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作者：Caroline Cassels  
出處：WebMD醫學新聞

　　December 23, 2009 — 有別於抗憂鬱效果，選擇性血清素再吸收抑制劑(SSRI)paroxetine(商品名Paxil，GlaxoSmithKline藥廠)對於人格有正面效果，研究者表示，這項研究發現有助於預測重度憂鬱病患的長期結果。
　　
　　西北大學Tony Z. Tang博士領導的一個大型安慰劑控制試驗顯示，重度憂鬱症(major depressive disorder，MDD)的病患，服用paroxetine者比服用安慰劑者有更大的人格改變，包括神經質明顯降低、外向明顯增加，即使控制憂鬱改善之後也是。
　　
　　研究者發現，服用paroextine的病患，與憂鬱改善程度相當的安慰劑組病患相比，神經質改善6.8倍、外向改善3.5倍。
　　
　　Tang博士向Medscape Psychiatry表示，使用paroextine的病患，神經質減少且外向增加，但是，更重要的是，如果你注意paroxetine組和安慰劑組的差異，這兩種人格面向的差異遠大於其憂鬱嚴重度的差異。
　　
　　如果經其他研究證實，這些結果將破除所謂的「狀況效果(state effect)」假設，該假設主張，使用SSRI治療時的任何人格改變，都是憂鬱症狀改善的直接結果。
　　
　　這項研究發表於12月的一般精神醫學誌(Archives of General Psychiatry)。
　　
　　【較大的人格改變】
　　根據研究者，對於MDD來說，高度神經質是一種比基因敏感性更大的人格風險因素，外向程度低也是；這兩種人格特性被視為與血清素系統有關，SSRI的關鍵治療目標為。
　　
　　為了探討SSRI治療對於神經質和外向的可能影響，研究者將年紀18-70歲的240名MDD病患隨機分組接受paroxetine (n = 120人)、安慰劑(n =60人)或認知治療(n = 60人)。
　　
　　該研究的主要結果是「NEO 五大人格因素量表(NEO-FFI)」的改變，這項量表是人格研究上廣為使用的自我評量量表，另外使用Hamilton量表測量憂鬱。
　　
　　在急性治療期之後，對認知治療和paroxetine治療有反應者進入一個為期12個月的持續期。對paroxetine治療有反應者被隨機分派到兩個小組：34人繼續服用相同劑量之該藥物，35人停止該藥並改給予安慰劑。對認知治療有反應的35個人，被允許以1個月的間隔進行最多3次的加強課程。
　　
　　研究者發現，與安慰劑組相比，即使控制憂鬱改善程度之後，服用paroxetine的病患報告指出較大的人格改變(P < .001；外向，P = .002)。
　　
　　再者，Tang博士指出，控制神經質(P = .46)或外向(P = .14)方面的改變之後，paroxetine的抗憂鬱效果不再明顯優於安慰劑。
　　
　　此外，作者們報告指出，雖然安慰劑組病患有明顯的憂鬱改善，他們的神經質或外向方面很少改變。
　　
　　認知治療組病患的人格改變大於安慰劑組(P≦.01)，但是控制憂鬱程度之後，神經質方面的效果不再顯著。
　　
　　【較低的復發比率】
　　Tang博士表示，重要的是，對paroxetine治療有反應者(P = .003)中，治療期間神經質減少可預測較低復發率，但是，對認知治療有反應者(P = .86)則否。
　　
　　Tang博士表示，我們對許多結論感到驚訝，最大的驚訝是，神經質改善可以預測長期結果。
　　
　　治療憂鬱之最大挑戰在於達到好的長期結果。他表示，初步反應與恢復很容易達到，但是一年內的復發率相當高，許多病患必須再回診。
　　
　　不過，他指出，本研究認為，神經質大幅改善病患的復發機會，比那些沒有改善神經質者降低許多。
　　
　　Tang博士表示，此發現相當令人驚訝，部份是因為醫師們一般不預期SSRI有任何的長期持續影響，但是這些資料似乎認為有持續的效果，這對長期結果很重要。
　　
　　他指出，我們的資料顯示，神經質改善最少的病患有84%復發，如果這些發現被再現確認，表示你可以預測哪些病患有復發高風險，而可以提供直接的適當資源來防止復發。
　　
　　【尚無臨床影響】
　　美國精神科協會前任理事長、密西根大學的Michelle Riba醫師接受Medscape Psychiatry邀請對該研究發現發表評論時表示，該研究對於憂鬱症的文獻做出一個重要貢獻。
　　
　　不過，她指出，醫師或許還不能將神經質作為一個臨床結果。
　　
　　她表示，雖然本研究在臨床上很有趣，我們並不傾向將神經質和外向作為每日臨床實務，因此我認為這些發現將不會、也不應改變目前的任何臨床實務。
　　
　　她指出，不清楚研究者何以選擇paroxetine作為研究藥物，它並非廣被使用的SSRI，因為它可能會干擾其他藥物。
　　
　　Riba醫師指出，NEO-FFI主要是研究工具，很少用在臨床實務，再者，她指出，研究對象年齡層太廣(18 – 70歲)，研究排除了厭惡社交、邊緣性和/或準分裂型患者，對於研究結果的一般化有所影響。
　　
　　Riba醫師表示，這是一個執行良好的研究，但醫師已經瞭解人格對於憂鬱是重要的，當病患使用標準抗憂鬱治療而未較佳時，我們通常會重起爐灶並探究會影響憂鬱的人格議題。
　　
　　作者們皆宣告沒有相關財務關係。


Targeting Neuroticism May Help Predict Long-Term Outcomes in Major Depression

By Caroline Cassels
Medscape Medical News

December 23, 2009 — The selective serotonin reuptake inhibitor (SSRI) paroxetine (Paxil, GlaxoSmithKline) appears to have a positive effect on personality that is separate and distinct from its antidepressant effects — a finding researchers say may assist in the prediction of long-term outcomes in patients with major depression.

