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The Dr. Hyman Show
Antidepressants Explained: Benefits, Risks, and Alternatives for Depression | Dr. James Greenblatt
00:55:02
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- [00:00]
Dr. Mark Hyman
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What percent are they affected for? Who are they affected for? And where are we failing with these medications?
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Dr. James Greenblatt
For too many years, the psychiatric community completely ignored what happens when you stop these medications. I call it withdrawal, they call it discontinuation syndrome. And it was just kind of eye opening when I had two people stop the same medicine. It was Celexa, and one person did it fine and the next one had these intractable, you know, brain zaps and suicidal thoughts. And I realized it's not the medicine, it's what's going on in that individual. And once we do the functional testing, we replete the D and the B12 or the Amino acids, we can safely withdraw someone from these antidepressants.
- [01:30]
Dr. Mark Hyman
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Dr. Greenblatt, welcome back to the podcast. It's so good to have you. Right now estimated that 18% of Americans suffered depression, 1 in 4 people in their life will have a major depressive episode. So this affects everybody at some level, either you or someone you know, I mean, I know many people have committed suicide. I know many people have been depressed. I. I've had that, my experience myself at different times in my life. And, and, you know, what we're learning about is, is really what you wrote about in your book, what you've been studying for the last 30, 40 years. You and I are kind of in the same generation and, you know, going, wait a minute. What we learned in medical school and what we learned in residency and what we, what we learned in our conferences and the orthodoxy doesn't actually explain what we're seeing. And we have to come up with a different set of explanations for the phenomena that we see in patients. And so I'm just super excited to dive in this topic with you and to help people with depression have hope where often they don't really help people understand that this is not a often psychiatric problem alone. It's a physiological problem. It's something that is in their system that can be identified and that can then be treated in a way that we don't treat in psychiatry, which is basically diagnose and medicate. And there's a whole realm of interventions and thinking and possibilities of helping people heal that have nothing to do with that. Now, there's nothing wrong with talk therapy. There's nothing wrong with medication, but they're the last resort when it comes to solving a problem that, you know, is affecting so many people. And we have to get to those root causes. So, Ken, take us back to the origin story a little bit. We've had you on the podcast before, but just briefly talk about your inspirations, because I think it matters. And I think, you know, you and I have very similar inspirations in terms of the leading thinkers and figures in the field of medicine, science, and psychiatry that have kind of helped us see things a little bit differently, starting with Linus Pauling and Abram Hoffer and Roger Williams. To talk a little bit about how each of those people have helped you think about psychiatry differently.
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Dr. James Greenblatt
Sure. I think you mentioned my three kind of hero mentors that defined my career. So, Linus Pauling, you mentioned two Nobel Prizes. It's a little frightening when I give talks and I ask people if anyone knows. No one raises their hand anymore. Elinus Pine got a Nobel Prize in chemistry and peace. And he wrote this article on orthomolecular psychiatry, was a title in Science magazine in the 60s, and basically was a very scientific, you know, on enzyme kinetics. And all he said is that perhaps we can think of mental illness as abnormal molecules, you know, in the brain, and maybe we could fix or treat it by optimizing these normal molecules. And he described many micronutrients. And then Abraham Hoffer was a psychiatrist that was able to utilize micronutrients for the treatment of those severe schizophrenics. And I've treated some of his patients that he treated 50 years ago that were called cured of schizophrenia by, you know, nutrient therapy. And I think it all starts with the biochemical individuality, which was. You mentioned Roger Williams. And, you know, that's how I start every one of my presentations. First chapter in Every book is helping people appreciate that they're different than their neighbor, and particularly with depression. Might be 10 individuals walking into your office or friends with depression, and there might be 10 different underlying factors.
