Exploring the Link Between Genetics and Brain Metabolism in Psychiatry with Dr. Harry Pantazopoulos

Harry: 
It provides more evidence for the idea that a ketogenic diet may be very beneficial for people with bipolar disorder, too, address some of the symptoms that can happen from overactivity of the amygdala.

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational only, and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

Dr. Harry Pantazopoulos, a psychiatry researcher at the University of Mississippi Medical School joins us to talk about a fascinating new study that he and colleagues did looking at gene expression as it relates to bioenergetics and metabolism in the brains of individuals with schizophrenia, bipolar disorder, and major depressive disorder, and how they’re similar, how they’re different.

What it might mean for potential therapy, like ketogenic therapy, in these disorders and what it might mean for future research. Now, some of this gets pretty technical, but it’s really fascinating about how looking at these mechanisms may inform our treatments in the future. So let’s hear from Dr. Pantazopoulos.

Dr. Pantazopoulos thank you so much for joining me today on Metabolic Mind. 

Harry: 
Oh, thank you for having me. 

Bret: 
Yeah. So, I want to talk to you about this study that you did really looking at the bioenergetics and how it applies to different brain regions and different diagnoses of mental disorders.

It’s very detailed and very interesting. But first, before we get into the details of the study, give us a little background on who you are and how you got into doing this type of research. 

Harry: 
Sure, I’m a Associate Professor of Psychiatry at the University of Mississippi Medical Center. I’ve studied psychiatric disorders for more than 20 years starting off at McLean Hospital in Harvard Medical School, and then eventually moving here to Mississippi to work with wonderful colleagues here.

And I’ve studied psychiatric disorders from the perspective of trying to know what’s happening in the brain of people with these disorders. So, we primarily use human postmortem brain samples from donors, and these are precious samples. So, we try to make the most out of what we have and get valuable information out of them. Our goal has been what are the molecular changes and the circuitry changes that are occurring in the brain of people with these disorders?

And how are people with schizophrenia, for example, different from people with bipolar disorder or people with major depression or autism spectrum disorder? That’s been a challenge, and it’s been a challenge in psychiatry. And can we find certain things that can help us guide treatment strategies and diagnostic strategies for these disorders?

Bret: 
Yeah. Yeah, very interesting. And so the paper that I want to talk about is titled Differential -I can’t even pronounce it, Differentially Altered Metabolic Pathways in the Amygdala of Subjects with Schizophrenia, Bipolar and Major Depressive Disorder. First of all, there’s a lot of words in there, but amygdala, tell us about the amygdala and why you specifically chose to study that part of the brain this study.

Harry: 
The amygdala is a very interesting structure for these disorders for a number of reasons. It’s a small almond-shaped structure is where it got the name amygdala from, the Greek word for alman, in our temporal lobe on either hemisphere. It’s involved in giving basically emotional significance to our sensory information, our information from our external environment.

And it’s long been thought to be involved in fear regulation, which it is, but we, what we’ve learned in the field more recently, it’s also important than regulating anxiety. And it’s important in giving positive, emotional information to external information, too. So. It’s involved in reward response.

It can also drive rewarding experiences. So, in these disorders, bipolar disorder, of course, there’s rapid changes in reward response from mania to depression where you have a higher drive for reward versus anhedonia or lack of reward during your depressive states. You have comorbid anxiety that occurs across these disorders.

The amygdala is really intricately involved in regulating all of these experiences. So, that’s why we were focused on understanding what’s happening within the amygdala and can help us guide treatment strategies for these disorders for specific symptoms. 

Bret: 
Yeah, thank you for that background. And now what I found really interesting was you, as the title says, you’re looking at altered metabolic pathways or bioenergetics or how energy is created.

And despite there being some overlap between bipolar disorder and depression and schizophrenia clinically, you can say there’s some overlap, but the findings were quite different between the different diagnoses. So, maybe walk us through that, like what was one of the main findings you found for schizophrenia when looking at the bioenergetics and metabolic pathways?

Harry: 
Yes, this was actually quite surprising to us because we went into the study thinking amygdala activity from brain imaging studies is increased in all of these disorders? At least from current study studies in the literature, higher activity at baseline for people with bipolar disorder, people with schizophrenia, suggestions for greater activity of the amygdala in major depression, too, especially when viewing emotional expression or images of faces with emotional expressions.

So we expected that bioenergetic findings, at least at the transcriptomic level, the gene expression level that we were examining, would be fairly similar across these disorders. But what we ended up finding is although these metabolic pathways and gene expression were altered in all of these disorders, they’re altered in very specific ways.

