Towards faster treatment for major depressive disorder

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Major depressive disorder is common, costly, and all-too-often a tragic cause of suicide. While current antidepressants - such as SSRIs - are effective in two thirds of patients, they typically require 4-8 weeks to show evidence of efficacy; too slow for suffering patients.

SCOTT THOMPSON
My name’s Scott Thompson, I'm the Chair of the Department of Physiology at the University of Maryland, School of Medicine. I am an electrophysiologist by training.

CHRIS HATZIS
Scott’s research is focused on understanding what goes wrong in the brain in patients suffering from depression and using that knowledge to identify new, faster-acting therapeutic strategies for treatment.

In February of 2020, Professor Scott Thompson was a special guest of The Florey Institute of Neuroscience and Mental Health, University of Melbourne. He took some time out for a chat about his work with Dr Andi Horvath.

ANDI HORVATH
Professor Scott, what does an electrophysiologist do?

SCOTT THOMPSON

Electrophysiologists use the electrical activity of nerve cells, they are excitable cells in the brain, and they use electrical and chemical communication to do their tasks. So, our job is to stick electrodes in or near the cells and record their electrical activity by way of eavesdropping on their function.

ANDI HORVATH
Eavesdropping, that’s what we like to do too. So, what do you eavesdrop on?

SCOTT THOMPSON
Yes, so our research is focused on the neurobiology of depression, what goes wrong in the brain when there is a case of depression and we would like to use that knowledge to offer up ideas for better, more effective, faster acting antidepressant drug treatments.

ANDI HORVATH
So tell us about antidepressants? We’re familiar with the SSRIs that came out in the 1980s. What’s next?

SCOTT THOMPSON
Right, so the SSRIs have been fantastic, they are effective in about two thirds of patients with depression, just absolutely life changing for those patients, in which they work. So fully a third of patients are not responsive to SSRIs, such as Prozac. The other big issue with the SSRIs is that they take about six to eight weeks to begin to alleviate the symptoms in patients with depression, that’s fantastic if it works. But it’s very problematic, you finally brought your loved one to the clinic, convinced them that they have a problem, the patient, the doctors, the families are working to pick the right SSRI, not all patients are equally effective to all variants of the drug. Then it takes six to eight weeks to find out that no, in fact, this drug at this concentration didn’t work. So now we’re going to change the concentration, we may change the drug, another six to eight weeks, another six to eight weeks. So really, it’s a very slow process and very problematic.

ANDI HORVATH
Define SSRI for us? How does it work?

SCOTT THOMPSON
Right, so an SSRI is a Selective Serotonin Reuptake Inhibitor. Serotonin is one of the brain's hormones that works to exert control over the activity of large populations of neurons in particular brain regions. The SSRIs act to inhibit its uptake from the brain. So, the serotonin is released by particular specialised nerve cells, it floats around, it binds to receptors, it does its job, and then it’s taken up by other cells and inactivated. SSRIs such as Prozac, inhibit that uptake process, so the serotonin lasts longer in the brain, it builds up to a higher concentration. We’ve known about the SSRIs, they were first discovered in the 1980s, and we know about how they work. The neuro-chemists, the medicinal chemists have managed to refine their chemical properties so that they're very potent, very effective, and have very few side effects.

What we don't know nearly as much about is why they work. What is it about serotonin, an elevation of serotonin will relieve the symptoms? Really our starting point was that we don't really know what is wrong in the brain with depression. If you don't know what’s wrong, you don't know how to design a rational strategy for fixing it. The SSRIs such as Prozac were discovered accidentally, they were being developed for treatment of problems with blood pressure, and lo and behold some patients reported that their mood was better. That’s really why we have them. It wasn't a rational design of somebody saying oh there’s not enough serotonin, what could we do to raise the level of serotonin.



ANDI HORVATH
So you've set out to find new alternatives to the SSRI. Where did you start?

SCOTT THOMPSON
Right, so we were doing basic research on a fundamental property of the structure of a neuron, and for reasons that are too complicated to go into, we decided to test whether serotonin would have any effect on this process. When we did that, we had one of those eureka moments, the process that we were interested in studying, I'm pretty sure wasn’t affected at all, although I can’t really remember. But our control response was affected, and so the serotonin had this ability to strengthen the communication between two nerve cells in a particular brain region. That really had never been described before, so that's good, that gets scientists excited obviously.

