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This is a tuberculosis ward,

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

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one in seven of all people

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died from tuberculosis.

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We had no idea
what was causing this disease.

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The hypothesis was actually

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it was your constitution
that made you susceptible.

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And it was a highly romanticized disease.

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It was also called consumption,

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and it was the disorder of poets

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and artists and intellectuals.

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And some people actually thought
it gave you heightened sensitivity

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and conferred creative genius.

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By the 1950s,

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we instead knew
that tuberculosis was caused

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by a highly contagious
bacterial infection,

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which is slightly less romantic,

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but that had the upside

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

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So doctors had discovered
a new drug, iproniazid,

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that they were optimistic
might cure tuberculosis,

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and they gave it to patients,

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and patients were elated.

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They were more social, more energetic.

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

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And unfortunately,

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this was not necessarily
because they were getting better.

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A lot of them were still dying.

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

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And that is how the first
antidepressant was discovered.

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So accidental discovery
is not uncommon in science,

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but it requires more
than just a happy accident.

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

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

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about my firsthand experience

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

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let's call it smart luck.

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But first, a bit more background.

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Thankfully, since the 1950s,

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

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

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we have closed our sanitoriums

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

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

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about infectious disease,

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we can say now
about psychiatric disorders.

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We are in the middle
of an epidemic of mood disorders

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

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One in four of all adults
in the United States

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suffers from mental illness,

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which means that if you haven't
experienced it personally

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or someone in your family hasn't,

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

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though they may not talk about it.

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Depression has actually now surpassed

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HIV/AIDS, malaria, diabetes and war

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as the leading cause
of disability worldwide.

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And also, like tuberculosis in the 1950s,

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we don't know what causes it.

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Once it's developed, it's chronic,

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lasts a lifetime,

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and there are no known cures.

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The second antidepressant we discovered,

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also by accident, in the 1950s,

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from an antihistamine
that was making people manic,

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imipramine.

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

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someone had to be able to recognize

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

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treat tuberculosis
or suppress allergies --

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could be used to do
something very different --

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treat depression.

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And this sort of repurposing
is actually quite challenging.

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

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they didn't really recognize
what they saw.

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They were so used to thinking about it

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from the framework
of being a tuberculosis drug

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that they actually just listed it

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as a side effect, an adverse side effect.

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As you can see here,

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

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And they were worried
that this might somehow interfere

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with their recovering from tuberculosis.

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

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and in patients that were
highly emotionally stable,

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

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

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they could not see the larger implications
for another disease.

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

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Functional fixedness
is a bias that affects all of us.

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

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in terms of its traditional
use or function.

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And mental set is another thing. Right?

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That's sort of this preconceived framework

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with which we approach problems.

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

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

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like, really great at repurposing.

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(Laughter)

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

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they were so strong --

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there was mania,
or people dancing in the halls.

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It's actually not that surprising
they were caught.

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

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So iproniazid and imipramine,

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

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

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One, they have terrible side effects.

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That includes liver toxicity,

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weight gain of over 50 pounds,

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suicidality.

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And two, they both
increase levels of serotonin,

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which is a chemical signal in the brain,

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or a neurotransmitter.

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

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may not have been that important,

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

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

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So we developed drugs
to more specifically focus on serotonin,

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the selective serotonin
reuptake inhibitors, so the SSRIs,

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the most famous of which is Prozac.

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And that was 30 years ago,

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

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

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but they still have a lot of side effects,

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including weight gain, insomnia,

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suicidality --

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and they take a really long time to work,

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

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

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

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And that means now, in 2016,

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we still have no cures
for any mood disorders,

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just drugs that suppress symptoms,

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

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versus an antibiotic.

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A painkiller will make you feel better,

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

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And it was this flexibility
in our thinking

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that let us recognize
that iproniazid and imipramine

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could be repurposed in this way,

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which led us to the serotonin hypothesis,

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which we then, ironically, fixated on.

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This is brain signaling, serotonin,

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from an SSRI commercial.

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

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

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by running double-blinded experiments

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

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

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and how we choose to study it.

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

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often to the exclusion of other things.

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We still have no cures,

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

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

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That means no matter how much time

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or money or effort we put into it,

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it will never lead to a cure.

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In the past few years,
doctors have discovered

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

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Calypsol,

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

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and it doesn't work on serotonin.

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It works on glutamate,
which is another neurotransmitter.

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And it's also repurposed.

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It was traditionally used
as anesthesia in surgery.

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But unlike those other drugs,

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which were recognized pretty quickly,

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it took us 20 years

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to realize that Calypsol
was an antidepressant,

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despite the fact that it's actually
a better antidepressant,

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probably, than those other drugs.

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It's actually probably because of the fact
that it's a better antidepressant

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that it was harder for us to recognize.

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There was no mania to signal its effects.

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So in 2013, up at Columbia University,

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I was working with my colleague,

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Dr. Christine Ann Denny,

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and we were studying Calypsol
as an antidepressant in mice.

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And Calypsol has, like,
a really short half-life,

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which means it's out of your body
within a few hours.

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And we were just piloting.

