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Diet and Nutrition in the Management of Depressive ...
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Dr. Burgess is going to be talking today about diet, nutrition, the microbiome exercise and the management of depression, depressive and cognitive disorders. Very excited. Thank you and welcome to this webinar for the Lifestyle Psychiatry Caucus of the American Psychiatric Association. And I am Dr. Gia Merlot. I'm a founding chair of the caucus, very excited to present this really important topic in the last four webinars that we've had. This is the one topic that keeps coming up, everyone wanted to hear about, so I could not think of a better person to do this than Dr. Burgess. Dr. Burgess has published numerous book chapters and publications, presented in national organizations and in fact, we did a webinar course, a four-hour course, Dr. Burgess' book on a similar topic on lifestyle psychiatry for the annual meeting this last year. And I can't imagine a better person. He's going to be joining the faculty of Stanford University School of Medicine, practicing lifestyle psychiatry in a few short days, weeks or months, whenever the license comes through. Thank you so much for joining us. And we look forward to learning from you today. Sure. Thanks for having me. Looking forward to it. So we're going to be talking about diet, nutrition, the microbiome and a touch about exercise and the management of depressive and cognitive disorders. So hypothesis from the Lancet psychiatry, emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology and gastroenterology. Now I like to make things simple. And what I would say is if it's good for you from the neck on down, it's good for you from the neck on up. The central nervous system evolved under the same conditions as the rest of the biological system intimately entrained by the foods that we eat and our balance of movement and rest. The Royal Australian and New Zealand College of Psychiatrists, their version of the APA has officially expanded the biopsychosocial model to the biopsychosocial lifestyle model as standard of care for mood disorders. Our very own American Psychiatric Association has published a textbook, Lifestyle Psychiatry. GIA is a publishing maniac. This is going to be one of three books published this year on lifestyle psychiatry, lifestyle medicine and a book to the public. There is substantial evidence for dietary interventions for depressive disorders, anxiety disorders, schizophrenia spectrum disorders, pediatric and developmental disorders and cognitive disorders. We're going to be talking about depressive and cognitive disorders today. Starting off with epidemiological evidence. So this was a meta-analysis of 20 prospective cohort studies, 21 cross-sectional studies, over 300,000 people. And what was found was the Mediterranean diet was associated with a 33% reduced risk of depression, anti-inflammatory diet was associated with a 26% reduced risk of depression and the alternative and healthy eating indices were associated with a 35% reduced risk of depression, although those were predominantly through cross-sectional studies. Diet and suicide in the same way that dying from a heart attack or stroke is the ultimate outcome in cardiovascular medicine, dying by suicide is the ultimate outcome in psychiatric medicine. This is a Japanese cohort study, close to 90,000 people and a 20-year follow-up. And what they found was individuals that ate the highest versus lowest quartiles of a prudent diet of high intakes of vegetables, fruits, potatoes, soy products, mushrooms, seaweed and fish had an association of 54% reduced rate of suicide over a 20-year period. Is it possible to relegate suicide as a rare cause of death rather than a top 10 cause of death, which it is currently in the United States? Not sure. Someone always asked, what did they account for in this cohort study? They accounted for quite a bit. It was a really well-designed study. Now these are observational studies, and if we are observing this in the environment, what could explain it? What mechanisms might explain how diet impacts psychiatric disorders? We'll start off with oxidative stress and inflammation is kind of a cerebral topic. We've heard these terms many, many times, but I like to break things down to simple terms. And how it works is anytime you're burning a calorie, whether that's a glucose, fatty acid, protein, you are involved in an oxidation process. You start off with glycolysis, you go to the Krebs cycle, and you end up with oxidative phosphorylation. The byproduct is ATP, which you want in a reactive oxygen species, which you don't want. Now what's a reactive oxygen species? It's an oxygen molecule, and instead of having two electrons at its most peripheral valence point, it has one electron at its most peripheral valence point. And this becomes an angry oxygen molecule. It's going to go around the cell and it's going to rip an electron off of anything it can get its hands on. That includes cell structures, monoamines, neurotransmitters, receptors, organelles, you name it. So now all of a sudden you have a protein that is damaged. Why? Because proteins will fold into the conformation that they fold into because of the electrical charges on the side chains of the amino acids. And once you rip an electron off of one of the amino acids, it's going to refold into a new shape. And now this is going to be a damaged protein that's no longer functional. This becomes an epitope. And the cell says, I don't recognize this protein that's going to bring the epitope up to the surface of the cell and say to the immune system, can you check this out? This doesn't look right. The immune system is going to say, absolutely, this is not a human protein. I don't know what it is. It's going to react. It's going to create an inflammatory reaction. Inflammatory reactions in and of themselves are oxidative processes because you're burning ATP left and right to get these inflammatory reactions. And so you end up in this cycle of oxidative stress and inflammation. We've heard those terms many times. Now it doesn't have to be that way. Now