對於重度憂鬱症併用抗憂鬱藥物治療比單用Fluoxetine更有效

作者：Deborah Brauser  
出處：WebMD醫學新聞

　　December 23, 2009 — 根據線上發表於12月美國一般精神醫學期刊(American Journal of Psychiatry)的雙盲比較研究，Mirtazapine併用fluoxetine、venlafaxine或 bupropion，比單用fluoxetine更可有效治療重度憂鬱症(major depressive disorder，MDD)且耐受良好。
　　
　　事實上，相較於單方治療者，在第42天時使用Hamilton憂鬱量表(Hamilton Depression Rating Scale[HAM-D])評分，併用組有平均4.5-4.8分的差距。
　　
　　加拿大安大略省渥太華大學心智健康研究中心的Pierre Blier博士寫道，此研究結果增加了證據證明，治療開始就併用抗憂鬱藥物的緩解可能性是單一藥物的兩倍。
　　
　　他們指出，不只達到治療重度憂鬱的緩解目標，也更早達到，這相當重要。
　　
　　【需改善以前的緩解率】
　　研究作者報告指出，在初次試用中，雖然單一抗憂鬱藥物一般可以有約50%至75%的病患獲得反應，單一藥物的緩解率只有大約30%。
　　
　　他們寫道，這是令人失望的結果，表示約三分之二的病患需要其他治療方式。
　　
　　目前的照護標準是藥物替代，可能有或可能沒有等待期，不過，因為實務上接受抗憂鬱藥物試用需持續至少6週，連續使用兩種不同藥物需要約3個月，病患通常在這段期間停止治療。
　　
　　雖然維持第一種藥物再加入第二種藥物以獲得緩解是另外一種常用方法，但此方法並未獲得證明比藥物替代更有效，也需要第一種試用完成，多數病患的反應或緩解皆延遲。
　　
　　以前的研究顯示，使用mirtazapine和選擇性血清素再吸收抑制劑(SSRI)paroxetine治療的MDD病患，改善程度優於使用單一種藥物。
　　
　　【Mirtazapine +SSRI之外的抗憂鬱藥物】
　　本研究中，Blier博士等人試圖比較從治療開始就使用Mirtazapine加SSRI之外的抗憂鬱藥物，改善效果是否優於單用fluoxetine者。
　　
　　總共有105名病患符合精神疾病診斷與統計手冊第4版之MDD規範(HAM-D 分數至少18分)，來自佛羅里達一地與加拿大兩地等三處。病患被隨機分到四組，接受fluoxetine20 mg/天的加安慰劑(n = 28人)、30 mg/天的mirtazapine加fluoxetine(n = 25人)、225 mg/天的venlafaxine (在14天內調整，n = 26人)、150 mg/天的bupropion (n = 26人)。
　　
　　研究作者解釋，因為mirtazapine與體重可能增加有關，我們篩選有較多活性且對體重無影響的抗憂鬱藥物來併用。
　　
　　病患的精神異常藥物在初步篩選之後停用，但是允許維持clonazepam、zopiclone和zolpiderm，以控制焦慮和其他症狀。
　　
　　初步結果測量為HAM-D分數之改變。治療反應定義為持續改善達50%以上，緩解定義為HAM-D分數在7分以下。
　　
　　研究也使用Montgomery-Asberg憂鬱量表和臨床整體臆斷(Clinical Global Impressions[CGI])嚴重度和改善程度作為評估。
　　
　　【Mirtazapine + Venlafaxine組表現最佳】
　　研究結束時，結果顯示，雖然bupropion、fluoxetine和venlafaxine併用組比單用fluoxetine組有較多病患達到治療反應(分別是65%、68%和73%相較於54%)，但並未達統計上的顯著差異。
　　
　　不過，在HAM-D分數上，這三個併用組比單一治療者有顯著的改善。
　　
　　在達到持續緩解的病患比率方面，單以fluoxetine治療組(25%)和fluoxetine併用組(52%)與venlafaxine併用組(58%)之間有統計上的差異。Bupropion併用組則為46%，無統計上的差異。
　　
　　單以fluoxetine治療之病患和使用fluoxetine、bupropion與venlafaxine併用的病患，42天時的Montgomery-Asberg 憂鬱量表分數差異分別是4.9、4.6和5.8分，都沒有達到統計上的顯著差異。
　　
　　在CGI嚴重度和改善程度分數方面，治療組之間也無顯著差異。
