In this episode of our podcast, we dive into the intriguing connection between the ketogenic diet and its effects on mental health disorders, with a special focus on schizophrenia. Our guest, Dr. Zoltan Sarnyai, a seasoned neuroscientist and professor at James Cook University, shares his extensive research on the neurobiological mechanisms underlying psychiatric disorders such as drug addiction, depression, and schizophrenia.
Dr. Sarnyai discusses his initial motivation towards exploring mental illness, propelled by a personal experience during his medical school years. The episode also covers his transition from psychopharmacology towards the potential of dietary interventions, particularly the ketogenic diet, as a therapeutic approach to treating severe mental conditions. Highlighting a range of case studies and his own research findings, Dr. Sarnyai elaborates on how ketogenic therapy might address the core issues of mental disorders by targeting systemic and brain glucose energy metabolism dysfunctions.
00:00 Welcome to the Show: Introducing Dr. Zoltan Sarnieh
00:56 The Fascinating Journey into Ketogenic Diet and Mental Health
06:57 A Deep Dive into the Science of Ketogenic Therapy
13:22 Exploring the Impact of Ketogenic Diet on Schizophrenia
36:17 The Future of Ketogenic Therapy: Challenges and Opportunities
47:15 Closing Thoughts and the Path Forward
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Transcript
Episode Transcript
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(00:00):
I'm so excited for this.
(00:01):
We have a very special guest ona podcast today.
Dr.
Zoltan Sarnieh is a medicallytrained neuroscientist, and he
is a professor and head of theLaboratory of Psychiatric
Neuroscience in the Institute ofTropical Health and Medicine,
James Cook University inAustralia.
He also has an active researchprogram in the neurobiological
(00:23):
mechanisms of stress andpsychiatric disorders, including
drug addiction, and depression.
Schizophrenia and depression.
And one of the leading voices inthe advancement of therapies for
severe mental disorders.
It's just an honor.
Dr.
Zoltan Sarnieh, welcome to theshow.
I'm happy to be here.
Thank you very much, Lawrence.
Thank you so much.
(00:44):
You know, Dr.
Zoltan, you know, you liveacross the world, first of all,
in Australia, and you stayed uplate for us today.
And so appreciative of that.
And so, and I'm very excited tobe.
Here with you today, I had agrowing fascination with the
ketogenic diet and it's meant,and it's effect on mental
health, you know, and itsbenefits, and I stumbled upon
(01:06):
your work through the MetabolicMind Foundation, run by the
Balzucchi family.
And you are doing such a suchgreat work for the advancement
of treatment in ways that aresaving people's lives and
renewing them in a major way.
And so, which is reallygroundbreaking, especially in
treating schizophrenia.
(01:27):
And so welcome.
And I'm glad to have you.
Thank you.
So for our listeners who are notfamiliar with your work, Dr.
Zoltan, can you briefly tell usa little bit about your
background and how you got intothis line of work?
How far back would you like meto start?
Just maybe how you got into, youknow, ketogenic diet and its
(01:48):
benefits in treating mentalhealth.
Yeah, so I've long beeninterested in mental illness,
even back to medical school.
Fascinated and scared at thesame time.
I have, I think one veryformative experience.
I was last year medical schooland we had our clinical
(02:10):
rotations among differentdepartments.
So I was at the psychiatrydepartment.
At my university in thehospital, and one day I went
home and my brother, who justfinished high school at the
time, asked me about somethingstrange happening with one of
his friends.
(02:30):
So he described the situation tome, that this young man locked
himself in a room.
Up in his room, he's not comingout, he closed the curtains,
he's not communicating with hismom at all, he's not taking any
food, and he's just behavingvery strangely.
So he asked me what, what Ithink, and I said, you know, it
(02:51):
doesn't look very good, to behonest.
And, you know, it remains to beseen, but it doesn't look good.
Next morning, literally nextmorning, I was in the hospital,
and this young man, the verysame young man, was brought in.
handcuffed by the police as heattacked his mother thinking
(03:12):
that his mother wants to killhim.
So he was immediatelyinstitutionalized.
I followed him for a few moreweeks while I was there and then
I graduated and just maybe ayear after I bumped into His
psychiatrist then asked himabout this young man, and he
said he unfortunately died,committed suicide, and it really
(03:36):
touched me deeply.
We were talking about an 18 yearold young man, whole life ahead
of him, and just like that, hewas gone.
So I became really interested intrying to understand how this
devastating mental illness comesabout and what we can do about
that.
(03:56):
Over the years, I becameinvolved in many aspects of what
you would callpsychopharmacology, how we can
treat mental illness drugs.
And this is what I teach at theuniversity.
So I had nothing conceptuallyagainst drug treatment in severe
mental illness at all, but I hadto realize that such treatment
(04:21):
has limited efficacy in certainpeople and have very significant
and quite devastating sideeffects in all of the people
taking that.
So that actually prompted me toreally try to think hard what
can be done in this situation.
When we try to understand themechanisms of severe mental
(04:43):
illness, our understanding isstill just at the beginning.
Think about the fact that thefirst clinically used
antipsychotic was introducedinto treatment in the 1950s,
1960s.
At the time, we had absolutelyno idea what's going on in our
brain, in terms of neurochemicalchanges, in terms of functional
(05:06):
activity of different brainregions.
We knew absolutely nothing,especially compared to what we
now know.
So those drugs originally werediscovered by complete
serendipity.
They were never ever designedspecifically to treat these
conditions.
They just found to be useful andhelpful from a medical point of
(05:30):
view and probably from thepatient's point of view a little
bit as well.
So these rocks were and stillare seriously lacking in their
ability to really make lifelivable and worth living for a
majority of individuals,unfortunately.
So if you look at the differenthypotheses explaining The causes
(05:56):
behind and the mechanisms behindsevere mental illness, the
leading hypothesis for a verylong time has been the dopamine
hypothesis that schizophrenia isbrought about by too much
dopamine, too hyperactivedopamine activity in the brain,
and the drugs that are used intheir treatment are blocking
(06:18):
those proteins that binddopamine and provide relief to
the patients.
And I always felt this is, uh,not the full picture.
It cannot be the full picture.
If we block the dopamine systemin the brain, yes, we probably
block psychotic delusionalthoughts.
But we block pretty mucheverything else as well.
(06:41):
You can imagine that's the sortof the major psychomotor pathway
coming out of the brain.
If we block it, yes, we can makesome symptoms disappear, but
nothing else.
So, it must be something a lotmore fundamental then.
And that gets me to, to yourquestion, really.
That was just a rather longintroduction to, to, to my real
(07:03):
answer to your question.
Again, a chance conversationwith a friend, former university
classmate, who was at the time aresearcher at UCLA, working on
cancer from a metabolicdirection.
And we had a very interestingconversation about the
importance of metabolism ofglucose.
Thank you.
(07:23):
And how abnormal glucosemetabolism contribute to whether
we can therapeutically targetcancer like that.
And it all made sense to me.
I remember back in medicalschool, we were taught that one
of the earliest symptoms ofcancer is actually unexplained
weight loss.
So all those cells are usingglucose to make DNA and RNA for
(07:47):
the extremely heavily dividingcells, building up the cancer
cells, rather than feeding theperson.
And that was a very attractiveidea to me, if I think about the
brain.
So energy metabolism, somethingabsolutely fundamental, required
for, All the functioning in thebrain, but especially
(08:08):
maintaining the most fundamentalprocess, the formation of action
potential, the electricalactivity of the brain.
Without proper provision ofbiological energy, our brain
would collapse immediately.
Mm-Hmm.
And you can imagine with moresubtle deficiencies, the brain
doesn't collapse.
(08:30):
The person is still functioning,brain is still functioning, but
it is mal functioning.
It's not functioning as itshould be.
So I became very interested inthat idea, conducted a few
experiments that was back in mytime in, in, in Cambridge,
England with a collaboratorthere.
And we found something veryinteresting.
We use the pharmacologicalanimal model of schizophrenia
(08:52):
and if you are interested, wecan talk about, you know,
modeling complex psychiatricdisorders in.
In, in rodents, which is aninteresting topic on its own,
but in this model, whichactually capitulates lots of the
behavioral abnormalities we seein schizophrenia, we also find
insulin resistant, elevatedglucose level, which are
(09:13):
features of acute first episodedrug treated individuals with,
with schizophrenia and bipolardisease.
So that further underlines to methat there are a systemic
metabolic abnormality in thewhole body, but in the brain as
well.
(09:33):
In the same experiment, we foundabnormal expression of genes
encoding for enzymes that areimportant in breaking down
glucose in the brain.
