1
00:00:08,060 --> 00:00:11,076
This is a tuberculosis ward,

2
00:00:11,100 --> 00:00:14,916
and at the time this picture was taken
in the late 1800s,

3
00:00:14,940 --> 00:00:17,556
one in seven of all people

4
00:00:17,580 --> 00:00:19,340
died from tuberculosis.

5
00:00:19,780 --> 00:00:22,540
We had no idea
what was causing this disease.

6
00:00:23,140 --> 00:00:25,196
The hypothesis was actually

7
00:00:25,220 --> 00:00:28,476
it was your constitution
that made you susceptible.

8
00:00:28,500 --> 00:00:31,236
And it was a highly romanticized disease.

9
00:00:31,260 --> 00:00:34,076
It was also called consumption,

10
00:00:34,100 --> 00:00:37,236
and it was the disorder of poets

11
00:00:37,260 --> 00:00:39,996
and artists and intellectuals.

12
00:00:40,020 --> 00:00:43,756
And some people actually thought
it gave you heightened sensitivity

13
00:00:43,780 --> 00:00:45,980
and conferred creative genius.

14
00:00:47,700 --> 00:00:49,836
By the 1950s,

15
00:00:49,860 --> 00:00:52,436
we instead knew
that tuberculosis was caused

16
00:00:52,460 --> 00:00:55,836
by a highly contagious
bacterial infection,

17
00:00:55,860 --> 00:00:58,036
which is slightly less romantic,

18
00:00:58,060 --> 00:01:00,316
but that had the upside

19
00:01:00,340 --> 00:01:03,676
of us being able to maybe
develop drugs to treat it.

20
00:01:03,700 --> 00:01:06,716
So doctors had discovered
a new drug, iproniazid,

21
00:01:06,740 --> 00:01:10,116
that they were optimistic
might cure tuberculosis,

22
00:01:10,140 --> 00:01:11,916
and they gave it to patients,

23
00:01:11,940 --> 00:01:13,716
and patients were elated.

24
00:01:13,740 --> 00:01:17,236
They were more social, more energetic.

25
00:01:17,260 --> 00:01:21,860
One medical report actually says
they were "dancing in the halls."

26
00:01:22,500 --> 00:01:24,116
And unfortunately,

27
00:01:24,140 --> 00:01:26,860
this was not necessarily
because they were getting better.

28
00:01:27,420 --> 00:01:29,620
A lot of them were still dying.

29
00:01:30,660 --> 00:01:37,260
Another medical report describes them
as being "inappropriately happy."

30
00:01:38,220 --> 00:01:41,820
And that is how the first
antidepressant was discovered.

31
00:01:42,980 --> 00:01:47,036
So accidental discovery
is not uncommon in science,

32
00:01:47,060 --> 00:01:50,196
but it requires more
than just a happy accident.

33
00:01:50,220 --> 00:01:53,660
You have to be able to recognize it
for discovery to occur.

34
00:01:54,500 --> 00:01:57,236
As a neuroscientist,
I'm going to talk to you a little bit

35
00:01:57,260 --> 00:01:58,676
about my firsthand experience

36
00:01:58,700 --> 00:02:01,916
with whatever you want to call
the opposite of dumb luck --

37
00:02:01,940 --> 00:02:03,556
let's call it smart luck.

38
00:02:03,580 --> 00:02:06,300
But first, a bit more background.

39
00:02:07,460 --> 00:02:10,116
Thankfully, since the 1950s,

40
00:02:10,139 --> 00:02:14,116
we've developed some other drugs
and we can actually now cure tuberculosis.

41
00:02:14,140 --> 00:02:17,796
And at least in the United States,
though not necessarily in other countries,

42
00:02:17,820 --> 00:02:19,316
we have closed our sanitoriums

43
00:02:19,340 --> 00:02:23,020
and probably most of you
are not too worried about TB.

44
00:02:23,900 --> 00:02:26,556
But a lot of what was true
in the early 1900s

45
00:02:26,580 --> 00:02:28,436
about infectious disease,

46
00:02:28,460 --> 00:02:31,100
we can say now
about psychiatric disorders.

