Could a drug prevent depression? | Rebecca Brachman | TEDxNewYork

Could a drug prevent depression? | Rebecca Brachman | TEDxNewYork

This is a tuberculosis ward, and at the time this picture was taken
in the late 1800s, one in seven of all people died from tuberculosis. We had no idea
what was causing this disease. The hypothesis was actually it was your constitution
that made you susceptible. And it was a highly romanticized disease. It was also called consumption, and it was the disorder of poets and artists and intellectuals. And some people actually thought
it gave you heightened sensitivity and conferred creative genius. By the 1950s, we instead knew
that tuberculosis was caused by a highly contagious
bacterial infection, which is slightly less romantic, but that had the upside of us being able to maybe
develop drugs to treat it. So doctors had discovered
a new drug, iproniazid, that they were optimistic
might cure tuberculosis, and they gave it to patients, and patients were elated. They were more social, more energetic. One medical report actually says
they were “dancing in the halls.” And unfortunately, this was not necessarily
because they were getting better. A lot of them were still dying. Another medical report describes them
as being “inappropriately happy.” And that is how the first
antidepressant was discovered. So accidental discovery
is not uncommon in science, but it requires more
than just a happy accident. You have to be able to recognize it
for discovery to occur. As a neuroscientist,
I’m going to talk to you a little bit about my firsthand experience with whatever you want to call
the opposite of dumb luck — let’s call it smart luck. But first, a bit more background. Thankfully, since the 1950s, we’ve developed some other drugs
and we can actually now cure tuberculosis. And at least in the United States,
though not necessarily in other countries, we have closed our sanitoriums and probably most of you
are not too worried about TB. But a lot of what was true
in the early 1900s about infectious disease, we can say now
about psychiatric disorders. We are in the middle
of an epidemic of mood disorders like depression and post-traumatic
stress disorder, or PTSD. One in four of all adults
in the United States suffers from mental illness, which means that if you haven’t
experienced it personally or someone in your family hasn’t, it’s still very likely
that someone you know has, though they may not talk about it. Depression has actually now surpassed HIV/AIDS, malaria, diabetes and war as the leading cause
of disability worldwide. And also, like tuberculosis in the 1950s, we don’t know what causes it. Once it’s developed, it’s chronic, lasts a lifetime, and there are no known cures. The second antidepressant we discovered, also by accident, in the 1950s, from an antihistamine
that was making people manic, imipramine. And in both the case of the tuberculosis
ward and the antihistamine, someone had to be able to recognize that a drug that was designed
to do one thing — treat tuberculosis
or suppress allergies — could be used to do
something very different — treat depression. And this sort of repurposing
is actually quite challenging. When doctors first saw
this mood-enhancing effect of iproniazid, they didn’t really recognize
what they saw. They were so used to thinking about it from the framework
of being a tuberculosis drug that they actually just listed it as a side effect, an adverse side effect. As you can see here, a lot of these patients in 1954
are experiencing severe euphoria. And they were worried
that this might somehow interfere with their recovering from tuberculosis. So they recommended that iproniazid
only be used in cases of extreme TB and in patients that were
highly emotionally stable, which is of course the exact opposite
of how we use it as an antidepressant. They were so used to looking at it
from the perspective of this one disease, they could not see the larger implications
for another disease. And to be fair,
it’s not entirely their fault. Functional fixedness
is a bias that affects all of us. It’s a tendency to only
be able to think of an object in terms of its traditional
use or function. And mental set is another thing. Right? That’s sort of this preconceived framework with which we approach problems. And that actually makes repurposing
pretty hard for all of us, which is, I guess, why they gave
a TV show to the guy who was, like, really great at repurposing. (Laughter) So the effects in both the case
of iproniazid and imipramine, they were so strong — there was mania,
or people dancing in the halls. It’s actually not that surprising
they were caught. But it does make you wonder
what else we’ve missed. So iproniazid and imipramine, they’re more than just
a case study in repurposing. They have two other things in common
that are really important. One, they have terrible side effects. That includes liver toxicity, weight gain of over 50 pounds, suicidality. And two, they both
increase levels of serotonin, which is a chemical signal in the brain, or a neurotransmitter. And those two things together,
right, one or the two, may not have been that important, but the two together meant
that we had to develop safer drugs, and that serotonin seemed
like a pretty good place to start. So we developed drugs
to more specifically focus on serotonin, the selective serotonin
