and at the time this picture was taken in the late 1800s,

這張照片拍攝於 19 世紀晚期，

one in seven of all people

那個時候，每七個人之中就有一個人

died from tuberculosis.

死於結核病。

We had no idea what was causing this disease.

當時沒人知道 這種疾病的病因是什麼。

The hypothesis was actually

只能猜想

it was your constitution that made you susceptible.

是因為體質因素讓人染病。

And it was a highly romanticized disease.

結核病當時還是 一種被高度浪漫化的疾病，

It was also called consumption,

它又被稱為憔悴症，

and it was the disorder of poets

被視為是詩人、藝術家

and artists and intellectuals.

和知識分子才有的失調病症。

And some people actually thought it gave you heightened sensitivity

有些人甚至認為它會讓人極為敏感

and conferred creative genius.

並賦予創造才華。

By the 1950s,

到了 1950 年代，

we instead knew that tuberculosis was caused

我們知道了結核病

by a highly contagious bacterial infection,

是由一種高傳染性的 細菌感染所引起，

which is slightly less romantic,

這就不那麼浪漫了。

but that had the upside

但這個發現也帶來了好消息，

of us being able to maybe develop drugs to treat it.

那就是我們可能 可以研發藥物治療結核病。

So doctors had discovered a new drug, iproniazid,

所以醫生發明了一種新藥 ──異菸鹼異丙醯肼，

that they were optimistic might cure tuberculosis,

希望可以治癒結核病。

and they gave it to patients,

他們把這種藥給病人用，

and patients were elated.

病人都欣喜若狂，

They were more social, more energetic.

變得更樂於社交，更充滿活力，

One medical report actually says they were "dancing in the halls."

一份醫療報告甚至稱病人們都 「在走廊上跳舞」。

And unfortunately,

不幸的是，

this was not necessarily because they were getting better.

這並不一定是因為 他們的病情有所好轉。

A lot of them were still dying.

許多病人仍瀕臨死亡。

Another medical report describes them as being "inappropriately happy."

另一份醫療報告說這些病人 「開心得不正常」。

And that is how the first antidepressant was discovered.

這就是第一種抗抑鬱劑的研發歷史。

So accidental discovery is not uncommon in science,

意外發現在科學中很常見，

but it requires more than just a happy accident.

但是僅僅有幸運的意外是不夠的。

You have to be able to recognize it for discovery to occur.

你還需要有辨識出它的能力。

As a neuroscientist, I'm going to talk to you a little bit

作為一個神經學家，

about my firsthand experience

我要和大家分享我自己的親身經歷。

with whatever you want to call the opposite of dumb luck --

我的經歷也充滿了意外，

let's call it smart luck.

就讓我們稱它為有心的意外吧。

But first, a bit more background.

首先，我要多講一些背景。

Thankfully, since the 1950s,

非常幸運地，自從1950 年代以來，

we've developed some other drugs and we can actually now cure tuberculosis.

我們研發了其他 可以治癒結核病的藥物。

And at least in the United States, though not necessarily in other countries,

儘管其他國家還可能存在結核病， 至少在美國

we have closed our sanitoriums

我們關閉了結核病療養院，

and probably most of you are not too worried about TB.

大多數人也不太擔憂患結核病。

But a lot of what was true in the early 1900s

但是 20 世紀早期，

about infectious disease,

關於傳染病的種種狀況

we can say now about psychiatric disorders.

現在正在精神疾病領域上演。

We are in the middle of an epidemic of mood disorders

我們正處於精神疾病氾濫的年代，

like depression and post-traumatic stress disorder, or PTSD.

抑鬱症和創傷後壓力疾患 就是精神疾病的兩個例子。

One in four of all adults in the United States

在美國，

suffers from mental illness,

每四個成年人中 就有一個患有精神病，

which means that if you haven't experienced it personally

這就意味著

or someone in your family hasn't,

即使你或你的家人沒有精神類疾病，

it's still very likely that someone you know has,

你認識的人當中 很可能有精神病患者，

though they may not talk about it.

即使他們不談論自己的疾病。

Depression has actually now surpassed

抑鬱症已經超過

HIV/AIDS, malaria, diabetes and war

愛滋病、瘧疾、糖尿病、戰爭，

as the leading cause of disability worldwide.

成為世界上導致殘疾的首要因素。

And also, like tuberculosis in the 1950s,

就像 1950 年代的結核病一樣，

we don't know what causes it.