47
00:02:31,820 --> 00:02:34,836
We are in the middle
of an epidemic of mood disorders

48
00:02:34,860 --> 00:02:38,620
like depression and post-traumatic
stress disorder, or PTSD.

49
00:02:39,300 --> 00:02:43,156
One in four of all adults
in the United States

50
00:02:43,180 --> 00:02:44,660
suffers from mental illness,

51
00:02:45,180 --> 00:02:48,316
which means that if you haven't
experienced it personally

52
00:02:48,340 --> 00:02:50,636
or someone in your family hasn't,

53
00:02:50,660 --> 00:02:53,916
it's still very likely
that someone you know has,

54
00:02:53,940 --> 00:02:55,580
though they may not talk about it.

55
00:02:57,220 --> 00:03:00,516
Depression has actually now surpassed

56
00:03:00,540 --> 00:03:05,396
HIV/AIDS, malaria, diabetes and war

57
00:03:05,420 --> 00:03:08,676
as the leading cause
of disability worldwide.

58
00:03:08,700 --> 00:03:12,316
And also, like tuberculosis in the 1950s,

59
00:03:12,340 --> 00:03:14,396
we don't know what causes it.

60
00:03:14,420 --> 00:03:16,356
Once it's developed, it's chronic,

61
00:03:16,380 --> 00:03:17,876
lasts a lifetime,

62
00:03:17,900 --> 00:03:20,220
and there are no known cures.

63
00:03:21,660 --> 00:03:23,876
The second antidepressant we discovered,

64
00:03:23,900 --> 00:03:26,356
also by accident, in the 1950s,

65
00:03:26,380 --> 00:03:29,580
from an antihistamine
that was making people manic,

66
00:03:30,860 --> 00:03:32,060
imipramine.

67
00:03:33,220 --> 00:03:36,876
And in both the case of the tuberculosis
ward and the antihistamine,

68
00:03:36,900 --> 00:03:38,596
someone had to be able to recognize

69
00:03:38,620 --> 00:03:41,036
that a drug that was designed
to do one thing --

70
00:03:41,060 --> 00:03:43,636
treat tuberculosis
or suppress allergies --

71
00:03:43,660 --> 00:03:46,396
could be used to do
something very different --

72
00:03:46,420 --> 00:03:47,620
treat depression.

73
00:03:48,380 --> 00:03:51,396
And this sort of repurposing
is actually quite challenging.

74
00:03:51,420 --> 00:03:55,356
When doctors first saw
this mood-enhancing effect of iproniazid,

75
00:03:55,380 --> 00:03:57,836
they didn't really recognize
what they saw.

76
00:03:57,860 --> 00:03:59,716
They were so used to thinking about it

77
00:03:59,740 --> 00:04:02,516
from the framework
of being a tuberculosis drug

78
00:04:02,540 --> 00:04:04,596
that they actually just listed it

79
00:04:04,620 --> 00:04:07,396
as a side effect, an adverse side effect.

80
00:04:07,420 --> 00:04:08,571
As you can see here,

81
00:04:08,596 --> 00:04:12,620
a lot of these patients in 1954
are experiencing severe euphoria.

82
00:04:13,900 --> 00:04:17,516
And they were worried
that this might somehow interfere

83
00:04:17,540 --> 00:04:20,396
with their recovering from tuberculosis.

84
00:04:20,420 --> 00:04:26,676
So they recommended that iproniazid
only be used in cases of extreme TB

85
00:04:26,700 --> 00:04:30,380
and in patients that were
highly emotionally stable,

86
00:04:31,220 --> 00:04:35,116
which is of course the exact opposite
of how we use it as an antidepressant.

87
00:04:35,140 --> 00:04:39,596
They were so used to looking at it
from the perspective of this one disease,

88
00:04:39,620 --> 00:04:43,540
they could not see the larger implications
for another disease.

89
00:04:44,380 --> 00:04:47,076
And to be fair,
it's not entirely their fault.

90
00:04:47,100 --> 00:04:49,876
Functional fixedness
is a bias that affects all of us.

91
00:04:49,900 --> 00:04:53,356
It's a tendency to only
be able to think of an object

92
00:04:53,380 --> 00:04:55,980
in terms of its traditional
use or function.