you can burn a calorie, you can eat glucose proteins, fatty acids, but if you are eating, you're going to, you're still going to produce that reactive acid species. You can't get away from that. That's the cost of living. But if you are eating an abundant amount of antioxidants in the milieu of the cell, then the antioxidants will donate an electron to that reactive oxygen species. And now you've just burned a calorie, but you are not creating neuronal damage or inflammation. So oxidative stress will damage any protein, including monoamines, receptors, downstream enzymatic cascades. So in and of itself, it can damage psychiatric health because of this. It also creates inflammatory cytokine processes. Now inflammatory cytokines increase monoamine reuptake transporters. I want you to think about that. These are the exact same things we are trying to block with our antidepressants. Inflammation increases monoamine reuptake transporters, decreasing the amount of monoamines in the synapses of the cell. This leads us to what is called the inflammatory hypothesis of depression. Very briefly, how do you feel when you have the flu, cold, COVID, you name it. Look at the CIGIE-CAHPS criteria and you have basically all of those symptoms. You're laying in bed, you feel terrible, you don't want to do anything, you don't want to talk to anybody, your sleep is all messed up, your appetite is all messed up. This is the inflammatory hypothesis of depression. Now why do we do that when we're sick with an infection? Well, the species has decided if you have those inflammatory compounds pumping through your system, remove yourself please from the rest of the species so that you do not get everybody else sick. In depression, these same inflammatory cytokines are not being utilized in a way that's helpful to people. They're being utilized, they're increased for a wide variety of reasons, but not due to an acute infection, but the same type of inflammatory processes that give you CIGIE-CAHPS and remove you from the species is also happening. So that's the inflammatory hypothesis of depression. Next mechanism is going to be nutrients as cofactors in the production of monoamines. This is quite simple. You start off with tryptophan and tyrosine, you end up with serotonin, dopamine, norepinephrine. And there are all of these vitamin and mineral cofactors in the production of these monoamines. If you have an insufficient or deficient nutrient, you're not going to produce the monoamines as well as how you would if you had enough of those vitamins and minerals. Let's give an example. So this is zinc. This is a meta-analysis of seven double-blinded randomized controlled trials with zinc, 319 patients, depressed adults. And these are the results. This is one outlier trial, but the rest of the studies all generally speaking were clinically significant if not statistically significant as well. And the results of the meta-analysis are quite clear. Now this was most effective in actually not as an adjunct, but actually as monotherapy. And it had a pretty substantial effect size of about 0.6, which is pretty impressive. So that's zinc. Folate and more to the point, methylfolate is a second nutrient that we can highlight for nutrient intervention for depression. Why methylfolate? Methylfolate is the form of folate that passes through the blood-brain barrier. And so if you are treating a psychiatric disorder with folate, you might as well go for the money shot and use methylfolate. Now what does methylfolate do? Methylfolate is going to increase, it's going to stabilize a compound called tetrahydrobiopterin. And tetrahydrobiopterin is a necessary cofactor in the rate-limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase. Now once you give the ingredients needed for these two enzymes to be humming away, you're going to produce more dopamine, norepinephrine, and serotonin. These are the rate-limiting enzymes. For how much these motors are humming, that's how much you're producing monoamines. And so this has been subjected to double-blind randomized controlled trials. This was SSRI-resistant depression, and so the intervention was to give an SSRI plus placebo or an SSRI with either 7.5 or 15 milligrams of methylfolate. And these are the results. For treatment-resistant depression, 7.5 milligrams of methylfolate didn't do anything. But the 15 milligrams, interestingly enough, had a doubling of the response rate. Placebo-subtracted response rate is about 18%. That's a number needed to treat around six. It's possible that we could even reduce that number needed to treat by running a couple labs. And so those individuals with a high S-adenosylmethionine to homocysteine ratio, or a low ratio if methionine is on top, or a high level of high-sensitivity CRP, or 4-HNE, which is a lipid peroxidation molecule, you could potentially target this intervention for these individuals because they are much more highly predicted to respond to methylfolate. So moving on to the microbiome. The microbiome's all the rage, the gut-brain access, really complicated stuff. Again, I'm going to simplify it quite a bit because simplicity is a beautiful thing. And so how it functionally works is if you're eating a fiber-rich diet, tons of fiber going to the colon, well, it's a payday for fiber-eating bacteria. The fiber-eating bacteria are going to be cultivated and they are going to thrive. If you feed yourself a fiber-deficient diet, well, the fiber-eating bacteria are going to die off. There's not enough food around and they're going to find an alternate fuel source. So now all you're feeding it is processed foods and animal products. Well guess what you are? You're not a processed food, but you are an animal product, and they find an alternate fuel source and they will literally start eating this mucosal membrane that's separating the fecal contents from the intestinal cells. So now the fecal contents are in direct proximity, direct proximity. They're also eating your intestinal cells, in direct proximity to the intestinal cells. This is an inflammatory party. And so now these bacteria are creating inflammation. It's no longer buffered. It's no longer buffered with the