Future of Precision Medicine & Nutritional Therapies for Mental Illness with Dr. Megan Kirk Chang

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 purposes 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.

Welcome back to Metabolic Mind, where today we’re going to talk about ketosis as an intervention for treatment-resistant depression. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re focusing on the intersection of metabolic health and mental health and metabolic therapies like ketogenic therapies as treatment for mental illness.

I’m Dr. Bret Scher, and today it’s my pleasure to interview Dr. Megan Kirk Chang. Now, Dr. Kirk Chang has a PhD in Kinesiology and Health Sciences and an advanced doctoral degree in Health Psychology. And she’s a Senior Researcher on the Health Behaviors Team at the University of Oxford. And as you hear in our discussion, she has a pretty diverse background of what she has studied, different non-pharmacologic interventions for treatment of mental health disorders, whether it’s PTSD or treatment-resistant depression.

And now she’s embarking on studies looking at ketogenic therapy, nutritional ketosis as an intervention for depression, and also for cognitive decline and potentially, even one for psychosis. So, she’s really starting to get into this field. And she comes from it, not from a ketogenic background, but from a pure scientific background.

Just as she says in this interview, there’s just too much of a signal that this could be beneficial to ignore. So, she wants to study it further. But as we hear there’s some barriers to looking at ketosis and some things to be considered. So, we talk about it from a research standpoint, but also about, what are the potential mechanisms?

How could this play out? How could this impact medical care? Which I think is so important to make sure we’re connecting the research to the end user and the medical care. And Dr. Kirk Chang does that well. Now, since our studies are just getting started, we couldn’t go into too many of the details, but we do talk a lot about the background and the hypothesis behind them.

And I look forward to having her on again when the trials are completed so we can talk about the results. But now remember, please, before we get on with the interview or channels for informational purposes only, we’re not providing group or individual healthcare or medical advice or establishing a provider patient relationship.

Changing your lifestyle, changing your medications come with definite risks. So, make sure you do that in conjunction with your physician, but use this interview as information, as a way to learn. And then bring the information to your healthcare team to see if it warrants any further intervention. So with that, let’s get on with this interview with Dr. Megan Kirk Chang.

Dr. Kirk Chang, thank you so much for joining me today at Metabolic Mind. 

Megan: 
Thank you so much, Bret. I’m really excited to be here. 

Bret: 
I’m excited to talk to you about the use or potential use of ketogenic therapy and nutritional ketosis for treatment in depression. At Metabolic Mind, we’ve talked a lot about a spectrum of serious mental illness, but it seems like a lot of the research we’ve seen focuses on bipolar disorder, schizophrenia, and maybe also depression.

But now we’re starting to see a few more studies pop-up specifically for depression. But first I want to read from your LinkedIn page about your interests and hear about how that has transitioned to depression. So, you say you research scalable cognitive behavioral health interventions that integrate mobile and digital health applications and wearable technology to identify biomarkers of mental illness and profile treatment effects via autonomic nervous system regulation.

Now that sounds pretty cool. That sounds pretty fascinating. But there was nothing in there about nutrition and nothing in there about ketosis. So, give us a little bit of your background, your research interests, and how that sort of has led to investigating ketosis for depression. 

Megan: 
Yeah, I think it’s a really great question.

And I feel like in my lifetime, I’ve had the good fortune now of being able to conduct research and be a part of different research teams across three different countries. Most recently, I’m now in the UK at the University of Oxford in the Nuffield Department of Primary Care. Previous to that, I came from Yale University in the Yale Center for Emotional Intelligence.

And then my doctoral work was done at York University in Toronto. And through each of those three experiences, I’ve had a very diverse exposure to different modalities, different ways to intervene with folks with mental health conditions, through different cognitive behavioral therapeutics, I’ll call it.

So, mindfulness-based stress reduction, exercise, low-intensity exercise, compassion cultivation training. And now, I find myself at the University of Oxford working in an incredible multidisciplinary team. We call it behavioral medicine, but also diet and nutrition as well.

