New Treatment For Bipolar: A New Ketogenic Therapy Study with Dr. Iain Campbell

Iain: 
So, we saw this clear correlation between mood and energy, and ketone level and reduced anxiety at reduced impulsivity. And I think this, what was particularly interesting, is you get into higher ketone levels, the effect seemed to be slightly more pronounced. So above two millimolar or something.

I’ve just done a survey on my Twitter, for example, just interested in patients response to this and many indicate that kind of over two millimolar seems to be the most effective. We saw indications of this in the study, that in the higher ketone levels, there might be better mood stabilization.

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.

Dr. Iain Campbell, a researcher at University of Edinburgh, who has used ketogenic therapy to treat his own bipolar depression, has now published a new paper with some really exciting and fascinating results about ketone levels and their correlation with mood symptoms in patients with bipolar disorder and also some really detailed imaging findings that kind of hint to the mechanism of why ketogenic therapy can be beneficial.

But he also talks about the changing landscape, how his study and others have drawn more attention to metabolic health, metabolic treatments for mental illness, how this landscaping is changing, and how that has led to very exciting news of their metabolic psychiatry hub at University of Edinburgh.

So let’s hear from Dr. Iain Campbell.

Dr. Iain Campbell, welcome back to Metabolic Mind. It’s so great to be able to chat with you again. 

Iain:
Great to see you. Thanks. 

Bret: 
Yeah, so we’re excited. We’ve talked so many times here about your work, but now you’ve got, I guess you could say, the big publication. You’ve had a number of different publications, but this is the one about the study that you did at the University of Edinburgh.

So I’d love to go over kind of the results and the impact and what you think it means. But let’s rewind for a second and just start, why was it so important for you to do this study on ketogenic interventions for patients with bipolar disorder? 

Iain: 
Yeah, so I live with bipolar disorder type II, and I experienced the kind of concomitant physical health and mental health symptoms of bipolar firsthand living this as a teenager and realizing that metabolic health is intricately interlinked to mental health.

And it really took, for like myself with many patients, it took a kind of a crash and a period of severe illness to realize this. And it was really during that time that I tried to think of anything I could do to improve my situation, and physical health was one of the only levers I could really grab.

I tried everything else. And so I began a kind of very strict form of the Atkins diet, which I didn’t understand was really a kind of form of ketogenic diet. At the time, I was doing it purely to lose weight. And I remember kind of a couple weeks into this, feeling my mind become clear for the first time.

And I always try to describe to people that bipolar, it doesn’t feel like sadness when you’re in depression. It feels more like kind of oxygen deprivation. It’s a very physical state. It’s a kind of state of a crisis in the physiology that you can’t really fully understand or describe, but it feels very much like a deprivation of oxygen, that it’s really uncomfortable to be alive in these states.

And for the first time in many decades, I felt this alleviate and to a degree that I’d never experienced before. I remember I was sitting on the bus on the way to work and I couldn’t understand what was happening at the time, but I knew I felt clear-headed and rational and able to be objective about my experience for the first time in many decades.

So, I started reading about, at first I didn’t know it was the diet, I just knew that I was having periods of wellness that I’d never experienced before. And eventually I learned about ketosis through watching videos from people such yourself, Dom D’Agostino talking about it online.

And I realized, ah it’s, this could be the thing that’s mediating the response. And I started measuring blood ketone levels. And over a year, I tracked them every three days with my mood. And I realized there was a correlation between my mood symptoms and the ketone level, which was something. Really what absolutely confirmed it for me was taking exogenous ketones and going out of ketosis and then transitioning back in and seeing that within a match of hours I could feel relief from quite severe symptoms and my family noticing this.

So that was kind of what led to doing this research. And for many years, there was no support for this area. It was very hard to, I was turned down for almost every grant or fellowship I applied for. But I was very fortunate to meet, Jan Baszucki, whose son Matt, of course, went through the same journey.

And so we launched the pilot study to investigate this for the first time. So, it was really the pilot study that started us off in understanding this on a scientific basis. 

