紐約時(shí)報(bào)雜志的長(zhǎng)文，追述人類和抑郁癥斗爭(zhēng)的歷史。人類對(duì)抑郁癥的認(rèn)識(shí)，從無(wú)知到了解，從回避到積極應(yīng)對(duì)，這是一個(gè)曠日持久的過(guò)程，并且還在進(jìn)行著。好消息是我們已經(jīng)越來(lái)越了解抑郁的機(jī)理，并且有越來(lái)越有效的治療方法。用知識(shí)武裝自己，戰(zhàn)勝抑郁。
翻譯者們和他們想說(shuō)的一句話：
@峰哥何峰 希望通過(guò)我的翻譯，把國(guó)外最準(zhǔn)確，最實(shí)時(shí)的信息帶給中文讀者！
@簡(jiǎn)里里 大家一起Have Fun 哈！
@雙末芥arolf
@Freddie Lyon (′?ω?｀)
@你才是懶貓 哈 有點(diǎn)心慌。。。
@瑜兒小 第一次翻譯心理類的文章，一起學(xué)習(xí)~
@小弱_人參淫家 最近對(duì)心理學(xué)的東西愈發(fā)感興趣了~
@卡帕的小紅狐
@sar
@驚蟄 水平不高求輕拍!~
@dseye 大家速度好快
@清凈 功夫不負(fù)有心人 下載瀏覽器/重啟電腦/耐心等待若干回合后 終于傳上來(lái)啦~~~~
（特別感謝@清凈！一晚上把未翻譯的部分都補(bǔ)上了）
@MichaBerri 速度真快 翻完了？嗯 校正
@Caren Nice to have fun.
@Anonymous 大家效率好高，時(shí)差黨跟不上啊啊～！
@木繞子日屯 希望以后多參與，嘿嘿
@摳鼻屎的人 太有效率了，而且質(zhì)量高
=========
原文來(lái)自紐約時(shí)報(bào)網(wǎng)站，鏈接
http://www.nytimes.com/2012/04/22/magazine/the-science-and-history-of-treating-depression.html April 19, 2012
Post-Prozac Nation
By SIDDHARTHA MUKHERJEE
2012年4月19日
后百憂解之國(guó)
作者 Siddhartha Mukherjee
Few medicines, in the history of pharmaceuticals, have been greeted with as much exultation as a green-and-white pill containing 20 milligrams of fluoxetine hydrochloride — the chemical we know as Prozac. In her 1994 book “Prozac Nation,” Elizabeth Wurtzel wrote of a nearly transcendental experience on the drug. Before she began treatment with antidepressants, she was living in “a computer program of total negativity . . . an absence of affect, absence of feeling, absence of response, absence of interest.” She floated from one “suicidal reverie” to the next. Yet, just a few weeks after starting Prozac, her life was transformed. “One morning I woke up and really did want to live. . . . It was as if the miasma of depression had lifted off me, in the same way that the fog in San Francisco rises as the day wears on. Was it the Prozac? No doubt.”
在藥物史中，幾乎沒有什么藥品會(huì)像一顆白綠相間的小藥丸那樣，受到市場(chǎng)的狂熱追捧。這種含20毫克鹽酸氟西汀的藥丸，就是我們熟知的百憂解。1994年，Elizabeth Wurtzel在她的自傳體小說(shuō)《百憂解之國(guó)》（譯注：后改編為電影）中描述了服用百憂解后近乎超現(xiàn)實(shí)的體驗(yàn)。 在服用抗抑郁藥劑之前，她的生活儼然是“一個(gè)崩潰的電腦程序：毫無(wú)情緒，沒有感覺，失去回應(yīng)，缺乏興致”，在各種自殺幻想中沉浮。然而在她服用了百憂解的幾周之后，人生發(fā)生了變化?！坝刑煸缟?，我醒來(lái)發(fā)現(xiàn)自己真的想要活下去……抑郁的瘴氣驅(qū)散了，就好像舊金山的霧氣消逝在晨光中一樣。是百憂解的緣故嗎？毫無(wú)疑問(wèn)?！?
Like Wurtzel, millions of Americans embraced antidepressants. In 1988, a year after the Food and Drug Administration approved Prozac, 2,469,000 prescriptions for it were dispensed in America. By 2002, that number had risen to 33,320,000. By 2008, antidepressants were the third-most-common prescription drug taken in America.
就像 Wurtzel, 數(shù)以百萬(wàn)的美國(guó)人欣然接受抗抑郁藥物。1988年，食品和藥物管理局批準(zhǔn)百憂解后的一年間，美國(guó)人消化了2,469,000份百憂解處方。到2002年，這個(gè)數(shù)字增長(zhǎng)到了33,320,000。到2008年，抗抑郁藥物成為美國(guó)第三大最常見的處方藥。
Fast forward to 2012 and the same antidepressants that inspired such enthusiasm have become the new villains of modern psychopharmacology — overhyped, overprescribed chemicals, symptomatic of a pill-happy culture searching for quick fixes for complex mental problems. In “The Emperor’s New Drugs,” the psychologist Irving Kirsch asserted that antidepressants work no better than sugar pills and that the clinical effectiveness of the drugs is, largely, a myth. If the lodestone book of the 1990s was Peter Kramer’s near-ecstatic testimonial, “Listening to Prozac,” then the book of the 2000s is David Healy’s “Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression.”
時(shí)間快進(jìn)到2012年，這些曾激發(fā)起人們極大熱情的抗抑郁藥物卻成了現(xiàn)代精神病藥物學(xué)的反面教材。人們認(rèn)為這些化學(xué)藥品被過(guò)度炒作，在處方中也被濫用，反映了我們正處于一種“嗜藥文化”中，即總想著為解決復(fù)雜的心理問(wèn)題找到捷徑。心理學(xué)家Irving Kirsch在其文章《皇帝的新藥》中堅(jiān)稱，抗抑郁藥物并不比糖片（譯注：安慰劑）更有用，在很大程度上，它的臨床療效也存疑。在20世紀(jì)90年代，如果說(shuō)最引人注目的書是Peter Kramer的《聆聽百憂解》，在這本書中他近乎狂喜地褒揚(yáng)了百憂解；那么21世紀(jì)伊始，最引人注目的書當(dāng)屬David Healy的《讓他們?nèi)シ冒賾n解吧——制藥工業(yè)和抑郁癥之間的危險(xiǎn)關(guān)系》。
In fact, the very theory for how these drugs work has been called into question. Nerve cells — neurons — talk to one another through chemical signals called neurotransmitters, which come in a variety of forms, like serotonin, dopamine and norepinephrine. For decades, a central theory in psychiatry has been that antidepressants worked by raising serotonin levels in the brain. In depressed brains, the serotonin signal had somehow been “weakened” because of a chemical imbalance in neurotransmitters. Prozac and Paxil were thought to increase serotonin levels, thereby strengthening the signals between nerve cells — as if a megaphone had been inserted in the middle.
事實(shí)上，這些藥物的工作機(jī)理飽受質(zhì)疑。神經(jīng)細(xì)胞-神經(jīng)元-它們之間通過(guò)神經(jīng)遞質(zhì)來(lái)傳遞化學(xué)信號(hào)。這些神經(jīng)遞質(zhì)有很多種形式，比如血清素、多巴胺和去腎上腺素。數(shù)十年來(lái)，在精神病學(xué)領(lǐng)域，一個(gè)關(guān)鍵的理論是：抗抑郁的藥物是為了提高人大腦中血清的水平。在抑郁癥患者的大腦中，血清素的信號(hào)水平由于神經(jīng)遞質(zhì)的水平不均而“被削弱”的。百憂解和Paxil是被認(rèn)為提高血清素水平的，以此來(lái)強(qiáng)化神經(jīng)細(xì)胞之間的信號(hào)水平——就像在兩者之間加了一個(gè)擴(kuò)音器。
But this theory has been widely criticized. In The New York Review of Books, Marcia Angell, a former editor of The New England Journal of Medicine, wrote: “After decades of trying to prove [the chemical-imbalance theory], researchers have still come up empty-handed.” Jonathan Rottenberg, writing in Psychology Today, skewered the idea thus: “As a scientific venture, the theory that low serotonin causes depression appears to be on the verge of collapse. This is as it should be; the nature of science is ultimately to be self-correcting. Ideas must yield before evidence.”
但是這個(gè)理論飽受爭(zhēng)議。在紐約書評(píng)（美國(guó)一個(gè)頗有影響力的書評(píng)期刊），《新英格蘭醫(yī)學(xué)雜志》的前任編輯Marcia Angell寫道：“即使經(jīng)過(guò)了數(shù)十年對(duì)于'化學(xué)平衡理論'的驗(yàn)證，研究者仍然毫無(wú)斬獲?！?Jonathan Rottenberg,在《今日心理學(xué)》中針對(duì)這個(gè)觀點(diǎn)如是說(shuō)：“作為科學(xué)冒險(xiǎn)，低血清致抑郁的理論正在崩潰的邊緣。事情也應(yīng)當(dāng)如此；科學(xué)的本質(zhì)歸根到底就是自我修正。想法必須讓位于證據(jù)?！?
