Untangling the Genetics of Mental Health with Dr Jay Lombard

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Untangling The Genetics of Mental Illness with Dr Jay Lombard

Once described as part Freud, part Sherlock Holmes, Dr Jay Lombard is an internationally acclaimed neurologist, author, and keynote speaker. Dr Lombard’s discoveries are regarded by key opinion leaders as fundamentally shifting the paradigm of psychiatric medicine.

In today’s episode, Dr Lombard shares with us his wholistic approach to brain health and neuropsychiatric conditions, and untangles the genetics of mental illness.

COVERED IN THIS EPISODE

[00:54] Introducing Dr Jay Lombard
[01:16] Merging psychiatry and neurology
[10:45] Genetics, biology and psychiatry
[14:57] The brain and the mind
[19:45] Untangling the genetics of mental illness
[20:43] Faecal matter transplants
[28:26] The origins of Genomind
[34:55] Bacterial genetics in our biome – Clostridium
[38:14] The gut-brain connection: immunology, neurology, psychiatry
[41:44] Neurodegeneration and depression
[43:50] What is the future of psychiatry?

   


Mark: Hi, everybody. Today we're talking with Dr Jay Lombard, an internationally acclaimed neurologist, author, and presenter, not to mention media personality, and a real legend in the field of neurology and psychiatry. Welcome, Jay. How are you?

Jay: Good, hello. Thank you very much. I love Australia and look forward to meeting you in person someday soon.

Mark: Yes, that will be a pleasure. I think we're all looking forward to that. Now I have to start. You've crossed the fields here, neurology and psychiatry. You come from neurology and the science of the brain. And my reading of some of your work is there's another almost a pseudo-science of the brain, the untestable hypotheses of psychiatry, bringing neurology and psychiatry together seems obvious, but it hasn't been done so far. And why is that? Why is psychiatry and neurology not part of a common profession?

Jay: That is the single best question I've ever heard in any interview that I've done so far, and I mean that very sincerely. So, I think we have to go back to actually Europe, with Kraepelin and Freud, who were both neurologists and Kraepelin, was very strongly an advocate that schizophrenia and other serious psychiatric diseases were organically based and proposed to be on infectious aetiology. At the same time, Freud was most influenced as a neurologist by people in France that were doing work with hysterical paralysis.

And psychiatry sort of took its early insights about the biology of the brain from Freud and his understanding of you know, what causes hysterical paralysis, and what would be the sort of underlying conflicts about that. And I think that you know, the reality is that both Freud and Kraepelin were onto something that if they were alive today would be very happy to see that people are beginning to think that psychiatric diseases are in fact, you know, biologically based, and not to dismiss the existential aspects about psychiatric diseases in a way either.

So, you know, for example, with Sigmund Freud, he talked about what was called the death drive, which was about you know, people wishing you know, that they would you know, die. And we know that that is a cellular process that is activated in patients with depression and other neurological diseases. It's a process called apoptosis or cell death. So I think that you know, both Freud and Kraepelin I think need to be brushed off for us to have a fuller understanding of the merger of neurology and psychiatry.

Mark: Right. Was that a divergence that was intentional, like they went different directions in opposition, or were they...both had core, you know, had a biological basis and then just drifted apart?

Jay: I think Kraepelin was talking about patients that clearly had you know, an identifiable organic syndrome. So people with psychosis, very clear that their biology was related to...the psychiatry relates to something biological. In Freud's case, Freud was really intuiting biological processes but didn't have the vocabulary of neuroscience to really describe them, except in metaphor. And there's actually work by Karl Friston out of Cambridge that has sort of re-explained the dynamics of Freud psychiatry based upon looking at MRI studies of patients with psychiatric diseases.

And that's I think a way of sort of rediscovering Freud's insights in a way that I think most psychiatrists don't even appreciate because they really converge both back on biology but also on meta biology if you will as well.