So that really put me on thetrajectory of looking into
potential therapeutic avenues tocircumvent an abnormal glucose
(09:55):
and energy metabolism.
And around the time, many otherresearchers became interested in
this field and Um, and excitingdata were coming out.
So I thought this is somethingvery, you know, seriously
worthwhile.
And then again, completelyaccidentally, I bumped into the
(10:15):
idea of ketogenic diet.
I was not at all in the dietfield, not at all.
I came from a sort of apsychopharmacology background
altogether.
So I think about epilepsy andthe fact that ketogenic diet is
effectively.
Controlling epilepsy inchildren, and it's been used for
(10:36):
over 100 years now, and then ifyou look at what ketogenic diet
does and what ketones do in thebrain, they circumvent this
glucose metabolism altogether.
And they feed other biologicalprocesses to make the biological
substrate of energy, ATP,adenosine, triphosphate, without
(11:00):
relying the glucose metabolism.
So I thought, wow, that's reallyinteresting.
We set up an experiment, anexperiment in a mouse model, to
test the idea.
Well, if you have a hypothesis.
Which you would like to test,you should never try on, try
that on human beings, becauseobviously it's not ethical, and
(11:23):
it's not practical either, andwe all have ideas, and not all
ideas actually work out all thetime.
So you have to do pre clinicalstudies to provide a proof of
concept that idea should work.
Uh, should be valid and furtherfollowed up in, in humans.
And we selected the model which,uh, actually based on strong
(11:45):
human findings.
So it's been known for a longtime that certain drugs of
abuse, such as AngelBus, whichis fancyclidine, and ketamine in
high doses can produce psychoticepisodes.
in indistinguishable fromschizophrenia.
And we know how these drugs act.
(12:06):
They block a certain receptor inthe brain called the glutamate
receptor, and that contributesin the behavioral abnormalities.
If we replicate this situationin mice, we can recapitulate the
main characteristics ofbehavioral and cognitive
features of human schizophrenia,which you can summarize into
(12:29):
positive, negative, andcognitive symptoms.
We, of course, don't knowwhether mice hallucinate and
have delusions.
We don't know, and they mostlikely, they don't, because
these are the products of thehuman brain, the non human
species.
probably do not exhibit anythingor experience anything like
that.
(12:50):
But there are parallels in themouse behavior that might be
sort of modeling and similar towhat you can find in humans.
We also identify that theseanimals have cognitive
abnormalities in their workingmemory, just like people with
schizophrenia.
We also, we also, demonstratedthat these mice actually have
(13:11):
social abnormalities.
They became asocial, they do notinteract socially with other
mice.
Again, an important feature ofpsychotic disorders.
So in this model, weadministered ketogenic diet,
mouse equivalent of ketogenicdiet, of course, to To our
surprise, to be honest with you,we were able to normalize the
(13:35):
entire behavioral spectrum.
So these animals recovered alltogether after three weeks on
ketogenic diet.
Of course, we demonstrated thatthey were in ketosis.
They had elevated betahydroxybutyrate, which is the
laboratory hallmark of beinginky.
They had very low circulatingglucose, as one would expect
(13:57):
from a diet that is very low inglucose.
That was the first demonstrationof the efficacy of ketogenic
diet in animal models,schizophrenia.
We published that in 19, in2015, and followed that up with
a number of other papers furtherinvestigating the same question
in different models.
And all of this are, is becausethere's a dire need to look for
(14:22):
other alternatives because ofthe drugs to treat schizophrenia
or severe mental disorders arenot doing the job.
Basically, It's only attachingitself into one receptors, which
can also have, you know, a wideranging side effects.
(14:43):
I appreciate that story and Iappreciate and we're going to
break it down in a second here.
It's just an amazing story.
When you.
Begun with that story with thefriend of your, was that the
friend of your brother?
He said, it's just a greatstory.
And that, you know, spark yourinterest into looking into more
(15:05):
of how you can, how does thiswork?
Right.
And it's just a great story.
And I want to, on your recentcase study in, was that in 2015?
You said, you talked about thefundamental mechanism of, you
know, is that when the ketogenicdiet came to your radar in 2015?
(15:26):
Yes, yes, yes, of course.
When you try to dig deeper inthe literature, you quickly
figure out that there is nothingnew under the sun.
People obviously thought aboutthat.
Long before, literally, therewas one publication from 1965,
small cohort of 10 women withschizophrenia put on a ketogenic
(15:52):
diet and showed very significantimprovement.
It wasn't a properly designedand run randomized controlled
clinical trial at all.
It was just switching them toketogenic diet, observing their
behavioral changes.
The diet wasn't properlydescribed, at least not at
(16:15):
today's publication standards.
But that was an indication.
And then fast forward to, Ithink it must have been 2008
when another case study waspublished.
That was one single individual,a lady who was 70 years old at
(16:35):
the time with chronicschizophrenia, under care,
multiple antipsychotic drugs.
very significant weight gain.
Actually, she was put on aketogenic diet to control the
weight gain, and to the surpriseof the doctors who managed, her
(16:55):
psychosis completelydisappeared.
She then, on her own, started totaper off and completely stopped
taking anti psychotic drugs.
And we are talking about someonewho had been suffering from
schizophrenia for the best partof her life.
And interestingly enough, thevery same patient was followed
(17:18):
up further and described 10years later.
And that's a paper ChristopherPalmer from Harvard contributed.
That lady, at the time, was 80years old, living on her own,
completely independently, stillon ketogenic diet, and
functioning perfectly well forher age.
(17:39):
Wow.
Wow.
And that's unheard of in thattime.
Yes, pretty much.
That was a surprisingly strongresponse, which you would almost
never see, probably never seeafter traditional foreign
political approaches.
I was reading the case study yousent me, it was, it's just a
(17:59):
fascinating read because Um, Ihad a, an experience with
psychosis firsthand myself whenI was about six, seven years ago
and ketogenic diet has reallyrenewed my life.
And so I really want to get intothat, but first let's, let's
explain to our listeners here,how was the use of the ketogenic
diet?
(18:20):
I know we identified that it wasbeing used in.
Epilepsy a hundred years ago,and it's, it hasn't, it's been
discovered for a hundred years,but, um, to manage severe mental
illness, how, what, how do weview ketogenic diet now for
schizophrenia?
How is it viewed now?
And what does the literature saytoday?
(18:44):
So I think first of all, we haveto point out that ketogenic diet
is not routinely clinicallyused.
to manage or treat schizophreniaand other psychotic disorders.
It is still very much in theexperimental phase.
We would like to understand whatit does, really, and how it's
(19:06):
doing it.
So what is the mechanism ofaction?
In order to have that kind ofunderstanding, case studies are
encouraging and absolutely needto be done and report.
But they, from a scientificpoint of view, they kind of fall
short of the strong scientificproof that is required for a
(19:31):
significant new claim, if yousee what I mean.
In order to have such data,randomized controlled clinical
trials need to be conducted.
So we have individuals with thedisorder of interest, in this
case schizophrenia and bipolardisease and schizoaffective
disorder, they are randomlyassigned to either ketogenic
(19:56):
diet or some other dietaryintervention.
And I think it is important thatit is a dietary intervention.
We have to keep in mind, inpsychiatry, patients do respond
to care.
They respond and improve if theyare being looked after, if they
(20:18):
are being talked to, if they arebeing asked.
So we have to control for that.
We have to control for that.
For example, in antidepressantresearch, antidepressant
clinical trials, there is a 50percent placebo response.
Because people suffering fromdepression get better by being
(20:44):
taken seriously, being talkedto, being regularly followed up,
having the ability to talk abouttheir condition.
That improves their condition.
But that's not the effect of thedrug, of course.
Or it's not the effect of thetreatment intervention.
And in a proper clinical trial,you need to sort that out.
(21:05):
in order to be able to provethat it is really your dietary
intervention is the one that isdoing the trick.
That's why the patient isn'teating, not because They are in
a clinical trial, and they areregularly talked to, so it's
very important.
We'll talk about the advancementof the ketogenic therapies in a
(21:27):
second here, but I want to, forour listeners, I want them to
understand what are theconventional common treatments
for individuals.
You know, I know, You talkedabout drugs that are used to
reduce symptoms and we, earlieryou talked about the positive,
negative and cognitive symptomswhere the three categories can
(21:48):
only possibly change, you know,the visual hallucination,
disordered thoughts, but wherethe fallout is, you know, it's
resistant in, you know, thenegative symptoms, which is, it
doesn't help with Emotionalresponse, lack of motivation,
and then the cognitive attentiondisorder.
That's absolutely correct.