For example, in people with bipolar disorder, we had a really strong upregulation or increased expression of gene pathways involved in carbohydrate metabolism, whereas that was not found in people with schizophrenia or major depression. People with schizophrenia instead had a downregulation of pathways involved in nucleotide metabolism.

And we saw some changes in lipid metabolism as well in people with major depression and a little bit in the bipolar disorder. But these were really distinct differences in metabolic pathways at the gene expression level in these disorders. So, I think for us, this is really exciting and not what we predicted, but it opens up a number of questions for us to follow up for how are these disorders similar or different and how can we develop therapeutic strategies based off of our knowledge of metabolism and its role in psychiatric disorders? 

Bret: 
Yeah. So, let’s dig a little deeper about what you just said about what you found in the patients with or by or in the subjects with bipolar disorder, that there was an upregulation in the genes involved with glucose metabolism.

So what do you hypothesize why that could be and what the implications might be for the etiology and potential treatment of bipolar disorder? 

Harry: 
There are a number of interpretations. Our approach at the moment that we believe it may reflect increased metabolism, glucose metabolism in this particular brain region that may contribute to that overactivity of the amygdala that’s been reported by brain imaging studies in people with bipolar disorders.

So too much activity in the amygdala could contribute to some of the dysregulation and reward behaviors, anxiety that occurs in this disorder, and on the other end, can also potentially contribute to depression. So, it could be that this is highly speculative and we would need to follow this up with more studies, but this increased glucose metabolism might be feeding onto a susceptibility for people with bipolar disorder based on genetic changes to having overactivity of this region. And we would need to find strategies to reduce that overactivity in this brain area. 

Bret: 
And, of course, one of the things we talk about frequently at Metabolic Mind is the use of ketogenic therapy. And one of the, one of the big metabolic changes in the brain is that the brain starts using more ketones and less glucose.

So, could you perceive that could be a potential treatment if there’s glucose overactivity or over metabolism to then decrease that by providing the brain with more ketones and less glucose as a fuel source? 

Harry: 
Yes, of course. That’s a great strategy, and I’m sure your audience is very familiar with the ketogenic therapy was first proposed for overactivity of the brain and epilepsy, people with epilepsy.

And if it seems to be at what we are seeing in people with bipolar disorder in the amygdala, overactivity of the amygdala, and now we know that there’s increased metabolism of carbohydrates so glucose metabolism.

So replacing that fuel from glucose to, through a ketogenic diet, could be a promising way of addressing this problem and normalizing brain activity of the amygdala, definitely. 

Bret: 
Yeah. Oh, and then let’s transition to a second to schizophrenia. In schizophrenia, it seemed like there were deficits in mitochondrial bioenergetics, like you could say a downregulation of energy production. Is that accurate? To sum up what you found? 

Harry: 
That was in the major depression subjects since, yeah, schizophrenia was a downregulation of nucleotide metabolism most strongly. Yep. 

Bret: 
So, explain that in layman’s term of nucleotide metabolism. 

Harry: 
So, nucleotides, they’re basically the building blocks for making our DNA and RNA. And we can create some of those endogenously, but sometimes you need some of these building blocks when you have a higher demand for these building blocks, whether you have a lot of RNA processing on gene expression or gene transcription or breakdown. You may need some more from external sources and you can get some of these nucleotides from a diet, for example.

Organ rich meats are enriched in nucleotides. A lot of legumes, fish are good sources of nucleotides. And if there’s a big decrease of nucleotide metabolism in schizophrenia, we can’t ask functional questions with our postmortem studies, of course, but we can hypothesize and these are things that we can follow up on with some additional studies.

And to ask more functional questions, we can think of how switching your diet to foods that are more enriched than nucleotides could help compensate for that decrease nucleotide metabolism. 

Bret: 
Yeah, that’s really interesting. So, more specific food choices, rich in the nucleotides to bypass that deficit.

So yeah, that’s a really interesting future study I could see there. But then we’d also mentioned a major depression, what you found, and there was a decrease in ATP production with what seems like a compensatory increase. And was that an increase in the nucleotide or the increase in the glucose bioenergetics?

Clarify that one for me. 

Harry: 
Yeah, increase in the nucleotides slightly. It was not as drastic as in changes that happen in schizophrenia in that pathway. But yet mostly it was the stronger decrease in mitochondrial energy metabolism, and that’s something that we had expected, honestly, to find the cross disorders and it only really popped out in the major depression group.

Bret: 
Yeah, so that is interesting that there is a hypothesis that it’s, there’s altered bioenergetics, altered energy production across the board in brain-based disorders, whether it’s dementia or whether it’s seizures, or whether it’s bipolar disorder, schizophrenia, or major depression. But for this directed study looking at schizophrenia, bipolar disorder, or major depression, you only saw that in major depression, right?