Is the “serotonin hypothesis” of depression really dead? Have we spent nearly 40 years heading down one path only to find ourselves no closer to answering the question how and why we become depressed? Must we now start from scratch and find a new theory for depression?
難道抑郁癥研究中的“血清素理論”真的行不通了嗎？難道我們朝著這個(gè)方向花了將近40年的時(shí)間，結(jié)果發(fā)現(xiàn)我們對(duì)于如何、為何會(huì)得患抑郁這個(gè)問(wèn)題的答案，幾乎毫無(wú)進(jìn)展？我們此時(shí)是否要重頭開始，選擇和尋找一個(gè)關(guān)于抑郁癥的新的理論？
Science may be self-correcting, but occasionally it overcorrects — discarding theories that instead need to be rejuvenated. The latest research suggests that serotonin is, in fact, central to the functioning of mood, although its mechanism of action is vastly more subtle and more magnificent than we ever imagined. Prozac, Paxil and Zoloft may never turn out to be the “wonder drugs” that were once advertised. But they have drastically improved our understanding of what depression is and how to treat it.
科學(xué)會(huì)進(jìn)行自我修正，但在有些情況下，會(huì)矯枉過(guò)正，拋棄了那些原本可以重獲新生的理論。最新的研究顯示，血清素確實(shí)對(duì)于調(diào)節(jié)心情起著關(guān)鍵作用，雖然血清素的工作機(jī)能比我們之前想象得遠(yuǎn)為微妙和神奇。百憂解、帕羅西汀、左洛復(fù)（抗抑郁藥物）也許永遠(yuǎn)不可能成為像之前廣告宣稱的“神器”，但它們?cè)诤艽蟪潭壬显黾恿巳藗儗?duì)于什么是抑郁癥以及如何來(lái)治療抑郁癥的認(rèn)識(shí)。
Our modern conception of the link between depression and chemicals in the brain was sparked quite by accident in the middle of the last century. In the autumn of 1951, doctors treating tubercular patients at Sea View Hospital on Staten Island with a new drug — iproniazid — observed sudden transformations in their patients’ moods and behaviors. The wards — typically glum and silent, with moribund, lethargic patients — were “bright last week with the happy faces of men and women,” a journalist wrote. Patients laughed and joked in the dining hall, as if a dark veil of grief had lifted. Energy flooded back and appetites returned. Many, ill for months, demanded five eggs for breakfast and then consumed them with gusto. When Life magazine sent a photographer to the hospital to investigate, the patients could no longer be found lying numbly in their beds: they were playing cards or dancing in the corridors.
上世紀(jì)中葉，關(guān)于抑郁癥和大腦中化學(xué)物質(zhì)之間的聯(lián)系的先進(jìn)認(rèn)知，在偶然機(jī)會(huì)中被或多或少地激發(fā)了。1951年秋，當(dāng)位于斯坦頓島的Sea View醫(yī)院的醫(yī)生用一種新藥－－異煙酰異丙肼來(lái)治療結(jié)核病病人時(shí)，醫(yī)生觀察到了這些病人的情緒和行為的突然變化。一名記者寫道，往常病房里住著垂死的病人，憂郁沉默，但上周病房里很明亮，病人露出開心的面龐。病人們?cè)诓蛷d里歡笑，似乎悲傷都已經(jīng)消散。大家都有了精神，有了食欲。許多病了幾個(gè)月的病人早餐要了五個(gè)雞蛋，吃得狼吞虎咽。當(dāng)《生活》雜志派一名攝像師來(lái)醫(yī)院進(jìn)行調(diào)查時(shí)，他發(fā)現(xiàn)病人不再木訥地躺在他們的病床上，相反，他們有的正在打牌，有的在走廊里跳舞。
If the men and women at Sea View were experiencing an awakening, then a few hundred miles south, others at Duke’s hospital encountered its reverse. In 1954, a 28-year-old woman was prescribed Raudixin to control her blood pressure. A few months later, she returned to the hospital, complaining of crying spells, dullness and lethargy. She felt futile, guilty and hopeless, she told her doctors. A few months later, when she returned, the sense of futility had turned into hostility. A 42-year-old woman prescribed Raudixin told her doctor that “God would cause her to become insane” before she could repent. The “feeling blue,” as another patient described it, persisted until the drug was discontinued. At another hospital, one patient treated with Raudixin attempted suicide. Several people had to be admitted to psychiatric wards and administered electroconvulsive therapy before the symptoms were alleviated.
如果在Sea View醫(yī)院的病人們感受到了一絲復(fù)蘇生機(jī)，那么在距離Sea View以南幾百英里的杜克醫(yī)院的病人們的經(jīng)歷恰恰相反。1958年，醫(yī)生給一位28歲的女性開了蘿芙堿來(lái)控制她的血壓。幾個(gè)月之后，她回到醫(yī)院，訴說(shuō)自己變得愛哭，反應(yīng)遲鈍，無(wú)精打采。她告訴醫(yī)生，她感到疲倦、內(nèi)疚、絕望。再過(guò)了幾個(gè)月，她再次到醫(yī)院來(lái)的時(shí)候，無(wú)力感已經(jīng)轉(zhuǎn)變成了敵意。另一位服用蘿芙堿的42歲女性告訴醫(yī)生，上帝會(huì)在她懺悔之前，把她變瘋的。另一位病人說(shuō)，“抑郁感”在停用這種藥后才消失了。在另一家醫(yī)院，一位服用蘿芙堿的病人試圖自殺。有些人甚至需要進(jìn)入精神病病房，進(jìn)行電痙攣療法才能緩解癥狀。
Psychiatrists and pharmacologists were quick to note these bizarre case reports. How, they wondered, could simple, seemingly unrelated chemicals like Raudixin or iproniazid produce such profound and opposite effects on mood? It was around this same time that scientists were learning that the brain itself was immersed in a soup of chemicals. In the early part of the century, scientists wondered how nerve cells talked to one another. By the late 1960s, evidence suggested that signals between neurons were carried by several chemicals, including the neurotransmitter serotonin. Might iproniazid and Raudixin have altered the levels of some neurotransmitters in the brain, thereby changing brain signaling and affecting mood? Strikingly so, scientists found. Raudixin — the “feeling blue” drug — drastically lowered the concentration of serotonin and closely related neurotransmitters in the brain. Conversely, drugs known to increase euphoria, like iproniazid, increased those levels.
精神病學(xué)家和藥理學(xué)家很快就注意到了這些奇怪的案例報(bào)告。他們感到困惑，那些簡(jiǎn)單且看來(lái)毫無(wú)聯(lián)系的化學(xué)物質(zhì)，比如蘿芙堿或異煙酰異丙肼，為何能對(duì)情緒產(chǎn)生如此強(qiáng)烈而又相反的影響？ 正在此時(shí)，科學(xué)家們弄明白了大腦是被浸沒在一碗充滿化學(xué)物質(zhì)的湯里的。20世紀(jì)初期，科學(xué)家們還在疑惑神經(jīng)細(xì)胞是如何互相交流的。 到了60年代末，有證據(jù)顯示，神經(jīng)元之間的信號(hào)是由一些化學(xué)物質(zhì)傳遞的，其中包括復(fù)合胺。難道是異煙酰異丙肼和蘿芙堿改變了大腦中某些神經(jīng)傳遞介質(zhì)的水平，從而改變了大腦的信號(hào)傳遞并影響了情緒嗎？令人驚奇的是，科學(xué)家們發(fā)現(xiàn)事實(shí)的確如此。蘿芙堿，那種讓人有“抑郁感”的藥，大幅降低了大腦中血清素和與其關(guān)聯(lián)的神經(jīng)遞質(zhì)的濃度。相反地，那些讓人精神愉悅的藥物，例如異煙酰異丙肼，卻增加了那些化學(xué)物質(zhì)的濃度。
These early findings led psychiatrists to propose a radical new hypothesis about the cause and treatment of depression. Depression, they argued, was a result of a “chemical imbalance” of neurotransmitters in the brain. In the normal brain, serotonin shuttled between mood-maintaining neurons, signaling their appropriate function. In the depressed brain, this signal had somehow gone wrong. The writer Andrew Solomon once evocatively described depression as a “flaw in love” — and certainly, the doctors using Raudixin at Duke had seen that flaw emerge grimly in real time: flaws in self-love (guilt, shame, suicidal thoughts), love for others (blame, aggression, accusation), even the extinction of a desire for love (lethargy, withdrawal, dullness). But these were merely the outer symptoms of a deeper failure of neurotransmitters. The “flaw in love” was a flaw in chemicals.