And then, not to mention,there's a wide range of side
(22:11):
effects that comes with that.
That, you know, we can get intolater on.
But doctor, what has been thechallenge to create a drug that
reduces all the symptoms, thatmitigates all the side effects?
So if you consider the morerecently developed and
introduced antipsychotics,called the second generation or
(22:32):
atypical antipsychotic drugs,that we don't close up the
others, they tend to produceRapid weight gain.
And on that background, insulinresistance and type 2 diabetes
and resulting cardiovasculardisorders emerge.
(22:52):
So people with schizophrenialive about 17 to 20 years
shorter than people who are nothaving schizophrenia.
And that's not because theycommit suicide.
Some of them, unfortunately, do.
But because of the earlycardiovascular diet that is
(23:13):
contributed by several differentthings, of course, the fact that
they are not able to go outbecause they avoid social
situations, they have theirfears, their delusions and
hallucinations, they don't goout, they tend not to exercise.
They tend not to, to eathealthy.
Some of the antipsychotic drugsactually preferentially increase
(23:37):
carbohydrate and the intake ofhighly palatable Western diet
type of food, which are heavilycontributory, heavily, heavy
contributors of insulinresistance and resulting
metabolic syndrome.
But at the same time, the drugsthemselves, Contribute to that
(23:58):
in a significant manner becauseas you mentioned, they bind to
certain neurotransmitterreceptors in the brain that
contribute in the behavioralimprovement on one hand, but at
the same time, they interactwith metabolic processes, they
interact with eating behavior,and these effects cannot be
(24:18):
separated with a pharmacologicalagent.
Yeah, yeah.
Which makes.
You know, researchers look intoanother direction for now, in
the study, it was, you know, youstudy, you sent me, it was
observed that the ketogenic diettherapy acts through multiple
mechanisms.
(24:39):
And you talked about a littlebit about that earlier.
So the emerging understanding isthat schizophrenia is a disease
of abnormal systemic and brainglucose and energy metabolism,
which is a level of insulinresistance to the brain.
Is that right?
Right.
I think that this is, this is agood summary of that hypothesis.
Probably, we cannot claim thatevery single individual having
(25:02):
the diagnosis of schizophreniaand bipolar have a condition
based on this mechanism, but itis not unlikely that some
percentage of them are.
underlie by an abnormal brainand systemic energy metabolism.
And this is what ketogenic dietable to circumvent and
(25:23):
beneficially influence andtherefore contribute to the
improvement of the symptoms.
At the core of the condition,rather than just the main output
psychomotor pathway beingblocked and therefore
hallucinations, delusions areeliminated.
So the hope with this metabolictherapeutic approach is that we
(25:47):
are aiming for the coreunderlying mechanism, which
involves abnormal glucosebreakdown, And also the abnormal
functioning, the impairment ofmitochondria.
So the mitochondria are thelittle tiny organelles within
every cell in the body.
(26:08):
that are capable of producingthe biological energy substrate,
the ATP molecule.
So the energy production, howdoes the ketogenic diet targets
and essentially heals themitochondria?
What's the mechanism there?
And then they fuse with othercells.
(26:28):
and took over the job ofproducing ATP and using oxygen
for that.
And that was around the time ofthe evolution of our Earth.
When the oxygen concentrationsuddenly increased in the
atmosphere, and if we have toomuch oxygen, and we can't deal
with that, and if tiny singlecell organisms do not have the
(26:52):
machinery to use that oxygen,they will die.
Because three oxygen radicalswill be produced, and those are
detrimental to cells.
And suddenly, these tiny littlecreatures, these mitochondria,
were able to utilize the extraamount of oxygen.
And they utilized it in a waythat they produced something
(27:12):
that is tremendously useful.
And that became tremendouslyuseful for their host cells.
mitochondria became integratedinto our cells.
And the other really interestingaspects of these spinary things
that they have their own genome,they have their own DNA, because
they are used to be freestandingcells on their own run.
(27:34):
So they produce proteins, theyproduce really important
proteins that are involved inmaking ATP in the mitochondria.
And then there is actually afair bit of evidence from human
studies that this ATP makingmachinery is also faulty in the
mitochondria of people withschizophrenia and bipolar
disease.
Dr.
Zoltan, thank you so much forexplaining that to us.
(27:57):
So essentially mitochondrialimpairments, like you talked
about, has always beenrecognized in schizophrenia.
Is that right?
It's long been recognized.
That's right.
Yeah.
Yeah.
There is, there is a lot ofevidence coming from different
cell types, even from peripheralcell types, blood cells, for
example, but there is a strongevidence supported by careful
(28:20):
and well conducted systematicreviews and meta analyses.
Clearly showing mitochondrialabnormalities.
There is some preclinicalevidence showing that in animal
models of schizophrenia, thetransplantation of healthy
mitochondria normalizes thesymptoms.
(28:40):
Which is a really strongevidence and support for the
contribution of the abnormalmitochondrial, the underlying
behavioral abnormalities.
And how does the ketogenic diettargets essentially in helos It,
could you repeat please?
My question was, you know, wetalked about how the ketogenic
(29:03):
diet is, you know, function inme, different me mechanistically
approach.
And one of these is.
fixing the mitochondriaimpairment.
What is the ketogenic diet?
So this is an area that is stillvery heavily investigated and we
still do not have the fullunderstanding.
But what happens in the bodyduring ketogenic diet is that
(29:25):
because of the lack of glucose,which is the primary source of
chemical energy in the humanbody, including the brain,
because of the lack of glucose,uh, the body relies on fat and
the metabolism of fat as energysource.
And that takes place in theliver, which converts these
(29:46):
fatty acids to ketone bodies.
And there are three differentketone bodies, acetone,
acetoacetate, and betahydroxybutyrate.
Acetone goes out by, through ourbreath, through the lungs, but
acetoacetate and betahydroxybutyrate They are able to
enter into the brain taken up bythe different brain cells,
(30:10):
neurons, but not only neurons,the other supporting cells, the
glial cells, also take up betaHypocyte butyrate and convert
beta Hypocyte butyrate to one ofthe intermediary molecules of
glucose metabolism calledglucose.
Thank you.
Acetyl Coing A and then it feedsinto the cycle that produces the
(30:33):
substrates for the production ofa TP in the end.
So that is certainly onemetabolism.
Beta hydroxybutyrate has severalother ways influencing neuro
function.
Um.
It's been recently demonstratedthat beta hydroxybutyrate is
also an epigenetic modifier.
(30:54):
So this is a big word, but whatit means, it interferes with the
ability of the DNA to open upand start expressing certain
genes.
So that's a really important andrecently discovered butyrate.
We do not yet understand howthis bit actually contributes in
(31:16):
improving mitochondrialfunction, but that is certainly
one possibility.
Another mechanism that certainlytakes place influences the
production of two keyneurotransmitters in the brain.
One is glutamate, the other oneis gaba.
So GABA or gaba amary acid isthe main inhibitor in
(31:38):
neurotransmitter in the brain.
Its job is to control thehyperactive, excitatory cell.
In response to ketogenic dietand beta hydroxybutyrate
administration, brain cellsproduce more GABA, more of this
inhibitory transmicron, and thatcould be a mechanism that is in
(32:00):
place.
For example, it is not unlikelythat some of the anti epileptic
effects of ketogenic diet ismediated by elevating GABA
levels.
And there is a completely newand uncharted territory here,
which I'm almost sure plays arole.
We are just at the beginning toreally decide here.
(32:21):
What is the role of the gutmicrobiome?
So think about this.
We are talking about a diet,something we eat.
So what we eat, when we eatsomething, that gets into our
gastrointestinal system, intothe stomach and into the small
intestines, large intestines.
(32:41):
And our intestinal system ispopulated by trillions of
bacteria that live in a happy,symbiotic relationship with us.
In fact, we have more bacterialcells in our body than human
cells.
Maybe we are just the carriersof the whole ecosystem of
(33:02):
bacteria.
So then, then ketogenic diet isadministered.
These bacteria change, ofcourse, because there are
bacteria that thrive on glucose,so those disappear, and there
are bacteria that can takeadvantage of beta iricebutyrate
and the fat.
Altered profile of the gutmicrobiome can be a really
(33:26):
important mechanism, because thegut microbiome does many
different things.
During the last ten years, Itwas discovered that the gut
microbiome directly influencesthe brain through several
different ways.
These bacteria produce chemicalsand these chemicals get into the
bloodstream and through thebloodstream, they get into the
(33:48):
brain.
And as I said, we are reallyjust at the beginning to see
very likely that the gutmicrobiome and their
metabolites, Circulatingmolecules produced by them play
a role.