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Dr. Mark Hyman
I think that's absolutely true. And I actually got to meet Abraham Hoffer and also Linus Pauling. Never Roger Williams, but I think he died before my time. But you know that. That paper you're talking about in Science magazine, by the way, which is this premier elite magazine. And Linus Pong was a biochemist, and he. He understood biochemistry in a way that most of us don't. I mean, he won the Nobel Prize for his work in the study of proteins and biochemistry. And the title of the paper was Orthomolecular Psychiatry. Ortho means to straighten. Like. Like orthopedics means to straighten bones. It's an ortho to correct molecules. Orthomolecular. And. And he talked about different nutrient needs. And it was a very. I mean, I read the paper. It's super geeky. I could barely understand. Half of it was very deeply scientific. But it really spoke to this idea that maybe our mental health was not simply just an emotional problem, although it often can be. If there's trauma and things that are quite serious, that happen when you're younger, those all influence us, but we shouldn't sort of assume that that's the problem, and we should start to look for things that are actually treatable. And in your work, you really. You kind of also talked about Roger Williams, who was the father of biochemical individuality. And, you know, I often. I often say the same thing as you, that if you. If you know the name of your disease, it doesn't mean, you know, what's wrong with you. Say I have depression. Well, that's just the definition that medicine has given to people who share a collective set of symptoms. They're hopeless, they're helpless, they have no interest in sex, they can't sleep, they have no appetite, whatever. There's a whole list of these things in the. In the medical categorization book, we call it DSM Fiber. It's helpful for grouping people in categories, but doesn't tell you anything about the why. And so you spend your life thinking about the why and asking really difficult questions, which is, how are these people all different? And like you said, you know, I. I always say this. You know, you have depression. It's not a Prozac deficiency. It's something that is often treatable.
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Take us through how you kind of
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unpack the fundamental root causes, the Drivers, the biological drivers of depression. Because most people think it's a chemical imbalance, right? Oh, just, it's a serotonin deficiency. So take this drug that makes you have more serotonin in your brain, right? That doesn't work. I mean the studies for mild to moderate depression really that these drugs are not much better than placebo and you know, they're often come with a lot of side effects. So take us through these, these major biological drivers that you talk about in your book.
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Dr. James Greenblatt
Well, I mean as you described there, there are many possibilities and you know, how do we assess where to go? And in the integrative and functional space, sometimes people get carried away with too many tests. But there's often, you know, very low hanging fruit. And I think the first part of the assessment is a good history and family history because we do know that depression runs in families and that helps us understand some micronutrients that could be deficient and some genetics like having variants of, you know, folate. MTHFR variants tend to be genetic.
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Dr. Mark Hyman
And that for people listening, that that's a, that's a particular gene that regulates folate metabolism, which is very involved in neurotransmitter function and mood. So even traditional psychiatrists understand that folate can be a treatment for some case of depression. And this is a gene that makes us different. So that's what that gene was just
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Dr. James Greenblatt
working in the inpatient psychiatry world for 30 years. One of the most common presentations that I see for those that are what we call treatment refractory, that don't get better with medicine, you know, are those with that kind of genetic variant. So looking at that gene is to me a critical component of a depression workup. Then you know, just simple vitamin deficiencies as you describe. B12, zinc and magnesium. I think one of the most significant and simplest and could dramatically change the public health implications of depression and suicide globally is just vitamin D deficiency. The research in 2025, I mean, everything you and I have been Talking about for 30 years, 2025 was a year that just solidified everything. I mean, so I have research articles now on low vitamin D and suicide, low zinc and suicide, low folate and suicide that just came out this year. And so we can't really argue with the stunning research that's just been blossoming.
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Dr. Mark Hyman
And everybody thinks, oh, you know, people in America have plenty of food, they eat a lot, they're not malnourished. Nonsense. When you look at the NHANES data, which is the government survey, the National Health and Nutrition Examination Survey where they go and test thousands of people every year, and they monitor history and their health conditions. They found over 90% of Americans have a deficiency in one or more nutrients at the minimum level to prevent a deficiency disease. Like how much vitamin C do you need to not get scurvy or vitamin D to not get rickets?
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Dr. James Greenblatt
Right.
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Dr. Mark Hyman
And so it's, it's omega 3s are probably 90%, 80% lower inefficient. Vitamin D, 45% magnesium, but the same in zinc, the same in iron. And these really affect your mood and your brain function. And so people think your brain is sort of like disembodied from the rest of your body. Like it's just this thing sitting up on top of your shoulders. And, and you know, the joke is that psychiatrists pay no attention to the brain and neurologists pay no attention to the mind. But you're a psychiatrist who's paying attention to the brain and how it works and what's needed for it to work. And nutrients are a huge factor. Talk about also sort of the, the gut brain issue, because I think that's a very big one that people don't necessarily understand is how could the gut be related to the, the brain? And, and by the way, like, does your psychiatrist ask you for a stool test when you go in with depression? Probably not, but maybe they should. Right, so take us through that whole understanding of how the gut function and the disturbances in the microbiome are linked to potential depression.