Bret: 
Yeah. I think it’s so powerful when someone has that personal experience and turns it into an academic endeavor to help others. And we’ve talked about it before that you said you almost felt a duty to get this out there so more people can learn about it because there are so many people living with depression, with bipolar disorder, with schizophrenia, with other serious mental illness, who aren’t getting the treatment that they would like to get back to their lives.

And so one, why not look for something that could offer that, which is like what you’ve said before? I’m sorry to put words in your mouth, but I know we’ve had these conversations before, and so I just, I don’t know. I find that so special and so passionate.

You’ve got a great team there at University of Edinburgh to do this study. So let’s talk about it. You ended up having 20 individuals with Euthymic Bipolar Disorder, and I think that’s important to define from the get go because it does lay out what the results mean.

So tell us what it means to have bipolar disorder and be euthymic for the inclusion criteria. 

Iain: 
So, this was a kind of pilot study, and pilot studies really to assess feasibility and safety of the intervention and understand the parameters for larger trials. So, we worked with  euthymic patients because this is the simplest approach for a pilot study, but euthymia and bipolar is not really euthymia, per se.

There’s a lot of studies showing that’s the subclinical symptoms in bipolar are quite severe and they persist throughout the person’s life. So, while you might be technically euthymic, it can be a real state of impairment and distress for people, even if you’re not in hospital. So, we had 27 patients, and 26 began, 20 completed the study.

And in these patients we carried out similar assessments to what I measured in myself with daily ketone measurements versus mood. So, every day we measured their mood and their ketone levels and we measured brain imaging parameters through magnetic resonance spectroscopy to understand what’s happening in the brain on, in ketosis and also metabolic parameters, weight, BMI, blood pressure and so forth.

So, we really got a sense of physical and mental health in the study. 

Bret: 
Yeah, and that’s another thing I find so interesting. You can see three buckets of results. The individual clinical changes, the mechanistic or brain imaging changes, and then the metabolic changes as well. And you saw some very interesting findings with all three of those.

So, let’s start with the clinical changes. So, since these individuals were in euthymia, they weren’t having episodes of mania or hypomania, or at least not diagnosed with a severe depressive episode. I guess you could say maybe you wouldn’t expect a whole lot of changes, but what did you see in terms of their response to ketosis?

Iain: 
So, to look for a subsyndromal symptom variation within clinical euthymia, we did daily measurements of what’s called ecological momentary assessment. So, they were all in the kind of bottom range of their traditional psychiatric rating skills by our conclusion criteria. But we looked for symptoms within that range, which can be quite significant for people with bipolar, using this EMA analysis.

So, we asked them every day to rate their mood on a scale of zero to a hundred, their energy, their impulsivity, anxiety, and speed of thought. And then we asked them to track their ketone level at the same time they took their mood reading. And at the end of the study, we analyzed this and looked for any relationship between the two. And I had personally seen this myself in my own data and I was quite surprised, I have to say, that we managed to see this in the study, we saw a significant correlation between mood and energy and ketone level and inversely with anxiety and impulsivity.

And it’s never been done in a kind of study, this approach before. It’s only something I tried as an N=1 experiment. So I was, it was very gratifying to see that this could translate to a clinical study and be effective. So we saw this clear correlation between mood and energy, and ketone level and reduced anxiety and reduced impulsivity.

And I think this, what was particularly interesting is you get into higher ketone levels, the effects seem to be slightly more pronounced. So above two millimolar or something. I’ve just done a survey on my Twitter, for example, just interested in patients response to this, and many indicate that kind of over two millimolar seems to be the most effective.

And we kind of saw indications of this in the study that in the higher ketone levels, there might be better mid stabilization, and this makes sense in the context of ketosis being an anti-seizure intervention in epilepsy. There’s literature on how ketone ranges being a more efficacious for seizure reduction.

So the kind of dose response relationship is particularly interesting because it may indicate there’s a kind of mechanism at play here between ketones and the improvement in symptoms. It’s a bit more evidence than just looking at kind of baseline and follow-up. We’re looking at kind of relationship between the ketone level and the symptoms.

Bret: 
I find that so interesting, and we can show the graph here for everybody to see. And looking at the graphs, it looks like the majority of the data come from ketone levels of maybe 1, 1.5. But then as you get above 2, there does appear to be this clear trend of improvement both for mood and impulsivity and energy, like you said, and anxiety, which is really interesting and opens up a lot of questions, right?