Some people even go so far aspeople call it the second brain
and it's thought to communicatelike with the brain plays a huge
(34:10):
role.
Yeah.
Yeah.
And what we cannot deny Dr.
Zoltan is just the stories thatwe have heard here today, right?
You talked about the 10 women in1965.
And in 2008, you talked aboutthe 70 year old woman, right?
(34:30):
That had chronic schizophrenia.
And now she's reporting to haveno hallucinations.
And she improved her energylevels and lots more case
studies with the same results.
Exactly.
We cannot deny what's going on.
Now, it's more on just what'sgoing on.
(34:53):
How do we explain this?
How do we now push this throughand advance the ketogenic diet
therapy for schizophrenia?
Now, doctor, my question foryou, what needs to happen now?
What else needs to happen?
Is it?
Do we need to control randomizedtrials before we can?
finally say that this is, thisshould be the standard care.
(35:18):
What needs to happen in yourmind?
In my view, having positive datafrom properly conducted
randomized controlled clinicaltrials with sufficient number of
patients enrolled, that isreally important.
It is also important tounderstand.
the potential side effects ofketogenic diet.
(35:40):
I would rather prefer to use theterm ketogenic therapy than
ketogenic diet.
We should consider the ketogenictherapy just like any other
pharmacological drugintervention.
Anything that has a beneficialeffect on the body will have
(36:01):
side effects, by definition.
These are biologically powerfulmolecules that do things in the
body.
So we need to understand whatthey are.
We need to understand whorespond to ketogenic diet and
ketogenic therapy and whowouldn't.
We need to understand that.
We have no reason to believethat everybody uniform will
(36:24):
respond to the diet.
No drug does that, actually.
So that is crucial.
It is, it is also important tosort out that it is the whole
diet, or is it the whole diet?
Or is it the ketones thatcirculate in our body as a
result of being in the dark?
(36:46):
We don't know that for sure,really.
We don't know.
And that's another importantquestion.
Because that in fact goes beyondscientific interest.
It has profound practicalapplications.
Do we need the dietary approach,or can we somehow alter the
metabolic process similar towhat ketogenic diet is doing
(37:09):
without actually having to be onthe diet?
Yeah.
Because as you know, being onany diet is very difficult.
Compliance.
Keeping a rigorous dietaryregime is hard, being that any
kind of diet, but ketogenic dietcan be particularly difficult to
(37:30):
start.
People who experience thebenefit of ketogenic diet, they
do not find at all difficult toremain on the diet because they
do realize that the significantimprovement in their condition.
There is, there is one otherissue here which needs to be
(37:52):
discussed, considered, and havesome sort of solution.
Mentioning an intervention whichinvolves ketogenic diet.
High fat containing food doesnot ring the right kind of bells
in the medical establishment.
(38:12):
But neither in the generalpublic.
As a result of decades ofpromoting low fat lifestyle.
Right.
And not considering thepotential consequences of the
high carbohydrate input.
We know now that the metabolicabnormalities are due to the
(38:33):
insulin resistance.
And insulin resistance developsas a result of the bombardment
of the body.
with refined carbohydrates overa long period of time.
And it is just becoming thefocus of attention, probably not
(38:55):
completely independently fromthe emergence of dietary
approaches, such as theketogenic diet and seeing the
beneficial effects of suchdietary interventions.
So essentially, doctor, you'resaying it has to go through the
standard due process and withthe wide ranging benefits of the
ketogenic diet.
(39:17):
I'm curious, how long would thattake?
Are we going to see it in ourlifetime?
Because like we talked about,ketogenic diet for epilepsy has
been around for a hundred yearsand we've seen That is a very
interesting point.
A profoundly interesting point.
And we, in the field ofpsychiatry, should learn from
(39:37):
neurology.
We should learn from the case ofketogenic therapy in epilepsy.
Because, as we mentionedalready, it was first described
and published in 1920 or 1921,so more than a hundred years
ago.
And it was found to beeffective.
(39:57):
As we said, diet is difficult.
And then the drugs came out, theanti epileptic drugs came out.
Those took over the fieldentirely.
Until about 20 years ago, EricKossoff and his colleagues at
Johns Hopkins Universityrevolutionized that field,
reintroducing ketogenic diet inthe management of childhood
(40:21):
epilepsy with great efficacy,and there are large scale meta
analyses published by CochraneReviews clearly demonstrating
efficacy of ketogenic diet inchildhood epilepsy.
And if you look around the worldtoday, pretty much all self
respecting childhood epilepsyclinics have a ketogenic diet
(40:43):
program.
It is beneficial, but you'reright.
We absolutely have to look atthat case closely and learn in
terms of the other side of yourquestion, how long will it take?
I don't think that it shouldtake that long, to be honest
with you.
And the reason for that is thatwe have much better tools now
(41:04):
than our colleagues back in thebeginning of the 20th century
had.
So now we can look intomechanisms relatively quickly.
We can set up the properclinical trials.
And there are major efforts.
You mentioned the Suzuki BrainResearch Foundation.
They are absolutely committed.
(41:25):
financially and in every mannerpossible to provide resources to
push this field forward.
And that is absolutely crucial.
That's very important for thefield.
Not only the, the financialsupport, but putting
investigators together to workas a team, which is actually
(41:48):
sometimes unique in sciencebecause we tend to be
competitive.
We tend to want to be theothers, want to publish first.
But what they are creating isactually quite different.
So my group is working on arandomized control trial for
ketogenic dieting, bipolardisorder, and schizophrenia.
And there are a few othergroups.
(42:10):
We're working on that as welland we talk to each other, we
talk to each other veryintensively.
We share ideas, we share data,we share clinical trial design,
and that is going to move thefield forward much faster.
I believe that everyone youmentioned, the Bazooki family,
yourself, everyone who's, youknow, working towards pushing
(42:34):
and advancing the ketogenic diettherapy for mental health
disorders.
Everyone has the same interestand that's to help people, you
know, get better, live theirlives, right?
You guys have empathy.
Back to your question, how longwill it take?
Another important aspect of thatis, how long does it take to
(42:55):
shift thinking in theprofession.
And it always takes time forvery obvious reasons, but I
think the tide is clearlyshifting and there is an
increasing appreciation ofunderlying brain and systemic
metabolic processes in severemental illness.
(43:17):
First of all, even the fact thatthe brain is not functioning
alone, the brain is very heavilyinteracting with the rest of the
body, psychiatry doesn't stophere.
The rest of the body alsocontributes to what makes us
human in terms of brainfunction.
(43:38):
And I think it is more and morewidely accepted, at least in the
research sphere.
of psychiatry.
That will trickle down topractitioners as well, probably
in, in the not so distantfuture.
And a new field, or subfield ifyou'd like, is being formed,
(43:59):
metabolic psychiatry.
New approach, a completelyrevolutionary approach to
understand severe mentalillness.
considering glucose and othermetabolic processes,
mitochondria and systemicmetabolism being all part of the
(44:20):
picture.
That's all great to hear Dr.
Zoltan.
That's amazing for people tohear.
Dr.
Zoltan, thank you so much forcoming on and sharing your story
and that we've learned a lottoday about how effective the
ketogenic diet therapy can befor our mental health.
Severe mental disorders likeschizophrenia, and I urge
(44:43):
everybody to relisten, really,uh, relisten to the episode,
take some notes.
There's a lot of things herethat are new and are very, you
know, if you know somebody who'ssuffering from schizophrenia,
right, or bipolar disorder isone as well, you can share this
information to them and so thatthey can have a more informed
(45:06):
decision.
Going forward.
Dr.
Zoltan, thank you so much forcoming on and sharing your story
once again.
Did we miss anything that youwant to share?
I think just one final remark.
I'd like to emphasize thatpeople with schizophrenia and
bipolar disease and otherpsychotic conditions, they
should consider ketogenictherapy as a medical
intervention, as a propermedical intervention.
(45:27):
It's a little bit beyond just alifestyle diet in that case.
Of course, ketogenic diet can bea lifestyle diet, and many
people are on ketogenic diet asa lifestyle diet.
But in the case of severe mentalillness, it needs to be
considered as a medicalintervention.
And proper medical support isrequired.
(45:48):
Measuring laboratory values.
blood glucose, insulin, bloodlipids.
There will be contraindications.
There will be people who willnot be suited for ketogenic
therapy because of theirunderlying systemic conditions.
And these are important thingsto consider because we have to
(46:09):
remember our main and mostimportant thing in medicine is
to do no harm.
And we absolutely would like toavoid that.
Absolutely.
Absolutely.
Thank you so much for thatstatement, Dr.
Zoltan, and where can they findyour work, doc?
