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Why Depression Isn’t What You Think | Lisa Monteggia | TED
Why Depression Isn’t What You Think | Lisa Monteggia | TED
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0:05
So when people find out that I study antidepressants,
0:09
they often ask,
0:11
how do they work?
0:12
And people are surprised to learn, we don't know.
0:18
And part of that surprise comes from the fact that we've been told
0:21
that depression is a chemical imbalance,
0:23
that you don't make enough serotonin.
0:26
And we know that antidepressants,
0:28
SSRIs are the most common antidepressant prescribed,
0:31
increase serotonin.
0:33
And so they think that what we're doing
0:35
is we're fixing depression by increasing serotonin.
0:39
But that's not the whole story.
0:41
In fact, that may not even be the story.
0:44
What I'm going to talk to you today about
0:46
is some of our work with ketamine,
0:47
a really remarkable drug that has rapid antidepressant effects.
0:51
And it doesn't correct a chemical imbalance.
0:54
It actually causes the brain to change, to adapt.
0:58
So when we talk about antidepressants, we first have to start with depression.
1:03
And everyone uses the term depressed.
1:04
We hear it all the time.
1:06
"I feel depressed, I feel sad, I have melancholy."
1:10
Creative expression of depression is very common.
1:14
For centuries, people have tried to express the feeling of depressed
1:18
or melancholy.
1:19
For example, Picasso, as illustrated in these paintings,
1:24
went through his blue period and his painting style changed.
1:28
It really portrayed a sense of sadness, of gloom.
1:33
We know that writers do this.
1:35
Poets, I mean, you can read a poem
1:36
and literally be moved to tears by the words.
1:39
Musicians.
1:41
How many sad songs do we hear?
1:43
Eric Clapton's "Tears in Heaven", about the loss of his son,
1:47
is heartbreaking.
1:50
But major depression is more than just sadness.
1:53
It's a serious medical condition,
1:56
especially left untreated.
1:59
Depression is really the dulling of emotion,
2:04
really losing interest
2:06
and sometimes completely withdrawing.
2:09
The symptoms of depression can vary.
2:12
Some people, it may impact more appetite,
2:15
others sleep.
2:17
It may have effects on concentration, memory.
2:21
A range of things.
2:22
So not everyone has the same symptoms.
2:24
But it's a serious illness.
2:26
Again, left untreated.
2:28
We know globally it affects over 280 million people worldwide.
2:33
So a huge number.
2:34
Everybody in this room knows someone
2:36
that's impacted by depression,
2:38
whether they tell you about it or not.
2:43
Moreover, depression is the leading cause of disability in the US.
2:47
Disability meaning really loss of productivity
2:50
both on the individual and family
2:52
and on society.
2:58
Part of the focus that comes from studying depression, though,
3:03
is really focused on antidepressants.
3:05
And we all have heard of antidepressants.
3:08
And how this came about was really completely randomly.
3:13
It was noticed that certain drugs had antidepressant effects,
3:19
and as people studied it,
3:20
they realized that if you increase serotonin,
3:23
you had an antidepressant effect.
3:25
So things like Prozac, Zoloft,
3:27
common antidepressants,
3:30
have been studied for decades,
3:32
and we've seen ads on TV,
3:34
in doctor's offices.
3:36
People openly talk about the idea we're increasing serotonin,
3:39
we're correcting our chemical imbalance.
3:42
But here's the thing.
3:44
If you look at individuals with depression,
3:47
many of them don't have decreased serotonin.
3:50
They have normal levels.
3:52
And that's a surprise to many people.
3:54
This idea that we had a measurable index of depression
3:57
just because it was less serotonin, many people talked about,
4:00
but it really wasn't true.
4:04
So that's been sort of surprising to many people.
4:07
But importantly,
4:09
SSRIs still are incredibly important treatment options.
4:15
They help many people.
4:16
They are life-changing and they are life-saving.
4:20
For many people, they really give them the will to live.
4:25
The thing about SSRIs is that when you take them,
4:28
you have this increase in serotonin very quickly,
4:32
but they take weeks to work.
4:34
They don't work quickly.
4:36
And so why do they take weeks to work?