Like good research can open up more questions than it provides answers, especially a pilot trial, which is like the purpose of it. You could see randomized control trials of keeping your ketones above 2, to keeping them below 2 or adding exogenous ketones or whatever.

So where do you hope this will go and what could be the next step to evaluate this further? 

Iain: 
So I think what’s really interesting is the pattern of results across, and this is something we’d like to translate into further RCTs, through the metabolic psychiatry that we set up that we could talk about, but essentially the kind of correlation between ketone level and improved mood outcomes.

We also observed in brain imaging a reduction in brain glutamate and taking together, this is quite interesting because the rising ketones in previous studies in epilepsy, for example, is associated with reduced glutamate activity. And we saw this in the brain scans of people with bipolar disorder over the eight week period that there are ketone levels increased and their brain glutamate decreased quite significantly.

And the reductions were 13.6% in the posterior cingulate cortex and 11.6% in the anterior cingulate cortex. In the context of the literature, these are large reductions in glutamate. People may be able to find other evidence, but when we reviewed, certainly the largest reduction we could find was an anti-seizure medication with about 6% reduction, 6.6% reduction.

So, ketosis was doing something that anti-seizure medication is doing in the brain to a larger degree than we’ve seen before or over just an eight week period. And I think with all this debate about diet and is diet helpful for mental health, when you see magnetic resonance spectroscopy markers like glutamate in the brain moving substantially like this, it is important to pay attention to results like that, especially given the links with anti-seizure treatments used in bipolar disorder.

So, we’d love to take these aspects of the study and do them on a larger basis with, say 300 participants, and look in larger numbers if we can see these effects in the wider population.

Bret: 
Yeah, and I think that is a great point about diet’s impact on the brain, but more importantly, how we have to talk about it. This is not just your average diet because this is the diet that changes your body’s physiology, changes your brain fuel, and that’s likely why there’s such a dramatic difference compared to maybe other interventions.

So, talking about the change in glutamate, tell us how that fits into this sort of metabolic overdrive theory that you’ve talked about before and published on. 

Iain: 
So, the most interesting aspect of ketosis for me is the link to epilepsy. It’s, I’m sure this has been mentioned many times in the show, but it’s evidence-based treatment for epilepsy, 13 RCTs over a hundred years of clinical use, and it reduces seizures substantially.

And we use anti-seizure medications to treat bipolar disorder. So, I think it’s reasonable to ask, are there shared markers and mechanisms we can look for in ketosis that relate to the effects in epilepsy? One of the primary markers in epilepsy is elevated glutamate in the brain. So, if you look at systematic review of epilepsy studies, elevated glutamate in the brain is common in epilepsy, and it’s an excitatory state in the brain.

And so when we saw this marker moving down in bipolar disorder with increased ketosis, I thought this was very interesting because this previous studies that have also kind of shown an exogenous ketones supplementation. And in my studies, that if you introduce ketones, glutamate in the brain decreases.

So, there’s some dynamic where when you turn up ketosis, it appears to turn down glutamate. And this is considered a marker of response to anti-seizure medication and epilepsy, this reduced glutamate in the brain. So, I published a paper in Nature of Molecular Psychiatry proposing that what’s happening potentially is that as you raise the level of ketones, it’s displacing glutamate as a metabolic fuel in the brain.

Glutamate is a highly active metabolite in the brain, and people, such as Dom D’Agostino, pointed out that glutamate is one of the most abundant neurotransmitters in the brain. It’s quite often overlooked, but it’s very active in the brain.

And if you look at the earliest research on glutamate, it was talked about as a metabolic energy substrate in the brain. With the kind of SSRI development in the 1960s, the whole focus went to neurotransmission, but really it plays very profound roles in brain energy metabolism. And they both play, and I guess where this really comes to crux, is that glutamate and ketones both into the TCA cycle, the citric acid cycle and mitochondria.