So, we’ve come together as a multidisciplinary team to bring all of our strengths together to develop what we think will be a really innovative approach to treating treatment-resistant depression, which we know is just increasing, especially since the pandemic. So, that’s just a brief overview of my good fortune of having the diversity, of doing a lot of different things across three different countries so far. 

Bret: 
Yeah, so you mentioned treatment-resistant depression. So, some people may be aware of that term and some people may not. Obviously, as it sounds, it means treatments aren’t working. But what is the general definition of treatment-resistant depression?

Megan: 
Yeah, it’s a really great question. And so how we define treatment-resistant depression are folks that have tried at least two antidepressant medications that have been prescribed by a psychiatrist or a general practitioner. They’ve had to have tried each of those medications for a period of about four weeks or so, but they still experience the presence of depressive symptoms.

And they’ve also received a diagnosis either through a clinical psychologist or a qualified professional that’s able to diagnose depression based on ICD-10 or DSM-5 criteria. 

Bret: 
Yeah, and I think it’s interesting, which says a lot about our medical society or approach in that it’s defined purely by medications, right?

It is not defined by if you’ve had any lifestyle or any therapy. That doesn’t factor into treatment-resistance. So, I’m curious, what you think about that? 

Megan: 
Oh my gosh. I could talk about this for hours. And prior to coming to this role and working with treatment-resistant depression, I worked primarily with adults that had post-traumatic stress disorder, and learning the ways that there are limitations in the way that post-traumatic stress disorder is diagnosed and quantified based on DSM-5 criteria.

And seeing how many people actually fall through the gaps of receiving a diagnosis so they can access appropriate treatment. It’s not so different to what I’m seeing here with treatment-resistant depression as well. Because there is a lot of folks that don’t want to have medication or don’t choose to participate in psychological talk therapy because maybe they had a bad experience or maybe they don’t have that connection.

They haven’t found that therapeutic alliance with somebody. but it doesn’t mean that their symptoms are any less valid. So, there’s a lot of room to grow, I think, in terms of how do we ensure people aren’t falling through the cracks of receiving appropriate and timely care.

Bret: 
Such a great point. So, what do you think the state of evidence is? It is a broad question that can go a lot of ways, but what is the state of evidence for nutrition as in as a therapeutic intervention for depression or specifically treatment-resistant depression? 

Megan: 
As I was preparing for our conversation today, I was thinking a lot about my experience with health promotion and health behavior change interventions. That when we think of exercise and mindfulness to an extent, people participate in those in their leisure time and it’s on their own volition that they choose that.

Whereas what I’m understanding with diet and nutrition, we can’t just decide to choose that on a whim. We need to consume foods in order to survive. I never really considered that previously. And so, as I’m someone that’s learning a ton right now, and I don’t come from a dietician background, I think that’s actually to my benefit because I don’t carry a biased opinion. I don’t carry any assumptions. I am really approaching this idea of ketogenic diets, this idea of, I just am curious of, if it works.

And if it does, how does it work? As opposed to previous experience with trying to prove that it does. So, I think it’s actually of benefit that I’m coming with a bit of a fresh perspective to this field. But obviously, with the mental health background and health behavior background, I think it can add a lot of value to intervention design.

But certainly, over the last, my gosh, decade, the proliferation of research looking at ketogenic diets for not just epilepsy, but other types of neurological or psychiatric disorders has exponentially increased. But also just as a consumer, whenever I go out to grocery shop or whenever I look at products to buy, I’m seeing more and more availability of keto-friendly products.

And I think I read somewhere that it’s now a $12 billion industry, projected to double, even triple, in the next two decades. So, it’s not going anywhere. And there’s got to be something, there’s got to be something here with the traction that it’s getting.

So, that just makes me really curious. And it’s an exciting time because, the other thing I wanted to add is that a lot of pharmacological treatments are really ineffective. There’s something happening where folks don’t want to be on medications, especially for psychosis or schizophrenia.