mucosa. And what does inflammation do? Inflammation causes more pores through cell-cell junctions. And so cell-cell junctions are going to loosen, the desmosomes are going to loosen, and now things can pass through. This is what happens in any inflammatory reaction. Now it's happening in the intestines. And now little bits of food products, little bits of bacteria, little bits of inflammatory compounds are passing directly from the intestines into systemic circulation. That is then going to impact the central nervous system, sometimes in a very precise way because of auto-molecular mimicry. For example, if a gluten molecule passes directly into systemic circulation, an antibody to gluten is going to form, and it just so happens that we have proteins that look a whole lot like gluten up in our central nervous system. And then the microbiome does all of this other stuff, produces short-chain fatty acids, neurotransmitters, chain-modulating agents, and it goes through all of these various mechanisms to impact the central nervous system. But it really does come down to the central idea that if you're eating a fiber-rich diet, you're going to cultivate fiber-eating bacteria, which tend to be very healthful for a human body. Here's a double-blind randomized controlled trial with a microbiome. This is clinical depression, eight-week trial, and we give them some bugs. And these are the results. Beck Depression Inventory goes way down. Insulin levels improve. Insulin sensitivity or resistance improves. High sensitivity CRP improves. Glutathione improves. Glutathione happens to be the number one antioxidant in the central nervous system. Moving on to, oh, I do want to comment on microbiome interventions. This is not from this study, but from the Sonnenbergs at Stanford. If you give probiotics, but people are not eating enough fiber, they don't have a substrate to grow on. And so you need to give probiotics plus the fiber in the diet in order for the intervention to work. Now, the best way to do that, in my personal opinion, is to just eat fermented foods because you're getting the substrate and the bacteria in one. Moving on to omega-3 fatty acids, essential fatty acids make up 20% of the dry weight of the brain. If those aren't affecting your central nervous system, what's affecting your central nervous system? They modulate everything. Omega-3 is going to be EPA and DHA. Omega-6 is going to be arachidonic acid. EPA is an anti-inflammatory precursor, whereas arachidonic acid is an inflammatory precursor. And you might say, oh, eat a bunch of EPA, limit the AA. Not exactly that easy because life is tricky. Because both arachidonic acid and DHA are important for brain volume. So if you're trying to maintain brain volume, you actually want both arachidonic acid and DHA. But as we kind of described earlier, depression, according to the inflammatory hypothesis of depression, depression is an inflammatory disease. And so we're going to focus on EPA, which is an anti-inflammatory compound. And here's a meta-analysis of double-blind randomized control trials, 23,000 people. And these are the results. The vast majority of these studies were successful in their own right. Some were neutral. Every once in a while, there was an outlier. But notice that this is EPA in patients that are diagnosed. Now if we look at the whole data, if you provide someone a DHA-predominant supplement, it does not impact depression 1 iota. If you give them an EPA-predominant supplement, it does with an effect size of about 0.6, which is a pretty impressive effect size. After we account for publication bias, it does reduce down to 0.4, but it's still a notable result. It is more effective in patients with a formal diagnosis of depression rather than subsyndromal depression, but it's only the EPA, only the EPA that will work for depression. Why is that? Because EPA is a potent PPAR-gamma agonist. What is that? That's an anti-inflammatory enzyme that's going to reduce inflammation in the central nervous system. DHA looks a whole lot like EPA. It's a key, it goes into the lock, but it doesn't turn the key. DHA is actually a competitive inhibitor to EPA. And so if you are providing an omega-3 fatty acid supplement for depression, not for brain volume, not for dementia, but for depression, you want an EPA predominant formula, 60-40 split, 70-30 split, 80-20 split, an EPA predominant formula so that the EPA will outpower, overpower the DHA in order to stimulate the Pbarg agonist. Okay, next. MDD treatments, so these are dietary interventions for depression. The SMILES trial, this is the first kind, not first, but the most recent well-designed landmark trial. This was 67 individuals with moderate to severe depression, 12-week intervention, standard of care, everybody got standard of care, but half the group got seven hours with a dietician recommending a Mediterranean diet versus seven hours with a social support conversation, befriending, they're calling it. Now, inclusion criteria is poor baseline diets. If you have a good diet and you are depressed, a dietary intervention is going to be low yield. If you are eating Twinkies, HoHos, pretzels, pizza, three times a day, seven days a week, maybe a dietary intervention where you're improving your baseline physiology is going to impact your depression disorder. And so this is according to the Montgomery Asperger Depression Scale, clinically significant and statistically significant reduction in depression scores. Remission from depression defined as less than 10 on the Montgomery Asperger Depression Scale is 8% for standard of care versus 32% for standard of care plus the dietary intervention. Now this is at 12 weeks. We know that if we extended this trial to a year, six months to a year, that standard of care would absolutely reach 32%, 40%, maybe 50%. If you're doing multiple medication trials, maybe up to 60% remission. The question is, would the dietary intervention have continued to make gains during that entire year? We don't know, the study wasn't done. Or would they both have regressed to the mean? We don't know. What we can say is that adding a dietary intervention to standard of care increased the rate of remission at 12 weeks for people with a poor baseline diet. Second study, virtually identical. This was the AMEND trial, a Mediterranean diet for men dietary intervention. And these were 72 young males with moderate to severe depression. And they focused on young males for several reasons. Men on average have less, they treat depression less frequently than females. Males on average have worse diets than females. And so could we give a dietary intervention to young males with depression? And that's what they did in the study. 