Mark: I'm sure Sigmund Freud would not recognise the psychiatry of today. In a strange sense psychiatry has become biological and pharmacological in a way that I suspect was never anticipated. But the pharmacology has been done in a bit of a vacuum, it is here's something that works. Do we know why? It seems that we had little understanding of it before we were applying very powerful drug therapies on the basis of it works, therefore we do it.

Jay: That's right. That's exactly right. And I think that... you know, I like to sometimes make a sort of tongue in cheek jokes that psychiatry has lost its mind. Meaning that you know, psychiatrists, at least in the U.S. very rarely do any type of even rudimentary therapy with their patients. They just prescribe medications, the medications that they prescribe are purely on an empirical basis. And essentially, treatment guidelines are established by pharmaceutical companies and not by best practices.

So this is sort of what we're up against, both as a company but also as a society, to help really teach psychiatrists more an understanding of systems biology, so they can actually use their medications more appropriately when they're indicated. But also understand that there are systemic processes that are critical to the manifestations of psychiatric diseases that are biologically based, and do not relate at all to the drugs that are currently available.

Mark: How did you cross into this area? So I'm guessing your training was purely in neurology.

Jay: No.

Mark: It isn't?

Jay: Actually, no. I actually started out in psychiatry training. So I trained after medical school at one of the major research schizophrenia sites in New York. It was called at the time Hillside Hospital. It's now part of a large corporate conglomerate called Northwell. But the Chief of Psychiatry there was a psychiatrist named John Kane, and the vice chairman was Jeff Lieberman. Jeff Lieberman went on to become the Chairman of Psychiatry at Columbia where he still is.

And they intrigued me with their research on the biology of schizophrenia. But the clinical training that I was receiving, in tandem with the research that was being done, there was no connect. It was just like, you know, the research was one thing, and the clinical application of conventional psychiatry was something totally different. So that's why I jumped ship to neurology, because I realised that then as well as now, the majority of psychiatrists have really a very rudimentary understanding of neuroscience.

And just to give you a quick anecdote, I was giving grand rounds at one of the medical schools a few years back on the neurobiology of PTSD and depression. And you know, all the residents were looking at me like I was talking in a different language. And after the grand rounds, I had an opportunity to have lunch with the chairman of psychiatry, who knew I had a look of disappointment on my face about the lack of interest or engagement that the residents of this top-notch medical school had.

And he said to me, "Psychiatrists did not, you know, sign up to be neuroscientists." And I said back to him, I said, "Well, how can they think about treating the brain without having a fundamental understanding of neuroscience? I mean, to me, you wouldn't go to a cardiologist who didn't understand every single blood vessel in the heart. You wouldn't you know, go to a neurosurgeon and have a tumour removed if he didn't know the difference between the basal ganglia and, you know, the frontal cortex. So why are we allowing clinicians to prescribe medications that profoundly changes the chemistry of the brain, without really understanding what you're doing other than the most you know, superficial way?"

Mark: It does seem as though psychiatry and biology have to eventually rejoin. It seems self-evident that biology is the basic description there, the physics, and the chemistry, and these basic sciences do take a priority over opinion-based medicine. But the journey has been a ridiculously difficult one, as far as I can see. Is that your experience too?

Jay: It has been a very difficult journey. The journey is not over I hope. But part of our mission, as a company is to really help not to give people answers to the questions, but to really give them the tools to understand the biology of patients with neuropsychiatric disease. So that they can actually, you know, address it in ways that are not just symptomatic, but are primarily addressing some of the fundamental, you know, biological problems of these conditions. And that's sort of my goal, and it has been a very long journey.