Is that what? 

Harry: 
Yeah, largely. And the way our analysis is conducted, bioinformatic analysis from our gene expression data, it groups genes into pathways, and then we look at what are the pathways that are the most enriched for genes that had increased expression or genes that have decreased express expression.

So the top pathways in terms of metabolic changes were those that we mentioned that increased carbohydrate metabolism in bipolar disorder, decreased nucleotide metabolism, schizophrenia, the energy metabolism in major depression. But it doesn’t mean that there aren’t some of these changes occurring in the other disorders.

They’re just at us much smaller extent. So we likely have some energy processing changes, mitochondrial changes occurring in each of these disorders, but the details of how these are happening are very different. 

Bret: 
And I guess I should clarify that I think I, the way I’ve been speaking about this, as if you’re actually measuring energy output or actually measuring a physiologic change, but what you were measuring is the genes that then could contribute to those changes more than, and not the changes themselves.

So that sort of begs the question. Would this be the foundation to then have studies and living subjects that measures the actual outputs, and rather than just the genetic transcriptions, but that tells you where to look specifically for those outputs? 

Harry: 
Exactly. This is, it’s a good unbiased start at examining how are these pathways different in these disorders.

But then looking at living subjects and looking at the actual metabolic changes, would this helps guide those studies? That’s exactly right, yeah. 

Bret: 
So, is that something that you think the University of Mississippi will take on or do you think someone else needs to swoop in to do that kind of study?

Harry: 
I think it’s something we would like to participate in with other collaborators. I think it’s a big study and working together with several groups, it’s the best approach I think for all of these studies. 

Bret: 
Yeah. Yeah, and it’s always interesting to see, okay, when a study is done like this, what does it mean for future studies and what does it mean for clinical care?

And the harder jump is probably clinical care, especially for a study like this. But what do you think a clinician can take away from this study to at least start, maybe, a building block for them about, treating patients with various psychiatric disorders? 

Harry: 
Yeah, that’s a good question.

As with all of these studies, we’re not there yet at guiding the clinical care, but I think it can at least give clinicians a clue of things to keep in mind when you’re considering dietary approaches in clinical care and diagnostic approaches, too. That it provides more evidence for the idea that a ketogenic diet may be very beneficial for people with bipolar disorder to address some of the symptoms that can happen from overactivity of the amygdala as well as if you look at the other aspect of it isn’t the main purpose of the ketogenic diet.

But on the ketogenic diet, you’re going to be most likely eating foods more rich in nucleotides that we talked about. And that could potentially address some of the decreased nucleotide metabolism we see in people with schizophrenia.

And in turn, this can also be maybe not as applicable to people with major depression, but can contribute to some of the energy metabolism problems in people with major depression as well. We would have to learn more in for exact exactly what’s happening within these pathways and how they interact with medications.

I think that’s a future strategy that we really want to get into is how does antipsychotic therapy or lithium or antidepressant therapies, how do they impact these energy pathways, whether it’s at the gene expression level or at the actual functional protein levels? And how would these medications interact with dietary strategies?

For example, if someone’s on a ketogenic diet and they have decreased nucleotide metabolism and they’re diagnosed as having schizophrenia, is an anti-psychotic going to help or is it going to cause problems with these two strategies? These are things we need to learn more of.

And I think that’s the way, that’s where we want to go with some of this research to guide clinical care. 

Bret: 
Yeah, it’s fascinating and somewhat overwhelming at the same time. One study like this opens up numerous other questions and multiple other studies that could and should be done to help bring it back to clinical care.

So as with a lot of good research, it almost brings up more questions than answers, but that’s part of the way for research. So I would implore any researchers out there, anybody at institutions out there listening to reach out to you and see about collaborations for getting all this done.

So, if people did want to contact you or learn more about you, where would they go? 

Harry: 
They’re welcome to come to our faculty website at the University of Mississippi Medical Center, Department of Psychiatry and find my webpage there. Email me at cpantazopoulos@umc.edu. I know Pantazopoulos is not the easiest name to remember and write down for an email. 

Bret: 
We’ll put it on the screen so people can see it.

Harry: 
Yeah, and I’m happy to talk with anybody that’s interested in collaborating. We would love to follow up on this research with several of the avenues we mentioned. And we also have a part of the analysis that we didn’t mention yet that suggests potential therapeutic strategies from our initial study.

We conducted this, it’s a predicting a broad way of predicting potential therapeutic targets. So, there’s a public database available of gene expression signatures in response to various drugs in different cell lines. And it’s very broad. Some of these are cancer drugs or cell lines that are not reflective of the brain, but it’s a good way of testing very broadly, if you give this drug what happens to the gene expression of cells.