93
00:04:56,740 --> 00:04:58,636
And mental set is another thing. Right?

94
00:04:58,660 --> 00:05:00,676
That's sort of this preconceived framework

95
00:05:00,700 --> 00:05:02,476
with which we approach problems.

96
00:05:02,500 --> 00:05:05,756
And that actually makes repurposing
pretty hard for all of us,

97
00:05:05,780 --> 00:05:09,316
which is, I guess, why they gave
a TV show to the guy who was,

98
00:05:09,340 --> 00:05:11,140
like, really great at repurposing.

99
00:05:11,660 --> 00:05:13,540
(Laughter)

100
00:05:14,180 --> 00:05:18,516
So the effects in both the case
of iproniazid and imipramine,

101
00:05:18,540 --> 00:05:19,916
they were so strong --

102
00:05:19,940 --> 00:05:22,156
there was mania,
or people dancing in the halls.

103
00:05:22,180 --> 00:05:25,316
It's actually not that surprising
they were caught.

104
00:05:25,340 --> 00:05:28,820
But it does make you wonder
what else we've missed.

105
00:05:30,020 --> 00:05:32,196
So iproniazid and imipramine,

106
00:05:32,220 --> 00:05:34,636
they're more than just
a case study in repurposing.

107
00:05:34,660 --> 00:05:37,636
They have two other things in common
that are really important.

108
00:05:37,660 --> 00:05:40,156
One, they have terrible side effects.

109
00:05:40,180 --> 00:05:42,796
That includes liver toxicity,

110
00:05:42,820 --> 00:05:45,796
weight gain of over 50 pounds,

111
00:05:45,820 --> 00:05:47,596
suicidality.

112
00:05:47,620 --> 00:05:51,796
And two, they both
increase levels of serotonin,

113
00:05:51,820 --> 00:05:54,156
which is a chemical signal in the brain,

114
00:05:54,180 --> 00:05:55,380
or a neurotransmitter.

115
00:05:56,380 --> 00:05:58,876
And those two things together,
right, one or the two,

116
00:05:58,900 --> 00:06:00,516
may not have been that important,

117
00:06:00,540 --> 00:06:04,276
but the two together meant
that we had to develop safer drugs,

118
00:06:04,300 --> 00:06:07,820
and that serotonin seemed
like a pretty good place to start.

119
00:06:08,660 --> 00:06:12,556
So we developed drugs
to more specifically focus on serotonin,

120
00:06:12,580 --> 00:06:16,236
the selective serotonin
reuptake inhibitors, so the SSRIs,

121
00:06:16,260 --> 00:06:18,996
the most famous of which is Prozac.

122
00:06:19,020 --> 00:06:20,996
And that was 30 years ago,

123
00:06:21,020 --> 00:06:24,220
and since then we have mostly
just worked on optimizing those drugs.

124
00:06:24,740 --> 00:06:27,956
And the SSRIs, they are better
than the drugs that came before them,

125
00:06:27,980 --> 00:06:30,076
but they still have a lot of side effects,

126
00:06:30,100 --> 00:06:32,996
including weight gain, insomnia,

127
00:06:33,020 --> 00:06:34,220
suicidality --

128
00:06:35,100 --> 00:06:37,436
and they take a really long time to work,

129
00:06:37,460 --> 00:06:39,996
something like four to six weeks
in a lot of patients.

130
00:06:40,020 --> 00:06:42,196
And that's in the patients
where they do work.

131
00:06:42,220 --> 00:06:45,076
There are a lot of patients
where these drugs don't work.

132
00:06:45,100 --> 00:06:48,476
And that means now, in 2016,

133
00:06:48,500 --> 00:06:52,316
we still have no cures
for any mood disorders,

134
00:06:52,340 --> 00:06:54,396
just drugs that suppress symptoms,

135
00:06:54,420 --> 00:06:58,476
which is kind of the difference between
taking a painkiller for an infection

136
00:06:58,500 --> 00:06:59,916
versus an antibiotic.

137
00:06:59,940 --> 00:07:01,796
A painkiller will make you feel better,

138
00:07:01,820 --> 00:07:04,900
but is not going to do anything
to treat that underlying disease.