Mark: I mean, it's a tough area, the complexity of the brain, which I think we all kind of imagine the mind is situated somehow, as a result of that complexity of the brain. It doesn't break down easily to an understanding. We can do PET scans, we can do imaging, we can do all kinds of things, but there is an innate complexity that I don't think we've ever got to grips with. And we have tools that initially anyway are fairly crude. You know, do you know about methylation? Do you know about ApoE? Do you know about... yes, we know these things. Do they translate directly? No, they don't. The complexity seems to be that in the right conditions, psychiatric disease or variations of normal psychiatric function, emerge. And if you don't know why then you're left with just hammers and screwdrivers to kind of put it back into place. And then no one asked the question. And so, from what I've read of your work, you're asking the right questions. And then you set up, you know, Genomind to go and take that a level further, which is, can we be predictive? Can we do good science here? Rather than just rely on that old DSM as the manual to tell us what disease is what?

Jay: That's right. And I think the keyword for listeners to understand is epigenetics because genetics is not deterministic. And that was I think the hardest first hurdle to overcome with physicians in psychiatry who had not been familiar with, you know, genetics in relation to psychiatry. And sorry, just a quick funny story when I was thinking about Genomind before even I built the company. I was taking my most recent vacation about eight years ago with my family, and I just happened to sit next to a child psychiatrist at this pool.

And he said, "You know, what do you do?" I said, "I'm a neurologist, but I'm thinking about starting a company that's going to use, you know, genetic biomarkers to help the psychiatrists." And he said, "Genetics has nothing to do with psychiatry." And I looked at him I said, "Listen, look at my two children. My two children, unless they're from different fathers, which may be the other possibility here you know, have very different rolling of the dice, but it's a genetic roll of the dice. How can you dismiss the genetics?"

And this is you know, before even, you know, the genome-wide association studies started teaching us a lot about the biology of psychiatry. And that was really sort of the inspiration to not only, you know, identify those key genes, but to understand what it is about those genes that drive psychiatric disease, so that we can actually you know, get at the core of the dysfunction.

And a very, I think good example for your listeners is the research that's been done on what are called ion channel genes. These are calcium and sodium channel genes that relate to the balance between depolarisation of the brain and hyperpolarisation of the brain. And you know, when you say to me, it's very, very complex, it's also... You know, Einstein once said that you know, "Make things as simple as possible, but not any simpler." And really understanding depolarisation and hyperpolarisation as a net you know, oscillatory system that becomes imbalanced in psychiatry is the way to really simplify and reduce very complicated concepts into something that, you know, even non-pharmacologists could understand.

And I think you know, that insight really comes from my experience as a neurologist because epilepsy is a very similar type of clinical phenomena where you have that imbalance between excitatory and inhibitory inputs in the brain.

Mark: That instability... I mean, the miracle of the brain is that it's stable at all with that...

Jay: That's right, exactly.

Mark: …with that amount of complexity. It is a miracle that it works at all. However, when it goes wrong, the brain... Can you tell me what's your concept of brain and mind? I mean, it's a basic underlying question in science. The mind is difficult to bring back to the biology, but it is clearly rooted in that biology. How do we link those two things together, the brain, the mind, before we get any further into epigenetics or genes that predispose? Are they linked at all?

Jay: Oh, well, 100% they are. In fact, you know, I think that there's you know, still, to my dismay personally, a prejudice amongst my colleagues in neuroscience, that there's no such thing as a mind, that it's all reduced just to brain. And I think that's a really very, very slippery slope when you arrive at that conclusion. And I think that you know, some of the work that Karl Friston again I mention him because I think that he and his research has really been the best to kind of see the soul in the machine, for lack of a better analogy. That you know, what is the soul in the machine? Where is the mind in the brain? And how does the mind actually relate to the brain?

So, first of all anatomically, the areas that we refer to as being mind or brain is called the default mode network, which is a converging area that's involved in emotion, memory, all sorts of you know, complex, higher consciousness level functionality. But what Friston has shown is that there's something called free energy, which can be assessed through certain types of modalities called diffusion imaging, that's able to assess essentially the rate of flow of information in the brain. And whether that information is formed in a coherent way or becomes fragmented as it does in conditions like schizophrenia. So, a lot of researchers in psychiatry are using this technology called DTI to identify you know, where the mind literally converges in a disease way on these brain pathways.