reuptake inhibitors, so the SSRIs, the most famous of which is Prozac. And that was 30 years ago, and since then we have mostly
just worked on optimizing those drugs. And the SSRIs, they are better
than the drugs that came before them, but they still have a lot of side effects, including weight gain, insomnia, suicidality — and they take a really long time to work, something like four to six weeks
in a lot of patients. And that’s in the patients
where they do work. There are a lot of patients
where these drugs don’t work. And that means now, in 2016, we still have no cures
for any mood disorders, just drugs that suppress symptoms, which is kind of the difference between
taking a painkiller for an infection versus an antibiotic. A painkiller will make you feel better, but is not going to do anything
to treat that underlying disease. And it was this flexibility
in our thinking that let us recognize
that iproniazid and imipramine could be repurposed in this way, which led us to the serotonin hypothesis, which we then, ironically, fixated on. This is brain signaling, serotonin, from an SSRI commercial. In case you’re not clear,
this is a dramatization. And in science, we try
and remove our bias, right, by running double-blinded experiments or being statistically agnostic
as to what our results will be. But bias creeps in more insidiously
in what we choose to study and how we choose to study it. So we’ve focused on serotonin now
for the past 30 years, often to the exclusion of other things. We still have no cures, and what if serotonin
isn’t all there is to depression? What if it’s not even the key part of it? That means no matter how much time or money or effort we put into it, it will never lead to a cure. In the past few years,
doctors have discovered probably what is the first truly new
antidepressant since the SSRIs, Calypsol, and this drug works very quickly,
within a few hours or a day, and it doesn’t work on serotonin. It works on glutamate,
which is another neurotransmitter. And it’s also repurposed. It was traditionally used
as anesthesia in surgery. But unlike those other drugs, which were recognized pretty quickly, it took us 20 years to realize that Calypsol
was an antidepressant, despite the fact that it’s actually
a better antidepressant, probably, than those other drugs. It’s actually probably because of the fact
that it’s a better antidepressant that it was harder for us to recognize. There was no mania to signal its effects. So in 2013, up at Columbia University, I was working with my colleague, Dr. Christine Ann Denny, and we were studying Calypsol
as an antidepressant in mice. And Calypsol has, like,
a really short half-life, which means it’s out of your body
within a few hours. And we were just piloting. So we would give an injection to mice, and then we’d wait a week, and then we’d run
another experiment to save money. And one of the experiments I was running, we would stress the mice, and we used that as a model of depression. And at first it kind of just looked
like it didn’t really work at all. So we could have stopped there. But I have run this model
of depression for years, and the data just looked kind of weird. It didn’t really look right to me. So I went back, and we reanalyzed it based on whether or not they had gotten
that one injection of Calypsol a week beforehand. And it looked kind of like this. So if you look at the far left, if you put a mouse in a new space, this is the box, it’s very exciting, a mouse will walk around and explore, and you can see that pink line
is actually the measure of them walking. And we also give it
another mouse in a pencil cup that it can decide to interact with. This is also a dramatization,
in case that’s not clear. And a normal mouse will explore. It will be social. Check out what’s going on. If you stress a mouse
in this depression model, which is the middle box, they aren’t social, they don’t explore. They mostly just kind of hide
in that back corner, behind a cup. Yet the mice that had gotten
that one injection of Calypsol, here on your right, they were exploring, they were social. They looked like they
had never been stressed at all, which is impossible. So we could have just stopped there, but Christine had also used
Calypsol before as anesthesia, and a few years ago she had seen that it seemed to have
some weird effects on cells and some other behavior that also seemed to last
long after the drug, maybe a few weeks. So we were like, OK, maybe this is not completely impossible, but we were really skeptical. So we did what you do in science
when you’re not sure, and we ran it again. And I remember being in the animal room, moving mice from box to box
to test them, and Christine was actually sitting
on the floor with the computer in her lap so the mice couldn’t see her, and she was analyzing
the data in real time. And I remember us yelling, which you’re not supposed to do
in an animal room where you’re testing, because it had worked. It seemed like these mice
were protected against stress, or they were inappropriately happy,
however you want to call it. And we were really excited. And then we were really skeptical,
because it was too good to be true. So we ran it again. And then we ran it again in a PTSD model, and we ran it again
in a physiological model, where all we did was give stress hormones. And we had our undergrads run it. And then we had our collaborators
halfway across the world in France run it. And every time someone ran it,