這些早期的發(fā)現(xiàn)引導(dǎo)精神病學(xué)家對(duì)抑郁癥的成因和治療提出了一種激進(jìn)的新假設(shè)。他們認(rèn)為，抑郁癥是大腦中的神經(jīng)遞質(zhì)“化學(xué)失衡”的結(jié)果。正常情況下，大腦中控制情緒的神經(jīng)元借助血清素往返穿梭，從而傳導(dǎo)恰當(dāng)?shù)男盘?hào)。而大腦處于抑郁時(shí)，這種傳導(dǎo)機(jī)制不知為何失靈了。作家Andrew Solomon曾把抑郁癥生動(dòng)地稱作“愛的瑕疵”———當(dāng)然，杜克醫(yī)院那些用蘿芙堿的醫(yī)生們已經(jīng)見識(shí)過(guò)這些瞬時(shí)發(fā)作的可怕缺陷了：缺乏自愛（產(chǎn)生內(nèi)疚、羞恥、自殺的想法），不懂關(guān)愛他人（歸咎、攻擊、譴責(zé)他人），甚至不存在愛的欲望（死氣沉沉、不斷逃避、精神遲鈍）。但是，這些只是外在癥狀，根源在于神經(jīng)遞質(zhì)深層次的傳導(dǎo)失敗?！皭鄣蔫Υ谩逼鋵?shí)是化學(xué)上的缺陷。
Powerful vindication for this theory came from the discovery of new medicines that specifically elevated serotonin concentrations. The first such drug, Zimelidine, was created by a Swedish researcher, Arvid Carlsson. Following Carlsson’s lead, pharmaceutical chemists threw their efforts and finances into finding serotonin-enhancing drugs, and the new giants of the antidepressant world were born in rapid succession. Prozac was created in 1974. Paxil appeared in 1975, Zoloft in 1977 (the trade names were introduced years later).
專門提高血清素濃度的新藥物的發(fā)現(xiàn)是對(duì)這個(gè)理論的有力證明。第一種這類藥物Zimelidine是由瑞典研究員Arvid Carlsson發(fā)明的。在Carlsson之后，藥劑師們將精力和財(cái)力投入到提高血清素類藥物的研究上，使得抗抑郁劑世界的新貴一個(gè)接著一個(gè)地出現(xiàn)：1974年的百憂解，1975年的帕羅西汀，還有1977年的左洛復(fù)（這些商業(yè)名稱是幾年以后引進(jìn)的）。
In 2003, in Boston, I began treating a 53-year-old woman with advanced pancreatic cancer. Dorothy had no medical problems until she developed an ominous sign known to every cancer specialist: painless jaundice, the sudden yellowing of skin without any associated pinch of discomfort. Painless jaundice can have many causes, but the one that oncologists know best, and fear most, is pancreatic cancer.
2003年在波士頓，我開始治療一個(gè)53歲的患有晚期胰腺癌的女人（譯注：?jiǎn)滩妓沟玫木褪且认侔?。Dorothy的身體一直很健康，直到她發(fā)現(xiàn)自己身上出現(xiàn)了無(wú)痛性黃疸（皮膚突然變黃而沒有疼痛感），這是每個(gè)癌癥專家都知道的患癌前的不祥預(yù)兆。出現(xiàn)無(wú)痛性黃疸的原因有很多種，但是對(duì)于腫瘤學(xué)家來(lái)說(shuō)，他們最熟悉也最擔(dān)心的，就是胰腺癌了。
In Dorothy’s case, the mass in the pancreas turned out to be large and fist-shaped, with malignant extensions that reached backward to grip blood vessels, and a solitary metastasis in the liver. Surgical removal was impossible, chemotherapy the only option.
在Dorothy的案例中，胰腺里的腫塊較大，拳頭狀，惡性的增生向后延伸到血管，并且癌細(xì)胞孤立轉(zhuǎn)移到了肝臟。手術(shù)摘除是不可行的，只有化療了。
The suddenness of the diagnosis struck her like an intravenous anaesthetic, instantly numbing everything. As we started chemotherapy in the hospital, she spent her mornings in bed sleeping or staring out of the window at the river below. Most disturbing, I watched as she lapsed into self-neglect. Her previously well-kept hair grew into a matted coil. The clothes that she had worn to the hospital remained unchanged. There were even more troubling signs: tiny abrasions in the skin that were continuously picked at, food left untouched by the bedside table and a gradual withdrawal of eye contact. One morning, I walked into what seemed like a daily emotional flare-up: someone had moved a pillow on the bed, Dorothy had been unable to sleep and it was somehow her son’s fault.
這個(gè)突如其來(lái)的診斷讓她覺得自己像是被打了靜脈麻醉注射劑,所有一切立刻變得麻木.當(dāng)我們?cè)卺t(yī)院里進(jìn)行化療時(shí),她整個(gè)早上都躺在床上睡覺或者呆望著窗外的河邊.最讓人煩擾的,是我眼睜睜的看著她陷入自我忽視之中.她之前那頭精心保養(yǎng)的秀發(fā)變得亂糟糟的一團(tuán).衣服也仍然是之前進(jìn)醫(yī)院時(shí)穿的那套.甚至還有更糟糕的跡象:皮膚上的細(xì)小傷疤天天被扒開,食物放在床邊的桌子上一動(dòng)未動(dòng),并且她漸漸回避起眼神交流.一天早上,我碰到一場(chǎng)看起來(lái)像是每日必有的情緒爆發(fā):有人把床上的枕頭移動(dòng)過(guò)了,Dorothy完全難以入睡,而匪夷所思地怪她兒子.
This grief, of course, was fully provoked by the somberness of her diagnosis — to not grieve would have been bizarre in these circumstances — but she recognized something troubling in her own reaction and begged for help. I contacted a psychiatrist. With her consent, we prescribed Prozac.
讓人絕望的診斷結(jié)果給她帶來(lái)了巨大的痛苦——在這種情況下不痛苦那才是奇葩——但她意識(shí)到了自己所感受到的混亂并且尋求了幫助。我聯(lián)系了一個(gè)精神病專家。在她的同意下，我們給她開了百憂解。
In the first weeks, we waited watchfully, and nothing happened. But when I saw her again in the clinic after a month and a half, there were noticeable changes. Her hair was clean and styled. Her cuts had disappeared, and her skin looked good. Yet she still felt sad beyond measure, she said. She spent her days mostly in bed. The drug certainly affected many of the symptoms of depression, yet had not altered the subjective “feeling” of it. It healed the flaws in her skin but not all the flaws in love.
開始地幾周，我們耐心觀察，但什么也沒有發(fā)生。但當(dāng)我一個(gè)半月之后再在診所看到她時(shí)，她有了顯著的變化。她的頭發(fā)干凈有型，皮膚上的傷痕已經(jīng)消失不見了，皮膚看起來(lái)也很好。但她說(shuō)仍舊感到十分悲傷。她大部分時(shí)間都是在床上度過(guò)的。顯然藥物影響了抑郁癥的許多癥狀，但是沒有改變患者的主觀感受。她皮膚上的傷痕得到了治愈，但是愛的缺陷并沒有獲得痊愈。
Any sane reader of this case would argue that a serotonin imbalance was not the initiating cause of Dorothy’s depression; it was, quite evidently, the diagnosis of a fatal disease. Should we be searching for a chemical cause and cure when the provocation of grief is so apparent?
任何正常的讀者在此時(shí)都會(huì)說(shuō)，很顯然致命疾病的診斷是Dorothy抑郁的起因，而不是血清素的失衡。當(dāng)悲痛的緣由是如此明顯時(shí)，我們應(yīng)該從化學(xué)角度去尋找病因和治愈方法嗎？
Pause for a moment, though, to consider the physiology of a heart attack. A heart attack can be set off by a variety of causes — chronic high blood pressure or pathologically high levels of “bad” cholesterol or smoking. Yet aspirin is an effective treatment of a heart attack regardless of its antecedent cause. Why? Because a heart attack, however it might have been provoked, progresses through a common, final pathway: there must be a clot in a coronary artery that is blocking the flow of blood to the heart. Aspirin helps to inhibit the formation and growth of the clot in the coronary artery. The medicine is clinically effective regardless of what events led to the clot. “Aspirin,” as a professor of mine liked to put it, “does not particularly care about your medical history.”
我們先偏題一下，來(lái)看看心臟病的發(fā)病機(jī)理。一系列原因都可以引起心臟病——慢性高血壓或者膽固醇的生理水平過(guò)高或者吸煙都有可能。但是無(wú)論起因是什么，阿司匹林對(duì)治療心臟病來(lái)說(shuō)都是有效的。為什么？因?yàn)椴还苁侨绾我鸬?，心臟病最終都會(huì)形成這么一種狀況：冠狀動(dòng)脈中必有一個(gè)凝塊阻擋血液流向心臟。阿司匹林能幫助抑制冠狀動(dòng)脈中的這種凝塊的形成和生長(zhǎng)。不論造成凝塊的起因是什么，這種藥物在臨床上都是有效的。就像我的一位教授說(shuō)的，“阿司匹林并不管你的病史。”
Might major depression be like a heart attack, with a central common pathway and with serotonin as its master regulator? There was certainly precedent in the biology of the nervous system for such unifying pathways — for complex mental states triggered by simple chemicals. Fear, for instance, was found to involve a common hormonal cascade, with adrenaline as the main player, even though its initiators (bears, spiders or in-laws) might have little resemblance to one another.
