Daniel Lodge, PhD Associate Professor at UT Health San Antonio talks about schizophrenia and research that may offer hope for the future.
Interview conducted by Ivanhoe Broadcast News in November 2018.
People say that this could be a long-term solution to a very difficult the issue.
Daniel Lodge: The aim of our research is to better understand the pathophysiology of schizophrenia – so what actually goes wrong in schizophrenia. We believe that by understanding pathophysiology we can develop novel treatments and our work is focused on short-term, medium-term, and long-term solutions for that. The work that we’re currently doing is looking at potentially permanent solutions to treat schizophrenia or an associated psychosis.
What is it about schizophrenia that is so difficult not only for outsiders to understand but for the people who have it and won’t take their medication?
Daniel Lodge: There are many issues associated with the diagnosis of schizophrenia. And one of the big ones is stigma. When people hear schizophrenia or psychosis, they immediately go to what they see in movies of the, quote, unquote, crazy person. And that’s not what schizophrenia is. Schizophrenia is a mental illness that can be effectively treated with antipsychotic drugs and therapy. When these drugs work, they work really well. We do have treatments. Unfortunately, there’s a problem that we don’t necessarily have treatments for everyone. What we need is additional research to try and understand what may be different in patients and then come up with novel therapies.
The second part of the big issues with them is they don’t take their medication. What comes first the chicken or the egg? They don’t take it, and they get sick or vice versa.
Daniel Lodge: The problem with current medications to treat schizophrenia is that they have side effects, things that patients don’t necessarily like. Because patients feel better when they’re on their medications, they’ll start to think they can stop taking them and get rid of those side effects. So they discontinue medication. The problem is that if they do that, their symptoms will likely appear again. It’s a difficult problem.
Describe some of the symptoms that are realistic.
Daniel Lodge: Patients typically have three different symptom domains. We have things called positive symptoms. And these are things that are in addition to normal behavior. So those are things like hallucinations, delusions and paranoia. In addition, people may have negative symptoms, which reflect a loss of function. Things that sort of mirror what you see in depression. Social withdrawal, an inability to get pleasure from things that are typically pleasurable. And then on top of that, there may be some subtle cognitive alterations as well. It’s a heterogeneous disorder. People present with different types of symptoms, but they can be quite debilitating.
Talk a little bit about the exact research that you’re doing with the cells.
Daniel Lodge: There’s a part of the brain called the dopamine system which we’ve known is associated with schizophrenia for over 50 years. Indeed, the drugs we use treat schizophrenia by targeting the dopamine system. The problem with that is that there doesn’t seem to be really overt pathology in that system. We think that the dopamine system is actually dysregulated and the pathology is actually somewhere else in the brain. That part of the brain is called the hippocampus and we and others have been looking at whether the hippocampus may be a new target for the treatment of schizophrenia.
So you’re saying that they sometimes manifest here, but they’re originating in the hippocampus, right?
Daniel Lodge: That’s exactly right.
What part of the brain did they originate from? And what’s that called?
Daniel Lodge: The hippocampus, we think, is a key side of pathology for schizophrenia.
Where have you been targeting?
Daniel Lodge: We’ve been targeting the hippocampus which is upstream of the dopamine system. What’s interesting about that is the dopamine system is typically associated with those positive symptoms – the hallucinations, the paranoia and the psychosis, not as much with the other symptom classes. We can treat those symptoms quite well with antipsychotic drugs. The other symptom classes aren’t as well treated. We think by targeting the hippocampus we may actually be able to target all three symptom domains.
To put it in layman’s terms, you’re essentially going to the trail head before it ever gets started?
Daniel Lodge: Yeah, as an Australian, I don’t know what that means. But, yes, that’s what we’re doing.
In Colorado. – I’m not sure what this question is?
Daniel Lodge: It’s no surprise that the brain is highly complex. And it’s not one brain region that does everything. And it’s not just one brain pathway that does everything. And so the heterogeneous nature of schizophrenia is because you have different brain regions and different brain pathways that are altered. We think that the hippocampus is one of those pathways and could be a site where we could go in and treat symptoms. But there are many other parts of the brain that may be associated with schizophrenia as well. It’s not an easy disease to understand nor to treat. But I think we’re making progress.