they confirmed the same thing. It seemed like
this one injection of Calypsol was somehow protecting
against stress for weeks. And we only published this a year ago, but since then other labs
have independently confirmed this effect. So we don’t know what causes depression, but we do know that stress
is the initial trigger in 80 percent of cases, and depression and PTSD
are different diseases, but this is something
they share in common. Right? It is traumatic stress like active combat or natural disasters or community violence or sexual assault that causes post-traumatic
stress disorder, and not everyone that is exposed to stress
develops a mood disorder. And this ability to experience
stress and be resilient and bounce back and not develop
depression or PTSD is known as stress resilience, and it varies between people. And we have always thought of it
as just sort of this passive property. It’s the absence of susceptibility factors and risk factors for these disorders. But what if it were active? Maybe we could enhance it, sort of akin to putting on armor. We had accidentally discovered
the first resilience-enhancing drug. And like I said, we only gave
a tiny amount of the drug, and it lasted for weeks, and that’s not like anything
you see with antidepressants. But it is actually kind of similar
to what you see in immune vaccines. So in immune vaccines,
you’ll get your shots, and then weeks, months, years later, when you’re actually exposed to bacteria, it’s not the vaccine in your body
that protects you. It’s your own immune system that’s developed resistance and resilience
to this bacteria that fights it off, and you actually never get the infection, which is very different
from, say, our treatments. Right? In that case, you get the infection,
you’re exposed to the bacteria, you’re sick, and then you take,
say, an antibiotic which cures it, and those drugs are actually working
to kill the bacteria. Or similar to as I said before,
with this palliative, you’ll take something
that will suppress the symptoms, but it won’t treat
the underlying infection, and you’ll only feel better
during the time in which you’re taking it, which is why you have to keep taking it. And in depression and PTSD — here we have your stress exposure — we only have palliative care. Antidepressants only suppress symptoms, and that is why you basically
have to keep taking them for the life of the disease, which is often
the length of your own life. So we’re calling our resilience-enhancing
drugs “paravaccines,” which means vaccine-like, because it seems
like they might have the potential to protect against stress and prevent mice from developing depression and post-traumatic
stress disorder. Also, not all antidepressants
are also paravaccines. We tried Prozac as well, and that had no effect. So if this were to translate into humans, we might be able to protect people who are predictably at risk against stress-induced disorders
like depression and PTSD. So that’s first responders
and firefighters, refugees, prisoners and prison guards, soldiers, you name it. And to give you a sense
of the scale of these diseases, in 2010, the global burden of disease was estimated at 2.5 trillion dollars, and since they are chronic, that cost is compounding
and is therefore expected to rise up to six trillion dollars
in just the next 15 years. As I mentioned before, repurposing can be challenging
because of our prior biases. Calypsol has another name, ketamine, which also goes by another name, Special K, which is a club drug and drug of abuse. It’s still used across the world
as an anesthetic. It’s used in children.
We use it on the battlefield. It’s actually the drug of choice
in a lot of developing nations, because it doesn’t affect breathing. It is on the World Health Organization
list of most essential medicines. If we had discovered ketamine
as a paravaccine first, it’d be pretty easy for us to develop it, but as is, we have to compete
with our functional fixedness and mental set that kind of interfere. Fortunately, it’s not
the only compound we have discovered that has these prophylactic,
paravaccine qualities, but all of the other drugs
we’ve discovered, or compounds if you will,
they’re totally new, they have to go through
the entire FDA approval process — if they make it before
they can ever be used in humans. And that will be years. So if we wanted something sooner, ketamine is already FDA-approved. It’s generic, it’s available. We could develop it for a fraction
of the price and a fraction of the time. But actually, beyond
functional fixedness and mental set, there’s a real other challenge
to repurposing drugs, which is policy. There are no incentives in place once a drug is generic and off patent
and no longer exclusive to encourage pharma companies
to develop them, because they don’t make money. And that’s not true for just ketamine.
That is true for all drugs. Regardless, the idea itself
is completely novel in psychiatry, to use drugs to prevent mental illness as opposed to just treat it. It is possible that 20, 50,
100 years from now, we will look back now
at depression and PTSD the way we look back
at tuberculosis sanitoriums as a thing of the past. This could be the beginning of the end
of the mental health epidemic. But as a great scientist once said, “Only a fool is sure of anything. A wise man keeps on guessing.” Thank you, guys. (Applause)