抑郁癥是否可能像心臟病一樣，有一個(gè)主要的共同發(fā)病途徑并且用血清素作為它的主要調(diào)節(jié)物？在神經(jīng)系統(tǒng)生物學(xué)中有這種統(tǒng)一途徑的先例——復(fù)雜的精神狀態(tài)是由簡(jiǎn)單的化學(xué)物質(zhì)引起的。例如，研究發(fā)現(xiàn)盡管引起恐懼的種種原因（熊，蜘蛛或者遺傳原因）之間可能幾乎沒有什么相似的地方，但都包含了一個(gè)主要由腎上腺素起作用的共同的荷爾蒙級(jí)聯(lián)。
But such a line of inquiry can’t tell us whether the absence of serotonin causes depression. For that, we need to know if depressed men and women have measurably lower levels of serotonin or serotonin-metabolites (byproducts of serotonin breakdown), in their brains. In 1975, pathologists performed autopsies on depressed patients to measure serotonin levels. The initial findings were suggestive: depressed patients typically tended to have lower levels of brain serotonin compared with controls. But in 1987, when researchers in Scandinavia performed a similar experiment with newer tools to measure serotonin more accurately, serotonin levels were found to be higher in depressed patients. Further experiments only deepened these contradictions. In some trials, depressed patients were found to have decreased serotonin levels; in others, serotonin was increased; in yet others, there was no difference at all.
然而，這一連串的探究都無(wú)法告訴我們抑郁是否由缺乏血清素引起的。為此，我們需要知道抑郁的人們大腦中是否是有相對(duì)較低的血清素或血清代謝物水平（血清代謝物指血清分解的副產(chǎn)物）。1975年，病理學(xué)家對(duì)抑郁病人驗(yàn)尸來(lái)測(cè)量他們的血清水平。最初的發(fā)現(xiàn)是有建設(shè)性的：與控制組相比，抑郁癥的病人的大腦血清水平通常較低。 但在1987年，當(dāng)斯堪的納維亞的研究人員使用更新的工具進(jìn)行了相似的試驗(yàn)，試圖更準(zhǔn)確地測(cè)量血清水平時(shí)，卻發(fā)現(xiàn)抑郁的病人具有更高的血清水平。之后的試驗(yàn)更是深化了這些矛盾。在一些試驗(yàn)中，會(huì)發(fā)現(xiàn)抑郁的病人有較低的血清素水平；在另一些試驗(yàn)中，血清素含量則會(huì)升高；此外還有一些試驗(yàn)，兩者的血清水平會(huì)相較無(wú)差。
What about the converse experiment? In 1994, male subjects at McGill University in Montreal were given a chemical mixture that lowered serotonin. Doctors then measured the fluctuations in the mood of the men as serotonin levels dipped in the blood. Though serotonin was depleted, most of them experienced no significant alterations in their mood.
相反的實(shí)驗(yàn)是怎樣的呢？1994年，蒙特利爾的麥吉爾大學(xué)給男性測(cè)試者一種能夠降低血清素水平的化學(xué)混合試劑。然后醫(yī)生來(lái)測(cè)量，隨著血液中血清素的降低，這些測(cè)試者的情緒變化。盡管血清素都耗盡了，但是絕大多數(shù)測(cè)試者的情緒并沒有顯著的變化。
At first glance, these studies seem to suggest that there is no link between serotonin and depression. But an important fact stands out in the McGill experiment: lowering serotonin does not have any effect on healthy volunteers with no history of depression, but serotonin-lowering has a surprisingly brisk effect on people with a family history of depression. In these subjects, mood dipped sharply when serotonin levels dropped. An earlier version of this experiment, performed at Yale in 1990, generated even more provocative findings. When depressed patients who were already responding to serotonin-enhancing drugs, like Prozac, were fed the serotonin-lowering mixture, they became acutely, often profoundly, depressed. Why would serotonin depletion make such a difference in a patient’s mood unless mood in these patients was, indeed, being controlled by serotonin?
初看上去，這些研究似乎表明， 血清素和抑郁癥之間并沒有任何關(guān)聯(lián)。但是，在麥吉爾的實(shí)驗(yàn)中卻突顯了一個(gè)重要的事實(shí)：降低血清素不會(huì)對(duì)那些從未有過(guò)抑郁癥病史的健康志愿者產(chǎn)生影響，但血清素的降低對(duì)有家族抑郁癥病史的人產(chǎn)生了極快的效用。在這些人中，當(dāng)血清素水平下降時(shí)，他們的情緒也急劇下降。而在1990年，由耶魯大學(xué)進(jìn)行的早期實(shí)驗(yàn)中，產(chǎn)生了更令人振奮的結(jié)果。當(dāng)那些已經(jīng)對(duì)能促使血清素升高的藥物（例如百憂解）產(chǎn)生反應(yīng)的患者服用降低血清素的藥物時(shí)，他們快速并強(qiáng)烈地陷入抑郁中。為什么血清素的降低能讓病人的情緒一落千丈？除非，這些患者的情緒，確實(shí)受到了血清素的操控。
Other experiments showed that though depressed patients generally didn’t have consistently lower levels of serotonin, suicidal patients often did. Might contemplating suicide be the most extreme form of depression? Or is it a specific subtype of mood disorder that is distinct from all the other forms? And if so, might depression have multiple subtypes — some inherently responsive to treatment with serotonin-enhancing drugs and some inherently resistant?
其他實(shí)驗(yàn)表明，抑郁癥患者并不是持續(xù)的處于血清素濃度極低的狀態(tài)，但有自殺傾向的病人卻是這樣。也許是因?yàn)樽詺⑹且钟舭Y最為極端的形式？或者自殺是一個(gè)不同于其他所有形式的特定類型的情緒障礙癥？如果是這樣，抑郁癥可能會(huì)有多個(gè)分支——一些形態(tài)的抑郁癥能夠?qū)υ鰪?qiáng)血清素的藥物做出反應(yīng)，而另一些這類藥物對(duì)其毫無(wú)效用。
We may not understand how serotonin-enhancing antidepressants work, but do we know whether they work at all?
我們可能還不了解血清素具體是如何發(fā)揮效用的，但退一步說(shuō)，血清素本身究竟是否有效？
In the late 1980s, studies examined the effect of Prozac on depressed subjects. Several of these trials showed Prozac reduced the symptoms of depression when compared with a placebo. Depression is usually assessed using a standardized rating scale of different symptoms. In general, some patients reported clinically meaningful improvements, although the effects were often small and varied from trial to trial. In real-world terms, such a change could be profound: a transformation in anxiety, the lifting of the ache of guilt, an end to the desire to commit suicide. But for other patients, the changes were marginal. Perhaps the most important number that emerged from these trials was the most subjective: 74 percent of the patients reported feeling “much” or “very much” better on antidepressants.
19世紀(jì)80年代末期有一些研究針對(duì)百憂解對(duì)抑郁癥的效果。其中一些實(shí)驗(yàn)顯示，和安慰劑相比，百憂解減少了抑郁癥或者的癥狀。抑郁癥通常由不同的癥狀的標(biāo)準(zhǔn)化評(píng)分來(lái)衡量。大部分情況下，很多患者在臨床表現(xiàn)上都有改進(jìn)，盡管效果甚微且因案例而異。在現(xiàn)實(shí)世界中，這點(diǎn)改變是有深遠(yuǎn)意義的，焦慮癥的轉(zhuǎn)變，悔恨感減輕，或者不再有自殺的意圖。而對(duì)其他的一些患者，改變卻是微小的?；蛟S這些實(shí)驗(yàn)產(chǎn)生的最重要的數(shù)據(jù)也是最主觀的：74%的患者反應(yīng)對(duì)抗抑郁藥物感覺”很好“或者”非常好“。
In 1997, a psychologist, Irving Kirsch, currently at the Harvard Medical School, set out to look at the placebo effect in relation to depression. In part, the placebo effect works because the psyche acutely modifies the perception of illness or wellness. Kirsch wondered how powerful this effect might be for drugs that treat depression — where the medical condition itself happens to involve an alteration of the psyche.