12 week intervention, virtually identical to the SMILES trial, except this time it was only three hours with a nutritionist versus three hours with the social support. And these are the results. Beck Depression Inventory. Moderate to severe depression at 12 weeks mild moderate depression. Pretty outstanding results. This is actually an oldie but goodie. This is the Coronary Health Improvement Project. This was a diet and lifestyle intervention that was created for coronary cardiovascular health. They designed this study because at this point they had given this intervention to 40,000 people. And after they gave this intervention to 40,000 people, they noticed, hey, people are in a better mood after the end of it. Let's study it for diet itself. And so this study was done all the way back in 2008 before anyone was really thinking about dietary interventions for psychiatric disorders. And it happens to be the largest dietary intervention study for depression that has ever been completed. This was a four-week intervention, 40-hour health education program teaching the role of diet and lifestyle on cardiometabolic diseases. And it was a six-week and six-month follow-up. And these are the results. These aren't the results. This is the diet that they recommended, a predominantly plant-based minimally processed foods such as whole grains, legumes, vegetables, fresh fruits, lower intakes of fat, sugar, salt, and animal-based protein. And these are the six-week and six-month follow-up. And regardless of the severity of depression, everyone with depression reduced, or on average, I should say, on average, everyone reduced their depressive scores. The authors wrote this. Lifestyle change programs such as CHIP designed to reduce cardiovascular risk can likewise have a profound influence on mental health. This comes back to the central theme. If it is good for you from the neck on down, it's gonna be good for you from the neck on up. This is the heart of lifestyle psychiatry. Quick study on exercise. I just like to talk about exercise briefly because it's just so great. This is a meta-analysis of 41 randomized controlled trials, 2,000 patients. And exercise is considered at this point an evidence-based treatment for a major depressive disorder. In fact, the European Psychiatric Association has officially made cardiovascular exercise first-line treatment equal to that of antidepressants and psychotherapy for the treatment of major depressive disorder. Let's look at effect sizes. The effect sizes of antidepressants, all of the meta-analyses say the effect size of antidepressants are from somewhere between 0.3 and 0.7. The SMILES trial, the effect size was 1.17. The AMEND study, 2.6, a massive effect size for those gentlemen with severe depression, moderate to severe depression and poor dietary baseline. And exercise, the average of the meta-analyses are around 0.95. Now, the dietary studies, we'll still have to do, you know, however many, 20 more studies to figure out what the effect size is eventually going to be. But it's quite provocative to have effect sizes this large for these lifestyle interventions. Take-home points, intervening upon the microbiome may improve depression. Omega-3, specifically an EPA-predominant formula may improve depression. Increasing nutrient cofactors may improve monoamine production. This is evidence for folate and zinc. Adjunct, Mediterranean and healthful whole foods diets appear to improve depression in patients with poor baseline diets. And exercise is an evidence-based intervention for depression with a relatively large effect size. Part two, moving on to cognitive disorders. So cognitive disorders and dementia, all the same mechanisms are at play. We have oxidative stress and inflammation, nutrients as cofactors in the production of neurotransmitters and the microbiome. All that stuff is still at play, but we're gonna focus on some additional mechanisms that relate to this longstanding disorder that's developing over a lifetime. And so it's all about brain volume. Do we maintain this brain volume? So brain volume, we're gonna be talking about cerebral blood flow. We're gonna be talking about brain-derived neurotrophic factor. And we're gonna be talking about homocysteine and how does diet intervene upon these things. Cerebral blood flow, we're actually gonna break up into chronic cerebral blood flow versus acute cerebral blood flow. Chronic cerebral blood flow is gonna come from intracranial arterial stenosis. So we've got blood vessels all throughout our system. And so if you have a clogged blood vessel in your heart, coronary artery disease, if you have clogged blood vessels in your arms and legs, you've got peripheral vascular disease. Well, lo and behold, we've got blood vessels going up to the central noggin. And these blood vessels are just as susceptible for getting stenosed, clogged up as any other blood vessel in our system. These are the carotid arteries of individuals without dementia. These are the carotid arteries of individuals with dementia. It is a dose-dependent response. The more stenosis you have, the higher your rates of dementia. How is this working? You can kind of think about it as just like you're strangling your brain. It's not like a stroke where you have this delta of immediate death, but you're strangling your brain over time so that all of the brain cells cannot survive. Some of them are gonna be picked away over time and the brain will start to lose volume. Here is an MRI study with diet and brain volume. This was 674 individuals, cross-sectional study, but they did an MRI on 674 individuals and looked at their diets. A high