So, my research website can befound at the James Cook
(46:32):
University's website.
If they Google my name, it willcome up.
With some recordings as well,and information about the
research, what we are doing, theclinical trial, what we are
preparing to start in hopefullythe very, very near future.
Yeah, and I'm happy to sharewhat we learned with anyone
(46:54):
who's interested.
Thank you so much, Dr.
Zoltan for coming on once again,and I really appreciate you for
sharing your journey here andsharing what you know and what
you've learned and what we canexpect in the future.
The future is bright for us, fora lot of people.
Thank you so much.
It's been my absolute pleasure,Lawrence.
Thank you very much for theopportunity.
Awesome.
I'm so excited for this.
(00:01):
We have a very special guest ona podcast today.
Dr.
Zoltan Sarnieh is a medicallytrained neuroscientist, and he
is a professor and head of theLaboratory of Psychiatric
Neuroscience in the Institute ofTropical Health and Medicine,
James Cook University inAustralia.
He also has an active researchprogram in the neurobiological
(00:23):
mechanisms of stress andpsychiatric disorders, including
drug addiction, and depression.
Schizophrenia and depression.
And one of the leading voices inthe advancement of therapies for
severe mental disorders.
It's just an honor.
Dr.
Zoltan Sarnieh, welcome to theshow.
I'm happy to be here.
Thank you very much, Lawrence.
Thank you so much.
(00:44):
You know, Dr.
Zoltan, you know, you liveacross the world, first of all,
in Australia, and you stayed uplate for us today.
And so appreciative of that.
And so, and I'm very excited tobe.
Here with you today, I had agrowing fascination with the
ketogenic diet and it's meant,and it's effect on mental
health, you know, and itsbenefits, and I stumbled upon
(01:06):
your work through the MetabolicMind Foundation, run by the
Balzucchi family.
And you are doing such a suchgreat work for the advancement
of treatment in ways that aresaving people's lives and
renewing them in a major way.
And so, which is reallygroundbreaking, especially in
treating schizophrenia.
(01:27):
And so welcome.
And I'm glad to have you.
Thank you.
So for our listeners who are notfamiliar with your work, Dr.
Zoltan, can you briefly tell usa little bit about your
background and how you got intothis line of work?
How far back would you like meto start?
Just maybe how you got into, youknow, ketogenic diet and its
(01:48):
benefits in treating mentalhealth.
Yeah, so I've long beeninterested in mental illness,
even back to medical school.
Fascinated and scared at thesame time.
I have, I think one veryformative experience.
I was last year medical schooland we had our clinical
(02:10):
rotations among differentdepartments.
So I was at the psychiatrydepartment.
At my university in thehospital, and one day I went
home and my brother, who justfinished high school at the
time, asked me about somethingstrange happening with one of
his friends.
(02:30):
So he described the situation tome, that this young man locked
himself in a room.
Up in his room, he's not comingout, he closed the curtains,
he's not communicating with hismom at all, he's not taking any
food, and he's just behavingvery strangely.
So he asked me what, what Ithink, and I said, you know, it
(02:51):
doesn't look very good, to behonest.
And, you know, it remains to beseen, but it doesn't look good.
Next morning, literally nextmorning, I was in the hospital,
and this young man, the verysame young man, was brought in.
handcuffed by the police as heattacked his mother thinking
(03:12):
that his mother wants to killhim.
So he was immediatelyinstitutionalized.
I followed him for a few moreweeks while I was there and then
I graduated and just maybe ayear after I bumped into His
psychiatrist then asked himabout this young man, and he
said he unfortunately died,committed suicide, and it really
(03:36):
touched me deeply.
We were talking about an 18 yearold young man, whole life ahead
of him, and just like that, hewas gone.
So I became really interested intrying to understand how this
devastating mental illness comesabout and what we can do about
that.
(03:56):
Over the years, I becameinvolved in many aspects of what
you would callpsychopharmacology, how we can
treat mental illness drugs.
And this is what I teach at theuniversity.
So I had nothing conceptuallyagainst drug treatment in severe
mental illness at all, but I hadto realize that such treatment
(04:21):
has limited efficacy in certainpeople and have very significant
and quite devastating sideeffects in all of the people
taking that.
So that actually prompted me toreally try to think hard what
can be done in this situation.
When we try to understand themechanisms of severe mental
(04:43):
illness, our understanding isstill just at the beginning.
Think about the fact that thefirst clinically used
antipsychotic was introducedinto treatment in the 1950s,
1960s.
At the time, we had absolutelyno idea what's going on in our
brain, in terms of neurochemicalchanges, in terms of functional
(05:06):
activity of different brainregions.
We knew absolutely nothing,especially compared to what we
now know.
So those drugs originally werediscovered by complete
serendipity.
They were never ever designedspecifically to treat these
conditions.
They just found to be useful andhelpful from a medical point of
(05:30):
view and probably from thepatient's point of view a little
bit as well.
So these rocks were and stillare seriously lacking in their
ability to really make lifelivable and worth living for a
majority of individuals,unfortunately.
So if you look at the differenthypotheses explaining The causes
(05:56):
behind and the mechanisms behindsevere mental illness, the
leading hypothesis for a verylong time has been the dopamine
hypothesis that schizophrenia isbrought about by too much
dopamine, too hyperactivedopamine activity in the brain,
and the drugs that are used intheir treatment are blocking
(06:18):
those proteins that binddopamine and provide relief to
the patients.
And I always felt this is, uh,not the full picture.
It cannot be the full picture.
If we block the dopamine systemin the brain, yes, we probably
block psychotic delusionalthoughts.
But we block pretty mucheverything else as well.
(06:41):
You can imagine that's the sortof the major psychomotor pathway
coming out of the brain.
If we block it, yes, we can makesome symptoms disappear, but
nothing else.
So, it must be something a lotmore fundamental then.
And that gets me to, to yourquestion, really.
That was just a rather longintroduction to, to, to my real
(07:03):
answer to your question.
Again, a chance conversationwith a friend, former university
classmate, who was at the time aresearcher at UCLA, working on
cancer from a metabolicdirection.
And we had a very interestingconversation about the
importance of metabolism ofglucose.
Thank you.
(07:23):
And how abnormal glucosemetabolism contribute to whether
we can therapeutically targetcancer like that.
And it all made sense to me.
I remember back in medicalschool, we were taught that one
of the earliest symptoms ofcancer is actually unexplained
weight loss.
So all those cells are usingglucose to make DNA and RNA for
(07:47):
the extremely heavily dividingcells, building up the cancer
cells, rather than feeding theperson.
And that was a very attractiveidea to me, if I think about the
brain.
So energy metabolism, somethingabsolutely fundamental, required
for, All the functioning in thebrain, but especially
(08:08):
maintaining the most fundamentalprocess, the formation of action
potential, the electricalactivity of the brain.
Without proper provision ofbiological energy, our brain
would collapse immediately.
Mm-Hmm.
And you can imagine with moresubtle deficiencies, the brain
doesn't collapse.
(08:30):
The person is still functioning,brain is still functioning, but
it is mal functioning.
It's not functioning as itshould be.
So I became very interested inthat idea, conducted a few
experiments that was back in mytime in, in, in Cambridge,
England with a collaboratorthere.
And we found something veryinteresting.
We use the pharmacologicalanimal model of schizophrenia
(08:52):
and if you are interested, wecan talk about, you know,
modeling complex psychiatricdisorders in.
In, in rodents, which is aninteresting topic on its own,
but in this model, whichactually capitulates lots of the
behavioral abnormalities we seein schizophrenia, we also find
insulin resistant, elevatedglucose level, which are
(09:13):
features of acute first episodedrug treated individuals with,
with schizophrenia and bipolardisease.
So that further underlines to methat there are a systemic
metabolic abnormality in thewhole body, but in the brain as
well.
(09:33):
In the same experiment, we foundabnormal expression of genes
encoding for enzymes that areimportant in breaking down
glucose in the brain.
So that really put me on thetrajectory of looking into
potential therapeutic avenues tocircumvent an abnormal glucose
(09:55):
and energy metabolism.
And around the time, many otherresearchers became interested in
this field and Um, and excitingdata were coming out.
So I thought this is somethingvery, you know, seriously
worthwhile.
And then again, completelyaccidentally, I bumped into the
(10:15):
idea of ketogenic diet.
I was not at all in the dietfield, not at all.
I came from a sort of apsychopharmacology background
altogether.
So I think about epilepsy andthe fact that ketogenic diet is
effectively.
Controlling epilepsy inchildren, and it's been used for
(10:36):
over 100 years now, and then ifyou look at what ketogenic diet
does and what ketones do in thebrain, they circumvent this
glucose metabolism altogether.