How did this all start? Is this something you stumbled across? Or you had a light bulb go off?
Daniel Lodge: With me personally, when I was in graduate school, I got interested in the brain. And the brain is one of the last areas of unknown. We don’t know how the brain works. We have ideas on how neurons work and we have ideas on what brain regions do, but we really are not fully capable right now of understanding the complexities of the human brain. For me, that’s fascinating. And then I got interested in what goes wrong in psychiatric illnesses such as addiction, depression and schizophrenia.
Is schizophrenia kind of like the other ones where the synapses don’t really touch? There’s some disconnect there that causes that addictive behavior.
Daniel Lodge: So in terms of the brain, it’s highly complex. You can have alterations in synapses, which is communication between brain cells. There are different types of neurons that can be differentially affected. I mentioned dopamine, dopamine is a neurotransmitter in a class of neurons. They’re involved in addiction as well as schizophrenia and other diseases. It’s interesting that people that take high amounts of a psychostimulant, such as amphetamine, can present with psychosis that is somewhat similar to the psychosis observed in schizophrenia because there are similar parts of the brain that are activated.
You guys are taking stem cells is that correct? And what precisely are you doing with them?
Daniel Lodge: What we think may be happening in schizophrenia – and this is based on some rodent work in our lab as well as human post-mortem data – is that there’s a particular type of cell that is affected in schizophrenia. What this cell does is it acts like a brake. It slows down the hippocampus. And we know that there’s a loss of function of these cells in schizophrenia that results in too much activity in the hippocampus. We think if we can replace these deficient cells, we can restore function and then reverse some of the symptoms.
Where did they come from? Where did the stem cells originate from?
Daniel Lodge: The preliminary studies that we’ve done use mouse embryonic stem cells. In the future, what we’d like to do is use human iPS cells. These are cells that are taken from skin or from blood that you can turn into stem cells. The first experimental approach was the easiest for us. We had mouse embryonic stem cells. We put them in a culture. And we turned them into the cell type known to be altered in schizophrenia. We transplant those into the brains of rats and we look at whether they reverse aberrant neuronal activity and behavior. And so far they do.
When you first saw that, were you jumping?
Daniel Lodge: When we first saw that, we were very excited. You know, it’s testing the primary hypothesis. If this is what we think is a key pathology in schizophrenia, then by putting these cells back, we should be able to treat it. And we were very excited to show that it looks that way.
In the scheme of things from the origination of the idea to having something that actually works in the open market, how is that process? And where are you on that timeline?
Daniel Lodge: Cell transplants and some other work with gene therapy could ultimately be a cure, but that’s a long way down the road. We still think that the hippocampus may be a viable target. And there are things that we can do today that will be able to engage that target and we can see if that has any therapeutic utility. So we’ve got short-term, medium and long-term goals – the stem cells and the gene therapy are a long-term goal. But there are targets in the hippocampus, which we think we can target in the next five to ten years.
Describe to me the first time that you took the cells out and you put them into the rat, you had success with that on the first hypothesis. How exactly does that happen?
Daniel Lodge: The first thing we do is we generate a model that we can use to look at symptoms for schizophrenia. It’s difficult to do as there is a limit to experiments that can be performed in humans. And so we need animal models to really get to that neurobiology. It’s also really difficult to model any inherently human disease in a rodent. We have rodents that display some alterations that are analogous to that seen in human patients. So we use these rodents. We put these stem cells in the hippocampus and then we look at neuronal activity. We saw pretty quickly that we were able to reverse aberrant neuronal activity and behavioral alterations in these models.
It’s sort of quieting the brain and calming it down like it’s in an intrastate.
Daniel Lodge: Yes, so the part of the brain that we think is overactive and that you can see is overactive using imaging studies in human patients is the hippocampus. And we put the cells just into that region, they have very specific and very local effects on the hippocampus to quiet that down. In turn, that quietens the dopamine system, which is what’s contributing to those positive symptoms.