adherence to a Mediterranean diet was associated with increased total brain matter volume, total gray matter volume, total white matter volume. High intakes of fish were associated with total brain volume, total gray matter volume, total white matter volume. Low consumption of red meat was associated with higher brain volume. All told, high versus low adherence to the Mediterranean diet was equal to five years worth of brain volume. Pretty impressive. Moving on to acute cerebral blood flow, this is gonna be nitric oxide production. And we're gonna come to flavanols. So here's chocolate, but it's any flavanol. It's gonna be wine, grapes, berries, green and black tea, chocolate, and all of them upregulate the enzyme nitric oxide synthase. So here's a randomized controlled trial, double-blind randomized controlled trial. Two identical trials, actually. One had a cohort of a group of mild cognitive impairment, the other were otherwise healthy individuals. 180 people total, eight-week study, three arms. And so they gave high flavanol chocolate versus intermediate flavanol chocolate versus low flavanol chocolate. And in a dose-dependent response, in a dose-dependent response, the high flavanol, intermediate flavanol versus low flavanol had significant improvements with the trail-making A test, trail-making B test, verbal fluency, improved blood pressure, improved lipid levels, and improved insulin response. Now, question, how do you do a double-blinded randomized controlled trial with chocolate? How do you do a double-blinded randomized controlled trial with chocolate? How do you fake the funk? And the answer is, you give them chocolate. But chocolate processed with alkali, otherwise known as Dutch processing, the alkali binds to the polyphenols of the chocolate, rendering them physiologically inert. Milk products will do the same thing with the milk alkali. And so we've all heard the message, dark chocolate, not milk chocolate. It's only half the message. It's dark chocolate not processed with alkali will give you the physiologically active chocolate. So flavanols increase nitric oxide synthesis in a use-dependent manner. So this is acute cerebral blood flow, a flow-mediated vasodilation. And so I can't see myself, so hopefully you can see me. And so here we're gonna have two people and we're gonna have one, both of them are gonna have the same arms. We're gonna have one arm just not doing anything. We're gonna have the other arm moving like this. And one of these people is going to receive a high flavanol chocolate. And the other person is going to receive a low flavanol chocolate, the placebo. This arm is not flow-mediated, use-dependent. This arm is gonna have the same amount of blood flow whether you ate the chocolate or not. But this arm, in a use-dependent manner, that chocolate is upregulating nitric oxide synthase more in the arm, in the people that ate the chocolate in the moving arm. And so in a use-dependent manner, whatever part of your body you are using after you've eaten chocolate or berries or you name it, a high polyphenol food, nitrous oxide, nitric oxide will be produced in that area of the body that you are using. And so that is important for a couple of reasons. One, the production maximizes at three hours later. So if you eat high quality chocolate, three hours later, you start thinking the whole lot, you're gonna improve your cognition at that mark. You could also use it for cardiovascular exercise and all sorts of other stuff. But it's related to this study. So this is a double-blind randomized controlled trial, three-month trial in 50 to 69-year-old people. I think this is like the perfect age to study cognitive impairment. And they gave them a low versus high flavanol chocolate. The outcomes were cognitive reaction time and blood flow to the dentate gyrus. What is the dentate gyrus, you ask? The dentate gyrus is located in your hippocampus. It happens to be the number one area associated with cognitive aging. It happens to be the only area in the brain that purportedly can still produce neuronal stem cells. And the amount of blood flow and volume in the dentate gyrus is directly correlated to cognitive aging. Now, chocolate will produce increased nitrous oxide, nitric oxide, in a use-dependent manner. And so in order to do this study, they developed a test that caused the dentate gyrus to light up. And this test was the ModBent test. And so you looked at a shape for 10 seconds, the screen went away for one second, and then you had to pick. It's this shape or this shape? It's this shape. You looked at a shape for 10 seconds, and then you have to pick. Is it this shape or this shape? Very subtle, it's this shape. And this test caused the dentate gyrus to light up. And so now we've got a use-dependent mechanism, and now we're gonna give the chocolate to the two groups. We're gonna light up both of their dentate gyruses, and in the chocolate group, in the chocolate group, it increased blood flow to the dentate gyrus equal to three decades worth of age reversal. So if you were 70 years old, you had the dentate gyrus blood flow volume of a 40-year-old. So chronic cerebral blood flow, diets that reduce the risk of intracranial arterial stenosis, reduce the risk of cognitive impairment by delivering chronic blood flow up to the central noggin. Acute cerebral blood flow, flavanol-rich foods, cacao, berries, transiently increase blood flow in a use-dependent manner, which may improve cognitive performance. Moving on to brain-derived neurotrophic factor. I'm gonna squeeze in some exercise here, although flavanol has increased brain-derived neurotrophic factor. But brain-derived neurotrophic factor is increasing brain volume. It is miracle growth for the brain. Interestingly enough, brain-derived neurotrophic factor, what it does globally is it increases nerve growth. And so I think what I want you to, it's a misnomer. It's found all throughout your system. And so it is also a contraction-induced protein. And so here I am contracting my arm, contracting my arm, contracting my arm. My arm's getting a little bit bigger, not that much bigger. I didn't contract it all that much. But if I'm contracting it a