Mark: Okay, so I mean, in the past, what happened was we waited for brain injury to see what was lost. And then tried to match what was lost with, you know, the Phineas Gage concept of remove the frontal lobes, what happens. And it was an observational kind of science that ended up in textbooks. Now you're saying that we can actually see the imaging or the networking or the information exchange that is the hallmark of normal versus abnormal function. Is that what I understood there?

Jay: I would tell you that yes, that's the emerging science of psychiatry. Is it ready for clinical prime time? Definitely not. And I think you know... And why Friston's name keeps coming up in our conversations is because what he has been able to show is that Freud's original notions about concepts that we have an ill-described technical term for, like will, you know, what does a person's will mean or lack of their will? That Friston has been able to show that is quantified through free energy assessments of brain imaging studies.

And it kind of, you know, what's interesting is Freud...again, Freud was looking at patients that did not have clear organic disease, right? They were not like Kraepelin's patient, that had you know, overt motor and you know, perceptual problems. These were patients that you know, just seemed like that they had nothing organically wrong with them. Freud knew there was something organic, but he didn't know how to really describe what that organicity was, as a neurologist.

And that's kind of, you know, how psychiatry began. And how probably psychiatry will end up revisiting Freud's notion and understanding that concepts like, you know, id and you know, the will, or superego really are anatomically based. And that is where the lack of cohesion in psychiatric disorders actually comes from.

Mark: I would like to just come back the area that you have focused on is less the imaging more, as I understand, the genetics how the individual person's genome, and the epigenetic expression of that, how these play out to create mind and mental illness or mental health. With all the complexity that we're seeing now, with epigenetics, with microbiome genetics, with environmental impact, stress impacts, how's the untangling of that? I mean, it's tough enough just to be looking at the genetics without having to go through every last detail of how that is manipulated by environments and internal-external environments that are largely out of our control, even nutrition.

So when you go down into the genetics, there's so many, many limiting factors. How do you compensate for those and understand why a person may have a mental illness? What can be done for that person with that mental illness?

Jay: That's a fantastic question. And I think the keyword is how do you untangle that web if you will? And so I think the first thing to understand is that the genetics of mental illness... or I rather actually change the terminology away from mental illness to neurodegeneration. Because we know that patients with depression, have untreated depression have a higher risk of developing dementia. So we really need to think of you know, these conditions PTSD, and depression left untreated, will become neurodegenerative conditions.

So I think we need to understand a little bit about the genetics, but also understand that you know, the genetics is very, very complicated, but what's not complicated is the transcriptome. Meaning that there's only you know, 23,000... I forget the number of, you know, genes with you know, millions and millions of different potential mutations. But at the level of the transcriptome that is actually more able to be comprehended clinically. And what's really exciting about those findings, is the convergence of functional medicine, and how a systems of biology approach to functional medicine can really help untangle that mystery.

So I'll give you just one very interesting example that happened literally, on a conversation I had with a patient of mine who's actually involved in research with a neurogenerative disease called Huntington's disease. And what he mentioned to me was very alarming because that disease is an unknown hereditary disease. It's basically, we know the gene, we've mapped the gene, you know, there's no doubt what causes that disease. But what he said to me today, which was very alarming is that the epidemiology of juvenile onset disease is growing. And that's you know, something that is alarming. That means that there's something environmental that is triggering a higher expression of this disease.

And so to make a long story short, because we could talk about this forever, is that what we're learning in neurology is that neurodegeneration it's very much the same in terms of its underlying pathophysiology. What's different is the location, and the proteins that are being affected, where in the brain and nervous system is what creates different clinical disorders.