So, we were studying this ability of serotonin to strengthen communication between brain cells, we worked out the processes. Then we asked ourselves, well would this have any bearing on why an SSRI acts to restore behaviours in our mice, or in humans with depression? That really sort of led us to formulate a hypothesis that the ability of Prozac and SSRIs to strengthen communication between brain cells, would be a mechanism of action if in fact in depression there was a weakening of that communication. Then one could imagine that an SSRI would act to restore normal transmission and that would explain why it worked. We set out to test that hypothesis, the best way to do science. We took mice that were displaying this anhedonic behaviour, we brought them back to the lab, and then we asked about the strength of communication between brain cells, in regions of the brain that we know are important for this sort of reward behaviour.

The places where decisions are made about what is pleasurable and what is not, at the heart of the symptoms of human depression. What we found in fact, was what we predicted, that communication between brain cells was weakened in these particular areas. This is a finding that’s been seen and confirmed in lots of other groups in lots of other laboratories in the world. Now we could put together what we call our working model, the thing that guides our research, that gives us a conceptual framework to think about depression. That is that at least part of the symptoms of human depression are due to impaired communication between brain cells in these brain regions. SSRIs and in fact several other known antidepressant drugs that we have looked at in a laboratory, act to restore this transmission in these brain regions. So now we have a mechanism that makes sense also, it works biologically, on a process that we know is important for the symptoms or the signs of human depression.

With that as a background then, we were ending every paper and every grant proposal with the sentence something to the effect of, and this should lead to better antidepressant drugs. So, I had two guys in my laboratory at that time, and I sort of challenged them with this. It’s like if we think we have this amazing unique insight into what’s wrong with the depression, why are we leaving it to other people to develop antidepressant drugs? Why don't we come up with an antidepressant drug candidate of our own? So, we did. We spent a lot of time thinking about it, talking about it, and we decided, well we were never going to make a better Prozac, right? Prozac has been refined through 40 years of medicinal chemistry; it is as good as any SSRI will ever be. No side effects, potent at its target, a perfect SSRI.

ANDI HORVATH
And there are very many variations on the theme of Prozac too?

SCOTT THOMPSON
There are, there's a lot of me too-ism in drug development and there’s a lot of me too’s for Prozac. We decided to instead try to make a better Ketamine, so maybe you know Ketamine is a - has been around forever. It was developed as a anti - it was developed as an anaesthetic.



ANDI HORVATH

Isn’t it a horse tranquiliser?

SCOTT THOMPSON

It is used as a horse tranquiliser, it has a lot of veterinary uses, it’s also used in patients, human patients, so kids in particular often get Ketamine as their anaesthetic of choice. It’s fast acting, it’s potent, and it’s safe. Around 20 or so years ago, it was again sort of serendipitously discovered that Ketamine exerted a rapid antidepressant action. So, whereas a Prozac takes six to eight weeks to work, within a matter of a few hours, depressed patients given Ketamine report an improvement in their mood and in their symptoms. A single administration of Ketamine produces an improvement in mood that lasts in most people’s hands, between a week and two weeks. So that’s great, that’s really good, that was revolutionary for thinking about depression. If a drug takes six to eight weeks to work, then you tend to think of a biological process that’s very slow, maybe changes in gene expression, you really have to get in there and make new proteins, plug them into the right place. Those are processes that just take time. But when a drug like Ketamine can come along and work in a matter of hours, then you really have to think of a different process.

ANDI HORVATH
Yeah, where can I get some?

SCOTT THOMPSON
Well now in the US you can, because Johnson and Johnson took Ketamine, which has been around forever, it’s off patient, it's a generic, costs about 20 cents for a dose...

ANDI HORVATH
Is it administered by nasal spray? Is that right?

SCOTT THOMPSON
Yes, so Johnson and Johnson came up with a way to formulate Ketamine in a way that it could be administered in a nasal spray, that’s great because that allows psychiatrists to deliver it in an office setting, not in a hospitalised setting. So that will increase access and hopefully lower costs as well.

So Ketamine is great, it has this rapid antidepressant action, but it comes with its own set of problems. It’s an anaesthetic right? It’ll knock you out if you take too much. It also produces a para-hallucinatory effect called dissociative effect. If you've heard of Ketamine, probably what you've heard of is that kids take it to be able to stay up and dance all night in raves and things like that. It has some mildly hallucinatory effects that people find pleasurable. Like all drugs that people find pleasurable, it’s then subject to abuse and habitual problems. So, Ketamine has this amazing action, but it has a host of side effects that will complicate its widespread use. It will complicate its widespread use and complicate its general applicability.