whole lot, the muscle is going to get bigger. And BDNF is a contraction-induced protein. The muscle's getting bigger. If it got so big, it would become a clumsy muscle. And so every time the muscle contracts, it also secretes a little bit of BDNF to increase neuronal growth into the muscle. So you have a proportional growth of muscles getting bigger with nerve endings intervening upon it. So you can have big muscles and still be a graceful human being. So brain-derived neurotrophic factor is a contraction-induced protein. It also is intervening upon the vasculature. And so in the vasculature, you have your smooth muscle surrounding the vasculature. And so as your heart is contracting and expanding, contracting and expanding, it's pushing a pulse of blood, pushing a pulse of blood, pushing a pulse of blood. And the blood vessels then react to it. It's expanding and contracting, expanding and contracting, expanding and contracting. And every time the blood vessel contracts, brain-derived neurotrophic factor, a contraction-induced protein, is secreted. And locally, it's going to help that blood vessel relax. It does vasodilation in the blood vessel, working along with nitric oxide. It also gets swept away throughout the bloodstream, passes right on through the blood-brain barrier. And up here, it increases brain volume. And so this was a landmark trial way back in 2011, 120 people, they had mild cognitive impairment, age 67, and they did 12 months of aerobic exercise versus stretching control group. And this was the measure of the hippocampus after one year. One year of cardiovascular exercise re-grew about two years worth of brain volume loss in the hippocampi. The stretching control group continued to age and shrink their hippocampi by the expected amount of 1 year of neuronal loss. The difference between these two groups with 1 year of cardiovascular exercise was 3 years of brain volume in the hippocampi. Exercise preferentially protects and regenerates the frontal and hippocampal brain regions. This is where the BDNF is most active. These are the centers of executive function, memory, and cognition, the very same centers targeted in dementia. Homocysteine and brain volume, final mechanism that we're going to discuss. So homocysteine is an inflammatory compound. It's increased by low B12, low folate, all of these other things. And homocysteine, we know about it because of cardiovascular medicine. High homocysteine is a risk factor for cardiovascular events. Why? Because homocysteine is a lipid peroxidizer and it's going to be peroxidizing, it's going to be oxidizing the plaques in your arteries and the lipids in your arteries that are maintaining the actual cells and it's going to cause inflammatory damage all throughout your cardiovasculature. It also passes right on through the blood-brain barrier. And there, what's in your brain? A whole lot of lipids. Homocysteine is a lipid peroxidizer. And the more homocysteine you have, the less brain you have. High levels of homocysteine are related to low volumes of hippocampi. High levels of homocysteine, overall cortical atrophy passes right on through the blood-brain barrier and the lipid peroxidizes brain volume loss. Can we intervene upon it? Yes, absolutely. Or at least here's a really convincing study that says we can. This is a double-blind randomized controlled trial with 800 people, three-year study. Again, 50 to 70 years old. I think that's the perfect age to research for improving cognition. Inclusion criteria is high homocysteine and normal B12s. Here, we're fairly convinced that the low folate is producing the high homocysteine, and so we give folate. At the end of three years, the folate group versus the placebo group, the folate group was 1.5 years younger for global cognitions, 1.7 years younger for sensory motor speed, 2.1 years younger for information processing speed, 4.7 years younger for memory, 6.9 years younger for delayed memory, all with just a little bit of folate. Now, granted, this is a highly selected group where they had high homocysteine and low B12, but functionally speaking, it's cheap enough and has a side effect profile mild enough that you probably could give this to a population without much harm and some benefit to those who would benefit from it. Moving on to the randomized controlled trials for diet and cognitive disorders. This was a PREDIMED subgroup. The PREDIMED study was the largest diet and lifestyle study that has ever been done in history. It was about 7,500 people. It was done in Europe, and the dietary intervention was a Mediterranean diet versus a so-called healthy diet, low-fat diet. They weren't actually low-fat, but that was the control group. It was such a large study that they actually did subgroup analyses, and so this is kind of like an observational study, kind of like a randomized controlled trial. And so here were about 450, 330 people at follow-up, and the intervention was Mediterranean diet supplemented by a high polyphenol extra virgin olive oil, or Mediterranean diet supplemented with nuts versus the healthy control group. I do want to talk about a high polyphenol extra virgin olive oil. So some olive oils are quite expensive, and they have high polyphenols. Why are they so expensive, and why do they have high polyphenols? This is why. When an olive is growing, when it's really tiny, when it's really tiny, if you take that olive and you squeeze it then, you're not going to get much olive oil. It's a really tiny olive, but it's going to be chock full of polyphenols. If you let that olive continue to grow into a big olive, you squeeze it, you're going to get a ton of olive oil. It's not going to be a high polyphenol olive oil. And so a high polyphenol olive oil is appropriately expensive because the same amount of plant and land is making a smaller amount of product. However, if you are going for the polyphenols, there's no comparison. You do want a high polyphenol olive oil for optimum mental health and physiological health. So this was the intervention, follow-up was about four years. And the Mediterranean diet plus olive oil and nuts either had a significant or trend toward improvement, significant, significant, or