139
00:07:05,700 --> 00:07:08,036
And it was this flexibility
in our thinking

140
00:07:08,060 --> 00:07:10,996
that let us recognize
that iproniazid and imipramine

141
00:07:11,020 --> 00:07:13,116
could be repurposed in this way,

142
00:07:13,140 --> 00:07:15,116
which led us to the serotonin hypothesis,

143
00:07:15,140 --> 00:07:18,140
which we then, ironically, fixated on.

144
00:07:18,980 --> 00:07:21,516
This is brain signaling, serotonin,

145
00:07:21,540 --> 00:07:22,796
from an SSRI commercial.

146
00:07:22,820 --> 00:07:25,180
In case you're not clear,
this is a dramatization.

147
00:07:25,660 --> 00:07:29,716
And in science, we try
and remove our bias, right,

148
00:07:29,740 --> 00:07:32,116
by running double-blinded experiments

149
00:07:32,140 --> 00:07:35,836
or being statistically agnostic
as to what our results will be.

150
00:07:35,860 --> 00:07:40,156
But bias creeps in more insidiously
in what we choose to study

151
00:07:40,180 --> 00:07:41,900
and how we choose to study it.

152
00:07:43,260 --> 00:07:46,836
So we've focused on serotonin now
for the past 30 years,

153
00:07:46,860 --> 00:07:49,100
often to the exclusion of other things.

154
00:07:49,860 --> 00:07:51,220
We still have no cures,

155
00:07:52,180 --> 00:07:55,596
and what if serotonin
isn't all there is to depression?

156
00:07:55,620 --> 00:07:57,676
What if it's not even the key part of it?

157
00:07:57,700 --> 00:07:59,876
That means no matter how much time

158
00:07:59,900 --> 00:08:02,636
or money or effort we put into it,

159
00:08:02,660 --> 00:08:04,580
it will never lead to a cure.

160
00:08:05,500 --> 00:08:08,076
In the past few years,
doctors have discovered

161
00:08:08,100 --> 00:08:13,020
probably what is the first truly new
antidepressant since the SSRIs,

162
00:08:13,540 --> 00:08:14,836
Calypsol,

163
00:08:14,860 --> 00:08:18,316
and this drug works very quickly,
within a few hours or a day,

164
00:08:18,340 --> 00:08:20,236
and it doesn't work on serotonin.

165
00:08:20,260 --> 00:08:22,940
It works on glutamate,
which is another neurotransmitter.

166
00:08:23,380 --> 00:08:24,876
And it's also repurposed.

167
00:08:24,900 --> 00:08:27,980
It was traditionally used
as anesthesia in surgery.

168
00:08:28,540 --> 00:08:30,196
But unlike those other drugs,

169
00:08:30,220 --> 00:08:32,035
which were recognized pretty quickly,

170
00:08:32,059 --> 00:08:33,756
it took us 20 years

171
00:08:33,780 --> 00:08:36,436
to realize that Calypsol
was an antidepressant,

172
00:08:36,460 --> 00:08:39,316
despite the fact that it's actually
a better antidepressant,

173
00:08:39,340 --> 00:08:40,956
probably, than those other drugs.

174
00:08:40,980 --> 00:08:45,076
It's actually probably because of the fact
that it's a better antidepressant

175
00:08:45,100 --> 00:08:46,995
that it was harder for us to recognize.

176
00:08:47,019 --> 00:08:49,100
There was no mania to signal its effects.

177
00:08:49,580 --> 00:08:52,676
So in 2013, up at Columbia University,

178
00:08:52,700 --> 00:08:54,276
I was working with my colleague,

179
00:08:54,300 --> 00:08:56,276
Dr. Christine Ann Denny,

180
00:08:56,300 --> 00:09:00,100
and we were studying Calypsol
as an antidepressant in mice.

181
00:09:00,660 --> 00:09:03,476
And Calypsol has, like,
a really short half-life,

182
00:09:03,500 --> 00:09:06,556
which means it's out of your body
within a few hours.

183
00:09:06,580 --> 00:09:07,996
And we were just piloting.

184
00:09:08,020 --> 00:09:10,276
So we would give an injection to mice,

185
00:09:10,300 --> 00:09:11,596
and then we'd wait a week,

186
00:09:11,620 --> 00:09:14,300
and then we'd run
another experiment to save money.