Those medications might help the mental health symptoms, but they’re also presenting other issues with metabolic syndromes or cardiovascular risk. And a lot of people are becoming more conscious and aware of how are they treating their bodies. So, I’m really excited about the direction that nutrition is going in terms of a novel approach for mental health.

Bret: 
Yeah, I think one thing we talk a lot about is the use of medications and how they can be lifesaving and how they can be so important. But for chronic treatment, they really fall short in many ways. One is not just treating acute mental symptoms, psychiatric symptoms. But allowing someone to live their full life and vibrant with like full emotional capacity and full clarity of thought, and that a lot of them, their side effects prevent that.

But then also, like you referred to the metabolic potential side effects, which are also very concerning. So that’s where nutrition can play a very important role either to help lower the dose of medications or not have medications or. Undo some of the side effects from the medications that nutrition can play all those roles.

But when you talk about nutrition for depression, everybody talks about Mediterranean diet. The one big Mediterranean diet study, which compared Mediterranean diet to standard American diet, my take is not exactly a surprise that it showed a benefit. Because I think you could do anything compared to a standard American diet, and it’s going to show a benefit most likely.

But is that really the state of evidence right now for nutrition, for depression? Is that, is that as good as it gets right now? 

Megan: 
It’s such a good point. I’m smiling because as somebody who’s not even a year into the UK, like the American diet is not so different from the UK diet. And the Mediterranean diet really certainly has benefits from healthy fat consumption, the emphasis on oily fish and whole grains and vegetables.

And what’s interesting in the work that I’m doing is actually looking at research comparing Mediterranean diet to ketogenic diet and the mechanisms with which these two diets work are different. And one of the studies that I am currently developing right now is actually a non-inferiority trial. It’s never been done before in academic research with psychiatric populations where we look at, is the ketogenic diet as effective as the Mediterranean diet?

Not better, not worse. We want to look at is it as effective? And if it is, we can get into something like precision medicine where we look at who is this going to benefit the most. Do we work with somebody who has multimorbidity? So somebody that’s got a psychiatric condition, but also maybe insulin resistance and maybe the ketogenic diet would be better suited for that individual, where the Mediterranean diet might be better suited for somebody else.

So, we’re in this exciting time where we’re starting to look at mechanistic work and testing out, not just self-reported measures, but looking at blood biomarkers, looking at gut microbiome markers, looking at saliva, cortisol, and how that shifts before and after implementing one of these diet interventions.

But I think there’s just, there hasn’t been enough time or funding to explore what combination of foods really actually produce and yield the greatest amount of change in somebody’s symptoms but also sustain them. And I think the Mediterranean diet has gotten a lot of publicity and it’s been around, it’s been in the research world a little bit longer.

But I think we’ll see that shift a little bit, and we’ll see a lot more, I am seeing a lot more research coming down the pipeline with ketogenic diets. 

Bret: 
Yeah, I really like how you’re comparing keto and Mediterranean rather than standard American because it’s just so important to have a better baseline. But as we talk about, also as we talk about here at Metabolic Mind, ketosis can come from many different diets, right?

There’s a Mediterranean keto diet. So, you could be on both those at the same time, but you alluded to the mechanism. So, what do you see as the main mechanistic differences or the main mechanism, unique mechanisms that ketosis has where you might see a difference for a treatment-resistant depression?

Megan: 
Yeah, such a good question. And what I’m discovering is the pathways, the mechanisms of change that occur through ketosis and this idea of a different source of fuel and energy for the body. It’s really multi-faceted, but some of the ones that I think have received the strongest evidence, we’re building upon evidence from animal research previously.

But we’re starting to see more mechanistic-based research in human samples. And right away, this idea of how a ketogenic diet supports the synthesis and pathways of neurotransmitters, particularly GABA, dopamine, serotonin. Really promoting, I don’t know, for lack of better words, I’m trying to make it more for a lay audience, but just helping these neurotransmitters that are affected by depression and are affected by low mood function, and the receptors are operating better than previously.