And then we can take those gene expression signatures, as we call them, compare them to the signatures that we saw in our study in people with bipolar disorder or schizophrenia or major depression, and predict which of these drugs could cause these changes or make them worse, and which drugs could potentially reverse these changes.

And through this analysis, we only found one group of drugs that looked fairly significant, that’s worth following up. But interestingly enough, that was ATPase inhibitors for people with bipolar disorder that are predicted to reverse some of the changes that we see in the amygdala.

And ATPase inhibitors, it’s part of the sodium potassium ATPase pump that regulates energy within cells, especially brain cells that are high, have a high demand for this energy. And that reflects upon that idea that brain cells in people with bipolar disorder may have this over overactive state from glucose metabolism.

And if ATPase inhibitors is, it’s known that they’re going to decrease glucose metabolism or slow down glucose metabolism. So it supports that and the same idea of the ketogenic therapy and what that may do. But it gets it down to a very specific target that we could follow up on and see other strategies of doing this in as a therapeutic approach.

And the ATPase pump is interesting because, and not only works, ATPase inhibitors work to decrease the energy of cells through the ATPase pump, but at a lower dosage or lower concentration, ATPase also works as a receptor. So if you give a ATPase inhibitors, such as a cardio to steroid, it bind to the ATPase as a receptor and promote other downstream gene expression changes.

And some of those changes have been shown to promote brain derived neurotrophic factor, which helps promote synapses and connections. And some of them work on what’s called the Wnt signaling pathway, which is a pathway that lithium maxon, that’s a good pharmacological approach for people with bipolar disorder.

And it brings to mind some of our other lines of research where we originally got into this study that I didn’t mention yet. Is that we’re interested in circadian rhythms and how they’re involved in people with bipolar disorder and mood disorders. And we know that there is a pretty strong association of circadian rhythm changes in people with bipolar disorder, but what does that actually mean in terms of changes in the brain, and how does that contribute to specific symptoms?

That’s been one of our longstanding questions. And we did find some clock genes that were also altered in our study here in people with bipolar disorder. And we know that metabolism is tightly linked with circadian rhythms. It’s a bidirectional relationship. So, it could be that metabolic changes are contributing to circadian rhythm disruption or vice versa.

and the fact that. our, a TPA inhibitor that came up as our top target. It’s involved in regulating potentially both, parts of the molecular clock that regulate circadian rhythms, but also, metabolic pathways. it’s promising. and the other major pathway that we found differentially altered in, our study, that we didn’t talk about yet in addition to brain metabolism, was inflammation.

So in people with bipolar disorder, we saw, increased gene expression for pathways involved inflammation or immune signaling. and that goes in line with, that over overactivity of the brain that can promote inflammation, and, oxidative stress processes. so a lot of these things that are shared features, within this disorder we could potentially be able to address from targeting selective parts of energy metabolism. 

Bret: 
Wow, that is interesting. Many other aspects of this study, and definitely the inflammation part, you could see how that could feed into ketogenic therapy as well, which can decrease neuroinflammation. But so interesting about the, about targeting the ATPase production with medications and how that has some overlap with the circadian rhythms and with lithium and things that we know contribute to bipolar disorder.

Really starting to tease out some mechanistic features there. So, I’m sure that would be very interesting future research, too. So, you clearly have your work cut out for you with many projects ahead to help answer all these questions, that’s for sure. But I thank you for, oh yeah, go ahead.

Harry: 
Oh, I’d just like to mention that we also, a lot of this work we did in collaboration with researchers from the University of Toledo Medical Center, Dr. Rob McCullum Smith and Dr. Sinead O’Donovan, who’s now at the University of Limerick. We like to work in teams so anybody that reaches out, we’re happy to collaborate.

Bret: 
Excellent. Excellent. I really appreciate you taking the time to help explain all this in such a great way because it can be hard to make sense of a lot of this because it’s so detailed and so specific. But I really appreciate you explaining it to us, and we look forward to future research that you’re going to publish and we can talk about more in the future.

Harry: 
That’s great. Thank you. Thank you for having me. 

Bret: 
Of course. I want to take a brief moment to let our practitioners know about a couple of fantastic free CME courses developed in partnership with Baszucki Group by Dr. Georgia Ede and Dr. Chris Palmer. Both of these free CME sessions provide excellent insight on incorporating metabolic therapies for mental illness into your practice.

They’re approved for a MA category one credits, CNE nursing credit hours, and continuing education credits for psychologists, and they’re completely free of charge on mycme.com. There’s a link in the description. I highly recommend you check them both out.

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