4:38
And that's the part that we really don't know.
4:41
But again, they increase serotonin.
4:43
So if it was simply fixing, it should happen quickly.
4:48
And so while again, they're incredibly important treatments,
4:52
they are life saving.
4:53
And if you're on an SSRI, you should continue to take your SSRI.
4:57
That's an important message.
4:59
But that's why some of the research
5:01
I’m going to talk to you today about ketamine,
5:03
which my lab and group has been studying now
5:05
for more than 15 years, has been so remarkable.
5:08
Ketamine, this is the structure of the drug.
5:11
What's been noticed is,
5:13
in a clinical study that had nothing to do with depression,
5:16
it was just an observation,
5:18
they gave a low dose of ketamine.
5:19
And some of you may have heard of ketamine.
5:21
At high levels, it's an anesthetic,
5:24
at more mid-level doses it's a party drug.
5:27
But what they were doing was a study with an incredibly,
5:29
incredibly low dose.
5:31
And for those individuals that were depressed
5:33
that received ketamine,
5:35
they had a rapid antidepressant effect --
5:37
not within weeks, within hours.
5:40
We didn't even know it was possible
5:42
to have an antidepressant effect that rapidly.
5:45
And so people have been studying why.
5:48
What is this rapid effect?
5:49
Because it really is remarkable.
5:52
And it doesn't just work in individuals that could be depressed.
5:55
It's really been studied in individuals that don't respond to SSRIs,
5:59
because not everyone responds.
6:02
And so it sounds pretty remarkable,
6:04
but it's important to mention up front that ketamine does have risks.
6:08
And as with any drug,
6:10
if it's not used correctly or given at very high levels,
6:14
it can have adverse effects.
6:16
So it's really, really important that things are followed
6:20
in a manner as they should be, not just more-is-better.
6:24
That is not the message.
6:26
So we started studying ketamine
6:28
and other groups did as well.
6:30
And the first thing, which we all know,
6:32
is that ketamine doesn't work on serotonin.
6:35
It doesn't increase serotonin like SSRIs.
6:39
Instead, it actually focuses
6:41
on a different neurotransmitter system called glutamate.
6:45
And glutamate is what's important in fast communication in your brain.
6:49
Now what’s interesting is that ketamine targets glutamate,
6:52
but it doesn't activate it.
6:54
It blocks it.
6:56
So why would blocking fast communication have any beneficial effect?
7:01
And what we've been able to show is that ketamine,
7:03
by blocking this fast communication,
7:06
what it does is it actually strengthens particular connections in the brain,
7:10
what we call synaptic plasticity.
7:12
It's just a change in your brain.
7:14
Your brain is able to adapt and strengthen connections.
7:17
And we think that's what's driving the antidepressant effect.
7:21
And so as we've been studying this and trying to understand,
7:24
OK, what does this mean?
7:26
How does this work?
7:29
What we've been able to show is that -- this is a nerve cell,
7:32
this is one of the cells that we think actually are strengthening connections.
7:37
As we're studying this and trying to understand it,
7:40
it's really providing a lot of different ways
7:42
of how we're framing what is depression.
7:45
So first of all, it's reshaping treatment.
7:48
This is not a chemical imbalance.
7:50
We are not correcting a chemical imbalance.
7:53
The idea that someone may be broken,
7:55
as people have talked about with depression,
7:57
they're broken, they can't make an essential amino acid,
8:01
essential transmitter like serotonin.
8:04
It's not the case because we're not correcting it.
8:07
We're not doing anything to it.
8:09
It's the idea that your brain can adapt and ketamine is able to tap into that.
8:14
So it changes the way that we're thinking about depression.
8:17
Moreover, it's changing how we're reframing the timing.
8:21
Instead of an antidepressant requiring weeks to work,
8:24
you can respond within hours, which is remarkable,
8:28
especially for individuals that didn't respond to SSRIs
8:32
that may have been depressed without treatment for decades.
8:36
And third, it's reframing hope.
8:39
The idea that there are treatments, that you're not broken,
8:42
that this is just a matter of getting your brain to respond,
8:46
to respond to treatment.