So for instance, if you have, protein aggregation in the hippocampus, that's where you're more likely to get MCI or Alzheimer's disease. If you have protein aggregation in motor neurons, you're more likely to get ALS. If you're more likely to have protein aggregation in the basal ganglia or the substantia nigra you're going to get Parkinson's disease. But the mechanisms of protein aggregation are overlapping. And what's overlapping about them is that there is dysfunction at the level of the gut microbiome that increasingly is being understood by you know, conventional neurologists that are doing conventional research on these diseases. To the point where I could tell you, many of them are on board with considering treatments for these conditions that you know, have never in my life had I ever dreamed a neurologist at a major teaching hospital would agree to, okay. And we're talking about things like probiotics and prebiotics and changing the gut microbiota with interventions that are totally non-pharmaceutical. To me, it comes full, full circle. So, you know...

Mark: It's an exciting time.

Jay: I think it's a very exciting time because you know, we're really seeing the first glimmers of how to actually both prevent these conditions, but also, you know, potentially how to treat them. And that's a very exciting time after being a neurologist for you know, 25 years to really finally tell patients that yes, I think we're really on the verge of some very, very significant clinical breakthroughs, not just in basic science, but clinically.

Mark: As a generalist, I get to send people to gastroenterologists and I've been impressed. There's a doctor over here, Tom Borody, who does faecal transplants for various conditions. The changes in the personality of a person after a faecal matter transplant, they always change. And the most common thing is, “I didn't even realise how depressed I was”, until a flora exchange, taking out inflammation, reducing a lot of their other symptoms done for other reasons, like clostridial infections. How big a difference it makes to what was previously called psychiatry. People drop their medications when that root cause is identified.

Jay: Yes! And you know, you're the second person that I heard this name... so maybe it's worth repeating both for me and for your listeners, who's doing FMT in Australia, because I just spoke to a gastroenterologist in New York and she mentioned the same name. So it's good people to know who this doctor is. And in fact, I would love to speak to him directly.

Mark: I'm sure you will when you're in Australia. Tom, he's an adorable person, he has to have had a tough skin to get through what he's done. Which is, you know, back in '95, we were doing faecal transplants for people with fatigue syndromes after antibiotics. And the outcomes were spectacularly successful. And I had a prior opinion that it would be a disaster that you could not do that without destroying a person's health. But Tom has kept on going, he's had enemies in the gastroenterology area, in the psychiatry area in every area around.

And it's amazing how eventually, truth emerges in a way that is quite fascinating. I don't think he was ever doing this for improving psychiatric conditions, but the improvement in the psychiatric state is unmissable when you have seen it happen.

Jay: That is amazing to hear that, and it's just inspiring to me because you know, I needed a lot of thick skin myself to be looking at the other side of things, no pun intended, in the case of faecal transplant therapies. And you know, I also need thick skin as a neurologist to be you know, speaking to my colleagues about suggesting this and being first mocked, then ignored, and now finally listened to. So it's great.

Mark: Well, the final step of course is it becomes so obvious that everyone knew it. They just didn't know that they knew it beforehand and then you get sidelined.

Jay: Yes. That's right.

Mark: They moved past you.

Jay: That's right.

Mark: You gave me a bit about the origins when you were thinking of Genomind. How did this progress from an idea to kind of a business and a science? How did you move it across there and what was your thinking along the way, and how has it emerged?

Jay: So the idea for Genomind started I think in 2009. I was at the time Chief of Neurology at Bronx Lebanon Hospital and doing, you know, just pretty much acute neurology care. And I had really missed my former practice, which was at the Brain Behavior Center, where I did sort of an amalgam of neurology and psychiatry, behavioural neurology, whatever you want to call it. And I was also doing consulting work for a biotech VC firm, looking at new technologies, you know, for different applications. And most of what I looked at was all “me too” technologies like okay, well, you know, we're taking Prozac and let's reconfigure Prozac so we can get through the FDA very fast. And you know, in that review process, I met Ron Dozoretz, who's a psychiatrist, by training, but is a person who formed the largest psychiatric insurance company in the world and had sold it, and was retired for about two weeks when I met him. Meaning that you know, he wanted something new to do, even though he was in his mid-70s at this point.