And so when you see these two types of metabolic fuel having an interrelationship, I think looking at the metabolic roles they share in the TCA cycle is an interesting perspective. And the last thing I would add is that this kind of glutamate in the brain is fueled by glycolysis and astrocytes, and glycolysis is the rapid burning of glucose.

So, when you have an intervention that’s reducing glucose, reducing glutamate in the brain, and has comparisons to epilepsy treatments, I think there’s something interesting there for bipolar that we really need to understand. 

Bret: 
Yeah, so there are a lot of big terms there so that the scientists and the researchers are going to grab onto that and know exactly what you’re talking about and hopefully run with it.

But but let’s take it from the clinical side. Somebody who has bipolar disorder and is thinking about starting a ketogenic diet or ketogenic therapy or is already doing it, would you say there’s enough here to say keep your ketones above two or make that your first priority?

What do you think about that? 

Iain: 
If they were adopting a ketogenic diet, would you recommend that ketone level? 

Bret: Yeah, would you recommend ketones above 2 based on your findings? 

Iain: 
So, I think we have this early pilot data in bipolar, but there’s a lot of literature in epilepsy examining ketosis and levels of ketones.

And many of the epilepsy studies find seizure reduction is correlated to ketone level, and particularly in the kind of higher levels of ketosis above 2, and in children above 4 millimolar is recommended by some hospitals. And certainly if you speak to epilepsy dieticIains, they’re aiming for these higher ketone levels, kind of 2 to 4 millimolar, but this is generally used in children who produce ketones, much more availably.

So, it is hard to say if that would translate to adults, but it does seem that there’s some correlation between seizure reduction and ketone level. And in our pilot study, we showed that there is a correlation between ketone level and the reduction mood symptoms.

So if you don’t get response from lower ketone levels, I think it does make sense to try these kind of 2 to 3 millimeter kind of ranges. 

Bret: 
With the caveat, of course, none of this is medical advice. This is, everybody has to be evaluated individually with their own provider. So, I think that’s really important.

But it’s key to talk about these hypotheses and these theories. And based on the evidence we have and so that even providing clinicIains can listen to this and say, okay, maybe if my patient isn’t responding the way I was hoping they would to ketogenic therapy, maybe I need to bump up their ketone level and see? Because evidence like yours suggests there’s a correlation.

So, I think that’s the important part of this discussion, is certainly not giving individual medical advice. Now the other important point about your study though is I would consider it a short study, as many pilots are in that six to eight week range, and maybe pushing it out to 12 or 16 weeks could potentially show even more profound benefits.

And so what have you found in talking to people in your experience about the duration of treatment? 

Iain: 
Yeah, I think in epilepsy, three months is considered the, a good trial length to see if seizure reduction can occur. And so in future trials in RCTs, we’d like to push out to longer time periods and some people, in epilepsy see for example, we’ll have seizure reduction several weeks in, some several days in, and some it’ll take two to three months. So there’s obviously kind of repair and mechanisms that are happening in the brain that are not fully understood yet. So, it’d be really interesting to look at mental health if you get some people responding earlier or later on in the process.

Bret: 
Yeah, all right. Now we’re talking a lot of numbers. We’re talking about ketone levels and mood and glutamate and 13% decrease. But the other really dramatic part was qualitative data that you got, the feedback from the participants. Can you share some of that or like some of the general feel for the feedback you got from the individual participants?

Iain: 
So, we did in our PPI group, interviews with the participants, and I feel this is really helpful because it gives a full picture of the person, not just the kind of, the numbers, but the actual, how they responded as a person? And there was a bunch of people at the end of the trial, over a third of the participants, who decided to, we asked them to come off the diet and part of the study was to measure the response coming off it.

And this group did not want to come off the diet because of the benefits they were experiencing. And so I interviewed them to ask them why this was and this happened in early epilepsy studies, and I wanted to understand in some detail.

And some of these patients describe quite profound benefits to their mental and physical health that we’ve been sharing at conferences and videos. And some of them have now gone on to become kind of patient advocates in their own right starting YouTube channels. There’s someone from a trial that’s writing a book about his experience with ketosis.