trend toward improvement for a global cognition, executive function, or memory. There was one that was quite a little bit outside of a trend toward improvement, but a very impressive study. The MIND diet, the Mediterranean DASH intervention for neurocognitive delay. So they said the DASH diet works great, Mediterranean diet works great, let's put them together and create the ultimate diet. That's the idea regarding the MIND diet. So it's basically a Mediterranean diet that is emphasizing berries, leafy greens, nuts, olive oil, all of these at the first line. They're all high polyphenol foods plus some fish and limits foods that are clearly unhealthy. This was a randomized controlled trial with 40 obese women, average age 48, intervention, the MIND diet versus a calorie controlled diet for three months, and cognitive performance on a comprehensive neuropsychological battery. These are the results. So homocysteines improving, amyloid beta improving, BDNF improving, forward digit span, backward digit span, letter number sequence task, symbol digit modality task, trail making A, trail making B, stroop test, audio visual learning test. Overall, the results are quite impressive. Two of them were not statistically significant, but the picture is quite clear. The MIND diet improved cognitive performance in this group of people where their average age was, what was it, 48. Now I will say that they just repeated this study, a 600 person massive randomized control trial on the MIND diet, and the results were not impressive. The MIND diet did not do any different than the calorie restricted diet. That was actually published in the New England Journal. I wish that I put the slides in. I apologize for that. One of the big differences between that study and this study was the age of inclusion. In that study, they started with 65-year-olds on up. So the study really does, I mean, it was miraculous, 600 person randomized control trial, amazing. Unfortunately, they do have to redo the study to make sure that they're including 50 to 65-year-olds. I think that's the appropriate age to intervene upon cognitive impairment. I think after 65, we're seeing this with some other studies, it becomes much more difficult. So this is an additional study. This is the Mediterranean diet versus the green Mediterranean diet, randomized control trial, 284 people, obese individuals, average age 50 again. So that perfect age for intervention, 18-month study, so a sizable study, healthy diet versus Mediterranean diet plus walnuts, Mediterranean diet plus walnuts, green tea, and this high polyphenol leafy green, which interestingly enough, you cannot purchase in the United States. The measure was hippocampal volume and lateral ventricle volume. And looking at all of them, all of the participants, it's really not until the age of 50 that the hippocampus starts shrinking. It's really not until the age of 50 that the lateral ventricle starts increasing. And so looking at that population, those that adhered to a, those that were in the Mediterranean diet group, they attenuated, they attenuated the volume loss in the hippocampus. They attenuated the volume gain in the lateral ventricles. Now taking it one step further, we told these people to eat walnuts. Some of them did. Some of them didn't. We told these people to eat green tea. Some of them did. Some of them didn't. We told these people to eat the high polyphenol leafy green. Some of them did. Some of them didn't. Now you're losing the intention to treat, but you are gaining treated as intentioned. And those that ate the high amounts of walnuts had attenuated volume loss. Those that ate a moderate or high amount of green tea, again, attenuated volume loss of the hippocampus. Those that actually ate the mankind, high amounts of the mankind, the high polyphenol leafy green, they actually gained volume in the hippocampus. They also did a subgroup analysis for red meat and those that ate the least amount of red meat, again, attenuated volume loss compared to those that ate more amount of red meat. Mediterranean diet and a high polyphenol Mediterranean diet appear to attenuate age-related hippocampal volume loss in an 18-month clinical trial. Take-home points, diets that reduce the risk of atherosclerosis and arteriosclerosis appear to improve chronic blood flow to the brain. Flavanols appear to increase nitric oxide, improving acute blood flow to the brain in a use-dependent fashion. Exercise and flavanols appear to increase brain-derived neurotrophic factor. Diets and nutrients that decrease homocysteine appear to maintain brain volume and cognitive function. The Mediterranean diet and the MIND diet appear to attenuate brain volume loss and improve cognitive performance and function. That's it. Thanks, everybody. I'll stop sharing. Oops. Where is everybody? We're here. Thank you so much, Jonathan. Sure. This was amazing. Dr. Burgess, we have a lot of questions, and I wanted to get started. There's a question in the chat, and I kind of answered it. Okay. Did you want to ... I put a link to Google. Yeah. Yeah. You're just going to have to Google it. There's a couple. Let me see if I can find my list. Gia's list is going to be just as good. There's a couple of websites. Let me open one of my notes and type in olive oil. Olive oil. Here we go. And so I'll just copy and paste these in here. It doesn't allow ... Zoom does not allow you to copy and paste, but you can click on the links. This ... Yeah. Well, there I am, defaming somebody. I apologize. Now, one of these is quite strong, Oli Health. Oh, my gosh. They have the smallest olives, and that one kind of takes a little getting used to. That's like almost a medicinal level of polyphenols. It's my favorite one. It's the one, when I eat it, I actually feel a little different, but just to warn you, that one, Oli Health US, that's a high amount of polyphenols. It's a bitter-tasting olive oil. Great. Great. Dr. Burgess, Dr. Viz, our president-elect of the APA, wants to talk about- Oh, yeah. Thank you. Hi, Dr. Viz. Thank you, Jia. Thank you, Dr. Burgess, for really this very comprehensive thing, not only show the studies, but also the handling