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Dr. James Greenblatt
Yeah, I mean, sometimes, you know, I make a joke that I'm more of a gastroenterologist than a psychiatrist because, I mean, even from, from the mouth down, like, you know, zinc deficiencies is common and we'll pick that up by someone not having taste. And then the digestive enzymes and hydrochloric acid. So if you don't digest food properly, you don't absorb the micronutrients. So I have a lot of patients who are spending money on very expensive organic food and these grass fed, you know, protein. But when we do testing, they have very low levels of amino acids, the building blocks, because they don't have enough digestive enzymes.
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Dr. Mark Hyman
Yeah.
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Dr. James Greenblatt
And then that sets the whole dysbiosis. And it's clear that now and again the research has just supported it. Dysbiosis, it's been related to every major psychiatric illness. I mean, Alzheimer's, depression, anxiety, anorexia. It's pretty stunning.
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Dr. Mark Hyman
It's true. I mean, I've had a lot of patients with gut issues that when you're an Actual psychiatrist. I'm, I'm not. I'm a family doctor. I've had some training in psychiatry, but I jokingly call myself the accident psychiatrist because I would treat people's gut issues and all these psychiatric problems would go away, whether it was OCD or depression or anxiety or even more serious things. You know, autism would improve and ADD would improve. And I was like, well, what's going on here? Right? You know, and so I think, you know, behavioral issues that improve. And I saw this over and over and I just. That's why I wrote the book Ultra Mind Solution Dec a decade and a half ago, because I was like, oh, wait a minute. There's more to the story than just, you know, these, these psychiatric diagnoses and drugs. And there's something else going on here that's affecting the brain and a lot. And a lot of the, the common pathway of, of this is, is inflammation. Um, even, even like the gut, we didn't talk about this, but like there's bacterial overgrowth, yeast overgrowth, leaky gut, all that stuff. Plus gluten is a big factor. And I want you to sort of touch on that because I think even without gut symptoms, you can have gluten sensitivity that creates an inflamed brain. And I want you to sort of unpack the brain inflammation story when it comes to depression, because I think that's a central unifying feature of a lot of the things that go wrong when
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Dr. James Greenblatt
the pharmaceutical companies get involved. You know, it must be important because, you know, there are pharmaceuticals looking for anti inflammatory drugs to treat depression. So there are many mechanisms and many paths to how inflammation affects depression. And we know the, you know, people are all now familiar with cytokines and all these inflammatory markers. Well, they target the brain and they decrease these neurotransmitters and they affect depression. And that's been known for many years. And inflammation is a common pathway. But there might be many, many paths to an inflamed brain. And simple ones are like sleep deprivation, inflammation, increased risk of depression, and suicide. And then we could talk about infections from COVID to Lyme to anything else. But, but I do want to go back to what you had mentioned about gluten, because gluten sensitivity or particularly celiac disease is one of the most commonly missed causes of depression and anxiety. I mean, literally complete remission and reversal of symptoms. And there are no GI symptoms. When they sit in your office, you're just complaining of fatigue and depression, and you find out they have celiac, which is an autoimmune disorder to gluten. You eliminate gluten, replete those nutrients and their depression is gone.
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Dr. Mark Hyman
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- [20:00]
It's true. I mean, I think gluten creates leaky gut that creates inflammation. Inflammation affects the brain, but also has other effects. Like there's a little mini proteins that get digested from gluten that can create brain inflammation and psychiatric symptoms. They're called gluteomorphins, well described in the literature and again, most doctors don't check for it. We test for these urinary peptides, we test for gluten sensitivity, but it's not even, it's not even full celiac. It could be non celiac gluten sensitivity, which may affect up to 20% of the population. And you know, I think that that's again, often missed. And again, you don't go to the psychiatrist and get a gluten sensitivity test. Right. So that's, that's part of the problem. Talk a little bit more about this whole sort of inflammatory phenomenon because I've seen a lot of literature and I'm seeing the psychiatrists talk about like treating depression with these major biologic drugs that are immune suppressants like the TNF alpha blockers that cost 50 grand a year and have cancer risk and immune, you know, increased infection risk. I just, I just think we're kind of misguided with that. And I think the question should be why is there inflammation? So can you talk more about this sort of neuroinflammatory phenomena and how it's sort of linked to depression and what the root causes of that are?