Another one recently appeared in a documentary film. I think it’s always, I think when you’re in the pilot stages of research and when you have a real need for new treatments, it’s important to pay attention to these kind of patient experiences because they’re quite rare in clinical trials to see this type of thing with people taking it on as a real interest and passion of their own to spread word about an intervention they’ve experienced in a trial.

You can probably find some of these testimonials online already from their own channels. But they describe, for example, improvements in cognitive functioning, improvements in memory, improvements in moods alongside physical health improvements. All, almost all, all except one of the participants during the trial lost weight.

And the average weight loss was 4.2 kilograms, which over eight weeks is quite a lot for people with bipolar because they’re on severe antipsychotic medications. That have significant side effects, metabolic side effects, and they remained on those medications and still experienced this weight loss.

So these were the kinds of things people described in these patient interviews, when they responded well to that. And again the pilot stages, not everyone will respond to intervention, but those who did, I think the responses are remarkable enough that we should try to understand the nature of these.

Bret: 
Yeah, and you put in a great point there that they stayed on their antipsychotic medications, which can have severe metabolic consequences as adverse effects. And yet still we’re able to lose up to 5% of their, around 5%, of their body weight, which is huge because these patients studies have shown they’re more prone to die prematurely from metabolic diseases.

So important to be able to address that as well. And a lot of these subjective reports seem just life changing, that people haven’t been able to find this degree of benefit from any other treatment but did from this. So, it seems like there’s a subset of individuals who just respond dramatically to ketogenic therapy.

Iain: 
I think, as part of the future work, will be to understand who might respond well to this and what characterizes those people and how can we identify, what type of people might respond well to metabolic treatment? So, I think, there’s been a real divide between physical and mental health where we’ve got this team studying physical health and this team studying mental health and this team treating it and this team treating, and I think that metabolic psychiatry is really bringing that back together in quite a significant way that affects both science and treatment.

Where we can not just accept the paradigm anymore, that we have to have hugely impaired physical health, which is how treatment works at the moment. Unfortunately, that many of the first line treatments just have severe metabolic dysfunction as a consequence, and I particularly feel for young people, because if you’re in high school and you put on 20 pounds in the course of 10 weeks taking your medication, which is not uncommon, it is devastating for that person’s life and their cardiometabolic.

A risk for the rest of their life, if they stay on. So, I think finding treatments that can have beneficial metabolic effects or at least ameliorate some of the side effects are really important. 

Bret: 
Yeah, that’s such an important point. And now you also mentioned that you’ve been presenting at conferences. So, I want to set the stage a little bit.

There’s the International Society of Bipolar Disorder, ISBD, and we were there together in Chicago in June of 2023. And you presented and Dr. Sethi and Dr. Ede presented, and there were maybe two presentations about metabolic health and bipolar disorder and then the 2024 version you were at in Iceland.

And what did you notice different about metabolic health and the two conferences? 

Iain: 
Yeah, we were there last year and we had one symposia with Georgia Ede and Shebani on ketogenic diet and metabolic psychiatry. And it really wasn’t a topic, and there was some people understandably when everything new comes along, there’s a bit of skepticism or interest and this year, the tone was very different.

I think people see how sensible this approach is and how much of a logical progression it is in the treatment of mental health. We have all these people with severe metabolic side effects of medication dying 10 years younger than other people in the population. And this is not really being addressed.

And so, on a very common sense level, everyone understands we must tackle metabolic health in mental health. It has to be a trajectory, but the kind of promise as well is that some of these metabolic treatments, like ketosis, have neurological effects in the brain that we’ve seen from epilepsy and neurological conditions.

So, that was a real point of excitement at the conferences. Yes, we absolutely need to improve metabolic health of people with serious mental illness. But look at how this is also affecting metabolic function in the brain. So, there’s quite a number of talks on metabolic psychiatry and ketogenic diets, and it was quite a thing to see the shift from just a year ago when this was less of a priority.

I suppose the thing I’m proud of is that it’s a patient priority. It came from patients. This idea that we need to improve our metabolic health, improve our metabolism, and the scientific community and psychiatry community has got behind it and supported it, and that’s such a positive thing I think. 

