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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

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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 by a highly contagious

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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

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drugs to treat it.

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So doctors had discovered a new drug,

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Iproniazid, that they were optimistic

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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 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 what 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 anti-depressant.

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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

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of an object 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
pre-conceived framework

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with which we approach problems.

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And that actually make 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

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of Iproniazid and Imipramine,

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they were so strong, right,

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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

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that we had to develop

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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

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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

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than the drugs that came before them,

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but they still have a lot 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, right,
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

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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 that we put into it,

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it will never lead to a cure.

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In the past few years,

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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,

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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,

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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. ???,

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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

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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

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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 Calpysol

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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
that it seemed to have

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some weird effects on cells
and some other behavior

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that also seemed to last

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long after the drug, maybe a few weeks.

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So we were like, okay,

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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 we really excited.

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And then we were really skeptical,

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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 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

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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,

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and in 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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Right? 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

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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, right,
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,

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and you actually never get the infection,

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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, right,
with this palliatave,

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you'll take something that will
suppress the symptoms,

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but it won't treat
the underlying infection,

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and you'll only feel better

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during the time in which you're taking it,

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which is why you have to keep taking it.

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And in depression, right, 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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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,

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because it seems like they might
have the potential

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to protect against stress

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and prevent mice from developing

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depression and post-traumatic
stress disorder.

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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

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against stress-induced disorders
like depression and PTSD.

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So that's first responders
and firefighters,

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refugees, prisoners and prison guards,

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soldiers, you name it.

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And to give you a sense

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of the scale of these diseases,

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in 2010, the global burden of disease

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was estimated at 2.5 trillion dollars,

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and since they are chronic,

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that cost is compounding
and is therefore expected to rise

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up to six trillion dollars
in just the next 15 years.

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As I mentioned before,
repurposing can be challenging

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because of our prior biases.

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Calypsol has another name,

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Ketamine,

355
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which also goes by another name,

356
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Special K,

357
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which is a club drug and drug of abuse.

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It's still used across the world
as an anesthetic.

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It's used in children.
We use it on the battlefield.

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It's actually the drug of choice
in a lot of developing nations

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because it doesn't affect breathing.

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It is on the World Health Organization
list of most essential medicines.

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If we had discovered Ketamine
as a paravaccine first,

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it'd be pretty easy for us to develop it,

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but as is, we have to compete
with our functional fixedness

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and mental set that kind of interfere.

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Fortunately, it's not the only compound
we have discovered

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that has these prophylactic,
paravaccine qualities,

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but all of the other
drugs we've discovered,

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or compounds if you will,
they're totally new,

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they have to go through
the entire FDA approval process,

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if they make it,

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before they can ever be used in humans.

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And that will be years.

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So if we want something sooner,

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Ketamine is already FDA-approved.

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It's generic, it's available.

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We could develop it for a fraction
of the price and a fraction of the time.

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But actually, beyond functional fixedness

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and mental set,

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there's a real other challenge
to repurposing drugs,

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which is policy.

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There are no incentives in place

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once a drug is generic and off patent
and no longer exclusive

385
99:59:59,999 --> 99:59:59,999
to encourage pharma companies
to develop them,

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because they don't make money.

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And that's not true for just Ketamine.

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That is true for all drugs.

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Regardless, the idea itself
is completely novel in psychiatry,

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to use drugs to prevent mental illness

391
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as opposed to just treat it.

392
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It is possible

393
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that 20, 50, 100 years from now,

394
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we will look back now
at depression and PTSD

395
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the way we look back
at tuberculosis sanitariums

396
99:59:59,999 --> 99:59:59,999
as a thing of the past.

397
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This could be the beginning
of the end of mental health epidemic.

398
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But as a great scientist once said,

399
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only a fool is sure of anything.

400
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A wise man keeps on guessing.

401
99:59:59,999 --> 99:59:59,999
Thank you guys.

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99:59:59,999 --> 99:59:59,999
(Applause)