So I said to him, you know, "You're a psychiatrist, I'm going to explain that I think that we could develop biomarkers you know, for treating psychiatry." So the first person he introduced me to was the head of NIH. And it was...

Mark: Wow, good introduction.

Jay: Yeah. And it was like with Francis Collins, you know, who's still head of NIH. And I'll never forget this. I think I was like at some restaurant with my wife for like, the rare date that we would have, and Ron called me up and goes, "Can you speak to Francis Collins about this idea you have?", I'm like sure, no problem, you know. So I got on the phone and discussed it with him. And then he put Ron back on the phone. So Ron said, "Okay, you know, it sounds like something that there's interest in the science community. Let's put together a company."

So the first thing I did was pick sort of the who's who, of genetics in psychiatry and neurology, by the way, because I had you know, wanted to bring neurologists and psychiatrists together for this project. So we identified, you know, really the who's who of psychiatry and neurology and they, you know, helped us to really do our due diligence on what biomarkers in the genetic field had been validated as being a useful signal for helping psychiatrists to understand the biology of their patient's psychiatric disease. And that's where really the company evolved from.

And where it's evolving to, is that now the neurologists on my SAB board are more deeply involved, because we created a new test called Mindful DNA, which is kind of interesting, right, the evolution. That's our second test that's about to be launched basically, any day now. I don't know when. But it's really based on you know, a functional medicine/systems biology approach. But it was developed with the leading geneticists at Harvard Medical School to make sure that we're staying in my swim lane here. Because you know, I never want to be regarded as being a “bleeding edge” person as opposed to a “leading edge” person. That's a tricky thing to do when you're talking about genetics and psychiatry.

Mark: Yeah, over here we have the prospects out. I mean, everywhere we have the prospects, we have a group called Genome.One here. They claimed just a couple of months ago that we're moving to a point where the whole of the human genome, the whole genome study on a person will be down in the affordable level of hundreds of dollars for the whole, you know, snapshot of the 23,000 genes. And while they're focused on, you know, the Huntington's, and the specific one genes now, the next big step forward in computing is the associations of those. What patterns develop, how do we understand their expression?

It's still an enormous job even with the... Thank God, we didn't have more. You know, we were expected to have 200,000 genes, we only have 23,000. It would have been a horrible job if we'd be more complicated than asparagus, thank God, we're less!

Jay: They still have problems that you know, most of the people are doing high-throughput sequencing, the entire whole exome sequencing basically or WES. And that is that most of the reports of those abnormalities, if they're not, you know, clearly associated with a disease, particularly in psychiatry, they're reported out as variations of unknown significance or VUS. It doesn't really help the clinician because you know, when you get a report back like that, that means that well, you know, it's a variation, we know, it's abnormal, but we don't know what it's linked to physiologically.

So you know, I kind of... I'm such a passionate geek about this is that I kind of forget about AI and forget about all those other modalities that claim to be able to interpret large bodies of data. As a clinician, when I get data on whole exome sequencing patients, I have to decode that data for my patients.

Mark: I know, it's the most heart-sinking feeling, isn't it? That here's 300 pages - what's wrong with me? And breaking that link of saying it is not all in your genes. There is much, much more to it than that, and it has to be simplified.

Jay: Yes. And especially when we know that there's, you know, 10 trillion, more bacterial genetics in our biome, or wherever you want to call it, than we have human genomes that really adds another layer of complexity. And you mentioned Clostridium. So Clostridium has been shown to actually hijack the human genome.

Mark: No, way really?

Jay: Yes. They're called transposons, in which the genetic machinery of Clostridium literally shuts off genes in the human genome that are able to produce bile acids. And the reason that Clostridium does this... and I really hate this bacteria because to me it is like...as a clinician…it's my number one adversary. And I tell you that not tongue in cheek because it is a very, very smart evolutionarily designed bacterium to elude detection in patients who are otherwise asymptomatic.