187
00:09:15,020 --> 00:09:17,156
And one of the experiments I was running,

188
00:09:17,180 --> 00:09:18,836
we would stress the mice,

189
00:09:18,860 --> 00:09:21,076
and we used that as a model of depression.

190
00:09:21,100 --> 00:09:24,436
And at first it kind of just looked
like it didn't really work at all.

191
00:09:24,460 --> 00:09:25,980
So we could have stopped there.

192
00:09:26,540 --> 00:09:29,436
But I have run this model
of depression for years,

193
00:09:29,460 --> 00:09:31,356
and the data just looked kind of weird.

194
00:09:31,380 --> 00:09:33,236
It didn't really look right to me.

195
00:09:33,260 --> 00:09:34,476
So I went back,

196
00:09:34,500 --> 00:09:35,996
and we reanalyzed it

197
00:09:36,020 --> 00:09:39,836
based on whether or not they had gotten
that one injection of Calypsol

198
00:09:39,860 --> 00:09:41,060
a week beforehand.

199
00:09:41,940 --> 00:09:43,956
And it looked kind of like this.

200
00:09:43,980 --> 00:09:46,116
So if you look at the far left,

201
00:09:46,140 --> 00:09:48,636
if you put a mouse in a new space,

202
00:09:48,660 --> 00:09:50,916
this is the box, it's very exciting,

203
00:09:50,940 --> 00:09:53,076
a mouse will walk around and explore,

204
00:09:53,100 --> 00:09:57,396
and you can see that pink line
is actually the measure of them walking.

205
00:09:57,420 --> 00:10:00,596
And we also give it
another mouse in a pencil cup

206
00:10:00,620 --> 00:10:02,676
that it can decide to interact with.

207
00:10:02,700 --> 00:10:05,916
This is also a dramatization,
in case that's not clear.

208
00:10:05,940 --> 00:10:09,636
And a normal mouse will explore.

209
00:10:09,660 --> 00:10:10,900
It will be social.

210
00:10:11,620 --> 00:10:12,996
Check out what's going on.

211
00:10:13,020 --> 00:10:15,916
If you stress a mouse
in this depression model,

212
00:10:15,940 --> 00:10:17,220
which is the middle box,

213
00:10:18,100 --> 00:10:19,996
they aren't social, they don't explore.

214
00:10:20,020 --> 00:10:23,300
They mostly just kind of hide
in that back corner, behind a cup.

215
00:10:24,020 --> 00:10:27,116
Yet the mice that had gotten
that one injection of Calypsol,

216
00:10:27,140 --> 00:10:28,340
here on your right,

217
00:10:29,060 --> 00:10:31,020
they were exploring, they were social.

218
00:10:31,740 --> 00:10:34,220
They looked like they
had never been stressed at all,

219
00:10:35,020 --> 00:10:36,220
which is impossible.

220
00:10:37,260 --> 00:10:38,980
So we could have just stopped there,

221
00:10:39,780 --> 00:10:44,076
but Christine had also used
Calypsol before as anesthesia,

222
00:10:44,100 --> 00:10:45,676
and a few years ago she had seen

223
00:10:45,700 --> 00:10:48,076
that it seemed to have
some weird effects on cells

224
00:10:48,100 --> 00:10:49,316
and some other behavior

225
00:10:49,340 --> 00:10:52,356
that also seemed to last
long after the drug,

226
00:10:52,380 --> 00:10:53,636
maybe a few weeks.

227
00:10:53,660 --> 00:10:54,916
So we were like, OK,

228
00:10:54,940 --> 00:10:57,116
maybe this is not completely impossible,

229
00:10:57,140 --> 00:10:58,636
but we were really skeptical.

230
00:10:58,660 --> 00:11:01,196
So we did what you do in science
when you're not sure,

231
00:11:01,220 --> 00:11:02,420
and we ran it again.

232
00:11:03,460 --> 00:11:06,476
And I remember being in the animal room,

233
00:11:06,500 --> 00:11:10,156
moving mice from box to box
to test them,

234
00:11:10,180 --> 00:11:13,796
and Christine was actually sitting
on the floor with the computer in her lap

235
00:11:13,820 --> 00:11:15,236
so the mice couldn't see her,

236
00:11:15,260 --> 00:11:17,516
and she was analyzing
the data in real time.