  1. Interesting. Repurposing is much easier for children btw, since they have few biases. Also, you talked about who to give the drug to to help with PTSD because we actually know what causes that, but who would you give it to for depression? We do not know what causes that. Depression often happens as children too. I suspect depression may be caused in similar ways to PTSD actually. Almost everyone I have ever talked to who has depression has had some form of suffering, be it bullying, abuse, neglect, rape, loss of home, loss of family members, loss of friends. Many things can cause depression, but I believe it only happens when these things really hit home with that person, and that is something very subjective, and also sometimes impossible to tell. Some people will be honest and tell you how much they are hurting, but others will lie and say they are fine. I would say that deep mental or emotional anguish is the cause of depression. Even that definition is very ambiguous. It is also not proven, just an educated guess from someone who knows people who suffer with this.

  2. drugs, drugs, drugs
    Did you know, that depression could be a symptom for some diseases or problems ? (not only stress and PTSD)
    It could be caused by wrong or unhealthy nutrition, lack of vitamins, some viruses or bacteria, autoimmune disease, hormone disorder, celiac disease or gluten sensitivity, anemia, etc.
    Find the cause, handle it and depression is gone.
    NO DRUGS !

  3. "we still have no cures for any mood disorders". complete and utter bullshit. ayahuasca is a known cure for people in most cases, not only is it an incredible anti-depressant it also deals with the underlying issues. i guess big pharma can't make billions about it!

  4. this is a very disturbing talk – she seems to admit that the drugs produced so far have minimum benefit and many harms while advocating the idea that having problems of living within a toxic culture are really 'diseases and disorders' of the mind rather than reactions any of us have when we suffer from the world, from loss, from pain, poverty, policy, ideology etc – then linking this new (very old drug) to these fictitious diseases she makes the same claim the psychiatrists have been making for decades with ZERO evidence that a drug is going to cure some underlying illness – the illness is cultural, systemic not in the brain – imagine being those mice, you live in a small cage with very little to do and then researchers deliberately cause you to suffer then give you a drug and suddenly the harms you experience are turned off so you just get on with it – this is some Orwellian stuff or actually its far closer to Huxley's view with Soma – the government is fucking you over again – just take some K, one to live, two for joy and three to numb you completely from the toxic culture before you – why not just give us all MDMA for breakfast – she clearly smells a blockbuster and given we've all been seduced into the pill taking culture they will make billions by causing even more harm than the SSRi's are currently doing and the benzos and barbs and those drugs marketed as anti psychotics – we live in a very ill world and this is going to make us far worse