But also with insulin resistance, we’re seeing a lot of great changes in blood biomarkers and then gut microbiome as well. That’s not my area of expertise and not my lane, but we’re seeing a greater diversity of healthy bacterias when you’re following ketogenic diet. And I think when we think about things like inflammation and systemic inflammation, that’s common to metabolic syndrome, diabetes, mental health disorders, dementia risk, ketogenic diet seems to act on all the risk factors that are connected to those three types of health conditions.

I think there’s room to grow though. And certainly with the work that we’re developing at Oxford, we hope to bring in more biological biomarker evidence so that it’s not just a self-reported, subjective level of change. But we’re actually saying, here’s the explanatory pathways with how this diet is working and how it’s shifting people to feel better.

Bret: 
Yeah, I think that’s a really great perspective because then, like you’re saying, you can identify the people who are most likely to benefit based on what seems to be the working mechanisms. When we talk about mechanisms with a drug, you can design a drug to have one mechanism, although many have multiple mechanisms. And with nutrition, with lifestyle, it might be harder to pinpoint to one mechanism, right?

There could be multiple different things that are going on because you talked about improved insulin resistance and metabolic health. You talked about GABA and neurotransmitters. Ketosis can, ketones can reduce inflammation with the NLRP3 inflammasome. And there can be multiple different mechanisms.

So, when you have something that’s not as clean as one mechanism, does that make it more challenging as a researcher to try and figure out what’s going on and how to relate it to people? Or is it providing more opportunity to find different avenues of potential improvement?

That make sense? 

Megan: 
I think it would depend on the researcher that you ask, and I’m certainly of the mindset that I actually believe it offers more opportunity. And what I am seeing, especially in mental health research and psychiatric treatment, is this idea of precision medicine. So, the right dose, the right time, the right person, the right intervention.

And somebody who’s acutely going through a traumatic experience and has extreme symptom severity might be better suited for a different type of treatment. You talked about pharmacotherapy or different medications than someone who has maybe done that and is now looking for a bit more of a maintenance perspective.

And so, maybe a lifestyle approach might be more suitable because they’re not in that acute stress phase? So, I think it’s actually an opportunity. The more mechanisms we can explore and understand, the more we can start to target treatment appropriately based on a person’s unique profile. Multimorbidity is becoming a greater challenge across the globe.

More and more people are living with multiple long-term conditions and maybe the ketogenic diet is more suitable for someone that has a profile of diabetes risk and mental health. Where Mediterranean diet would be more suitable for a maybe a younger person that only has a mental health condition presenting at the time.

It’s tough to say, but this idea of personalized targeted treatment, I think it’s a great opportunity. The more we can explore, the more we can understand, the more we can start to identify where people are going to fit in, and who’s going to benefit the most. 

Bret: 
And, it doesn’t always have to be an either or, also right?

Like I guess you could say, standard of care treatment shouldn’t be, here’s your pill, see you later. It should be, here’s a medication, you can try improving your diet, improving your exercise, going to psychotherapy. So, even with ketosis, maybe there’s a role and there probably is a role for all of those factors as well.

So, as you’re designing a trial, as a researcher, is that something you need to build in to make sure both groups are getting appropriate other treatment, comprehensive treatment besides just a dietary intervention? 

Megan: 
Absolutely, we would never ethically tell someone that they should stop pharmacotherapy or talk therapy.

Those are the standard, most recommended, most validated treatments for individuals. But having this as an adjunctive option to maybe further enhance recovery or further enhance symptom reduction, I think is really important. 

Bret: 
So, we’ve talked a lot about sort of the background and almost like we’re dancing around the actual trials, but you’ve already alluded to, I think, more than one trial that you’re doing around this.

So, can you describe the trials a little bit and let us know if they’re enrolling? And if people want to participate, what they can do? 

Megan: 
Yes, for sure. So, the one I’ll speak to that’s currently in development, we haven’t even met as a team. But there is a trial underway right now looking at comparing ketogenic diet with the Mediterranean diet for folks that are older adults, who have a first degree relative that have dementia.

