出，這個停經後婦女的大型前瞻性世代中，在平均5.9年的追蹤期間，新使用TCA或SSRI與冠心症(coronary heart disease，CHD)風險略為增加有關。
　　
　　相對的，相較於未使用抗憂鬱藥物的婦女，研究者報告指出，根據傾向分層模式與多變項校正，使用SSRI者的中風發生率增加45%、死亡風險增加32%，使用TCA者的各種原因死亡風險相對高出67%(風險比[HR]為1.67；95%信心區間[CI]為1.33 - 2.09)，TCA也增加中風風險，不過沒那麼顯著。
　　
　　Smoller醫師向Medscape Psychiatry表示，相較於抗憂鬱藥物，憂鬱更是心血管疾病(cardiovascular disease，CVD)的明確風險因素，因此，並不是說停止用抗憂鬱藥物可以除去前述風險，相反的，未治療的憂鬱症本身更具風險，但是，如果婦女對服用藥物有顧慮時，有其他替代方法可用來治療憂鬱，像是認知行為治療也有效。
　　
　　【探究關聯】
　　為了進行分析，在第一次追蹤訪視之後，研究者檢視新使用抗憂鬱藥物和初次發生CHD、致命或非致命中風、各種原因死亡的關聯。
　　
　　納入縱向世代觀察研究婦女的第一次追蹤訪視是在三年時；至於納入三個重複的臨床試驗之一的婦女，在開始後一年進行追蹤訪視。
　　
　　總共有136,293名停經後婦女納入WHI，加入研究時沒有服用抗憂鬱藥物的婦女、有至少一次追蹤訪視的婦女被納入此次分析。
　　
　　在追蹤期間，5,496名婦女初次使用抗憂鬱藥物，使用抗憂鬱藥物者的多項CVD風險因素高於未使用者。為了表達可能的干擾因素，研究者根據邏輯回歸模式獲得一個傾向分數。
　　
　　未使用抗憂鬱藥物者的每1000人-年中風年度比率為2.99，SSRI使用者為4.16。未使用抗憂鬱藥物者的每1000人-年死亡率為7.79，SSRI使用者為12.77。TCA使用者的每1000人-年死亡年度比率為14.14。
　　
　　如同研究者指出的，與SSRI有關的中風風險大多為出血性的(HR為2.12；95% CI為1.10 - 4.07)，SSRI的缺血性中風風險未達統計上的顯著(HR為1.21；95% CI為0.80 - 1.83)。
　　
　　相對的，SSRI和TCA都與所有致命的中風風險增加有關(分別是HR, 2.10；95% CI，1.15 - 3.81；與HR，2.56；95% CI，1.26 - 5.26)。
　　
　　表. CV事件與所有世代的年度比率(觀察研究與臨床試驗)

使用抗憂鬱藥物情況	人數 (n)	CHD 事件 (n)	每 1000 人 - 年之 CHD 年度比率	中風事件 (n)			每 1000 人 - 年之年度比率
追蹤期間未使用	130,797	2843	3.81	2232	2.99	5881	7.79
使用 SSRI	3040	73	4.73	64	4.16	201	12.77
使用 TCA	1490	41	5.18	39	4.92	114	14.14
使用其他的或多種的抗憂鬱藥物	966	26	5.38	22	4.55	66	13.42

　　【關鍵問題】
　　一個關鍵問題是，使用抗憂鬱藥物與CV發病率及死亡率之間的關聯，是真正與藥物有關或者是其他CV風險因素如憂鬱本身的潛在差異。
　　
　　如同Smoller醫師向Medscape Psychiatry解釋的，本研究使用的傾向分數可幫助控制風險因素，可解釋使用和未使用抗憂鬱藥物者之間的CV結果差異，但是你無法完全歸咎於憂鬱本身，這些風險因素有一些可能和藥物有關。
　　
　　他接著表示，如果你注意所有世代的年度死亡率，使用和未使用抗憂鬱藥物者之間的絕對差異很小，所以我們認為必須衡量未治療憂鬱症和使用抗憂鬱藥物時的CV疾病與死亡率風險，因為我們知道這將對病患的生活品質有重大影響。
　　
　　杜克大學醫學中心的Christopher O'Connor博士受邀發表評論時表示，認同這些試驗的最困難部份在於，使用抗憂鬱藥物治療的病患可能有其他難以控制的死亡與CV風險因素。
　　
　　他們也指出，該研究無法完整表達那些開始使用抗憂鬱藥物但是沒有治療反應者的情況，而這些病患可能有更高的死亡風險。
　　
　　然而，他們指出，來自迄今最大型婦女世代研究的這些發現，提供一個新的警訊：使用抗憂鬱藥物者，在此一特定人口中有一些負面後遺症，此風險應被視為有礙於治療憂鬱。
　　
　　國家心肺與血液研究中心資助WHI計畫。Smoller醫師宣告擔任Eli Lilly的顧問，且接受Hoffman-La Roche Inc、Enterprise Analysis Corporation以及MPM Capital等的獎助金，他也擔任Roche Diagnostic Corporation的諮詢委員。O'Connor博士宣告沒有相關財務關係。