And they feed other biologicalprocesses to make the biological
substrate of energy, ATP,adenosine, triphosphate, without
(11:00):
relying the glucose metabolism.
So I thought, wow, that's reallyinteresting.
We set up an experiment, anexperiment in a mouse model, to
test the idea.
Well, if you have a hypothesis.
Which you would like to test,you should never try on, try
that on human beings, becauseobviously it's not ethical, and
(11:23):
it's not practical either, andwe all have ideas, and not all
ideas actually work out all thetime.
So you have to do pre clinicalstudies to provide a proof of
concept that idea should work.
Uh, should be valid and furtherfollowed up in, in humans.
And we selected the model which,uh, actually based on strong
(11:45):
human findings.
So it's been known for a longtime that certain drugs of
abuse, such as AngelBus, whichis fancyclidine, and ketamine in
high doses can produce psychoticepisodes.
in indistinguishable fromschizophrenia.
And we know how these drugs act.
(12:06):
They block a certain receptor inthe brain called the glutamate
receptor, and that contributesin the behavioral abnormalities.
If we replicate this situationin mice, we can recapitulate the
main characteristics ofbehavioral and cognitive
features of human schizophrenia,which you can summarize into
(12:29):
positive, negative, andcognitive symptoms.
We, of course, don't knowwhether mice hallucinate and
have delusions.
We don't know, and they mostlikely, they don't, because
these are the products of thehuman brain, the non human
species.
probably do not exhibit anythingor experience anything like
that.
(12:50):
But there are parallels in themouse behavior that might be
sort of modeling and similar towhat you can find in humans.
We also identify that theseanimals have cognitive
abnormalities in their workingmemory, just like people with
schizophrenia.
We also, we also, demonstratedthat these mice actually have
(13:11):
social abnormalities.
They became asocial, they do notinteract socially with other
mice.
Again, an important feature ofpsychotic disorders.
So in this model, weadministered ketogenic diet,
mouse equivalent of ketogenicdiet, of course, to To our
surprise, to be honest with you,we were able to normalize the
(13:35):
entire behavioral spectrum.
So these animals recovered alltogether after three weeks on
ketogenic diet.
Of course, we demonstrated thatthey were in ketosis.
They had elevated betahydroxybutyrate, which is the
laboratory hallmark of beinginky.
They had very low circulatingglucose, as one would expect
(13:57):
from a diet that is very low inglucose.
That was the first demonstrationof the efficacy of ketogenic
diet in animal models,schizophrenia.
We published that in 19, in2015, and followed that up with
a number of other papers furtherinvestigating the same question
in different models.
And all of this are, is becausethere's a dire need to look for
(14:22):
other alternatives because ofthe drugs to treat schizophrenia
or severe mental disorders arenot doing the job.
Basically, It's only attachingitself into one receptors, which
can also have, you know, a wideranging side effects.
(14:43):
I appreciate that story and Iappreciate and we're going to
break it down in a second here.
It's just an amazing story.
When you.
Begun with that story with thefriend of your, was that the
friend of your brother?
He said, it's just a greatstory.
And that, you know, spark yourinterest into looking into more
(15:05):
of how you can, how does thiswork?
Right.
And it's just a great story.
And I want to, on your recentcase study in, was that in 2015?
You said, you talked about thefundamental mechanism of, you
know, is that when the ketogenicdiet came to your radar in 2015?
(15:26):
Yes, yes, yes, of course.
When you try to dig deeper inthe literature, you quickly
figure out that there is nothingnew under the sun.
People obviously thought aboutthat.
Long before, literally, therewas one publication from 1965,
small cohort of 10 women withschizophrenia put on a ketogenic
(15:52):
diet and showed very significantimprovement.
It wasn't a properly designedand run randomized controlled
clinical trial at all.
It was just switching them toketogenic diet, observing their
behavioral changes.
The diet wasn't properlydescribed, at least not at
(16:15):
today's publication standards.
But that was an indication.
And then fast forward to, Ithink it must have been 2008
when another case study waspublished.
That was one single individual,a lady who was 70 years old at
(16:35):
the time with chronicschizophrenia, under care,
multiple antipsychotic drugs.
very significant weight gain.
Actually, she was put on aketogenic diet to control the
weight gain, and to the surpriseof the doctors who managed, her
(16:55):
psychosis completelydisappeared.
She then, on her own, started totaper off and completely stopped
taking anti psychotic drugs.
And we are talking about someonewho had been suffering from
schizophrenia for the best partof her life.
And interestingly enough, thevery same patient was followed
(17:18):
up further and described 10years later.
And that's a paper ChristopherPalmer from Harvard contributed.
That lady, at the time, was 80years old, living on her own,
completely independently, stillon ketogenic diet, and
functioning perfectly well forher age.
(17:39):
Wow.
Wow.
And that's unheard of in thattime.
Yes, pretty much.
That was a surprisingly strongresponse, which you would almost
never see, probably never seeafter traditional foreign
political approaches.
I was reading the case study yousent me, it was, it's just a
(17:59):
fascinating read because Um, Ihad a, an experience with
psychosis firsthand myself whenI was about six, seven years ago
and ketogenic diet has reallyrenewed my life.
And so I really want to get intothat, but first let's, let's
explain to our listeners here,how was the use of the ketogenic
diet?
(18:20):
I know we identified that it wasbeing used in.
Epilepsy a hundred years ago,and it's, it hasn't, it's been
discovered for a hundred years,but, um, to manage severe mental
illness, how, what, how do weview ketogenic diet now for
schizophrenia?
How is it viewed now?
And what does the literature saytoday?
(18:44):
So I think first of all, we haveto point out that ketogenic diet
is not routinely clinicallyused.
to manage or treat schizophreniaand other psychotic disorders.
It is still very much in theexperimental phase.
We would like to understand whatit does, really, and how it's
(19:06):
doing it.
So what is the mechanism ofaction?
In order to have that kind ofunderstanding, case studies are
encouraging and absolutely needto be done and report.
But they, from a scientificpoint of view, they kind of fall
short of the strong scientificproof that is required for a
(19:31):
significant new claim, if yousee what I mean.
In order to have such data,randomized controlled clinical
trials need to be conducted.
So we have individuals with thedisorder of interest, in this
case schizophrenia and bipolardisease and schizoaffective
disorder, they are randomlyassigned to either ketogenic
(19:56):
diet or some other dietaryintervention.
And I think it is important thatit is a dietary intervention.
We have to keep in mind, inpsychiatry, patients do respond
to care.
They respond and improve if theyare being looked after, if they
(20:18):
are being talked to, if they arebeing asked.
So we have to control for that.
We have to control for that.
For example, in antidepressantresearch, antidepressant
clinical trials, there is a 50percent placebo response.
Because people suffering fromdepression get better by being
(20:44):
taken seriously, being talkedto, being regularly followed up,
having the ability to talk abouttheir condition.
That improves their condition.
But that's not the effect of thedrug, of course.
Or it's not the effect of thetreatment intervention.
And in a proper clinical trial,you need to sort that out.
(21:05):
in order to be able to provethat it is really your dietary
intervention is the one that isdoing the trick.
That's why the patient isn'teating, not because They are in
a clinical trial, and they areregularly talked to, so it's
very important.
We'll talk about the advancementof the ketogenic therapies in a
(21:27):
second here, but I want to, forour listeners, I want them to
understand what are theconventional common treatments
for individuals.
You know, I know, You talkedabout drugs that are used to
reduce symptoms and we, earlieryou talked about the positive,
negative and cognitive symptomswhere the three categories can
(21:48):
only possibly change, you know,the visual hallucination,
disordered thoughts, but wherethe fallout is, you know, it's
resistant in, you know, thenegative symptoms, which is, it
doesn't help with Emotionalresponse, lack of motivation,
and then the cognitive attentiondisorder.
That's absolutely correct.
And then, not to mention,there's a wide range of side
(22:11):
effects that comes with that.
That, you know, we can get intolater on.
But doctor, what has been thechallenge to create a drug that
reduces all the symptoms, thatmitigates all the side effects?
So if you consider the morerecently developed and
introduced antipsychotics,called the second generation or
(22:32):
atypical antipsychotic drugs,that we don't close up the
others, they tend to produceRapid weight gain.
And on that background, insulinresistance and type 2 diabetes
and resulting cardiovasculardisorders emerge.
(22:52):
So people with schizophrenialive about 17 to 20 years
shorter than people who are nothaving schizophrenia.
And that's not because theycommit suicide.
Some of them, unfortunately, do.