So, they are at a higher risk of potential early onset or dementia risk later in life, and who do report certain mental health symptoms. And so, we’re looking again at this idea of comparing in a non-inferiority trial context, ketogenic diet versus the most widely recommended diet for dementia prevention, which is the Mediterranean diet.

And I’m excited about that because usually those diets are compared to a placebo or standard American diet, as you said. So, it’s an exciting time to see, in a unique intervention design, what might happened. I’m curious about that. And then with treatment-resistant depression, we’re in the final stages of launching a randomized trial to explore two exciting nutritional interventions.

I’ll leave it at that at the moment. To see what the effects are on treatment-resistant depression and looking at gut microbiome and salivary cortisol level mechanisms before and after. 

Bret: 
Very interesting. Great, I encourage people to look you up and if they want to learn more, or if they’re able to learn more about those trials.

When we talk about nutrition, the world of nutrition, the US News and World Report come, as if it’s a medical journal, comes out ranking the best diets, and you hear reports online about how dangerous a keto diet can be. And a big part of my message is that is just really faulty and misinterpretation of the evidence.

But as a researcher, does that provide a challenge? If you say, I want to study a ketogenic intervention, are there more barriers to doing that than there are to studying a Mediterranean diet or a vegetarian diet? Have you come across any of that? 

Megan: 
Yeah, I think that’s a really, it’s a really timely question, and I can’t help but draw comparisons from what we’ve gone through, collectively, in the last four years with the pandemic and how scientific evidence often gets overlooked with radical ideas that aren’t grounded in evidence.

So, we’ve seen this kind of happen with the pandemic, and I think, in maybe not as an extreme way, I think a lot of people don’t fully understand what a ketogenic diet might be. And I think there’s been situations where there’s been this radicalized idea of it’s just eating burger patties, bacon and eggs all the time.

Our approach from a research perspective is really emphasizing nutritional value and understanding that the ketogenic diet is looking at predominantly 60 to 90% of your intake is healthy, high-fat content. There’s adequate protein, 1 to 1.7 grams per kilogram of weight. And then this idea of 50 grams or less of carbohydrates, kinf of a standard ketogenic diet. But we’re emphasizing whole foods, vegetables, health-oriented colorful plates. We’re not radicalizing this diet to say just eat steak every single meal. And to each their own. I’m not here to place judgment.

But I think there’s been situations where we’ve missed what ketogenic diet actually means. So, as a researcher, it is a challenge because we want to emphasize that we are health-focused. And we’re working with registered dieticians. And one of our collaborators works for the FDA in the UK and she’s brilliant, and informing the nutritional content of the trial to make sure that it’s high in nutrition and good quality nutrients. So yeah, that’s what I’ll say about that is. 

Bret: 
Yeah, I think that’s well said. But it is interesting, there are people who are thriving on a carnivore diet, only eating meat, where try and get that by IRB or try and get that by a dietician committee and forget about it because of the barriers that are in place.

So, to do a research study, I think it is important to present it the way you presented it to get buy-in. 

Megan: 
Yeah, and I think you make a good point, too, that we do have a very stringent screening criteria where folks, who have certain kidney-related conditions, or we just don’t know enough yet about the ketogenic diet from an academic research perspective.

So, we are treading very cautiously and making sure that the people that would come forward for our study are appropriately screened for pre-existing conditions that might be further exacerbated by radically changing their diet. We’ve put really stringent measures in place to make sure that safety is first.

And yes, it’s gone through a very rigorous ethical approval process, my gosh. And so, I do feel very confident that we’ve developed across the multiple trials that are underway, we’ve developed really great safeguarding and safety procedures for the diet. But also to make sure if there is a retriggering of mental health symptoms, we’ve got psychiatrists, support clinician scientists that are available to support the team in that as well. So, I do feel very confident in that. 

Bret: 
Yeah, I think the way you answered that really presented the, I don’t know, juxtaposition is the right word, between research and what a lot of people are doing in clinical practice.