  5. shes talking about immunizing people from the culture, turning peoples emotions into other things – how many millions have already had their sense of self distorted by the SSRIs and what used to be called major tranquilizers and chemical lobotomist antics to make and save some money, to gain more power and control of what it means to be human what is normal and what is not

  6. I find this video very interesting and I'm amazed by this research. As Rebecca has already mentioned that there is 1 in every 4 adults who experiences mental illness every year. This means many people are at risk for getting mental disease. Though people are trying to avoid stress, they face it in every day to day life. It is unavoidable and some people are very sensitive. Such people are at higher risk. As there is no cure for the mental disease, prevention is the best option. Though people are involved in stress reduction program, relaxation techniques but people go there after getting stress which is not much effective. But the vaccine prevents stress which is responsible for mental disorder. For the prevention of infectious communicable diseases, vaccines had played a main role. It has been proved through research. Through the complete vaccination, those diseases are almost eradicated. So I think that vaccines for mental illness will also act strong for its prevention. The vaccines should be produced. From the utilitarian perspective, the outcome will be good and every person will be benefitted from it. Thus, researchers should do more research and think about the need and benefits of vaccine in preventing mental illness.

  7. Depression is not an illness. It is just a mental condition like apathy. For example: sadness it's the opposite to happiness, and when you want to change your mood and have fun you just look for activities that will make you happy; like doing something funny to end your boring. We all have positive and negative emotions, they all are the result of our actions and the way we see the life and how we interact with this universe. When we are depressed, we are in a mental condition caused by some kind of lost: like an emotional lost of a relative, a lost a job or anything that went wrong and we just don't know how to handle that situation. And before someone got depressed; he or she goes through different emotions like becoming angry, then sad, then bored and then apathetic, an emotion that's the result of frustration when you can't get or do what you want. And that APATHY IS CALL DEPRESSION BY THE PSYCHIATRISTS AND PSYCHOLOGISTS . And that Negative emotion APATHY is then labeled illness to force people to take pills to "cure" and emotion, which is just a natural response to the world we live on.
    In other words you cannot cure depression because is not an illness it's and negative emotion. So the only thing to do is changing a negative emotion for a positive-one. How? 1st you must put your attention outside your problems and to your environment and look for things to do that will make you happy. Any activities to interact with others and avoid to stay home alone and help to keep your mind busy in positive thoughts. Don't drink alcohol or smoke and don't take drugs, because those things will keep you from freeing yourself of depression. Look at the children, how they are happy with little and simple things. Because happiness is made of anything positive you can do in your life. Anything. Some are happy by helping others, some by watching the sunset, others by dancing and others just for being alive. The secret to happiness is in your hands, just get up and start again to get your goals, this time don't give up. Do little things that together mean a lot. And remember that only you can stop yourself of getting what you want. Good luck on your way to happiness!

  8. This is a very thought provoking talk. It's true that many drugs were repurposed. A good example is Viagra which was original developed for high blood pressure. I'm just surprised why the medical community hasn't adopted Ketamine as a cure for depression. Is it because of the lack of human trials? Rebecca Brachman is right to say that antidepressant is there to suppress the symptons without really treating the actual disease thus a patient would require to take this for the rest of his or her life. Why aren't psychiatrist using paravaccine to treat depression? Do drug companies have anything to do with this as cured patients pf depression will mean diminished revenue for them? Will so many in the world sufferring from depression, this is a multi billion dollar business for drug companies. A cure for depression will kill this business.

  9. My friend is battling bipolar disorder, major depression, anxiety, and ptsd. She attempted suicide twice. I have depression, and anxiety. Mental health is a huge problem nobody wants to talk about.

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