But because of the earlycardiovascular diet that is
(23:13):
contributed by several differentthings, of course, the fact that
they are not able to go outbecause they avoid social
situations, they have theirfears, their delusions and
hallucinations, they don't goout, they tend not to exercise.
They tend not to, to eathealthy.
Some of the antipsychotic drugsactually preferentially increase
(23:37):
carbohydrate and the intake ofhighly palatable Western diet
type of food, which are heavilycontributory, heavily, heavy
contributors of insulinresistance and resulting
metabolic syndrome.
But at the same time, the drugsthemselves, Contribute to that
(23:58):
in a significant manner becauseas you mentioned, they bind to
certain neurotransmitterreceptors in the brain that
contribute in the behavioralimprovement on one hand, but at
the same time, they interactwith metabolic processes, they
interact with eating behavior,and these effects cannot be
(24:18):
separated with a pharmacologicalagent.
Yeah, yeah.
Which makes.
You know, researchers look intoanother direction for now, in
the study, it was, you know, youstudy, you sent me, it was
observed that the ketogenic diettherapy acts through multiple
mechanisms.
(24:39):
And you talked about a littlebit about that earlier.
So the emerging understanding isthat schizophrenia is a disease
of abnormal systemic and brainglucose and energy metabolism,
which is a level of insulinresistance to the brain.
Is that right?
Right.
I think that this is, this is agood summary of that hypothesis.
Probably, we cannot claim thatevery single individual having
(25:02):
the diagnosis of schizophreniaand bipolar have a condition
based on this mechanism, but itis not unlikely that some
percentage of them are.
underlie by an abnormal brainand systemic energy metabolism.
And this is what ketogenic dietable to circumvent and
(25:23):
beneficially influence andtherefore contribute to the
improvement of the symptoms.
At the core of the condition,rather than just the main output
psychomotor pathway beingblocked and therefore
hallucinations, delusions areeliminated.
So the hope with this metabolictherapeutic approach is that we
(25:47):
are aiming for the coreunderlying mechanism, which
involves abnormal glucosebreakdown, And also the abnormal
functioning, the impairment ofmitochondria.
So the mitochondria are thelittle tiny organelles within
every cell in the body.
(26:08):
that are capable of producingthe biological energy substrate,
the ATP molecule.
So the energy production, howdoes the ketogenic diet targets
and essentially heals themitochondria?
What's the mechanism there?
And then they fuse with othercells.
(26:28):
and took over the job ofproducing ATP and using oxygen
for that.
And that was around the time ofthe evolution of our Earth.
When the oxygen concentrationsuddenly increased in the
atmosphere, and if we have toomuch oxygen, and we can't deal
with that, and if tiny singlecell organisms do not have the
(26:52):
machinery to use that oxygen,they will die.
Because three oxygen radicalswill be produced, and those are
detrimental to cells.
And suddenly, these tiny littlecreatures, these mitochondria,
were able to utilize the extraamount of oxygen.
And they utilized it in a waythat they produced something
(27:12):
that is tremendously useful.
And that became tremendouslyuseful for their host cells.
mitochondria became integratedinto our cells.
And the other really interestingaspects of these spinary things
that they have their own genome,they have their own DNA, because
they are used to be freestandingcells on their own run.
(27:34):
So they produce proteins, theyproduce really important
proteins that are involved inmaking ATP in the mitochondria.
And then there is actually afair bit of evidence from human
studies that this ATP makingmachinery is also faulty in the
mitochondria of people withschizophrenia and bipolar
disease.
Dr.
Zoltan, thank you so much forexplaining that to us.
(27:57):
So essentially mitochondrialimpairments, like you talked
about, has always beenrecognized in schizophrenia.
Is that right?
It's long been recognized.
That's right.
Yeah.
Yeah.
There is, there is a lot ofevidence coming from different
cell types, even from peripheralcell types, blood cells, for
example, but there is a strongevidence supported by careful
(28:20):
and well conducted systematicreviews and meta analyses.
Clearly showing mitochondrialabnormalities.
There is some preclinicalevidence showing that in animal
models of schizophrenia, thetransplantation of healthy
mitochondria normalizes thesymptoms.
(28:40):
Which is a really strongevidence and support for the
contribution of the abnormalmitochondrial, the underlying
behavioral abnormalities.
And how does the ketogenic diettargets essentially in helos It,
could you repeat please?
My question was, you know, wetalked about how the ketogenic
(29:03):
diet is, you know, function inme, different me mechanistically
approach.
And one of these is.
fixing the mitochondriaimpairment.
What is the ketogenic diet?
So this is an area that is stillvery heavily investigated and we
still do not have the fullunderstanding.
But what happens in the bodyduring ketogenic diet is that
(29:25):
because of the lack of glucose,which is the primary source of
chemical energy in the humanbody, including the brain,
because of the lack of glucose,uh, the body relies on fat and
the metabolism of fat as energysource.
And that takes place in theliver, which converts these
(29:46):
fatty acids to ketone bodies.
And there are three differentketone bodies, acetone,
acetoacetate, and betahydroxybutyrate.
Acetone goes out by, through ourbreath, through the lungs, but
acetoacetate and betahydroxybutyrate They are able to
enter into the brain taken up bythe different brain cells,
(30:10):
neurons, but not only neurons,the other supporting cells, the
glial cells, also take up betaHypocyte butyrate and convert
beta Hypocyte butyrate to one ofthe intermediary molecules of
glucose metabolism calledglucose.
Thank you.
Acetyl Coing A and then it feedsinto the cycle that produces the
(30:33):
substrates for the production ofa TP in the end.
So that is certainly onemetabolism.
Beta hydroxybutyrate has severalother ways influencing neuro
function.
Um.
It's been recently demonstratedthat beta hydroxybutyrate is
also an epigenetic modifier.
(30:54):
So this is a big word, but whatit means, it interferes with the
ability of the DNA to open upand start expressing certain
genes.
So that's a really important andrecently discovered butyrate.
We do not yet understand howthis bit actually contributes in
(31:16):
improving mitochondrialfunction, but that is certainly
one possibility.
Another mechanism that certainlytakes place influences the
production of two keyneurotransmitters in the brain.
One is glutamate, the other oneis gaba.
So GABA or gaba amary acid isthe main inhibitor in
(31:38):
neurotransmitter in the brain.
Its job is to control thehyperactive, excitatory cell.
In response to ketogenic dietand beta hydroxybutyrate
administration, brain cellsproduce more GABA, more of this
inhibitory transmicron, and thatcould be a mechanism that is in
(32:00):
place.
For example, it is not unlikelythat some of the anti epileptic
effects of ketogenic diet ismediated by elevating GABA
levels.
And there is a completely newand uncharted territory here,
which I'm almost sure plays arole.
We are just at the beginning toreally decide here.
(32:21):
What is the role of the gutmicrobiome?
So think about this.
We are talking about a diet,something we eat.
So what we eat, when we eatsomething, that gets into our
gastrointestinal system, intothe stomach and into the small
intestines, large intestines.
(32:41):
And our intestinal system ispopulated by trillions of
bacteria that live in a happy,symbiotic relationship with us.
In fact, we have more bacterialcells in our body than human
cells.
Maybe we are just the carriersof the whole ecosystem of
(33:02):
bacteria.
So then, then ketogenic diet isadministered.
These bacteria change, ofcourse, because there are
bacteria that thrive on glucose,so those disappear, and there
are bacteria that can takeadvantage of beta iricebutyrate
and the fat.
Altered profile of the gutmicrobiome can be a really
(33:26):
important mechanism, because thegut microbiome does many
different things.
During the last ten years, Itwas discovered that the gut
microbiome directly influencesthe brain through several
different ways.
These bacteria produce chemicalsand these chemicals get into the
bloodstream and through thebloodstream, they get into the
(33:48):
brain.
And as I said, we are reallyjust at the beginning to see
very likely that the gutmicrobiome and their
metabolites, Circulatingmolecules produced by them play
a role.
Some people even go so far aspeople call it the second brain
and it's thought to communicatelike with the brain plays a huge
(34:10):
role.
Yeah.
Yeah.
And what we cannot deny Dr.
Zoltan is just the stories thatwe have heard here today, right?
You talked about the 10 women in1965.
And in 2008, you talked aboutthe 70 year old woman, right?
(34:30):
That had chronic schizophrenia.
And now she's reporting to haveno hallucinations.
And she improved her energylevels and lots more case
studies with the same results.
Exactly.
We cannot deny what's going on.
Now, it's more on just what'sgoing on.
(34:53):
How do we explain this?
How do we now push this throughand advance the ketogenic diet
therapy for schizophrenia?