The behavior in the rat was that observable for you? You can see that?
Daniel Lodge: We have neurophysiological alterations that we can examine by directly recording the activity of brain regions. And that sort of correlates with imaging studies in patients. But we can do behavioral tests looking at things such as cognition, which we have similar cognitive tests in rats than what we’re doing in humans. When we saw that this was also effective at treating a cognitive deficit, we got really excited because these symptoms that are difficult to treat.
Are you injecting this with a needle? Is that how it’s going in?
Daniel Lodge: Yes, we use a cannula that we implant into the brain. And we inject them directly into the brain under anesthesia.
Anything else I’ve missed?
Daniel Lodge: One of the questions we get is, how do we test cognition in a rat? And there’s a test that we use in humans. And it’s been translated to rodents. Basically what we do is we have two little pots. And they have different scents. And they have different digging material inside those pots. We hide a cheerio in that and the rat learns where the cheerio is. We initially tell them that they’ve got to go to the pot that smells like clove. And so once they learn that, we trick them. And now that pot isn’t the one that contains cheerio and maybe the one that smells like nutmeg is. A rat model for schizophrenia has trouble with that. After that, things get increasingly difficult and we say, well, scent is no longer what the rat has to pay attention to. It has to pay attention to the digging material that’s inside the pot. Again, that’s something that’s difficult for them to do. And it’s actually analogous to test that we can do in patients using touch pads and iPads where analogous tasks are problematic for patients as well. So it’s a way to look at a cognitive function in a rodent model.
It’s the same thing with humans with dementia, doing the puzzles, the crossword puzzles and things to keep your mind sharp. Same thing happens with them. But what you found when you put the stem cells in those rats was…
Daniel Lodge: When we put the stem cells into our rodent model, we could reverse those deficits in cognitive function. It typically takes them twice as long to do the task but after the cell transplants our rats were now performing just like the control animals.
Was that the very first time that you saw it happen, that’s how you did it?
Daniel Lodge: That was the first time that we’d seen it in a cognitive task. So typically we’ve been focused on dopamine. And we have drugs that treat the dopamine system. This is sort of moving a little bit away from dopamine to look at those other symptom domains that may not be as well treated by conventional therapies.
Eventually at the end of the long, long road, what would you want to see happen?
Daniel Lodge: Our hope is that in the immediate future and in the long term that we come up with new and novel treatments for psychiatric diseases, such as schizophrenia. We think this is a piece of the puzzle. And we’re excited by it. You know, I think it would be good for patients to know that there are people working on this and that there are another number of different avenues to generate novel therapies. And so there is hope for the patients.
I don’t know if it’s how much it’s inherited, but when a person is first born are the symptoms met? When would the treatments start with somebody?
Daniel Lodge: It’s a great question. We think a lot of the pathology that happens in schizophrenia occurs in utero during development. But the symptoms don’t appear until late adolescence or early adulthood. One of the things that we know is that the sooner you can get someone in treatment and therapy, the better the prognosis may be.
Down the road a 13 year old comes in with symptoms that have them in utero, that didn’t manifest, they suddenly do. Then when this is all said and done, how would that person be treated?
Daniel Lodge: At the moment, we can treat that person. Counseling is a very big part of a schizophrenia treatment plan as is the right medication. Finding the right medication can be problematic. It can take some time. Ultimately, we want more treatment options. Treatment options that have better side effect profile and that are better at treating all three symptom domains. So our hope is that our research leads to treatments that would be better than conventional treatments, and really have dramatic effects on the patient’s well-being.
So very, very specifically you got a 13-year-old boy, he’s manifesting symptoms. We’re down the road a piece, what happens to him? Does he go in the hospital and get a shot? Or, what’s the transmissions is what I’m getting at?
Daniel Lodge: Ultimately, what we’re looking for is a new therapy probably in a pill form that that patient can take when they first present with psychotic symptoms, something that will not only treat the positive symptoms but also negative cognitive symptoms with relatively few side effects.
END OF INTERVIEW
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