抑鬱症目前病因不明。

Once it's developed, it's chronic,

一旦發病，

lasts a lifetime,

這種慢性病會持續一生，

and there are no known cures.

而且目前無法治癒。

The second antidepressant we discovered,

在 1950 年代， 我們從一種抗組織胺藥中

also by accident, in the 1950s,

意外地發現了第二種抗抑鬱的藥物。

from an antihistamine that was making people manic,

這種會使人感到興奮的藥物

imipramine.

是伊米帕明。

And in both the case of the tuberculosis ward and the antihistamine,

在這兩個關於 結核病和抗組織胺藥例子中，

someone had to be able to recognize

必須要有人意識到

that a drug that was designed to do one thing --

原本發明用來 治療結核病或過敏的藥物，

treat tuberculosis or suppress allergies --

可能用在非常不同的方面──

could be used to do something very different --

治療抑鬱症。

treat depression.

這種改變用途的作法其實困難重重。

And this sort of repurposing is actually quite challenging.

當醫生第一次見到異菸鹼異丙醯肼 對情緒的影響時，

When doctors first saw this mood-enhancing effect of iproniazid,

他們並沒有意識到這個成效，

they didn't really recognize what they saw.

他們一貫的想法就是

They were so used to thinking about it

異菸鹼異丙醯肼 是治療結核病的藥物，

from the framework of being a tuberculosis drug

以至於他們認為他們所見到的 是藥物的副作用，

that they actually just listed it

而且是不良的副作用。

as a side effect, an adverse side effect.

像這張圖片中顯示的，

As you can see here,

1954 年很多病人患有嚴重的欣快症。

a lot of these patients in 1954 are experiencing severe euphoria.

醫生甚至擔心

And they were worried that this might somehow interfere

這會影響病人的結核病情。

with their recovering from tuberculosis.

所以他們建議，只有病症十分嚴重，

So they recommended that iproniazid only be used in cases of extreme TB

而且病人情緒十分穩定時， 才使用異菸鹼異丙醯肼，

and in patients that were highly emotionally stable,

這與我們今天用這種藥物來 抗抑鬱的情形正好相反。

which is of course the exact opposite of how we use it as an antidepressant.

他們太習慣從結核病的角度 來考量這種藥物，

They were so used to looking at it from the perspective of this one disease,

以至於他們不能意識到 它對其他疾病更大的作用。

they could not see the larger implications for another disease.

說句公道話，這也不是他們的錯，

And to be fair, it's not entirely their fault.

我們所有人都受功能固著影響。

Functional fixedness is a bias that affects all of us.

功能固著使我們看到一種事物時，

It's a tendency to only be able to think of an object

傾向只想到其傳統固有的 作用和功能。

in terms of its traditional use or function.

思維定式是另一回事，對吧？

And mental set is another thing. Right?

那是我們處理問題的時候

That's sort of this preconceived framework

所使用的先入為主框架。

with which we approach problems.

這使得我們都很難 為事物想出新用途，

And that actually makes repurposing pretty hard for all of us,

所以那些總能舊物新用的人

which is, I guess, why they gave a TV show to the guy who was,

才有機會上電視吧！

like, really great at repurposing.

（笑聲）

(Laughter)

異菸鹼異丙醯肼和伊米帕明 藥效都很強，

So the effects in both the case of iproniazid and imipramine,

服用的人會變得狂躁，

they were so strong --

有些人會興奮得在走廊上跳舞。

there was mania, or people dancing in the halls.

所以發現他們的抑鬱作用 不讓人意外。

It's actually not that surprising they were caught.

但這讓我們不免懷疑， 是不是漏了什麼。

But it does make you wonder what else we've missed.

異菸鹼異丙醯肼和伊米帕明

So iproniazid and imipramine,

不僅僅是舊藥新用的例子，

they're more than just a case study in repurposing.

他們還有另外兩個重要的共同點。

They have two other things in common that are really important.

第一，他們都有巨大的副作用，

One, they have terrible side effects.

包括肝中毒、

That includes liver toxicity,

體重增加超過 20 公斤、

weight gain of over 50 pounds,

自殺傾向等。

suicidality.

第二，他們都會增加 血清素的分泌量。

And two, they both increase levels of serotonin,

血清素是大腦中的一種化學信號，

which is a chemical signal in the brain,

或稱為神經傳遞質。

or a neurotransmitter.