237
00:11:17,540 --> 00:11:18,916
And I remember us yelling,

238
00:11:18,940 --> 00:11:22,236
which you're not supposed to do
in an animal room where you're testing,

239
00:11:22,260 --> 00:11:23,836
because it had worked.

240
00:11:23,860 --> 00:11:28,236
It seemed like these mice
were protected against stress,

241
00:11:28,260 --> 00:11:31,316
or they were inappropriately happy,
however you want to call it.

242
00:11:31,340 --> 00:11:33,780
And we were really excited.

243
00:11:34,820 --> 00:11:38,300
And then we were really skeptical,
because it was too good to be true.

244
00:11:38,860 --> 00:11:40,060
So we ran it again.

245
00:11:40,740 --> 00:11:43,476
And then we ran it again in a PTSD model,

246
00:11:43,500 --> 00:11:45,916
and we ran it again
in a physiological model,

247
00:11:45,940 --> 00:11:48,156
where all we did was give stress hormones.

248
00:11:48,180 --> 00:11:49,796
And we had our undergrads run it.

249
00:11:49,820 --> 00:11:53,940
And then we had our collaborators
halfway across the world in France run it.

250
00:11:54,780 --> 00:11:57,996
And every time someone ran it,
they confirmed the same thing.

251
00:11:58,020 --> 00:12:00,836
It seemed like
this one injection of Calypsol

252
00:12:00,860 --> 00:12:03,620
was somehow protecting
against stress for weeks.

253
00:12:04,180 --> 00:12:06,036
And we only published this a year ago,

254
00:12:06,060 --> 00:12:10,140
but since then other labs
have independently confirmed this effect.

255
00:12:10,940 --> 00:12:12,860
So we don't know what causes depression,

256
00:12:13,460 --> 00:12:17,156
but we do know that stress
is the initial trigger

257
00:12:17,180 --> 00:12:19,516
in 80 percent of cases,

258
00:12:19,540 --> 00:12:21,756
and depression and PTSD
are different diseases,

259
00:12:21,780 --> 00:12:23,796
but this is something
they share in common.

260
00:12:23,820 --> 00:12:25,636
Right? It is traumatic stress

261
00:12:25,660 --> 00:12:28,556
like active combat or natural disasters

262
00:12:28,580 --> 00:12:31,036
or community violence or sexual assault

263
00:12:31,060 --> 00:12:33,340
that causes post-traumatic
stress disorder,

264
00:12:33,980 --> 00:12:39,596
and not everyone that is exposed to stress
develops a mood disorder.

265
00:12:39,620 --> 00:12:42,516
And this ability to experience
stress and be resilient

266
00:12:42,540 --> 00:12:46,700
and bounce back and not develop
depression or PTSD

267
00:12:47,500 --> 00:12:49,756
is known as stress resilience,

268
00:12:49,780 --> 00:12:51,636
and it varies between people.

269
00:12:51,660 --> 00:12:54,996
And we have always thought of it
as just sort of this passive property.

270
00:12:55,020 --> 00:12:57,556
It's the absence of susceptibility factors

271
00:12:57,580 --> 00:12:59,660
and risk factors for these disorders.

272
00:13:00,620 --> 00:13:02,500
But what if it were active?

273
00:13:03,420 --> 00:13:04,916
Maybe we could enhance it,

274
00:13:04,940 --> 00:13:07,100
sort of akin to putting on armor.

275
00:13:08,220 --> 00:13:12,820
We had accidentally discovered
the first resilience-enhancing drug.

276
00:13:13,740 --> 00:13:16,516
And like I said, we only gave
a tiny amount of the drug,

277
00:13:16,540 --> 00:13:18,116
and it lasted for weeks,

278
00:13:18,140 --> 00:13:21,356
and that's not like anything
you see with antidepressants.

279
00:13:21,380 --> 00:13:25,700
But it is actually kind of similar
to what you see in immune vaccines.