mechanisms. One question I have is how come there are so many studies on Mediterranean diet and very few studies on whole food plant-based diet? Yeah. I mean, it's a good question. I think one of the reasons potentially is kind of related to some Harvard School of Public Health and studies, which demonstrated that the Mediterranean diet seems to have more staying power with people. And so if you put people, if you randomize people to various diets and you follow them for 18 months, three years, people do tend to adhere to the Mediterranean diet better than the other diets. So maybe there's something inherent in satiety. I think a lot of it, quite frankly, does have to do with our European background and the influence of that on the field of medicine. I would love to see more studies on the Okinawan diet. I mean, they're the longest-lived people in the world. Aardvark diet. Aardvark diet. Yeah. The whole food diet. The whole food plant-based diet. Yeah. I would love to see those, but we don't have them. So we're an evidence-based field. I can only speak to what the evidence is. Thank you. Thank you. Other questions, thoughts? So Chad, you sent me a direct message. Did you want to unmute yourself or would you like to do it? I'll just read it out. Should we be prescribing a certain diet for all adult depressed patients or geriatric patients who are inpatient? Oh, I love it. If you're asking me my personal opinion versus what is standard of care, those are slightly two different ideas. Yes, I do think that we should be looking at individuals who have a poor baseline diet and in the very least having a nutrition consult, but ideally recommending them to reduce or eliminate their processed foods. I think that in terms of dietary interventions, reducing or eliminating processed foods is probably the single most important. So first and foremost, improving diet quality. I have, interestingly enough, I used to kind of do kind of really amazing cooking and all sorts of stuff. And it was quite elaborate, kind of like a symphony of food. I have personally, I almost consider it cheating, but I've kind of switched to some products that are basically freeze dried plants. It's just a collection of like 50 feet freeze dried plants. And I finally come to terms with it because of a stock analogy, which is if you, there's some evidence that if you invest in index funds, diversified portfolio, you will do better than 96% of stockbrokers that pick individual stocks. And I started going, well, these are basically index funds, they're freeze dried plants. And I've been doing great on them, quite frankly, for five years. And I wonder whether or not that might actually have a functional future because they are very convenient. Dietary interventions are really tough. This is cultural, like what you were raised with, all of your friends, it is so embedded. You have been eating these foods since you were a baby and to change all of the habits that need to be changed in order to change your diet, it is quite the endeavor. Plus, you are bombarded with trillions of dollars worth of advertising and junk food everywhere. It's tough. It's really tough. But in my ideal world, yes, we would all have a dietary intervention, particularly targeted towards individuals with a poor baseline diet and get them to have a healthier diet. And I do think that psychiatric outcomes would be substantially better. That's my own personal view. Do you think we should be starting that directly inpatient? Like when a patient comes in, should we say, hey, as part of your medication profile, we should be giving this level of a diet? If you have the resources to do that, then yes. But our system isn't, you know, this is my passion. How often do I bring it up? It depends on the patient. I do think that it's my duty to at least tell them about it. But I don't have the resources of, you know, a 40-hour health education program yet. I do think that hopefully some of these dietary interventions and lifestyle interventions will eventually create some type of protocol that can be easily implemented for a broad collection of patients. But in the very least, you can introduce the idea. And for those that are industrious, there's a ton of cooking classes on YouTube that they can utilize. They can start improving their skills or get live cooking classes. My own academic history is through Harvard School of Public Health, David Eisenberg. He is a huge proponent as cooking classes as a necessary component for any dietary intervention. Not just telling people what to eat, but showing them that it's delicious and how to do it is clearly going to give them improved resources to follow through with these recommendations.
Video Summary
In an enlightening presentation by Dr. Burgess, he delves into the role of diet, nutrition, exercise, and the microbiome in managing depression and cognitive disorders. The discussion underlines the significance of employing a lifestyle psychiatry approach, evident through various compelling studies. Dr. Burgess emphasizes the notion that a diet beneficial for cardiovascular health is also crucial for mental health, advocating for dietary interventions like the Mediterranean Diet. Evidence shows that such dietary regimes can substantially reduce depression risk and improve cognitive function through mechanisms like oxidative stress reduction, enhanced cerebral blood flow, and anti-inflammatory effects. His exploration also highlights the impact of nutritional cofactors on monoamine production and how fiber-rich diets can foster a healthy microbiome, influencing mental health. Additionally, he emphasizes the role of omega-3s, especially EPA, in managing depression due to their anti-inflammatory properties. Exercise is lauded as a highly effective treatment for depression, equated in efficacy to medication and therapy, fostering brain volume and function. Dr. Burgess advocates for incorporating nutritional and lifestyle modifications as a standard approach in psychiatric treatment.
Keywords
diet
nutrition
exercise
microbiome
depression
cognitive disorders
Mediterranean Diet
omega-3s
lifestyle psychiatry
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