單一種副作用可能不那麼重要，

And those two things together, right, one or the two,

但是這兩種副作用同時出現，

may not have been that important,

使得研發更安全的藥物十分必要。

but the two together meant that we had to develop safer drugs,

血清素就是我們研發新藥的起點。

and that serotonin seemed like a pretty good place to start.

所以我們研發了 專門針對血清素的藥物，

So we developed drugs to more specifically focus on serotonin,

選擇性血清素再吸收抑制劑， 又稱 SSRIs。

the selective serotonin reuptake inhibitors, so the SSRIs,

百憂解是 SSRIs 中最著名的了。

the most famous of which is Prozac.

這是 30 年前的事情了，

And that was 30 years ago,

自那之後，我們主要 就在優化這些藥物。

and since then we have mostly just worked on optimizing those drugs.

SSRIs 比之前的藥物要好，

And the SSRIs, they are better than the drugs that came before them,

但是他們仍然有很多副作用，

but they still have a lot of side effects,

包括體重增加、失眠、

including weight gain, insomnia,

自殺傾向。

suicidality --

SSRIs 發揮藥效也非常緩慢，

and they take a really long time to work,

很多病人要服用四到六週才能見效。

something like four to six weeks in a lot of patients.

這還是對病人有效的情況。

And that's in the patients where they do work.

對於另一些病人， 這類藥是無效的。

There are a lot of patients where these drugs don't work.

這就意味著直到現在，2016 年，

And that means now, in 2016,

我們仍然沒有 治療任何精神病的藥物，

we still have no cures for any mood disorders,

只有可以緩解症狀的藥物。

just drugs that suppress symptoms,

這其中的區別就像是治療感染時， 是服用止痛藥，

which is kind of the difference between taking a painkiller for an infection

還是服用抗生素。

versus an antibiotic.

止痛藥可以減緩症狀，

A painkiller will make you feel better,

但是並不能治療 引起這些症狀的疾病。

but is not going to do anything to treat that underlying disease.

我們思維的可變通性

And it was this flexibility in our thinking

讓我們意識到 異菸鹼異丙醯肼和伊米帕明

that let us recognize that iproniazid and imipramine

可以被用作治療抑鬱症，

could be repurposed in this way,

也使我們注意到血清素，

which led us to the serotonin hypothesis,

諷刺的是，我們就此 失去了可變通性。

which we then, ironically, fixated on.

這是來自一個 SSRI 廣告的

This is brain signaling, serotonin,

血清素大腦訊號。

from an SSRI commercial.

這是誇大的表現形式。

In case you're not clear, this is a dramatization.

在科學領域，我們盡力去除偏見，

And in science, we try and remove our bias, right,

像是進行雙盲實驗，

by running double-blinded experiments

或不預設實驗結果 以免干擾統計過程。

or being statistically agnostic as to what our results will be.

但是我們的研究方向和研究方法

But bias creeps in more insidiously in what we choose to study

也是偏見的一種潛在表現形式。

and how we choose to study it.

我們專注於血清素的研究 已經達 30 年之久，

So we've focused on serotonin now for the past 30 years,

放棄了很多研究其他藥物的機會。

often to the exclusion of other things.

我們仍然沒有找到治療方法，

We still have no cures,

萬一血清素不足以治癒抑鬱症呢？

and what if serotonin isn't all there is to depression?

萬一血清素不是 治癒抑鬱症的關鍵呢？

What if it's not even the key part of it?

那將會意味著

That means no matter how much time

不管我們投入多少時間、 金錢或心血，

or money or effort we put into it,

我們仍然不能治癒抑鬱症。

it will never lead to a cure.

過去的幾年間，

In the past few years, doctors have discovered

醫生研發了自 SSRIs 以來 第一種真正的新抗抑鬱劑，

probably what is the first truly new antidepressant since the SSRIs,

可利普索 (Calypsol)。

Calypsol,

這種藥見效很快， 幾個小時到一天就見效，

and this drug works very quickly, within a few hours or a day,

而且不是透過血清素發揮作用，

and it doesn't work on serotonin.

而是透過另一種神經傳遞質 ──麩胺酸──發揮作用的。

It works on glutamate, which is another neurotransmitter.

這也是舊藥新用的例子。

And it's also repurposed.

那本來是手術中的麻醉藥。

It was traditionally used as anesthesia in surgery.

不像之前的幾種藥物