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So we would give an injection to mice,

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and then we'd wait a week,

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and then we'd run
another experiment to save money.

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And one of the experiments I was running,

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we would stress the mice,

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and we used that as a model of depression.

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And at first it kind of just looked
like it didn't really work at all.

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So we could have stopped there.

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But I have run this model
of depression for years,

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and the data just looked kind of weird.

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It didn't really look right to me.

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So I went back,

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and we reanalyzed it

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based on whether or not they had gotten
that one injection of Calypsol

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a week beforehand.

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And it looked kind of like this.

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So if you look at the far left,

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if you put a mouse in a new space,

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this is the box, it's very exciting,

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a mouse will walk around and explore,

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and you can see that pink line
is actually the measure of them walking.

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And we also give it
another mouse in a pencil cup

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that it can decide to interact with.

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This is also a dramatization,
in case that's not clear.

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And a normal mouse will explore.

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It will be social.

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Check out what's going on.

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If you stress a mouse
in this depression model,

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which is the middle box,

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they aren't social, they don't explore.

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They mostly just kind of hide
in that back corner, behind a cup.

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Yet the mice that had gotten
that one injection of Calypsol,

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here on your right,

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they were exploring, they were social.

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They looked like they
had never been stressed at all,

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which is impossible.

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So we could have just stopped there,

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but Christine had also used
Calypsol before as anesthesia,

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and a few years ago she had seen

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that it seemed to have
some weird effects on cells

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and some other behavior

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that also seemed to last
long after the drug,

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maybe a few weeks.

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So we were like, OK,

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maybe this is not completely impossible,

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but we were really skeptical.

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So we did what you do in science
when you're not sure,

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and we ran it again.

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And I remember being in the animal room,

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moving mice from box to box
to test them,

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and Christine was actually sitting
on the floor with the computer in her lap

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so the mice couldn't see her,

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and she was analyzing
the data in real time.

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And I remember us yelling,

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which you're not supposed to do
in an animal room where you're testing,

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because it had worked.

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It seemed like these mice
were protected against stress,

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or they were inappropriately happy,
however you want to call it.

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And we were really excited.

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And then we were really skeptical,
because it was too good to be true.

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So we ran it again.

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And then we ran it again in a PTSD model,

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and we ran it again
in a physiological model,

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where all we did was give stress hormones.

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And we had our undergrads run it.

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And then we had our collaborators
halfway across the world in France run it.

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And every time someone ran it,
they confirmed the same thing.

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It seemed like
this one injection of Calypsol

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was somehow protecting
against stress for weeks.

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And we only published this a year ago,

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but since then other labs
have independently confirmed this effect.

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So we don't know what causes depression,

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but we do know that stress
is the initial trigger

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in 80 percent of cases,

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and depression and PTSD
are different diseases,

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but this is something
they share in common.

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Right? It is traumatic stress

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like active combat or natural disasters

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or community violence or sexual assault

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that causes post-traumatic
stress disorder,

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and not everyone that is exposed to stress
develops a mood disorder.

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And this ability to experience
stress and be resilient

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and bounce back and not develop
depression or PTSD

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is known as stress resilience,

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and it varies between people.

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And we have always thought of it
as just sort of this passive property.

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It's the absence of susceptibility factors

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and risk factors for these disorders.

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But what if it were active?

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Maybe we could enhance it,

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sort of akin to putting on armor.

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We had accidentally discovered
the first resilience-enhancing drug.

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And like I said, we only gave
a tiny amount of the drug,

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and it lasted for weeks,

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and that's not like anything
you see with antidepressants.

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But it is actually kind of similar
to what you see in immune vaccines.

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So in immune vaccines,
you'll get your shots,

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and then weeks, months, years later,

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when you're actually exposed to bacteria,

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it's not the vaccine in your body
that protects you.

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It's your own immune system

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that's developed resistance and resilience
to this bacteria that fights it off,

286
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and you actually never get the infection,

287
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which is very different
from, say, our treatments. Right?

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In that case, you get the infection,
you're exposed to the bacteria,

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you're sick, and then you take,
say, an antibiotic which cures it,

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and those drugs are actually working
to kill the bacteria.

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Or similar to as I said before,
with this palliative,

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you'll take something
that will suppress the symptoms,

293
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but it won't treat
the underlying infection,

294
00:14:00,900 --> 00:14:04,236
and you'll only feel better
during the time in which you're taking it,

295
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which is why you have to keep taking it.

296
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And in depression and PTSD --

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here we have your stress exposure --

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we only have palliative care.

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Antidepressants only suppress symptoms,

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and that is why you basically
have to keep taking them

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for the life of the disease,

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00:14:20,700 --> 00:14:22,900
which is often
the length of your own life.

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So we're calling our resilience-enhancing
drugs "paravaccines,"

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which means vaccine-like,

305
00:14:29,740 --> 00:14:32,236
because it seems
like they might have the potential

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to protect against stress

307
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and prevent mice from developing

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depression and post-traumatic
stress disorder.

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00:14:40,780 --> 00:14:44,220
Also, not all antidepressants
are also paravaccines.