在1997年，一位名叫Irving Kirsch的心理學(xué)家（現(xiàn)在哈佛醫(yī)學(xué)院）開始觀察有關(guān)抑郁癥的安慰劑效應(yīng)。安慰劑效應(yīng)有作用，一部分是因?yàn)樗剐闹歉淖兞藢?duì)疾病和健康的認(rèn)知。Kirsch想知道這種效應(yīng)對(duì)于用來(lái)治療抑郁癥有多有效，因?yàn)閼n郁癥恰好涉及到心智的改變問(wèn)題。
To measure this effect, Kirsch combined 38 trials that included patients who had been given antidepressants, placebos or no treatment and then applied mathematical reasoning to estimate how much the placebos contributed to the improvements in mood. The analysis revealed two surprises. First, when Kirsch computed the strength of the placebo effect by combining the trials, he found that 75 percent of an antidepressant’s effect could have been obtained merely by taking the placebo. When Kirsch and his collaborators combined the published and unpublished studies of antidepressants (they obtained the unpublished data from the F.D.A. via the Freedom of Information Act), the effects of the antidepressants were even more diluted — in some cases, vanishingly so. Now, the placebo effect swelled to 82 percent (i.e., four-fifths of the benefit might have been obtained by swallowing an inert pill alone). Kirsch came to believe that pharmaceutical companies were exaggerating the benefits of antidepressants by selectively publishing positive studies while suppressing negative ones.
為了測(cè)量這種效應(yīng)，Kirsch結(jié)合了38個(gè)試驗(yàn)，其中包括使用抗抑郁藥物、安慰劑或者沒有治療的病人，然后用數(shù)學(xué)推理來(lái)估算安慰劑對(duì)情緒的促進(jìn)作用。分析結(jié)果中有兩點(diǎn)讓人驚訝。首先，當(dāng)Kirsch通過(guò)綜合試驗(yàn)來(lái)計(jì)算安慰劑的效用時(shí)，他發(fā)現(xiàn)，僅僅服用安慰劑能發(fā)揮抗抑郁藥物作用的75%。當(dāng)Kirsch和他的合作者將那些對(duì)抗抑郁藥物發(fā)表或者未發(fā)表的研究結(jié)合起來(lái)（他們從食品和藥品管理局，通過(guò)“信息自由法”，獲得未發(fā)表的數(shù)據(jù)），抗抑郁藥物的作用更小，甚至在一些個(gè)案中，幾乎沒有。目前，安慰劑效應(yīng)已經(jīng)膨脹到了百分之82（也就是說(shuō)，通過(guò)服食一枚毫無(wú)藥性的藥丸，即可實(shí)現(xiàn)4/5的作用）。 Kirsch開始相信，制藥公司是通過(guò)有選擇地發(fā)表正面研究，并且抑制負(fù)面研究，從而夸大了抗抑郁藥物的益處。
But there are problems in analyzing published and unpublished trials in a “meta-trial.” A trial may have been unpublished not just to hide lesser effects but because its quality was poor — because patients were enrolled incorrectly, groups were assigned improperly or the cohort sizes were too small. Patients who are mildly depressed, for example, might have been lumped in with severely depressed patients or with obsessive-compulsives and schizophrenics.
但是解釋'試驗(yàn)元'中發(fā)表的和發(fā)表的試驗(yàn)卻有點(diǎn)麻煩.一個(gè)沒被發(fā)表的試驗(yàn)不僅僅是因?yàn)槠溆绊戄^小,還有可能是其質(zhì)量較差--因?yàn)檫x擇了錯(cuò)誤的病人,分組不當(dāng)或分組樣本量太小。舉個(gè)例子,那些患有輕度抑郁的病人也許會(huì)和重度抑郁患者/強(qiáng)迫癥患者/精神分裂癥患者集中到一組。
In 2010, researchers revisited Kirsch’s analysis using six of the most rigorously conducted studies on antidepressants. The study vindicated Kirsch’s conclusions but only to a point. In patients with moderate or mild depression, the benefit of an antidepressant was indeed small, even negligible. But for patients with the most severe forms of depression, the benefit of medications over placebo was substantial. Such patients might have found, as Andrew Solomon did, that they no longer felt “the self slipping out” of their hands. The most severe dips in mood were gradually blunted. Like Dorothy, these patients most likely still experienced sorrow, but they experienced it in ways that were less self-destructive or paralyzing. As Solomon wrote: “The opposite of depression is not happiness, but vitality, and my life, as I write this, is vital.”
2010年,研究者用最嚴(yán)謹(jǐn)?shù)膶?duì)抗抑郁劑的研究中的六個(gè)研究重新審視了Kirsch的解釋.這為Kirsch的結(jié)論提供了辯護(hù),不過(guò)僅僅是其中的一個(gè)方面。對(duì)于患有中度或者輕度抑郁癥的患者,抗抑郁劑的效果微乎其微。但對(duì)那些有著最嚴(yán)重形式的抑郁癥患者來(lái)說(shuō)藥物治療而不是安慰劑會(huì)帶來(lái)更大的益處。這些病人也許會(huì)發(fā)現(xiàn),就像Andrew Solomon一樣,他們?nèi)詴?huì)持續(xù)性的感到悲傷,但是是以一個(gè)不那么自我毀滅或者讓人陷入癱瘓的方式來(lái)經(jīng)受痛苦。正如Solomon寫的:'抑郁的反面并不是快樂(lè),是生機(jī),而我的一生,就像我寫的一樣,是生機(jī)勃勃的。'
These slippery, seemingly contradictory studies converge on a surprisingly consistent picture. First, patients with severe depression tend to respond most meaningfully to antidepressants, while patients with moderate or mild depression do not. Second, in a majority of those who do respond, serotonin very likely plays an important role, because depleting serotonin in depressed patients often causes relapses. And third, the brain-as-soup theory — with the depressed brain simply lacking serotonin — was far too na?ve.
這些不靠譜、似乎矛盾的研究匯聚起來(lái)卻成為一副極為統(tǒng)一的圖畫。首先，抗抑郁藥物對(duì)重度抑郁的患者往往最見效，對(duì)中度或者輕微程度的抑郁患者則并非如此。其次，對(duì)抗抑郁藥物有反應(yīng)的患者中的大多數(shù)，血清素很有可能起到了至關(guān)重要的作用，因?yàn)楫?dāng)抑郁癥患者血清素減少時(shí)通常會(huì)舊病復(fù)發(fā)。再次，大腦即湯羹的理論，即抑郁癥僅僅是因?yàn)榛颊叽竽X缺乏血清素—這個(gè)理論太輕率。
As is often the case in science, a new theory emerged from a radically different line of inquiry. In the late 1980s, a neuroscientist named Fred Gage became interested in a question that seemed, at first, peripheral to depression: does the adult human brain produce new nerve cells?
就像科學(xué)中經(jīng)常發(fā)生的那樣，新的理論往往是從一系列完全不同的質(zhì)問(wèn)中引發(fā)出來(lái)。19世界80年代末期，一位名叫Fred Gage的神經(jīng)學(xué)家對(duì)一個(gè)起初似乎和抑郁癥沒有關(guān)系的問(wèn)題產(chǎn)生了興趣：成人的大腦會(huì)生成新的神經(jīng)細(xì)胞么？
The dogma in neurobiology at the time was that the adult brain was developmentally frozen — no new nerve cells were born. Once the neural circuits of the brain were formed in childhood, they were fixed and immutable. After all, if new neurons were constantly replacing old ones, wouldn’t memories decay in that tide of growth? But Gage and other scientists revisited old findings and discovered that adult mice, rats and humans did, in fact, experience the birth of new neurons — but only in two very specific parts of the brain: in the olfactory bulb, where smells are registered, and in the hippocampus, a curl of tissue that controls memories and is functionally linked to parts of the brain that regulate emotion.
當(dāng)時(shí)的神經(jīng)生物學(xué)的教條這樣解釋，成人的大腦已完全發(fā)育成型——不會(huì)再有新的神經(jīng)細(xì)胞生成。一旦兒童時(shí)期神經(jīng)結(jié)構(gòu)形成就固定不變。畢竟，如果新的神經(jīng)細(xì)胞不斷替代了原本的，是否記憶也會(huì)隨這種替換而減退呢？但Gage和其他科學(xué)家重新審視了以往的研究結(jié)果并發(fā)現(xiàn)，成年小鼠、大鼠和人類事實(shí)上會(huì)生成新的神經(jīng)元-－不過(guò)只在兩個(gè)非常特定的大腦部位：嗅覺泡，即感受嗅覺的部位，還有海馬體，即控制記憶并在功能上連接著大腦中調(diào)節(jié)情緒的部位的卷狀組織。
Could there be a connection between emotion and neuronal birth in the hippocampus? To find out, Gage and his collaborators began to study stressed mice. When mice are chronically stressed — by sudden changes in their living environments or by the removal of their bedding — they demonstrate behavioral symptoms like anxiety and lethargy and lose their sense of adventurousness, features that mimic aspects of human depression. Researchers found that in these mice, the burst of nerve cells in the hippocampus also diminished.