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Dr. James Greenblatt
Yeah, no, no, you're absolutely right. It's a little frustrating to me. And partly the reason I wrote the book is to help people dig deeper because to just say inflammation is the cause of depression and you can use a $10,000 drug or curcumin, it's not going to necessarily help. So, yeah, you hit the nail on the head. We got to find the root cause. And that's why it still takes a psychiatrist an hour to do an evaluation, because that Root cause could be early trauma. We know trauma as a child creates chronic inflammation. It could be those infections, it could be food allergy. We mentioned gluten, it could be sleep deprivation. I mentioned vitamin D. But vitamin D deficiency just kind of sets up the immune system to be hyperactive. So we're always digging deeper. Could be obesity, it could be ultra processed foods. I mean, the list is long, but we all know what it is. Stress, I guess, is probably the most overwhelming direct path to inflammation. So to just tell someone to take a drug or supplement without having a more personalized path is just not going to be as effective.
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Dr. Mark Hyman
Let's just touch on a few more things then, when I want to talk about one of the key themes in your book, which I think is really unusual when it comes to psychiatry, which is what I would be calling the biomarkers of mental health. Like, doctors don't think about how do I test for blood tests or other diagnostic tests that tell me what's the root cause of these psychiatric problems or depression. And I, I think you can practice medicine or psychiatry without knowing your biomarkers and how they relate to different conditions. And you, you really dive deep into that. But before we go onto that, I want to sort of touch a little bit more on the hormonal imbalances that relate to depression that are common and also the sort of blood sugar and metabolic story, because there's a lot of work on Harvard around that with Chris Palmer. You've had him on the podcast talking about, you know, the mitochondria and insulin resistance in the brain and how that links to depression. But there's also thyroid cortisol, sex hormones. So can you kind of walk us briefly through how this sort of hormone metabolic phenomena are driving depression?
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Dr. James Greenblatt
It, it just adds to that list of, you know, what we want to look for in an assessment for a depressed patient. So clearly, you know, hormones, and for many, it could be thyroids, probably the most common. And, you know, when we're in medical school, you know, I, I, I, you know, if we have to take a test what causes depression, we have to check a box. Low thyroid. So, but then when we get out in training, we don't think as mental health professionals that it's thyroid. But thyroid's probably the most common that we see. But certainly low testosterone and, you know, dysregulation of estrogen and progesterone can all contribute to depression. What I have found most helpful in my practice, and the simplest is look at precursors to these hormones and simple blood tests like pregnenolone and DHEA can often be low and really the simplest path to supporting all the hormones.
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Dr. Mark Hyman
Yeah, so. So doing a good hormonal assessment is key. Looking at thyroid, looking at cortisol, sex hormones. And it varies. I mean, even, you know, as older men, you can get low testosterone that can affect mood. Women, obviously, menopause, can have hormonal issues. Pms, all that can be related to mood issues. Premenstrual dysphoric disorder. They're actually in. They took Prozac and renamed it Seraphim and called it a drug for pms, you know, which always made me laugh. But, you know, these things have to get looked at in depth. And there. And the good news is there are ways to look at these things. There are ways to look at all those factors. And I think, you know, one of the biggest things affecting people is insulin resistance and blood sugar issues. And they have to do with a lot of psychiatric problems, whether it's, you know, I've had people with panic attacks because of blood sugar swings or night sweats. But even more mood instability, depression can be a factor. So that's something easy to fix. And again, something often not looked at.
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Dr. James Greenblatt
Yeah, I mean, I think Chris Palmer's work and Georgia Eade and a number of other people have really kind of put this kind of understanding of insulin resistance as a factor in mood disorders and major psychiatric disorders and also as a treatment path. I think that many of our patients will get better on a kind of diet that's kind of supportive of higher protein and lower carbs. Sometimes it's hard to sustain ketogenic diet long term, but it's a powerful tool for mental health clinicians to support recovery. We've seen pretty dramatic changes.