280
00:13:26,180 --> 00:13:29,116
So in immune vaccines,
you'll get your shots,

281
00:13:29,140 --> 00:13:32,516
and then weeks, months, years later,

282
00:13:32,540 --> 00:13:34,876
when you're actually exposed to bacteria,

283
00:13:34,900 --> 00:13:37,356
it's not the vaccine in your body
that protects you.

284
00:13:37,380 --> 00:13:38,756
It's your own immune system

285
00:13:38,780 --> 00:13:42,916
that's developed resistance and resilience
to this bacteria that fights it off,

286
00:13:42,940 --> 00:13:45,076
and you actually never get the infection,

287
00:13:45,100 --> 00:13:48,156
which is very different
from, say, our treatments. Right?

288
00:13:48,180 --> 00:13:51,996
In that case, you get the infection,
you're exposed to the bacteria,

289
00:13:52,020 --> 00:13:55,876
you're sick, and then you take,
say, an antibiotic which cures it,

290
00:13:55,900 --> 00:13:59,140
and those drugs are actually working
to kill the bacteria.

291
00:13:59,780 --> 00:14:02,276
Or similar to as I said before,
with this palliative,

292
00:14:02,300 --> 00:14:05,156
you'll take something
that will suppress the symptoms,

293
00:14:05,180 --> 00:14:07,876
but it won't treat
the underlying infection,

294
00:14:07,900 --> 00:14:11,236
and you'll only feel better
during the time in which you're taking it,

295
00:14:11,260 --> 00:14:13,196
which is why you have to keep taking it.

296
00:14:13,220 --> 00:14:15,916
And in depression and PTSD --

297
00:14:15,940 --> 00:14:17,916
here we have your stress exposure --

298
00:14:17,940 --> 00:14:20,556
we only have palliative care.

299
00:14:20,580 --> 00:14:23,076
Antidepressants only suppress symptoms,

300
00:14:23,100 --> 00:14:25,956
and that is why you basically
have to keep taking them

301
00:14:25,980 --> 00:14:27,676
for the life of the disease,

302
00:14:27,700 --> 00:14:29,900
which is often
the length of your own life.

303
00:14:30,940 --> 00:14:35,156
So we're calling our resilience-enhancing
drugs "paravaccines,"

304
00:14:35,180 --> 00:14:36,716
which means vaccine-like,

305
00:14:36,740 --> 00:14:39,236
because it seems
like they might have the potential

306
00:14:39,260 --> 00:14:41,076
to protect against stress

307
00:14:41,100 --> 00:14:44,516
and prevent mice from developing

308
00:14:44,540 --> 00:14:47,300
depression and post-traumatic
stress disorder.

309
00:14:47,780 --> 00:14:51,220
Also, not all antidepressants
are also paravaccines.

310
00:14:52,300 --> 00:14:53,916
We tried Prozac as well,

311
00:14:53,940 --> 00:14:55,300
and that had no effect.

312
00:14:56,060 --> 00:14:59,076
So if this were to translate into humans,

313
00:14:59,100 --> 00:15:01,676
we might be able to protect people

314
00:15:01,700 --> 00:15:03,956
who are predictably at risk

315
00:15:03,980 --> 00:15:07,836
against stress-induced disorders
like depression and PTSD.

316
00:15:07,860 --> 00:15:10,996
So that's first responders
and firefighters,

317
00:15:11,020 --> 00:15:15,156
refugees, prisoners and prison guards,

318
00:15:15,180 --> 00:15:17,260
soldiers, you name it.

319
00:15:18,220 --> 00:15:22,020
And to give you a sense
of the scale of these diseases,

320
00:15:22,620 --> 00:15:25,676
in 2010, the global burden of disease

321
00:15:25,700 --> 00:15:29,540
was estimated at 2.5 trillion dollars,

322
00:15:30,060 --> 00:15:31,596
and since they are chronic,

323
00:15:31,620 --> 00:15:34,836
that cost is compounding
and is therefore expected to rise

324
00:15:34,860 --> 00:15:38,100
up to six trillion dollars
in just the next 15 years.

325
00:15:39,460 --> 00:15:41,039
As I mentioned before,

326
00:15:41,064 --> 00:15:45,140
repurposing can be challenging
because of our prior biases.