情緒和海馬體產(chǎn)生的神經(jīng)元之間會(huì)有聯(lián)系嗎？為了找到答案，Gage和他的同伴開始研究應(yīng)激的小白鼠。當(dāng)小鼠處于慢性應(yīng)激狀態(tài)時(shí) ——通過(guò)突然改變它們的生存環(huán)境或者移除它們的墊子—— 小白鼠在行為上的癥狀表現(xiàn)為焦慮或者昏睡并且不再冒險(xiǎn)嘗試，與人類的抑郁癥特點(diǎn)相似。研究人員發(fā)現(xiàn)，這些小白鼠海馬體中神經(jīng)細(xì)胞的激活率也發(fā)生了減少。
The converse turned out to be true as well. When mice are housed in an “enriched” environment — typically containing mazes, nesting materials and toys — they become more active and adventurous. They explore more; they learn faster; they seek pleasure. Enrichment, in short, acts behaviorally like an antidepressant. When Gage examined the brains of these enriched mice, he found that more neurons were being born in the hippocampus.
反之亦然.當(dāng)小白鼠在一個(gè)豐富的環(huán)境中安家--一般有迷宮,筑巢材料和玩具--它們變得更加活躍也更具冒險(xiǎn)性.它們探索得更多，學(xué)習(xí)得更快，還自己找樂(lè)子。簡(jiǎn)而言之,豐富性,在行為上會(huì)起到抗抑郁劑的效果.當(dāng)Gage檢測(cè)了這些在豐富環(huán)境中的小白鼠,他發(fā)現(xiàn)它們的海馬體中有更多神經(jīng)元的產(chǎn)生.
At Columbia University, another neuroscientist, René Hen, was intrigued by Gage’s studies. Hen, working with other researchers, began to investigate the link between Prozac and nerve growth. The birth of neurons in the mice takes about two or three weeks — about the same time it takes for antidepressants to take effect. Might the psychiatric effects of Prozac and Paxil be related to the slow birth of neurons and not serotonin per se?
在哥倫比亞大學(xué)，另一位神經(jīng)科學(xué)家René Hen被Gage的實(shí)驗(yàn)激發(fā)了。Hen和其他研究人員開始研究Prozac和神經(jīng)生長(zhǎng)的關(guān)系。新生的小白鼠神經(jīng)元大約需要兩到三周——正是抗抑郁藥生效所需的時(shí)間。那么，氟西汀和帕羅西汀的精神影響是否與神經(jīng)元的緩慢新生而非血清素有關(guān)？
Hen began to feed his mice Prozac. Over the next few days, their behaviors changed: anxiety they had exhibited decreased, and the mice became more adventurous. They looked for food in novel environments and were quick to adopt newly learned behaviors. And newborn neurons appeared in the hippocampus in precisely the location that Gage found with the environmentally enriched mice. But when Hen selectively blocked the birth of neurons in the hippocampus, the adventurousness and the food-exploration instincts of the Prozac-fed mice vanished. Prozac’s positive effects, in other words, depended on the birth of nerve cells in the hippocampi of these mice.
Hen 開始向這些小白鼠喂食百憂解。在接下來(lái)的幾天，小白鼠的行為發(fā)生了變換，焦慮減少了，并且小白鼠變的更加活躍。小白鼠在全新的環(huán)境中找尋食物，接受新的行為也很迅速。新的神經(jīng)元在這些小白鼠的海馬體中出現(xiàn)，位置正是Gage實(shí)驗(yàn)中那些在豐富環(huán)境中小白鼠生成新神經(jīng)元的位置。然而當(dāng)Hen選擇性的阻斷了海馬體中神經(jīng)元的生長(zhǎng)后，使用了百憂解的小白鼠的活躍特征和找尋食物的本能消失了。也就是說(shuō)，百憂解的正面效果依賴于這些小白鼠海馬體中神經(jīng)元細(xì)胞的生成。
In 2011, Hen and his colleagues repeated these studies with depressed primates. In monkeys, chronic stress produces a syndrome with symptoms remarkably similar to some forms of human depression. Even more strikingly than mice, stressed monkeys lose interest in pleasure and become lethargic. When Hen measured neuron birth in the hippocampi in depressed monkeys, it was low. When he gave the monkeys antidepressants, the depressed symptoms abated and neuron birth resumed. Blocking the growth of nerve cells made Prozac ineffective.
2011年，Hen和他的同事通過(guò)抑郁的靈長(zhǎng)類動(dòng)物重復(fù)了上述實(shí)驗(yàn)。用猴子作實(shí)驗(yàn)時(shí)，慢性長(zhǎng)期壓力產(chǎn)生的癥狀和人類抑郁的癥狀大部分相似。比小白鼠更為明顯的是，受壓的猴子不愿找尋樂(lè)趣而且無(wú)精打采。Hen測(cè)量了受壓猴子海馬體中的神經(jīng)元生長(zhǎng)后發(fā)現(xiàn)，生長(zhǎng)的不多。給猴子服用抗抑郁藥物后，抑郁癥狀減少且神經(jīng)元開始生長(zhǎng)。阻止神經(jīng)細(xì)胞的生長(zhǎng)使得百憂解無(wú)效。
Hen’s experiments have profound implications for psychiatry and psychology. Antidepressants like Prozac and Zoloft, Hen suggested, may transiently increase serotonin in the brain, but their effect is seen only when new neurons are born. Might depression be precipitated by the death of neurons in certain parts of the brain? In Alzheimer’s disease, areas of the brain involved in cognition degenerate, resulting in the characteristic dementia. In Parkinson’s disease, nerve cells involved in coordinating movement degenerate, resulting in the characteristic trembling. Might depression also be a degenerative disease — an Alzheimer’s of emotion, a dementia of mood? (Even our language begins to fail in this description. Dementia describes a breakdown of “mentation” — thinking — but we lack a similar word for a degeneration of mood: is it disaffection?)
Hen的實(shí)驗(yàn)對(duì)精神病學(xué)和心理學(xué)有深遠(yuǎn)的影響，Hen 認(rèn)為Prozac和Zoloft之類的抗抑郁藥物只是暫時(shí)的提高大腦中血清素的含量，但是只在新的神經(jīng)元生成時(shí)這些藥物才有效。難道抑郁癥是因?yàn)榇竽X中某些部位神經(jīng)元的死亡而引發(fā)？阿爾茨海默癥中，神經(jīng)細(xì)胞和行動(dòng)衰退有關(guān)聯(lián)，導(dǎo)致典型的發(fā)抖。難道抑郁癥也是一種功能退化疾病——之中情感的阿爾茨海默癥，一種情緒的癡呆？（我們的語(yǔ)言也無(wú)法描述。癡呆描述了精神狀態(tài)的衰竭，但是我們?nèi)鄙僖粋€(gè)描述情緒衰退的類似的詞語(yǔ)：可以用“情緒功能退化”嗎？）
And how, exactly, might the death of neurons in the tiny caul of the hippocampus (a part of the brain typically associated with the storage of memory) cause this disorder of mood? Traditionally, we think that nerve cells in the brain can form minuscule biological “circuits” that regulate behaviors. One set of nerve cells, for instance, might receive signals to move the hand and then relay these signals to the muscles that cause hand movement. It is easy to imagine that dysfunction of this circuit might result in a disorder of movement. But how does a circuit of nerves regulate mood? Might such a circuit store, for instance, some rules about adapting to stress: what to say or do or think when you are sick and nauseated and facing death and your son has moved a pillow? Did such a degeneration provoke a panic signal in the brain that goaded Wurtzel’s deadly reverie: cellular death leading to thoughts of suicide.
海馬體（大腦中典型的和存儲(chǔ)記憶有關(guān)的部位）細(xì)小胎膜中這個(gè)神經(jīng)元的死亡是如何引起情緒的紊亂的？傳統(tǒng)上我們認(rèn)為大腦中的神經(jīng)細(xì)胞會(huì)形成細(xì)小的管理行為的生物結(jié)構(gòu)。例如，一組神經(jīng)細(xì)胞接收移動(dòng)手的信號(hào)然后將這些信號(hào)轉(zhuǎn)播給已發(fā)手部活動(dòng)的肌肉。這一生物機(jī)構(gòu)的機(jī)能失調(diào)會(huì)引發(fā)行為紊亂，這一點(diǎn)很好理解?？墒巧窠?jīng)結(jié)構(gòu)如何管理情緒？難道這個(gè)神經(jīng)結(jié)構(gòu)存儲(chǔ)著一些例如規(guī)則之類，有關(guān)適應(yīng)壓力的：生病時(shí)、惡心時(shí)、面對(duì)死亡時(shí)、兒子移動(dòng)枕頭時(shí)這些情況下你要說(shuō)什么你要怎么思考？是不是這種大腦神經(jīng)結(jié)構(gòu)衰退引發(fā)恐慌的訊息從而激發(fā)了Wurtzel尋死的念頭——細(xì)胞死亡引發(fā)自殺的意圖？
And how, then, does the birth of cells heal this feeling? Are new circuits formed that restore vitality, regenerating behaviors that are adaptive and not destructive? Is this why Prozac or Zoloft takes two or three weeks to start working: to become “undepressed,” do we have to wait for the slow rebirth of new parts of the brain?