Bret: 
Yeah, really impressive. And I’m really encouraged to hear the change in just one year. It’s such an important academic and clinical conference that there’d be such a change. And as part of that, University of Edinburgh has exciting news too about a metabolic psychiatry hub showing more of this evolution and this change.

So, tell us about that as well. 

Iain: 
Yeah, so for so long, I applied for grants and for funding to work in this area for about eight years. I’ve been tracking ketones and interest in this, and there was never any interest in this and nobody would, but just in the last kind of year, really because of the Baszuckis funding research and pilot trials, we now have an evidence base that people are realizing this is an important and significant research trajectory.

And so we reapplied to all these kind of funding schemes that we did before, and unsuccessfully, and the most competitive in the UK is the MRC funding scheme. They funded 32 Nobel Prize winning projects, the most prestigious kind of funder in the UK.

And you only get one application from each university so it’s incredibly competitive. And then you’re also competing against every other university in the UK. I tried, I applied with professor Daniel Smith who leads the hub. And we basically tried to show that this is a patient priority that we need to treat metabolic dysfunction, serious mental illness.

And so we were awarded about 4 million from the MRC to set up a center to study this. And this was co-funded by Baszucki Group. And we’re really grateful for this because it means we can do five years of really intensive research. And it establishes this as a really important research trajectory in the European research landscape certainly with MRC supporting it.

And I think they just see that this is something patients really want to investigate. And so I’m grateful from the funders, for the psychiatrist, for so many people that I have got behind this. And one of the things I just wanted to mention is a lot of the people who drove this forward in the initial stages are now having full-time jobs and positions and opportunities in this, which is really great to see.

One of the people that helped me most in surviving this illness was my father, and we did all our early research together, and he works in the hub. Professor Daniel Smith supported this before there was any funding or attention to this. He really did an act of service to patients, and this has now become, he’s now the head of a large hub in MRC. And our dieticIains and collaborators, psychiatrists will be involved in the future trials that we do.

So, it’s really helped the ecosystem here as well. 

Bret: 
Yeah, so amazing to hear, and we’ve talked about it before. If you’re not doing drug-based therapy, there’s a steeper hill to climb to get funding and to get attention for it. And especially if it’s something that’s considered maybe fringe, like a ketosis is sometimes considered not correctly unjustly.

But sometimes it’s considered fringe within the medical and research community. So for you to get that kind of grant to get, be now like you said, be able to do five years of intensive research to be able to fund people that have full-time positions in this work is phenomenal. So you and your team deserve just such a huge congratulations and thank you for all the work you’re doing. And we’re excited that the study has come out on top of the other papers you’ve published in this area.

And I’m sure there’s more coming down the road. So what can we expect next from you and your team? 

Iain: 
We have five work streams in the metabolic psychiatry hub, and we have genetics work stream, population health data work stream, clinical trials, patient involvement and engagement. And across the work streams, we’re basically trying to just do exactly what we did in the pilot trial.

Go from patient priorities and experiences feeding into research design leading to clinical trials, and this feeding back to new treatments for patients. So, we’re really focused on treatments for patients that are more effective through metabolic approaches.

And ketosis we’ll be examining in pilot trials and clinical trials alongside other metabolic treatments. We have some expertise in the department on circadiain rhythm and circadiain management and sleep and things like this that can be synergistic with metabolic treatments. So, we really are very driven to produce results for patients through this hub.

That’s our main focus is we have to come out of this with something tangible that benefits patients because we’ve had so few new treatments in the past 50 years, and I think we’re all very much aligned on that goal. 

Bret: 
Yeah, I love that. Keeping the focus on changing people’s lives, helping the patients who need the help the most.

So, I think that’s fantastic. Thank you again so much for taking the time to speak with us and share all this exciting new evidence and how that landscape is changing in the exciting future that lies ahead. If people wanted to learn more about you and your work or the metabolic psychiatry hub, where would you direct them to go?

Iain: 
And so on Twitter, X IainCampbellPhD. Metabolicpsychiatryhub.com has all the updates on the hub, and I’d love to hear from anyone that wants to email. My emails are available on Twitter. 

Bret: 
Wonderful. I well, thank you again, Iain. It’s been a pleasure talking to you. Thanks for listening to the Metabolic Mind Podcast.

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