A large placebo-controlled trial led by Tony Z. Tang, PhD, Northwestern University, Evanston, Illinois, showed patients with major depressive disorder (MDD) taking paroxetine underwent greater personality change than those taking placebo, including a significant reduction in neuroticism and a marked increase in extraversion, even after controlling for depression improvement.

Investigators found patients taking paroextine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement.

"People on paroxetine had a reduction in neuroticism and an increase in extraversion, but probably more important than that is if you look at the difference between the paroxetine group and the placebo group, the difference on those 2 personality dimensions are much bigger than on their difference of depression severity," Dr. Tang told Medscape Psychiatry.

If replicated, these results may lay waste to the so-called "state effect" hypothesis, which asserts that any personality changes that occur during SSRI treatment are the direct result of improvement in depressive symptoms.

The study is published in the December issue of the Archives of General Psychiatry.

Greater Personality Change

According to the investigators, high neuroticism is a personality risk factor that reflects much of the genetic vulnerability to MDD, and low extraversion may increase risk as well. Both personality traits have been linked to the serotonin system, the key therapeutic target for SSRIs.

To explore the potential effect of SSRI treatment on neuroticism and extraversion, the investigators randomly assigned 240 MDD patients aged 18 to 70 years to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60).

The study's main outcome measure was change in the NEO Five-Factor Inventory (NEO-FFI), a widely used self-report measure used in personality research, and the Hamilton Rating Scale for Depression.

Following an acute treatment phase, responders to cognitive therapy and paroxetine entered a 12-month continuation phase. Paroxetine responders were randomly assigned to 2 subgroups — 34 continued taking the medication at the same dose, and 35 were withdrawn from the active drug and given the placebo. The 35 participants who responded to cognitive therapy were allowed up to 3 booster sessions scheduled 1 month apart.

The investigators found that patients who received paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (P < .001; extraversion, P = .002).

Further, Dr. Tang pointed out the advantage of paroxetine over placebo in terms of its antidepressant effect was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14).

In addition, the authors report that although placebo patients exhibited substantial depression improvement, they experienced little change in neuroticism or extraversion.

Patients in the cognitive therapy group experienced a greater personality change than placebo (P ? .01), but its effect on neuroticism was no longer significant after controlling for depression.

Lower Relapse Rates

Importantly, said Dr. Tang, neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P = .003) but not among cognitive therapy responders (P = .86).

"We were surprised by quite a few of the findings — one of the biggest surprises was how well neuroticism improvement predicted long-term outcomes," said Dr. Tang.

The biggest challenge in treating depression is achieving good long-term outcomes. "Initial response and recovery comes fairly easily, but relapse rates are high so that within a year, a large proportion of patients end up back in the clinic," he said.

However, he added, this study suggests the chances of relapse in patients who experience a large improvement in neuroticism are much, much lower than those who recover but who do not show much neuroticism improvement.

"This finding is very surprising partly because physicians don't generally expect any type of long-lasting impact from [SSRIs] but these data seem to suggest there might be an enduring effect and that this could be very important to long-term outcomes," said Dr. Tang.

"Our data show that 84% of patients who showed the least amount of neuroticism improvement relapsed. If these findings can be replicated, it suggests that you could predict which patients are at high risk of relapse and direct the appropriate resources towards them to prevent it from occurring," he added.

No Clinical Implications Yet

Asked by Medscape Psychiatry to comment on the study findings, Michelle Riba, MD, from the University of Michigan in Ann Arbor, and a past president of the American Psychiatric Association, said the study makes an important contribution to the depression literature.

However, she pointed out, physicians probably should not be targeting neuroticism as a clinical outcome just yet.

"Although this study is interesting clinically, we don't tend to look at neuroticism and extraversion in everyday clinical practice, and so I don't think these findings will, or should, change anyone's clinical practice today," she said.

She added that it was unclear why the investigators chose paroxetine as the study drug, as it is not as widely used as other SSRIs because of its propensity to interfere with other medications.

Dr. Riba noted that the NEO-FFI is largely a research tool and not in wide use in clinical practice. Furthermore, she noted the wide age range of subjects (18 - 70 years) and the fact that excluding individuals with antisocial, borderline, and/or schizotypal disorders from the study may affect the generalizability of the findings.

"This is a well-done study, but clinicians already understand that personality is important in depression. When a patient is not getting better with standard antidepressant treatment, we often go back to the drawing board and look at the personality issues that may be affecting the depression," said Dr. Riba.

The authors have disclosed no relevant financial relationships.

Arch Gen Psych. 2009;66:1322-1330.