Rebecca Brachman – Scientist and entrepreneur
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.
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.