ANDI HORVATH
When you were in the lab deciding things to test on your mice, how is it that you came to choose Ketamine?



SCOTT THOMPSON
So when we decided we were going to try and come up with a better antidepressant compound, Prozac, well known, well characterised, but slowly acting. We wanted something that would be fast, so we decided to model our efforts in trying to create something that would work as quickly as Ketamine, but not carry its side effects.


ANDI HORVATH
Did you try other molecules?

SCOTT THOMPSON
We tried a different class of compounds. Again, sort of trying to think of how Ketamine works, the idea is that you are having this mildly dissociative hallucinatory response, because Ketamine has this mildly hallucinatory effect, and it does that because it activates cells throughout your brain. So, we decided that really what you want then, is a drug that activates cells like Ketamine does, but doesn't do it everywhere in the brain. We came up with a class of molecules that would target particular structures really limited to the brain's reward circuitry. In rats and mice, these drugs are silver bullets, just like we had hoped, they exert this rapid antidepressant-like action in rats and mice that are displaying this anhedonic phenotype. No side effects that we could see with all the sorts of tests that reveal the side effects of Ketamine. So, in our hands, this is a Ketamine like rapid antidepressant novel candidate, without the side effects.

ANDI HORVATH
This is a little bit reminiscent of the Timothy Leary LSD movement, that suggested hallucinogens were actually good for your brain. How do these hallucinogenics affect serotonin?

SCOTT THOMPSON
It turns out there are 14 different receptor molecules for this neurotransmitter serotonin, which is the target of the SSRI such as Prozac. Hallucinogenic drugs like psilocybin, LSD, mescaline, all of these compounds are potent activators of all 14 of these receptors. Through our work studying SSRIs and how they strengthen communication in brain cells, we know a few of those are really, seem to be essential to that antidepressant response.

Turns out we also know the receptor that is critical for the hallucination that is produced by psilocybin and LSD, and that is the 5HT2 receptor. We don't think the 5HT2 receptor is necessary for the antidepressant response, hence our taking the fun out of psilocybin. We think it should be possible to block the hallucinations and retain the rapid antidepressant response. This is an experiment that’s been done in people already, we know that you can give psilocybin in combination with a compound that blocks this one critical receptor. Those people do not hallucinate anymore in response to psilocybin, that’s good, we have the means to do this.

We know that psilocybin produces an antidepressant response in depressed people, that’s good, and now there are groups that are working to test this anti-hallucination in combination with psilocybin in patients. In my laboratory we are currently performing these experiments in mice, in hopes of producing some evidence that will encourage these efforts in people. We’re very excited about this, because if we could block the hallucinations it would greatly increase the ability to use a compound like psilocybin by making it more available, you wouldn’t need to come and spend all day in the clinic, we wouldn’t have to worry about how you're going to drive home while you're seeing pink elephants walking down the sidewalk.

ANDI HORVATH
So you're making a socially and family friendly antidepressant, that works fast?

SCOTT THOMPSON
Yes, well hopefully.

ANDI HORVATH
Just out of curiosity, what’s surprised you about this research?

SCOTT THOMPSON
It's always surprising to a scientist when your hypothesis that you start with actually works out. I think most of us would say, more likely it fails somewhere along the way, so the surprising thing is that so far so good.

ANDI HORVATH
What misconceptions do we encounter from scientists or the public?

SCOTT THOMPSON

I don't know if I would call this a misconception, but certainly its limitation is making that giant leap from a mouse to a human being. Mice are not small fuzzy humans. Human psychiatry, human psychology, way more complicated than mouse psychology. It’s always a bit of a leap of faith to take something that works in mice and ask whether it will work in people. So, with our novel antidepressant compounds, we are now currently trying to raise the money to get the approval to do that kind of work in patients. We would have to prove that our compounds are safe in people before they can be administered in depressed patients, to find out if they are in fact effective.

ANDI HORVATH
What is the relationship between stress, anxiety and depression?

SCOTT THOMPSON
Stress is one of the biggest known predictors of who will become depressed. We know that the sensitivity to stress is partly determined by a genetic background. You may experience the same stress that I experience, I will get depressed, you won't. There’s a lot that we don't know about that, it’s very complicated obviously. There’s no single factor that one could identify, but many, many studies, time after time, have shown that the more stressful life events you experience, losing a job, losing a loved one, the more likely you are to become depressed. In fact, the most...

