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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 of us

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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

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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

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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 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 an 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,
a lot of these patients in 1954

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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

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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

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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

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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

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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

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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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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

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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

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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

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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

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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,

257
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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.

259
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And we had our undergrads run it.

260
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And then we had our collaborators
halfway across the world in France run it.

261
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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

263
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was somehow protecting
against stress for weeks.

264
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And we only published this a year ago,

265
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but since then other labs
have independently confirmed this effect.

266
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So we don't know what causes depression,

267
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but we do know that stress
is the initial trigger

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in 80 percent of cases,

269
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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

273
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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

276
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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,

280
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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

283
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and risk factors for these disorders.

284
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But what if it were active?

285
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Maybe we could enhance it,

286
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sort of akin to putting on armor.

287
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We had accidentally discovered

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the first resilience-enhancing drug.

289
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And like I said, we only gave
a tiny amount of the drug,

290
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and it lasted for weeks,

291
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and that's not like anything
you see with antidepressants.

292
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But it is actually kind of similar
to what you see in immune vaccines.

293
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So in immune vaccines,
you'll get your shots,

294
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and then weeks, months, years later

295
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when you're actually exposed to bacteria,

296
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it's not the vaccine in your body
that protects you.

297
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It's your own immune system

298
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that's developed resistance and resilience
to this bacteria that fights it off,

299
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and you actually never get the infection,

300
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which is very different
from, say, our treatments. Right?

301
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In that case, you get the infection,
you're exposed to the bacteria,

302
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you're sick, and then you take,
say, an antibiotic which cures it,

303
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and those drugs are actually working
to kill the bacteria.

304
00:13:52,680 --> 00:13:55,176
Or similar to as I said before,
with this palliative,

305
00:13:55,200 --> 00:13:58,056
you'll take something
that will suppress the symptoms,

306
00:13:58,080 --> 00:14:00,776
but it won't treat
the underlying infection,

307
00:14:00,800 --> 00:14:04,136
and you'll only feel better
during the time in which you're taking it,

308
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which is why you have to keep taking it.

309
00:14:06,120 --> 00:14:08,816
And in depression and PTSD --

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here we have your stress exposure --

311
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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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00:14:18,880 --> 00:14:20,576
for the life of the disease,

315
00:14:20,600 --> 00:14:22,800
which is often
the length of your own life.

316
00:14:23,840 --> 00:14:28,056
So we're calling our resilience
enhancing drugs "paravaccines,"

317
00:14:28,080 --> 00:14:29,616
which means vaccine-like,

318
00:14:29,640 --> 00:14:32,136
because it seems
like they might have the potential

319
00:14:32,160 --> 00:14:33,976
to protect against stress

320
00:14:34,000 --> 00:14:37,416
and prevent mice from developing

321
00:14:37,440 --> 00:14:40,200
depression and post-traumatic
stress disorder.

322
00:14:40,680 --> 00:14:44,120
Also, not all antidepressants
are also paravaccines.

323
00:14:45,200 --> 00:14:46,816
We tried Prozac as well,

324
00:14:46,840 --> 00:14:48,200
and that had no effect.

325
00:14:48,960 --> 00:14:51,976
So if this were to translate into humans,

326
00:14:52,000 --> 00:14:54,576
we might be able to protect people

327
00:14:54,600 --> 00:14:56,856
who are predictably at risk

328
00:14:56,880 --> 00:15:00,736
against stress-induced disorders
like depression and PTSD.

329
00:15:00,760 --> 00:15:03,896
So that's first responders
and firefighters,

330
00:15:03,920 --> 00:15:08,056
refugees, prisoners and prison guards,

331
00:15:08,080 --> 00:15:10,160
soldiers, you name it.

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00:15:11,120 --> 00:15:12,896
And to give you a sense

333
00:15:12,920 --> 00:15:14,920
of the scale of these diseases,

334
00:15:15,520 --> 00:15:18,576
in 2010, the global burden of disease

335
00:15:18,600 --> 00:15:22,440
was estimated at 2.5 trillion dollars,

336
00:15:22,960 --> 00:15:24,496
and since they are chronic,

337
00:15:24,520 --> 00:15:27,736
that cost is compounding
and is therefore expected to rise

338
00:15:27,760 --> 00:15:31,000
up to six trillion dollars
in just the next 15 years.

339
00:15:32,360 --> 00:15:35,496
As I mentioned before,
repurposing can be challenging

340
00:15:35,520 --> 00:15:38,040
because of our prior biases.