Now, doctor, my question foryou, what needs to happen now?
What else needs to happen?
Is it?
Do we need to control randomizedtrials before we can?
finally say that this is, thisshould be the standard care.
(35:18):
What needs to happen in yourmind?
In my view, having positive datafrom properly conducted
randomized controlled clinicaltrials with sufficient number of
patients enrolled, that isreally important.
It is also important tounderstand.
the potential side effects ofketogenic diet.
(35:40):
I would rather prefer to use theterm ketogenic therapy than
ketogenic diet.
We should consider the ketogenictherapy just like any other
pharmacological drugintervention.
Anything that has a beneficialeffect on the body will have
(36:01):
side effects, by definition.
These are biologically powerfulmolecules that do things in the
body.
So we need to understand whatthey are.
We need to understand whorespond to ketogenic diet and
ketogenic therapy and whowouldn't.
We need to understand that.
We have no reason to believethat everybody uniform will
(36:24):
respond to the diet.
No drug does that, actually.
So that is crucial.
It is, it is also important tosort out that it is the whole
diet, or is it the whole diet?
Or is it the ketones thatcirculate in our body as a
result of being in the dark?
(36:46):
We don't know that for sure,really.
We don't know.
And that's another importantquestion.
Because that in fact goes beyondscientific interest.
It has profound practicalapplications.
Do we need the dietary approach,or can we somehow alter the
metabolic process similar towhat ketogenic diet is doing
(37:09):
without actually having to be onthe diet?
Yeah.
Because as you know, being onany diet is very difficult.
Compliance.
Keeping a rigorous dietaryregime is hard, being that any
kind of diet, but ketogenic dietcan be particularly difficult to
(37:30):
start.
People who experience thebenefit of ketogenic diet, they
do not find at all difficult toremain on the diet because they
do realize that the significantimprovement in their condition.
There is, there is one otherissue here which needs to be
(37:52):
discussed, considered, and havesome sort of solution.
Mentioning an intervention whichinvolves ketogenic diet.
High fat containing food doesnot ring the right kind of bells
in the medical establishment.
(38:12):
But neither in the generalpublic.
As a result of decades ofpromoting low fat lifestyle.
Right.
And not considering thepotential consequences of the
high carbohydrate input.
We know now that the metabolicabnormalities are due to the
(38:33):
insulin resistance.
And insulin resistance developsas a result of the bombardment
of the body.
with refined carbohydrates overa long period of time.
And it is just becoming thefocus of attention, probably not
(38:55):
completely independently fromthe emergence of dietary
approaches, such as theketogenic diet and seeing the
beneficial effects of suchdietary interventions.
So essentially, doctor, you'resaying it has to go through the
standard due process and withthe wide ranging benefits of the
ketogenic diet.
(39:17):
I'm curious, how long would thattake?
Are we going to see it in ourlifetime?
Because like we talked about,ketogenic diet for epilepsy has
been around for a hundred yearsand we've seen That is a very
interesting point.
A profoundly interesting point.
And we, in the field ofpsychiatry, should learn from
(39:37):
neurology.
We should learn from the case ofketogenic therapy in epilepsy.
Because, as we mentionedalready, it was first described
and published in 1920 or 1921,so more than a hundred years
ago.
And it was found to beeffective.
(39:57):
As we said, diet is difficult.
And then the drugs came out, theanti epileptic drugs came out.
Those took over the fieldentirely.
Until about 20 years ago, EricKossoff and his colleagues at
Johns Hopkins Universityrevolutionized that field,
reintroducing ketogenic diet inthe management of childhood
(40:21):
epilepsy with great efficacy,and there are large scale meta
analyses published by CochraneReviews clearly demonstrating
efficacy of ketogenic diet inchildhood epilepsy.
And if you look around the worldtoday, pretty much all self
respecting childhood epilepsyclinics have a ketogenic diet
(40:43):
program.
It is beneficial, but you'reright.
We absolutely have to look atthat case closely and learn in
terms of the other side of yourquestion, how long will it take?
I don't think that it shouldtake that long, to be honest
with you.
And the reason for that is thatwe have much better tools now
(41:04):
than our colleagues back in thebeginning of the 20th century
had.
So now we can look intomechanisms relatively quickly.
We can set up the properclinical trials.
And there are major efforts.
You mentioned the Suzuki BrainResearch Foundation.
They are absolutely committed.
(41:25):
financially and in every mannerpossible to provide resources to
push this field forward.
And that is absolutely crucial.
That's very important for thefield.
Not only the, the financialsupport, but putting
investigators together to workas a team, which is actually
(41:48):
sometimes unique in sciencebecause we tend to be
competitive.
We tend to want to be theothers, want to publish first.
But what they are creating isactually quite different.
So my group is working on arandomized control trial for
ketogenic dieting, bipolardisorder, and schizophrenia.
And there are a few othergroups.
(42:10):
We're working on that as welland we talk to each other, we
talk to each other veryintensively.
We share ideas, we share data,we share clinical trial design,
and that is going to move thefield forward much faster.
I believe that everyone youmentioned, the Bazooki family,
yourself, everyone who's, youknow, working towards pushing
(42:34):
and advancing the ketogenic diettherapy for mental health
disorders.
Everyone has the same interestand that's to help people, you
know, get better, live theirlives, right?
You guys have empathy.
Back to your question, how longwill it take?
Another important aspect of thatis, how long does it take to
(42:55):
shift thinking in theprofession.
And it always takes time forvery obvious reasons, but I
think the tide is clearlyshifting and there is an
increasing appreciation ofunderlying brain and systemic
metabolic processes in severemental illness.
(43:17):
First of all, even the fact thatthe brain is not functioning
alone, the brain is very heavilyinteracting with the rest of the
body, psychiatry doesn't stophere.
The rest of the body alsocontributes to what makes us
human in terms of brainfunction.
(43:38):
And I think it is more and morewidely accepted, at least in the
research sphere.
of psychiatry.
That will trickle down topractitioners as well, probably
in, in the not so distantfuture.
And a new field, or subfield ifyou'd like, is being formed,
(43:59):
metabolic psychiatry.
New approach, a completelyrevolutionary approach to
understand severe mentalillness.
considering glucose and othermetabolic processes,
mitochondria and systemicmetabolism being all part of the
(44:20):
picture.
That's all great to hear Dr.
Zoltan.
That's amazing for people tohear.
Dr.
Zoltan, thank you so much forcoming on and sharing your story
and that we've learned a lottoday about how effective the
ketogenic diet therapy can befor our mental health.
Severe mental disorders likeschizophrenia, and I urge
(44:43):
everybody to relisten, really,uh, relisten to the episode,
take some notes.
There's a lot of things herethat are new and are very, you
know, if you know somebody who'ssuffering from schizophrenia,
right, or bipolar disorder isone as well, you can share this
information to them and so thatthey can have a more informed
(45:06):
decision.
Going forward.
Dr.
Zoltan, thank you so much forcoming on and sharing your story
once again.
Did we miss anything that youwant to share?
I think just one final remark.
I'd like to emphasize thatpeople with schizophrenia and
bipolar disease and otherpsychotic conditions, they
should consider ketogenictherapy as a medical
intervention, as a propermedical intervention.
(45:27):
It's a little bit beyond just alifestyle diet in that case.
Of course, ketogenic diet can bea lifestyle diet, and many
people are on ketogenic diet asa lifestyle diet.
But in the case of severe mentalillness, it needs to be
considered as a medicalintervention.
And proper medical support isrequired.
(45:48):
Measuring laboratory values.
blood glucose, insulin, bloodlipids.
There will be contraindications.
There will be people who willnot be suited for ketogenic
therapy because of theirunderlying systemic conditions.
And these are important thingsto consider because we have to
(46:09):
remember our main and mostimportant thing in medicine is
to do no harm.
And we absolutely would like toavoid that.
Absolutely.
Absolutely.
Thank you so much for thatstatement, Dr.
Zoltan, and where can they findyour work, doc?
So, my research website can befound at the James Cook
(46:32):
University's website.
If they Google my name, it willcome up.
With some recordings as well,and information about the
research, what we are doing, theclinical trial, what we are
preparing to start in hopefullythe very, very near future.
Yeah, and I'm happy to sharewhat we learned with anyone
(46:54):
who's interested.
Thank you so much, Dr.
Zoltan for coming on once again,and I really appreciate you for
sharing your journey here andsharing what you know and what
you've learned and what we canexpect in the future.
The future is bright for us, fora lot of people.
Thank you so much.
It's been my absolute pleasure,Lawrence.
Thank you very much for theopportunity.
Awesome.
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