ANDI HORVATH

It is a genuine brain effect that you've seen in mice?

SCOTT THOMPSON
I think a common misconception, you asked about misconceptions. I think a common misconception is that depression is a sign of bad character, right, one of the more hopeful aspects of life today, and we need all the hopeful signs we can have, is that the stigma of mental illness is slowly beginning to be erased, and that is an incredibly hopeful sign. If your child has a flu, you don't hesitate to ask your friends who is treating them, what drugs are they taking, how’s that going, how are you dealing with it? But if you have a loved one or a child, a family member who’s experiencing depression, we all experience this reluctance to come forward and ask our friends, and rely on our friends to give us advice, give us support.

That stigma of mental health as a character flaw, keeps people from seeking treatment, it leads patients to spend years locked in a closet, denying to their loved ones and their friends, that they are in fact experiencing depression. I hope that this stigma is gradually going away and that we can all come together as a community to support those of us with afflicted - you wouldn’t suffer in silence with a flu, you would reach out for help, and that’s what we need for mental health.

ANDI HORVATH
We all get colds, we all get sad, and sometimes we all get a bit too sad. Professor Scott, how do you make a mouse depressed?

SCOTT THOMPSON
That's a great question. There’s a variety of models that we use. We know that stress is one of the most important epidemiological predictors for human depression, those people who suffer stressful life events, loss of a loved one, loss of a job. In the US we have to worry about losing our medical insurance, those kinds of things can really push people over the deep end and into true clinical depression. All of the mouse models that people use are based on producing chronic stress in animals, there are different ways to do it. The most common ones I think are a little bit like your life and my life, every day in the morning, in the afternoon, something happens that’s just annoying and stressful, it’s not life threatening, but it’s just annoying.

If that happens to you day after day after day, you may experience depression, so that's kind of what we try to do in the laboratory. We bring the mice down to the lab for 30 minute or so every day, day after day for about three weeks, and subject them to something that’s stressful. Not life-threatening stress, but annoying stress. We take them out of a cage with their friends and we put them in a cage with a bunch of strange mice they’ve never seen before. We make them stand around in wet cage bedding. We subject them to strobe lights, to loud noise, to a quick dunk in a bath of cold water. It’s not stressful, they don't fear for their lives, but again every day they know they're going to get brought down to the laboratory, and those mean scientists are going to do something to them, that they really don't like. If you do that for three weeks every day in a row, you end up with a mouse then that displays this anhedonic phenotype that we talked about before.

This behavioural change that persists, you do three weeks of chronic stress and that loss of ability to respond to rewarding stimuli will persist for weeks afterwards. That's one model. Another one we use is kind of the grade school model of depression I like to think of it. You may remember the bad bully in grade school who stole your lunch and kicked you and tripped you on the playground and all that sort of stuff. So, we take a mouse and we put it in a cage with a big bad bully, the big bad bully beats up our test mouse, and we make the test mouse stay in the cage with the bully, separated so he’s not physically harmed. But stay in the cage with the bully for several hours. You do that again day after day after day for about two or three weeks, and you end up with a mouse that also loses his ability to respond to rewarding stimuli.

ANDI HORVATH

I didn't know there were bully mice.

SCOTT THOMPSON
There are, mice are very social, but they're also animals.



ANDI HORVATH
Right, so there’s an alpha mouse?

SCOTT THOMPSON
Animals, they're animals.

ANDI HORVATH
They're animals. Professor Scott, leave us with a shareable idea. Next time we’re popping an antidepressant, what would you like us to think about?

SCOTT THOMPSON

I guess a shareable idea I'd like to leave everybody with, is that mental health is a sickness, it’s not just a character flaw, it's not your mind, it’s actually your brain. It is no different than any other medical condition. There is something physically wrong with the cells in your brain, and so you are not to suffer alone, you are to seek help for that, just like you would for any other medical condition, and know that help is on the way. There are drugs that will work for almost everybody with depression. It may take a while to find the right drug, but you will get better.

ANDI HORVATH

Professor Scott Thompson, thank you.

SCOTT THOMPSON
My pleasure.

CHRIS HATZIS
Thank you to Scott Thompson, Professor and Chair of the Department of Physiology and Professor of Psychiatry at the University of Maryland School of Medicine. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on February 12, 2020. You’ll find a full transcript on the Pursuit website. Production, audio engineering and editing by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis. Join us again next time for another Eavesdrop on Experts.