And what Clostridium does, biologically, is repress a gene called bile acid hydroxylase, which converts primary bile acids to secondary bile acids. And the secondary bile acids, in turn, become depressed in patients, which allows more Clostridium overgrowth so that you know, for its purposes, it's doing good as it kills the host. But it doesn't do good for the host who has that bacterium that's hijacked its bile acid genes.

Mark: Those bile acids are really important for maintaining diversity, the secondary bile acids for diversity, and so I suppose its interest is - cut down diversity, dominate. And it has no secondary love of its host beyond its ability to multiply.

Jay: Exactly.

Mark: Clever, clever bug.

Jay: It's a clever bug, but it hasn't met my brain yet and it's about to.

You know, the good thing about this data is that right now... you know, there's clinical trials that actually one of my colleagues on my board Rudy Tanzi to give him a shout out because they're using what we call secondary bile acids. The abbreviation is called TDCA which is, stands for taurodeoxycholic acid. So it's a reduced bile acid that's basically bioavailable. And they're showing clinically, that the use of this slows the progression of ALS.

So, of course, I have all my ALS patients on this compound, it's safe, it's approved, for over-the-counter use. And so far so good. I don't want to be presumptuous and say that this is the only thing that we're going to be able to do or have to do for ALS. But it's a biologically very sound explanation for what we're doing when we treat these patients.

Mark: You are expanding well beyond on the field of Neurology in the classical sense. However, my understanding is the neurology of the gastrointestinal tract is in a sense its own field, our immunology and neurology from the gut, and it's linked with the brain. Seems an incredibly important component of psychiatric disease, neurological disease, and it seems that largely unexplored so far.

Jay: I call it sort of the next wave, I think that we're about to see really an explosion of data about our understanding of the gut microbiome.

Mark: And the breaking down of some of those specialties, it's not neurology, or gastroenterology, or psychiatry, until the links are made as you know, Genomind seems to be doing. Until the links are made to cross those boundaries, we are crippled in the way that we think about the illnesses, mental illnesses, and normality of the brain.

Jay: Yup. And I think that that's going to, you know, change in real time...

Mark: Do you?

Jay: For patients.

Mark: I want to ask you a question, it's bugged me now for 30 years. This idea that psychiatry is a science because what we're doing is rebalancing the neurotransmitters, we're using drugs, and the implication is everything is about a neurotransmitter balance, and if we get the pill, right and change the neurotransmitters, we're restoring a person to so-called normality. And it doesn't seem to have a science behind it, but that is the narrative that every person who feels depressed, sad, anxious, keeps on getting from psychiatry. Is there evidence for that? Or is that just mythology that we made up to validate the drugs?

Jay: I think we've all drunk that Kool-Aid, to a certain extent, that all psychopharmacologists, you know, sort of have been essentially guided by those concepts. Because, as you said earlier, that drugs were discovered and then we figured out how... I mean, they were basically discovered by accident. So whether it was Lithium or Thorazine that they were used for other purposes and then oh, wow, my patient’s less agitated, you know, what is this drug doing?

So I think if I had to not discard the baby with the bathwater in regards to the notion that neurotransmitter imbalances are at some level deeply related to psychiatric disease, the answer is yes. But with the caveat, and that is primarily the glutamate-GABA cycle. So those two neurotransmitters are still very much in play both in terms of psychopharmacological manipulation, but also non-pharmaceutical manipulation as well.

The serotonin-dopamine story, I think that they're kind of like the amyloid hypothesis, they're sort of epiphenomena related to you know, decompensatory mechanisms that the brain tries to achieve because of glutamate imbalances. So like in schizophrenia for instance, we know that there's, you know, less prefrontal glutamate, and it creates you know, abnormalities in dopamine circuitries, and other pathways as well. So I think the answer is more nuanced than yes, neurotransmitters and no neurotransmitters. I think it’s more specific than that.