　　
　　至於與治療有關的副作用，各組的坐姿收縮壓或脈搏沒有顯著變化。不過，單一治療組的體重並未明顯增加(平均+0.1公斤)，併用組則增加(fluoxetine，3.1公斤；bupropion，2.7公斤；venlafaxine，2.2公斤；P < .001)。
　　
　　各組的其他副作用與退出率相當。
　　
　　作者們報告指出，併用mirtazapine和venlafaxine似乎進行得特別順利；接受此種治療的組別達到最高的緩解率，CGI分數為1分[一點也不嚴重]的病患最多，沒有因為缺乏療效而退出者。
　　
　　所有有明顯反應的病患中，隨意停用一種藥物造成約40%的案例復發。
　　
　　【停用期】
　　有66位病患進行6個月的「停用與延長期」追蹤。這段期間，fluoxetine併用組與單一治療組都換成只使用fluoxetine，其他兩個併用組換成只使用mirtazapine。
　　
　　研究者報告指出，這部份的研究結果顯示，最初接受mirtazapine和fluoxetine或venlafaxine併用治療的病患約有半數復發，接受fluoxetine單一治療或併用mirtazapine和bupropion者有四分之一復發。
　　
　　研究作者寫道，延長期的觀察發現，實質上意味著治療之初即併用抗憂鬱藥物治療的意義。此方法不只耐受良好且比單一治療更有效，但是，如果因為副作用而無法耐受、或對於併用治療有經濟負擔，可以停止一個藥物。
　　
　　他們指出，事實上，超過半數病患在這6個月的延長期間並未復發。
　　
　　【有力的資料】
　　梅約診所醫學院精神與藥物科學教授Elliott Richelson醫師在Medscape Psychiatry的訪問中表示，以一個控制良好的方法，研究者證明併用治療對於憂鬱症治療的重要性。Richelson醫師與本研究無關。
　　
　　他指出，憂鬱症的照護標準是緩解，也就是憂鬱症狀或徵兆不再出現，如果你未達到緩解，可能會在幾個月或一年後有全面發作的憂鬱。在這個為期較短的研究中得到的緩解率是相當傑出的，一般只會看到反應率。
　　
　　Richelson醫師表示，良好的抗憂鬱藥物比較研究很罕見，我認為這篇研究是相當難得的。雖然每一組只有約20名病患，這些是難以進行的昂貴研究，所發現的資料相當有力。
　　
　　他接著表示，幾年來，加州精神藥物專家Steven Stahl醫師提出，併用mirtazapine和venlafaxine是「加州的火箭燃料」，但是我沒有看到有關的控制試驗。這次的併用結果讓人印象深刻，如同研究中併用的其他藥物，未來，這將是治療憂鬱之每日臨床實務中的好方法。
　　
　　他表示，他只有一個小小提醒：不論你何時開始同時使用兩種藥物，如果你有紅疹等嚴重副作用，而你不知道哪種藥物引起時，你必須兩種都停用。這雖罕見，但這也是我在實務上一般不會同時開始使用兩種藥物的原因 。但是，基於讓憂鬱病患緩解的重要性，我認為本研究讓我們有如何使用此方法的好指引。
　　
　　Organon Pharmaceuticals支持本研究。研究作者報告與Organon、Biovali、Lundbeck、Eli Lilly、Wyeth以及AstraZeneca有財務關係。Richelson醫師是授權給AstraZeneca藥廠之潛在抗憂鬱藥物科技專利的共同發明人。
　　
　　Am J Psychiatry. 線上發表於2009年12月15日。


Combination Antidepressant Therapy More Effective for MDD Than Fluoxetine Alone

By Deborah Brauser
Medscape Medical News

December 23, 2009 — Mirtazapine used in combination with fluoxetine, venlafaxine, or bupropion is more effective and as well tolerated in treating major depressive disorder (MDD) as fluoxetine alone, according to results from a new double-blind comparison study published in the December issue of the American Journal of Psychiatry.