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We tried Prozac as well,

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and that had no effect.

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So if this were to translate into humans,

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we might be able to protect people

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who are predictably at risk

315
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against stress-induced disorders
like depression and PTSD.

316
00:15:00,860 --> 00:15:03,996
So that's first responders
and firefighters,

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00:15:04,020 --> 00:15:08,156
refugees, prisoners and prison guards,

318
00:15:08,180 --> 00:15:10,260
soldiers, you name it.

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And to give you a sense
of the scale of these diseases,

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in 2010, the global burden of disease

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00:15:18,700 --> 00:15:22,540
was estimated at 2.5 trillion dollars,

322
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and since they are chronic,

323
00:15:24,620 --> 00:15:27,836
that cost is compounding
and is therefore expected to rise

324
00:15:27,860 --> 00:15:31,100
up to six trillion dollars
in just the next 15 years.

325
00:15:32,460 --> 00:15:34,039
As I mentioned before,

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repurposing can be challenging
because of our prior biases.

327
00:15:38,860 --> 00:15:40,380
Calypsol has another name,

328
00:15:41,100 --> 00:15:42,300
ketamine,

329
00:15:43,380 --> 00:15:44,940
which also goes by another name,

330
00:15:45,460 --> 00:15:46,876
Special K,

331
00:15:46,900 --> 00:15:49,300
which is a club drug and drug of abuse.

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00:15:50,540 --> 00:15:53,636
It's still used across the world
as an anesthetic.

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00:15:53,660 --> 00:15:56,516
It's used in children.
We use it on the battlefield.

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00:15:56,540 --> 00:15:59,516
It's actually the drug of choice
in a lot of developing nations,

335
00:15:59,540 --> 00:16:01,396
because it doesn't affect breathing.

336
00:16:01,420 --> 00:16:06,100
It is on the World Health Organization
list of most essential medicines.

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00:16:06,580 --> 00:16:10,140
If we had discovered ketamine
as a paravaccine first,

338
00:16:10,820 --> 00:16:13,676
it'd be pretty easy for us to develop it,

339
00:16:13,700 --> 00:16:17,556
but as is, we have to compete
with our functional fixedness

340
00:16:17,580 --> 00:16:20,380
and mental set that kind of interfere.

341
00:16:21,700 --> 00:16:25,556
Fortunately, it's not
the only compound we have discovered

342
00:16:25,580 --> 00:16:29,020
that has these prophylactic,
paravaccine qualities,

343
00:16:29,700 --> 00:16:31,900
but all of the other drugs
we've discovered,

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00:16:32,780 --> 00:16:34,956
or compounds if you will,
they're totally new,

345
00:16:34,980 --> 00:16:38,596
they have to go through
the entire FDA approval process --

346
00:16:38,620 --> 00:16:42,196
if they make it before
they can ever be used in humans.

347
00:16:42,220 --> 00:16:43,876
And that will be years.

348
00:16:43,900 --> 00:16:46,156
So if we wanted something sooner,

349
00:16:46,180 --> 00:16:48,556
ketamine is already FDA-approved.

350
00:16:48,580 --> 00:16:51,276
It's generic, it's available.

351
00:16:51,300 --> 00:16:55,460
We could develop it for a fraction
of the price and a fraction of the time.

352
00:16:56,380 --> 00:17:00,756
But actually, beyond
functional fixedness and mental set,

353
00:17:00,780 --> 00:17:04,356
there's a real other challenge
to repurposing drugs,

354
00:17:04,380 --> 00:17:05,579
which is policy.

355
00:17:06,179 --> 00:17:08,395
There are no incentives in place

356
00:17:08,419 --> 00:17:12,155
once a drug is generic and off patent
and no longer exclusive

357
00:17:12,179 --> 00:17:14,516
to encourage pharma companies
to develop them,

358
00:17:14,540 --> 00:17:15,969
because they don't make money.

359
00:17:16,380 --> 00:17:19,500
And that's not true for just ketamine.
That is true for all drugs.

360
00:17:20,579 --> 00:17:26,236
Regardless, the idea itself
is completely novel in psychiatry,

361
00:17:26,260 --> 00:17:30,156
to use drugs to prevent mental illness

362
00:17:30,180 --> 00:17:31,540
as opposed to just treat it.

363
00:17:32,740 --> 00:17:37,796
It is possible that 20, 50,
100 years from now,

364
00:17:37,820 --> 00:17:41,916
we will look back now
at depression and PTSD

365
00:17:41,940 --> 00:17:45,156
the way we look back
at tuberculosis sanitoriums

366
00:17:45,180 --> 00:17:46,380
as a thing of the past.

367
00:17:47,180 --> 00:17:52,420
This could be the beginning of the end
of the mental health epidemic.

368
00:17:53,380 --> 00:17:56,580
But as a great scientist once said,

369
00:17:57,900 --> 00:18:00,156
"Only a fool is sure of anything.

370
00:18:00,180 --> 00:18:02,220
A wise man keeps on guessing."

371
00:18:04,044 --> 00:18:05,284
Thank you, guys.

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00:18:05,780 --> 00:18:09,846
(Applause)