那么，細(xì)胞的生成如何治愈這些感受？是否新的結(jié)構(gòu)生成重新恢復(fù)活力，重生有適應(yīng)能力且不具破壞性的行為？這就是為何Prozac或者Zoloft要花上兩到三周才開始起效的原因嗎？為了“擺脫抑郁”，我們必須要等待大腦中新的部分的緩慢重生嗎？
If an answer to these questions exists, it may emerge from the work of Helen Mayberg, a neuroscientist at Emory University. Mayberg has been mapping anatomical areas of the brain that are either hyperactive or inactive in depressed men and women. Tracing such sites led her to the subcallosal cingulate, a minuscule bundle of nerve cells that sit near the hippocampus and function as a conduit between the parts of the brain that control conscious thinking and the parts that control emotion. Think of the subcallosal cingulate as a potential traffic intersection on the road between our cognitive and emotional selves.
如果這些問(wèn)題存在答案的話，那可能是來(lái)自埃默里大學(xué)Helen Mayberg的工作，Mayberg了解了抑郁癥患者大腦中活躍和非活躍結(jié)構(gòu)區(qū)域。追蹤這些部位后她找到了胼胝體下區(qū)色帶，即海馬體胖的一個(gè)細(xì)小神經(jīng)細(xì)胞束，其功能是連接大腦中控制意識(shí)和控制情緒的部位，可以將胼胝體下區(qū)色帶比作人類認(rèn)知和情緒之路的潛在交叉點(diǎn)。
When Mayberg stimulated this area of the brain with tiny bursts of electricity using probes in patients resistant to antidepressant therapy, she found remarkable response rates: about 75 percent of them experienced powerful changes in their moods during testing. Seconds after stimulation began, many patients, some of them virtually catatonic with depression, reported a “sudden calmness” or a “disappearance of the void.” The stimulator can be implanted in patients and works like a depression pacemaker: it continues to relieve their symptoms for years. When the battery runs low, patients slowly relapse into depression.
Mayberg用探測(cè)器輕微電擊對(duì)抗抑郁藥物治療有抵抗力的患者的大腦這一部位時(shí)，
她發(fā)現(xiàn)了顯著的反應(yīng)比率：75%的患者的情緒在測(cè)試時(shí)經(jīng)歷了強(qiáng)烈的變化。刺激開始后幾秒鐘，很多患者幾乎沒有了抑郁的狀態(tài)，據(jù)說(shuō)是“忽然的冷靜”或者“空虛的消失”。刺激器可以植入患者，作為抑郁起搏器來(lái)使用：持續(xù)緩解患者的癥狀。電池電量低時(shí)，患者的抑郁又舊病復(fù)發(fā)。
At first glance, Mayberg’s studies would appear to bypass the serotonin hypothesis. After all, it was electrical, not chemical, stimulation that altered mood. But the response to Mayberg’s electrical stimulation also seemed to be linked to serotonin. The subcallosal cingulate is particularly rich in nerve cells that are sensitive to serotonin. Researchers found that if they blocked the serotonin signal in the brains of depressed rats, the pacemaker no longer worked.
乍一看，Mayberg的研究避開了血清素一說(shuō)。畢竟，她的研究是基于電擊而不是化學(xué)藥品刺激而引起的情緒變動(dòng)。但是Mayberg的電擊的反應(yīng)和血清素一說(shuō)還是有關(guān)聯(lián)的。在胼胝體下區(qū)色帶這個(gè)部位，對(duì)血清素敏感的神經(jīng)細(xì)胞異常豐富，研究人員發(fā)現(xiàn)，如果他們阻止了抑郁小白鼠大腦中的血清素信號(hào)，起搏器就不再有效。
A remarkable and novel theory for depression emerges from these studies. Perhaps some forms of depression occur when a stimulus — genetics, environment or stress — causes the death of nerve cells in the hippocampus. In the nondepressed brain, circuits of nerve cells in the hippocampus may send signals to the subcallosal cingulate to regulate mood. The cingulate then integrates these signals and relays them to the more conscious parts of the brain, thereby allowing us to register our own moods or act on them. In the depressed brain, nerve death in the hippocampus disrupts these signals — with some turned off and others turned on — and they are ultimately registered consciously as grief and anxiety. “Depression is emotional pain without context,” Mayberg said. In a nondepressed brain, she said, “you need the hippocampus to help put a situation with an emotional component into context” — to tell our conscious brain, for instance, that the loss of love should be experienced as sorrow or the loss of a job as anxiety. But when the hippocampus malfunctions, perhaps emotional pain can be generated and amplified out of context — like Wurtzel’s computer program of negativity that keeps running without provocation. The “flaw in love” then becomes autonomous and self-fulfilling.
這些研究引發(fā)了對(duì)抑郁癥顯著且新穎的理論?；蛟S，有些形式的抑郁癥源于刺激、遺傳、環(huán)境或者壓力導(dǎo)致海馬體中神經(jīng)細(xì)胞的死亡。在未患抑郁癥的人的大腦中，海馬體的神經(jīng)細(xì)胞結(jié)構(gòu)會(huì)向胼胝體下區(qū)色帶發(fā)送信號(hào)，從而管理情緒。色帶繼而整合這些信號(hào)并轉(zhuǎn)播至大腦中更有意識(shí)的部位，因?yàn)槲覀兙涂梢詫⑶榫w或者行為登記在其中。而在抑郁病患者的大腦中，海馬體中神經(jīng)細(xì)胞的死亡使這些信號(hào)發(fā)生紊亂——部分信號(hào)為打開狀態(tài)而部分信號(hào)為關(guān)閉狀態(tài)——因而就將意識(shí)登記為了悲傷和焦慮?！耙钟羰呛翢o(wú)征兆的情緒痛楚”，Mayberg說(shuō)。她還說(shuō)到，“在未患抑郁癥的人的大腦中，海馬體幫助人們將情緒要素放置進(jìn)一個(gè)背景中“——告知我們的大腦，譬如，愛的失去表現(xiàn)為悲傷，或者事業(yè)的表現(xiàn)為焦慮。但是當(dāng)海馬體的功能受損時(shí)，可能情緒的痛楚會(huì)在沒有緣由的情況下產(chǎn)生并擴(kuò)大——就如Wurtzel那永遠(yuǎn)運(yùn)行的消極電腦程序。”愛的瑕疵“就會(huì)自動(dòng)生成并且自我實(shí)現(xiàn)。
We “grow sorrowful,” but we rarely describe ourselves as “growing joyful.” Imprinted in our language is an instinct that suggests that happiness is a state, while grief is a process. In a scientific sense too, the chemical hypothesis of depression has moved from static to dynamic — from “state” to “process.” An antidepressant like Paxil or Prozac, these new studies suggest, is most likely not acting as a passive signal-strengthener. It does not, as previously suspected, simply increase serotonin or send more current down a brain’s mood-maintaining wire. Rather, it appears to change the wiring itself. Neurochemicals like serotonin still remain central to this new theory of depression, but they function differently: as dynamic factors that make nerves grow, perhaps forming new circuits. The painter Cézanne, confronting one of Monet’s landscapes, supposedly exclaimed: “Monet is just an eye, but, God, what an eye.” The brain, by the same logic, is still a chemical soup — but, God, what a soup.
我們會(huì)'變得沮喪,'但是我們很少形容自己'變得快樂(lè)'.深植于我們語(yǔ)言中的是一種本能,暗示著快樂(lè)是一種狀態(tài),而悲傷則是一個(gè)過(guò)程.在科學(xué)意義上也是如此,化學(xué)上對(duì)抑郁的假說(shuō)從靜態(tài)到動(dòng)態(tài)--由'狀態(tài)'到'過(guò)程'.這些新的研究表明,像帕羅西汀或者百憂解這樣的抗抑郁劑,也許并不是被動(dòng)的增強(qiáng)信號(hào).它并不像之前假設(shè)的那樣,單純?cè)黾友逅鼗蛳虼竽X的情緒保持線路傳送更多的電流.取而代之的是,它更傾向于改變線路本身.像血清素一類的神經(jīng)化學(xué)物質(zhì)仍在這個(gè)新的抑郁癥理論中占據(jù)核心地位,但是其起得作用不同了:作為使神經(jīng)生長(zhǎng)的動(dòng)力,甚至也許形成新的回路.畫家Cezanne在莫奈的一幅風(fēng)景畫前感慨:'莫奈只是一個(gè)視角,但是,天吶,多牛X的視角.'依這個(gè)邏輯來(lái)說(shuō),大腦就只是富含化學(xué)元素的一碗羹而已--但是,天吶,這是多牛x的一碗羹啊!
There are, undeniably, important gaps in this theory — and by no means can it claim to be universal. Depression is a complex, diverse illness, with different antecedent causes and manifestations. As the clinical trials show unequivocally, only a fraction of the most severely depressed patients respond to serotonin-enhancing antidepressants. Do these patients respond to Prozac because their depression involves cellular death in the hippocampus? And does the drug fail to work in mild to moderate depression because the cause of that illness is different?