Because a lot of the doctors who are practicing with ketogenic therapy would probably shake their head at all that you don’t need to worry about. Kidney disease, you don’t need to worry about all these medical conditions. It’s proven to be safe in clinical practice. But for an IRB for a research study, it’s very different.

And it’s the same for medications, right? You have to have hundreds of exclusion criteria when you’re designing these studies, and it could be frustrating for some. But that’s the way research is done. So, I think it really makes sense from a research stand. I, for one, am very interested to see what you come up with, and I’m very thankful that there are researchers like you doing this type of research. And looking at your background, you’re not a ketosis researcher.

You didn’t come up studying only ketosis. So it’s, I think that’s what shows that we’re really reaching, don’t know if you want to call it mainstream or a broader research audience, that people are recognizing, hey, this is something that deserves to be looked at. And not just from the group who already believes it and already thinks it’s the greatest thing in the world, but from a group who says, we need to study this further because it looks like there’s a signal there.

So, kind of a broad thing to leave it as, but what do you see as the kind of the future of ketosis research or the future of therapeutic ketosis interventions? And where do you see this going? 

Megan: 
it’s interesting. I look back at the populations that I’ve had the privilege of health coaching, counseling, and supporting through an 8 week, 6 week, 12 week behavioral intervention, whether it’s exercise, yoga, compassion, et cetera.

And I think about, had I known what I know now about the importance of diet in terms of your mental well-being, and especially the literature that I’ve been really drowning myself to understand in terms of how does this diet work, how does ketogenic diet work for folks that have the most difficult, challenging psychiatric symptoms.

I think if I could go back, knowing what I know now and be able to offer this as an addition and an add-on to what we were doing, I do wonder what the impact would’ve been. And I worked with men with prostate cancer who were on androgen-deprivation therapy. So, their hormones were out of whack.

They were experiencing very close to what women experience menopausal symptoms. I think about the PTSD participants, as you talked about earlier, who are on a concoction of different medications and are walking through life numb to their sense of aliveness. I think about those people as I continue to evolve as a researcher and establish my own independent research identity.

Of like had I known what I know now about the importance of what we put into our body, could that have made an even greater difference than what we did previously? And so, I carry that with me as a motivation as I continue to go down this path. I think there’s too much evidence supporting the efficacy of a ketogenic diet for people with mental and metabolic conditions, there’s too much there to ignore it.

And I think, as I said earlier, one of the benefits I feel I bring to the field is that I’m not a business owner. I don’t have a stake in a ketogenic diet company. I’m coming at this really from a curiosity lens of does it work? And if it does, how does it work? I’m not interested in proving it does. The proof will happen regardless. I’m just curious about it.

And I think that’s what’s needed in academic research is someone that has that lens of curiosity, and I really feel like I bring that. Yeah, it’s an exciting time. I don’t see it going anywhere. If anything, I think, what’s going to be the challenge is finding and securing funding to keep evolving this work and really establishing this kind of nutritional program as a recommended treatment, even policy change, like I see that happening.

I don’t see it happening today, but certainly I’m hopeful that the more people that can continue to do this work, the more we’re going to save lives. And we’re going to help people return to their sense of aliveness. And as a researcher, that ultimately has always been the thread. No matter what institution I’ve been at, no matter what project I’ve been working on. It’s how do I help people return to their sense of aliveness.

And I’m really excited to be a part of a team at Oxford to be doing that through ketogenic diet. 

Bret: 
Wow. What a great answer. Just a great answer as a scientist and a researcher with an open mind. But then bringing it back to the patient and the people you want to help in the end. So, thank you.

Thank you for that. Thank you for taking the time to sit down with us, and maybe we’ll have you again when the trials are done and we can talk about the results. 

Megan: 
Oh, I hope you do because I’m so excited to see what we find, and I would be thrilled to do that. So, thank you for your time today as well. 

Bret: 
Thanks for listening to the Metabolic Mind Podcast.

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