327
00:15:45,860 --> 00:15:47,380
Calypsol has another name,

328
00:15:48,100 --> 00:15:49,300
ketamine,

329
00:15:50,380 --> 00:15:51,940
which also goes by another name,

330
00:15:52,460 --> 00:15:53,876
Special K,

331
00:15:53,900 --> 00:15:56,300
which is a club drug and drug of abuse.

332
00:15:57,540 --> 00:16:00,636
It's still used across the world
as an anesthetic.

333
00:16:00,660 --> 00:16:03,516
It's used in children.
We use it on the battlefield.

334
00:16:03,540 --> 00:16:06,516
It's actually the drug of choice
in a lot of developing nations,

335
00:16:06,540 --> 00:16:08,396
because it doesn't affect breathing.

336
00:16:08,420 --> 00:16:13,100
It is on the World Health Organization
list of most essential medicines.

337
00:16:13,580 --> 00:16:17,140
If we had discovered ketamine
as a paravaccine first,

338
00:16:17,820 --> 00:16:20,676
it'd be pretty easy for us to develop it,

339
00:16:20,700 --> 00:16:24,556
but as is, we have to compete
with our functional fixedness

340
00:16:24,580 --> 00:16:27,380
and mental set that kind of interfere.

341
00:16:28,700 --> 00:16:32,556
Fortunately, it's not
the only compound we have discovered

342
00:16:32,580 --> 00:16:36,020
that has these prophylactic,
paravaccine qualities,

343
00:16:36,700 --> 00:16:38,900
but all of the other drugs
we've discovered,

344
00:16:39,780 --> 00:16:41,956
or compounds if you will,
they're totally new,

345
00:16:41,980 --> 00:16:45,596
they have to go through
the entire FDA approval process --

346
00:16:45,620 --> 00:16:49,196
if they make it before
they can ever be used in humans.

347
00:16:49,220 --> 00:16:50,876
And that will be years.

348
00:16:50,900 --> 00:16:53,156
So if we wanted something sooner,

349
00:16:53,180 --> 00:16:55,556
ketamine is already FDA-approved.

350
00:16:55,580 --> 00:16:58,276
It's generic, it's available.

351
00:16:58,300 --> 00:17:02,460
We could develop it for a fraction
of the price and a fraction of the time.

352
00:17:03,380 --> 00:17:07,756
But actually, beyond
functional fixedness and mental set,

353
00:17:07,780 --> 00:17:11,356
there's a real other challenge
to repurposing drugs,

354
00:17:11,380 --> 00:17:12,579
which is policy.

355
00:17:13,179 --> 00:17:15,395
There are no incentives in place

356
00:17:15,419 --> 00:17:19,155
once a drug is generic and off patent
and no longer exclusive

357
00:17:19,179 --> 00:17:21,516
to encourage pharma companies
to develop them,

358
00:17:21,540 --> 00:17:22,969
because they don't make money.

359
00:17:23,380 --> 00:17:26,500
And that's not true for just ketamine.
That is true for all drugs.

360
00:17:27,579 --> 00:17:33,236
Regardless, the idea itself
is completely novel in psychiatry,

361
00:17:33,260 --> 00:17:37,156
to use drugs to prevent mental illness

362
00:17:37,180 --> 00:17:38,540
as opposed to just treat it.

363
00:17:39,740 --> 00:17:44,796
It is possible that 20, 50,
100 years from now,

364
00:17:44,820 --> 00:17:48,916
we will look back now
at depression and PTSD

365
00:17:48,940 --> 00:17:52,156
the way we look back
at tuberculosis sanitoriums

366
00:17:52,180 --> 00:17:53,380
as a thing of the past.

367
00:17:54,180 --> 00:17:59,420
This could be the beginning of the end
of the mental health epidemic.

368
00:18:00,380 --> 00:18:03,580
But as a great scientist once said,

369
00:18:04,900 --> 00:18:07,156
"Only a fool is sure of anything.

370
00:18:07,180 --> 00:18:09,220
A wise man keeps on guessing."

371
00:18:11,044 --> 00:18:12,284
Thank you, guys.

372
00:18:12,780 --> 00:18:16,846
(Applause)