8:48
And that, I think, is a really important message
8:50
of how we're thinking about the future.
8:52
As we continue to study ketamine,
8:55
there are many different aspects that we're looking at.
8:58
And so, you know,
8:59
with this diagram, we're showing two nerve cells
9:01
and just a neurotransmitter in this case ketamine, actually,
9:06
which targets the glutamate system.
9:08
Glutamate is being released and activated.
9:11
As we're looking at how it's sort of causing this disruption,
9:14
this blocking of transmission,
9:16
we're actually thinking,
9:17
are there other ways to trigger this plasticity?
9:20
Some people are looking at when you take ketamine,
9:22
you have this window of plasticity.
9:24
Do you respond to therapy better during that time?
9:26
Or what about to other drugs perhaps brain stimulation.
9:32
We also have been looking at it
9:33
from a context of, can we extend ketamine's antidepressant effects?
9:39
So as we look at this plasticity,
9:41
what's important to remember is that it's like a painting analogy.
9:46
If you have a blank canvas and you paint,
9:50
you're adding something new,
9:51
but then you can dial in the colors.
9:54
You can make them vibrant,
9:56
more brighter or less brighter, however you want.
10:00
Ketamine is not painting the canvas.
10:02
It's not creating new memories.
10:04
What it's doing is it's alleviating that despair.
10:08
And some people describe, with depression,
10:11
someone noted that, before ketamine treatment,
10:15
because they didn’t respond to SSRIs,
10:17
that they were really living in a dark room with no windows.
10:22
And they couldn't get out.
10:24
After taking ketamine,
10:25
it didn't make it a party house.
10:27
What it did is it made it seem like the light was lifted and there was a door.
10:33
And it provided hope.
10:36
What ketamine is doing, in the painting analogy,
10:39
is it’s actually able to dial in --
10:41
to lift the sort of despair, if you will.
10:45
And that's important.
10:46
So as we target this plasticity, we think about how can the brain adapt,
10:49
how can it change,
10:51
one of the things we're doing
10:53
is that this antidepressant effect doesn't last forever.
10:55
Like flowers in a vase.
10:58
Ketamine treatment lasts a few days and then it wanes.
11:01
So one of the things we've been able to do
11:03
is actually initiate studies to look at giving ketamine,
11:09
triggering this antidepressant effect
11:11
and then can we sustain it longer
11:14
so that you don't have to have another treatment so soon?
11:18
And we're doing this through targeting, this plasticity,
11:21
this adaptability in the brain.
11:24
And we think that's quite powerful,
11:25
because again, it's not about having to fix something
11:28
because again, given all the different symptoms,
11:31
people have different levels --
11:33
if it were a matter of fixing something.
11:35
All we're trying to do is to tap in to the brain's ability to change.
11:41
And so where are we going with this?
11:44
Well, ketamine, as I've told you, is a really remarkable treatment.
11:48
But it's not for everyone, and it's not without potential harm.
11:52
If you are currently taking an SSRI, you should continue to take the SSRI.
11:57
This is the first line of treatment for depression.
12:01
It's for individuals that don't respond really,
12:03
that have been most studied in terms of taking ketamine.
12:07
If you're interested in it,
12:08
you should talk to your health care provider.
12:11
But we're using ketamine to try to understand, again,
12:13
how do you generate an antidepressant effect?
12:16
And the idea that it's not just an imbalance, again,
12:20
that someone is not broken,
12:22
maybe their brain is just sort of stuck.
12:24
And ketamine allows you to adapt, to change.
12:27
And that, again, is what we think the response is.
12:31
And so as we continue to study ketamine,
12:33
we and other labs,
12:34
we're trying to understand how can we make this better?
12:38
How can we make this safer to work for more people?
12:41
And how can we sustain the effect?
12:44
And I think those are all really powerful messages of hope,
12:48
because it's not just about seeking treatment today,
12:51
which is incredibly important,
12:53
but also for our children and our grandchildren and for others.
12:57
Because this is a global issue
12:59
and this is something that there's a lot of work going on
13:02
that's really creating a lot of excitement in the field.
13:06
And it's also the power of scientific research.
13:08
Thank you.
13:10
(Applause)