Mark: Well, one thing that I know you have experience in is neurodegeneration and that discussion that we had just a while back where the depression is a neurodegenerative disorder. Do you have a sense of does depression, and circumstances and a person's life degenerate the brain? Is it that the depression is a kind of signal for degeneration, or are these people predisposed that way so that neurodegenerative changes bring on depression? Do you have a cause and effect relationship there or they are associated?

Jay: Yeah, I think there's an association, not a cause and effect. I think it's very hard to say which comes first, you know, the depression or the degeneration, or… I think it's not causal. But I think that we should go back and think about the word depression for a second because the word tells us a lot about what the biology of depression actually is. And what depression means biologically, is essentially a repression of normal mitochondrial function, that mitochondrial pathways become literally depressed. And that those pathways also involve the immune system, the nervous system, and just about, you know, every other organ system that requires mitochondrial functionality to produce ATP in the brain.

And that's why there's been a lot of interesting data on using, you know, mitochondrial augmentation strategies for depression. And there’s good clinical data that those compounds whether it's acetylcarnitine or CoQ10, or creatine or even, you know, primarily using ketones showing improvement in clinical depression based upon their ability to increase mitochondrial function.

Mark: So we are machines, we do work as machines and the mind emerges from that. If you look into your crystal ball, if we're saying where are we 10 years from now, do you have a kind of trajectory, a way that you think that we are going, or an endpoint that we'll reach an understanding, please?

Jay: I don't think we have to wait 10 years. I think within the next 18 months we'll have the trajectory very clearly defined.

Mark: Okay. And clinical tools for doctors is how long after you get the trajectory defined? In five years’ time will I be able to look at studies such as you know, Genomind studies, studies about the microbiome, do you think it's reasonable that we'll have a different way of considering psychiatry and psychiatric disease for truly getting the causes and repairing, or will we still be fumbling through this in five years' time?

Jay: Well, I don't have a crystal ball about the rest of society, but I do have my own crystal ball and tell you that it's not 10 years away. What's maybe 10 years away is the application of the science more broadly than it is right now. But as far as you know, to answer to your question, I think we have a very clear understanding about, you know, both pathophysiology on both the genetic-epigenetic basis and what we can do clinically, to help patients with these intractable diseases. This is you know, my lifelong mission and I'm not waiting 10 more years because my patients don't have 10 more years to wait.

Mark: It's a fascinating story. I'm busting for you to get over here to Australia for us to have longer discussions on this because opening up this area of mind, body, the brain, and the gut, and all this, it's going to be a massive effort. But the conversation has started and I think doctors are starting to realise that biology does underpin most things even those ghosts in the machine that we've treated in this odd way for over 100 years.

So I honour you. It's fantastic work that you are doing and leading in this area. I think that we're escaping from the old group of 100, 200 years ago where the mind was just mysterious and we left it at that in the hands of people who gave their opinions, delivered drugs and then didn't actually get to the cause. So thank you very much for your work. I look forward to seeing you when you get over here.

Jay: My pleasure, thank you for the time.

Mark: Thank you, Jay.


Untangling the genetics of mental illness


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Dr Jay Lombard

Dr Jay Lombard is an internationally acclaimed neurologist, author, and keynote speaker who creates solutions for brain health and intractable neurological disorders. Dr Lombard integrates biological, psychological, and existential components in his holistic treatment approach. He is the co-founder and creator of Genomind, a medicine company utilizing genetic testing to improve neuropsychiatric conditions, including Alzheimer’s, Autism, and Depression. Founder of TedMed, Jay Walker, describes Dr. Lombard as “part Freud, part Sherlock Holmes.” Dr Lombard’s discoveries have been regarded by key opinion leaders as fundamentally shifting the paradigm of psychiatric medicine.