In fact, patients treated with these combinations had mean differences of 4.5 to 4.8 points on the Hamilton Depression Rating Scale (HAM-D) by day 42 compared with those treated with monotherapy.

"The study results, which add to a growing body of evidence, suggest that use of antidepressant combinations from treatment initiation may double the likelihood of remission compared with use of a single medication," write Pierre Blier, MD, PhD, University of Ottawa Institute of Mental Health Research, Ontario, Canada, and colleagues.

"Not only is remission the goal of treatment for major depression, but achieving it as early as possible is of critical importance," they add.

Past Remission Rates Needed Improvement

Although a response to a single antidepressant is generally obtained in about 50% to 75% of patients in a first trial, remission rates are generally only around 30% with a single agent, report the study authors.

"This is a disappointing result indicating that additional treatment measures must be taken in about two-thirds of patients," they write.

The current standard of care is drug substitution, with or without an elimination period. However, because it is accepted practice that an antidepressant drug trial should last at least 6 weeks, 2 consecutive attempts using different medications would require almost 3 months, with patients often stopping treatment during this period.

Although maintaining a first drug and then adding a second to obtain remission is another common approach, this method has not proven to be any more effective than drug substitution, and it still requires a first trial completion and delayed response or remission for most patients, note the authors.

Past studies have shown that MDD patients treated with mirtazapine and the selective serotonin reuptake inhibitor (SSRI) paroxetine showed more improvements than those treated with either drug alone.

Mirtazapine + Antidepressants Other Than SSRIs

In this study, Dr. Blier and his team sought to compare whether mirtazapine plus antidepressants other than SSRIs, given from treatment initiation on, could produce improvements superior to those from fluoxetine alone.

A total of 105 patients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria for MDD (and having a score of at least 18 on the HAM-D) were enrolled at 3 sites, including 1 in Florida and 2 in Canada. The patients were then randomly assigned to 4 groups and received a 20 mg/day dose of fluoxetine plus placebo (n = 28) or a 30 mg/day dose of mirtazapine plus the fluoxetine dose (n = 25), a 225 mg/day dose of venlafaxine (titrated in 14 days, n = 26), or a 150 mg/day dose of bupropion (n = 26).

Given mirtazapine's association with potential weight gain, "we selected more activating and weight-neutral antidepressant drugs...to combine with it," explain the study authors.

The patients' psychotropic drugs were discontinued after initial screening, but clonazepam, zopiclone, and zolpiderm were allowed to manage anxiety and other symptoms.

The primary outcome measure was a change in HAM-D score. Treatment response was defined as a sustained improvement of 50% or more, and remission was defined as a HAM-D score of 7 or less.

The investigators also used the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impressions (CGI) severity and improvement scales for their evaluations.

Mirtazapine + Venlafaxine Group Performs Best

Results at the end of the study showed that although the bupropion, fluoxetine, and venlafaxine combination groups had more patients that achieved a treatment response compared with the group treated with fluoxetine alone (65%, 68%, and 73% vs 54%, respectively), this was not found to be statistically significant.

However, all 3 combination groups did have significantly greater improvements on the HAM-D compared with those receiving monotherapy.

The proportion of patients achieving a sustained remission was also statistically different between the fluoxetine-only treatment group (25%) and both the fluoxetine combination (52%) and the venlafaxine combination (58%) groups. The 46% rate from the bupropion combination group was not deemed statistically different.