Antidepressants Linked to Increased Risk for Death, Stroke in Postmenopausal Women
By Pam Harrison
Medscape Medical News
December 22, 2009 — Postmenopausal women taking either a tricyclic antidepressant (TCA) or a selective serotonin-reuptake inhibitor (SSRI) appear to be at increased risk for all-cause mortality, and SSRIs users seem to be at increased risk for hemorrhagic and fatal stroke, although the absolute event risks are low, according to an analysis from the Women's Health Initiative (WHI) study.
In an article published in the December issue of the Archives of Internal Medicine, Jordan Smoller, MD, from Massachusetts General Hospital, Boston, and colleagues report that new use of either a TCA or an SSRI during a mean follow-up of 5.9 years was not significantly associated with an increased risk for coronary heart disease (CHD) in this large prospective cohort of postmenopausal women.
In contrast, compared with women who did not use antidepressants, "those using SSRIs had a 45% increased relative risk of incidence stroke and a 32% increased risk of death in models stratified on propensity and adjusted for multiple covariates," the investigators report. TCA use in turn was associated with a 67% higher relative risk for all-cause death (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.33 - 2.09). The TCAs also increase stroke risk, but not significantly so.
"Depression is still a much more established risk factor for cardiovascular disease (CVD) than antidepressants, so it's not as though not taking an antidepressant removes the risk because then you have untreated depression, which itself is risky," Dr. Smoller told Medscape Psychiatry. "But if a woman is concerned about taking medication, there are alternative treatments for depression, such as cognitive behavioral therapy, which can be effective."
Association Explored
For the analysis, investigators examined the association between new antidepressant use and first occurrence of CHD, fatal or nonfatal stroke, and all-cause mortality occurring after the first follow-up visit.
The first follow-up visit for women enrolled in the longitudinal cohort observational study was at 3 years; for women enrolled in 1 of the 3 overlapping clinical trials it took place at 1 year after baseline.
A total of 136,293 postmenopausal women were involved in the WHI, and women taking no antidepressants at study entry and who had at least 1 follow-up visit were included in the analysis.
During the follow-up interval, 5496 women initiated antidepressant treatment. Antidepressant users had higher levels of several CVD risk factors than nonusers. To address potential confounders, investigators obtained a propensity score from a logistic regression model.
Annualized rates per 1000 person-years of stroke with no antidepressant use were 2.99 vs 4.16 for SSRI users. Death rates for non–antidepressant users were 7.79 per 1000 person-years and 12.77 for SSRI users. Annualized mortality rates for TCA users were 14.14 deaths per 1000 person-years.
As investigators point out, the excess risk for stroke seen in association with SSRIs was largely hemorrhagic (HR, 2.12; 95% CI, 1.10 - 4.07), whereas the risk for ischemic stroke with SSRI use did not reach statistical significance (HR, 1.21; 95% CI, 0.80 - 1.83).
In contrast, both the SSRIs and the TCAs were associated with an increased risk for all fatal strokes (HR, 2.10; 95% CI, 1.15 - 3.81; and HR, 2.56; 95% CI, 1.26 - 5.26, respectively).
Table. CV Events and Annualized Rates in All Cohorts (Observational Study and Clinical Trials)

AD Status	Participants (n)	CHD Events (n)	CHD Annualized Rate/1000 Person-Years	Stroke Events (n)			Annualized Rate/1000 Person-Years
No AD at Follow-up	130,797	2843	3.81	2232	2.99	5881	7.79
Incident SSRI	3040	73	4.73	64	4.16	201	12.77
Incident TCA	1490	41	5.18	39	4.92	114	14.14
Incident other or multiple ADs	966	26	5.38	22	4.55	66	13.42

Key Question
A key question is whether the association between antidepressant use and CV morbidity and mortality is truly related to drug exposure or to underlying differences in other CV risk factors, including depression.
As Dr. Smoller explained to Medscape Psychiatry, the propensity score used in this study did help control for risk factors that could have explained differences in CV outcomes between antidepressant users and nonusers, "but you can't fully tease out the effect that depression itself and some of these risk factors may have had vs the contribution of the medication."
He continued, "If you look at the annualized death rates in all cohorts, the absolute differences [between AD users and nonusers] is very small, so our findings have to be weighed against the risk of CV disease and mortality associated with untreated depression vs antidepressant use because we know it can have a dramatic effect on the ability of patients to enjoy life."
In an invited commentary, Christopher O'Connor, MD, and Mona Fiuzat, PharmD, from Duke University Medical Center, Durham, North Carolina, agreed that the most difficult aspect of these trials is that patients who are likely to be treated with antidepressants have additional risk factors for mortality and CV risk that are difficult to control for.
They also point out that the study cannot fully address situations in which patients begin treatment with antidepressants but do not respond to treatment, and that these patients may represent the highest-risk mortality group.
Nevertheless they indicate that the findings — in the largest cohort of women yet studied — provide "additional warning" that antidepressant use does have certain negative consequences in this particular demographic and that its risks should be considered against the potential benefits of treating depression.
The WHI program is funded by the National Heart, Lung, and Blood Institute. Dr. Smoller has served as a consultant for Eli Lilly and received honoraria from Hoffman-La Roche Inc, Enterprise Analysis Corporation and MPM Capital. He has also served on an advisory board for Roche Diagnostic Corporation. Dr. O'Connor has disclosed no relevant financial relationships.
Arch Intern Med. 2009;169: 2128-213;2140-2141.