不可否認(rèn)的是，這理論中有重要的漏洞 -- 并且無(wú)論如何都不能說(shuō)這理論是普遍適用的。抑郁是一個(gè)復(fù)雜，多樣的疾病，有不同的前因和體現(xiàn)。臨床實(shí)驗(yàn)已經(jīng)一致證明，serotonin-enhancing antidepressants ［血清素含量提高型抗抑郁藥物］只對(duì)抑郁最嚴(yán)重的患者中的一部分人起作用。Prozac對(duì)這些病人起作用是因?yàn)樗麄兊囊钟舾ｑR體中的細(xì)胞死亡有關(guān)么？這藥物對(duì)輕度、中度病人無(wú)效，是否因?yàn)椴∫虿煌?
The differences in responses to these drugs could also be due to variations in biological pathways. In some people, neurotransmitters other than serotonin may be involved; in yet others, there may be alterations in the brain caused by biological factors that are not neurotransmitters; in yet others, there may be no identifiable chemical or biological factors at all. The depression associated with Parkinson’s disease, for instance, seems to have little to do with serotonin. Postpartum depression is such a distinct syndrome that it is hard to imagine that neurotransmitters or hippocampal neurogenesis play a primary role in it.
對(duì)這些藥物不同的反應(yīng)也可能是因?yàn)樯锫窂降牟煌?。一些人可能涉及到神?jīng)遞質(zhì)而非血清素；而對(duì)另外一些人，大腦中存在一些不是神經(jīng)傳導(dǎo)素的生物因素引起的變化；還有一些人，根本就沒有刻意確認(rèn)的化學(xué)物質(zhì)或者生物因素。比如說(shuō)，和帕金森癥相關(guān)的抑郁癥就和血清素關(guān)系不大。產(chǎn)后抑郁癥又是一個(gè)比較特殊的癥狀，很難想象神經(jīng)傳導(dǎo)素或者海馬趾神經(jīng)形成對(duì)其有關(guān)鍵作用。
Nor does the theory explain why “talk therapies” work in some patients and not in others, and why the combination of talk and antidepressants seems to work consistently better than either alone. It is very unlikely that we can “talk” our brains into growing cells. But perhaps talking alters the way that nerve death is registered by the conscious parts of the brain. Or talking could release other chemicals, opening up parallel pathways of nerve-cell growth.
理論既沒有解釋為何“談話治療法”對(duì)一些病人有效果而對(duì)別的病人沒效果，也沒有解釋談話和抗抑郁藥物的綜合使用比兩者單獨(dú)使用效果更好。我們不可能通過(guò)“談話”使大腦生成細(xì)胞。但是也許大腦某個(gè)控制意識(shí)的部分記錄了聊天會(huì)改變神經(jīng)死亡的方式.抑或是因?yàn)檎勗捒梢葬尫牌渌瘜W(xué)物質(zhì)，打開了神經(jīng)細(xì)胞生長(zhǎng)的平行路徑。
But the most profound implications have to do with how to understand the link between the growth of neurons, the changes in mood and the alteration of behavior. Perhaps antidepressants like Prozac and Paxil primarily alter behavioral circuits in the brain — particularly the circuits deep in the hippocampus where memories and learned behaviors are stored and organized — and consequently change mood. If Prozac helped Dorothy sleep better and stopped her from assaulting her own skin, might her mood eventually have healed as a response to her own alterations of behavior? Might Dorothy, in short, have created her own placebo effect? How much of mood is behavior anyway? Maybe your brain makes you “act” depressed, and then you “feel” depressed. Or you feel depressed in part because your brain is making you act depressed. Thoughts like these quickly transcend psychiatry and move into more unexpected and unsettling realms. They might begin with mood disorders, but they quickly turn to questions about the organizational order of the brain.
但是，最為重要的結(jié)果和如何理解神經(jīng)生長(zhǎng)、情緒變化和行為改變中間的關(guān)聯(lián)是有關(guān)系的。或許Prozac和Paxil這些抗抑郁藥物主要改變大腦中的行為結(jié)構(gòu)——尤其是海馬體內(nèi)部負(fù)責(zé)存儲(chǔ)和組織記憶以及既定行為繼而改變情緒的結(jié)構(gòu)。如果Prozac幫助Dorothy有了更好的睡眠并抑制她不再毀壞自己的皮膚，她的情緒最終因?yàn)樗陨淼男袨楦淖兊靡灾斡藛?？?jiǎn)而言之，Dorothy生成了她自己的安慰效果嗎？哪些情緒是行為？可能你的大腦使你“行為”抑郁，繼而你“感受”抑郁?；蛟S你感到抑郁一部分是因?yàn)槟愕拇竽X使你行為抑郁。類似的考慮很快就超越了精神病學(xué)的領(lǐng)域并進(jìn)入了一個(gè)更不可預(yù)知更混亂的領(lǐng)域。因?yàn)榍榫w紊亂而起，但是迅速的轉(zhuǎn)向有關(guān)大腦組織秩序的問(wèn)題了。
John Gribbin, a historian of science, once wrote that seminal scientific discoveries are inevitably preceded by technological inventions. The telescope, which situated the earth and the planets firmly in orbit around the sun, instigated a new direction in thinking for astronomy and physics. The microscope, taking optics in a different direction, ultimately resulted in the discovery of the cell.
科學(xué)史家John Gribbin曾經(jīng)寫到過(guò)，開創(chuàng)性的科學(xué)發(fā)現(xiàn)總是不可避免的被技術(shù)發(fā)明超越。望遠(yuǎn)鏡的出現(xiàn)使人們認(rèn)識(shí)到地球和行星是緊緊圍繞太陽(yáng)運(yùn)轉(zhuǎn)的，也使得人們對(duì)于天文學(xué)和物理學(xué)有了新的認(rèn)識(shí)。望遠(yuǎn)鏡使得光學(xué)朝著不同的方向發(fā)展，正是這樣，才有了后來(lái)細(xì)胞的發(fā)現(xiàn)。
We possess far fewer devices to look into the unknown cosmos of mood and emotion. We can only mix chemicals and spark electrical circuits and hope, indirectly, to understand the brain’s structure and function through their effects. In time, the insights generated by these new theories of depression will most likely lead to new antidepressants: chemicals that directly initiate nerve growth in the hippocampus or stimulate the subcallosal cingulate. These drugs may make Prozac and Paxil obsolete — but any new treatment will owe a deep intellectual debt to our thinking about serotonin in the brain. Our current antidepressants are thus best conceived not as medical breakthroughs but as technological breakthroughs. They are chemical tools that have allowed us early glimpses into our brains and into the biology of one of the most mysterious diseases known to humans.
我們能夠用來(lái)探尋有關(guān)情緒情感這個(gè)未知宇宙的設(shè)備仍然很少。目前，我們只能綜合化學(xué)治療、電療和希望（心理療法？），通過(guò)這三鐘療法所產(chǎn)生的效果，間接地了解大腦的構(gòu)造及其所屬功能。但是隨著時(shí)間的推移，這些有關(guān)抑郁的新理論所形成的深刻見解將會(huì)最終極大的推動(dòng)新的抗抑郁藥劑的產(chǎn)生：新的藥物將直接刺激生長(zhǎng)在海馬或下扣帶回深部的神經(jīng)生長(zhǎng)。這些新藥物的投入使用可能會(huì)使百憂解和帕羅西汀退出市場(chǎng)，不過(guò)任何一種新的治療都會(huì)影響我們大腦中5-羥色胺的含量從而影響大腦的思維能力。我們目前的抗抑郁藥劑研究有著最為先進(jìn)的理念，但技術(shù)上的突破卻遠(yuǎn)不及醫(yī)學(xué)上的。是化學(xué)科學(xué)上的成功，讓我們能夠初窺人類的大腦，以及初始這生物學(xué)領(lǐng)域內(nèi)為人所知的最神秘的疾病之一。
Siddhartha Mukherjee is an assistant professor of medicine in the division of medical oncology at Columbia University. He is the author of ''Emperor of All Maladies: A Biography of Cancer.’’
Siddhartha Mukherjee 是哥倫比亞大學(xué)腫瘤科的醫(yī)學(xué)系助理教授。他的著作有《病中之王：癌癥傳記》。
Editor: Ilena Silverman
This article has been revised to reflect the following correction:
Correction: May 6, 2012
An article on April 22 about depression and the drugs used to treat it misidentified a drug that affects serotonin levels in the brain. It is iproniazid, not isoniazid.
編輯：Ilena Silverman
本文已經(jīng)根據(jù)以下做出糾正：
糾正：2012年5月6日
四月22日的有關(guān)抑郁癥及其藥物治療的文章搞錯(cuò)了一款影響大腦中 serotonin 水平的藥物名稱。該藥物是 iproniazid, 而不是 isoniazid.