Montgomery-Asberg Depression Rating Scale score differences at day 42 between the patients treated with the fluoxetine monotherapy and those treated with the fluoxetine, bupropion, and venlafaxine combinations were 4.9, 4.6, and 5.8 points, respectively, none of which reached statistical significance.

There were also no significant differences between the treatment groups on the CGI severity and improvement scores.

For treatment-related adverse events, there were no significant changes in sitting systolic blood pressure or pulse in any of the groups. Although the monotherapy group did not experience significant increases in weight (mean, +0.1 kg), those in the combination groups did (fluoxetine, 3.1 kg; bupropion, 2.7 kg; venlafaxine, 2.2 kg; P < .001).

Other adverse events and drop-out rates were comparable among all groups.

"The combination of mirtazapine and venlafaxine seemed to perform particularly well; the group receiving this treatment achieved the highest remission rate, had the highest number of patients with a score of 1 [not at all] on the CGI severity scale, and had no dropouts attributed to lack of efficacy," report the authors.

Among all patients who had had a marked response, a blind discontinuation of 1 agent produced a relapse in about 40% of the cases.

Discontinuation Phase

A 6-month "discontinuation and prolongation phase" followed-up 66 of the patients. In this phase, those from both the fluoxetine combination and monotherapy groups switched to receiving fluoxetine only. The other 2 combination groups switched to receiving mirtazapine monotherapy.

Results from this part of the study showed that "about half the patients who initially received combination treatment with mirtazapine and fluoxetine or venlafaxine relapsed, compared with about a quarter of those who initially received fluoxetine monotherapy or combination treatment with mirtazapine and bupropion," report the study authors. About half of the relapses occurred within the first month of the prolongation.

"The observations in the prolongation phase have practical implications for the use of antidepressant combinations from treatment initiation," write the study authors. "Not only is the approach as well tolerated and more efficacious than monotherapy, but if a drug becomes intolerable due to side effects or if the combination becomes a financial burden, 1 drug could be stopped."

"In fact, more than half the patients in the 6-month prolongation did not relapse," they add.

Strong Data

"In a very well controlled fashion, the investigators have demonstrated the importance of combination therapy in the treatment of depression," said Elliott Richelson, MD, professor of psychiatry and pharmacology at the Mayo Clinic College of Medicine, Jacksonville, Florida, in an interview with Medscape Psychiatry. Dr. Richelson was not associated with this trial.

"The standard of care for treatment of depression is remission, which is total absence of any signs or symptoms of the depression," he added. "If you don't achieve remission, then it's likely that you're going to have a recurrence of full-blown depression down the road by several months or a year. The remission rates in this relatively short study were excellent. They're the levels you usually see in response."

Dr. Richelson said that good combination comparison studies of antidepressants are rare. "I think this is unique in that regard. Although each group only had about 20 patients, these are expensive, hard studies to do, and the data found here is strong."

He continued, "For years, [California psychopharmacologist] Dr. Steven Stahl has said that the combination of mirtazapine and venlafaxine is 'California rocket fuel,' but I wasn't aware of any controlled trial looking at that. The results here for that combination are quite impressive, as are the combinations with the other drugs in this study. Going forward, this is a good approach in everyday clinical practice to treat depression."

He said that he has only 1 minor caution: "Whenever you start 2 drugs at the same time, if you get a serious side effect such as a rash, you don't know which drug did it and you have to stop both. That's a rare event, but that's why in my practice I generally don't start 2 drugs at the same time. But given the importance of getting patients who are depressed into remission, I think this study gives us good guidance as to how to approach that."

This study was supported by Organon Pharmaceuticals. The study authors have reported financial relationships with Organon, Biovali, Lundbeck, Eli Lilly, Wyeth, and AstraZeneca. Dr. Richelson is a coinventor on patents that have been issued on potential antidepressant technology licensed to AstraZeneca.

Am J Psychiatry. Published online December 15, 2009.