341
00:15:38,760 --> 00:15:40,280
Calypsol has another name,

342
00:15:41,000 --> 00:15:42,200
ketamine,

343
00:15:43,280 --> 00:15:44,840
which also goes by another name,

344
00:15:45,360 --> 00:15:46,776
Special K,

345
00:15:46,800 --> 00:15:49,200
which is a club drug and drug of abuse.

346
00:15:50,440 --> 00:15:53,536
It's still used across the world
as an anesthetic.

347
00:15:53,560 --> 00:15:56,416
It's used in children.
We use it on the battlefield.

348
00:15:56,440 --> 00:15:59,416
It's actually the drug of choice
in a lot of developing nations

349
00:15:59,440 --> 00:16:01,296
because it doesn't affect breathing.

350
00:16:01,320 --> 00:16:06,000
It is on the World Health Organization
list of most essential medicines.

351
00:16:06,480 --> 00:16:10,040
If we had discovered ketamine
as a paravaccine first,

352
00:16:10,720 --> 00:16:13,576
it'd be pretty easy for us to develop it,

353
00:16:13,600 --> 00:16:17,456
but as is, we have to compete
with our functional fixedness

354
00:16:17,480 --> 00:16:20,280
and mental set that kind of interfere.

355
00:16:21,600 --> 00:16:25,456
Fortunately, it's not
the only compound we have discovered

356
00:16:25,480 --> 00:16:28,920
that has these prophylactic,
paravaccine qualities,

357
00:16:29,600 --> 00:16:31,800
but all of the other drugs
we've discovered,

358
00:16:32,680 --> 00:16:34,856
or compounds if you will,
they're totally new,

359
00:16:34,880 --> 00:16:38,496
they have to go through
the entire FDA approval process,

360
00:16:38,520 --> 00:16:39,776
if they make it,

361
00:16:39,800 --> 00:16:42,096
before they can ever be used in humans.

362
00:16:42,120 --> 00:16:43,776
And that will be years.

363
00:16:43,800 --> 00:16:46,056
So if we wanted something sooner,

364
00:16:46,080 --> 00:16:48,456
ketamine is already FDA-approved.

365
00:16:48,480 --> 00:16:51,176
It's generic, it's available.

366
00:16:51,200 --> 00:16:55,360
We could develop it for a fraction
of the price and a fraction of the time.

367
00:16:56,280 --> 00:16:59,376
But actually, beyond functional fixedness

368
00:16:59,400 --> 00:17:00,656
and mental set,

369
00:17:00,680 --> 00:17:04,256
there's a real other challenge
to repurposing drugs,

370
00:17:04,280 --> 00:17:05,480
which is policy.

371
00:17:06,079 --> 00:17:08,296
There are no incentives in place

372
00:17:08,319 --> 00:17:12,056
once a drug is generic and off patent
and no longer exclusive

373
00:17:12,079 --> 00:17:14,415
to encourage pharma companies
to develop them,

374
00:17:14,440 --> 00:17:15,868
because they don't make money.

375
00:17:16,280 --> 00:17:19,400
And that's not true for just ketamine.
That is true for all drugs.

376
00:17:20,480 --> 00:17:26,136
Regardless, the idea itself
is completely novel in psychiatry,

377
00:17:26,160 --> 00:17:30,056
to use drugs to prevent mental illness

378
00:17:30,080 --> 00:17:31,440
as opposed to just treat it.

379
00:17:32,640 --> 00:17:34,216
It is possible

380
00:17:34,240 --> 00:17:37,696
that 20, 50, 100 years from now,

381
00:17:37,720 --> 00:17:41,816
we will look back now
at depression and PTSD

382
00:17:41,840 --> 00:17:45,056
the way we look back
at tuberculosis sanitoriums

383
00:17:45,080 --> 00:17:46,280
as a thing of the past.

384
00:17:47,080 --> 00:17:52,320
This could be the beginning of the end
of the mental health epidemic.

385
00:17:53,280 --> 00:17:56,480
But as a great scientist once said,

386
00:17:57,800 --> 00:18:00,056
only a fool is sure of anything.

387
00:18:00,080 --> 00:18:02,120
A wise man keeps on guessing.

388
00:18:04,000 --> 00:18:05,240
Thank you guys.

389
00:18:05,680 --> 00:18:08,280
(Applause)