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Dr. Mark Hyman
I know it's, it's, it's powerful. Just those simple changes in diet and lifestyle make a huge difference, and that's gotta be the foundation of any mental health approach. So let's kind of dive into. You know, we've covered a lot of the issues, from nutritional deficiencies to gut issues to inflammation causes, to hormonal balances to genetic factors. All these are really important to assess. And one of them we didn't talk about yet was toxins, which I think is also important. So maybe we can touch on toxins, then we can dive into the. How do we diagnose the root causes through testing.
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Dr. James Greenblatt
Yeah, it is a frightening door to open, but we have to assess. I mean, I think in a standard psychiatric practice, the two most common things we see is mercury and copper and both high and low copper. High copper usually is contributing to irritability associated with depression. And low copper, we see a lot in celiac or people supplementing too much with zinc also has been a path to depression. But any of the kind of heavy metals can contribute to brain dysfunction. One of, you know, in kids we see lead. Still, it's frightening. A lot of copper, a lot of mercury are the most common.
- [27:23]
Dr. Mark Hyman
I know, I mean, I, I often told the story, but I, I first got into functional medicine because I had mercury poisoning after living in China and eating a lot of fish and all this stuff. And I was so depressed. I mean, I knew I wasn't emotionally depressed. I knew I was physiologically depressed because I'd always been a very happy person. And I'm like, something's wrong and I don't need Prozac. Which is basically what the doctors were telling me to do. And I'm like, no, there's something else. And I actually figured out that it was mercury. I chelated myself and it went away. So I think people don't realize there's so many roads to roam depending on what your issue is. So the question is, how do you figure out what your particular issue is? And how do we give people hope to help navigate this complex field? Because what I always say is test, don't guess, right, test, don't guess. And that helps you guide precise treatment decisions, track your progress, see how you're doing, tell us how you start, you know, thinking about the workup of someone diagnostically with depression and what are the kinds of diagnostic tests we should be looking at that we're not doing for mental illness?
- [28:25]
Dr. James Greenblatt
Yeah, no, it's really important. I, you know, I, I just read an article, a group of people figuring out the DSM 6, the next version they commented on, we're still not ready to include biomarkers. So we're going 20 more years without a concept of biomarkers, and there's just 20, if not 100, that you and I know contribute to depression. But our colleagues who are kind of controlling this next manual for psychiatry are still way, way out of it. So, you know, the workup again, has to include a history because stress and trauma just plays a role in everything. And we have to be sensitive to that history and family history, because a lot of choice of supplements depend on family histories. Even though the patient might not suffer if there's a family history of addiction, it helps me fine tune my treatment. But a basic nutritional workup, nutritional deficiencies, and that would include B vitamins and D and hormones and those precursors to hormones like pregnenolone and dha. And then in a functional psychiatry practice, we like to add genetic testing, looking at MTHFR and a few other genes. We like to add, looking at amino acid levels and fatty acid levels, and a molecule called cryptopyrl, which has tremendous implications. So it's a urine test. And so we try to have a comprehensive assessment, as we've been talking about for years, to be able to find that personalized treatment plan.
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Dr. Mark Hyman
Yeah, I think you're talking about things that we do all the time. We look at all the nutrient levels, you know, homocysteine, methylmonic acid, which are B vitamin markers for B12, Folate, B6, and those really are important. You know, we look at zinc, we can look at red cell magnesium, we can look at, like you said, copper, even lithium levels in place like the hair, and they can be very helpful. And we look for heavy metals, we look for toxins, we look for change in the microbiome through stool testing. We can look for inflammatory levels in the body. We can look for insulin resistance through looking at lipids and blood sugar and insulin levels and A1C. So there's so many ways of looking at things and. And we can also look at all the hormonal issues that complete thyroid testing and sex hormone testing and cortisol testing. Like you mentioned, pregnant alone. These are all things that should be standard part of practice. Even gluten sensitivity, food sensitivities. These are real things that can drive mental health issues. And most doctors don't think about it. They don't know how to test it, they don't know how to order it, and they don't know how to interpret it. And it's unfortunate. It's not their fault. They just don't learn about it because the orthodoxy hasn't accepted this yet. But I'm excited about kind of your book because it lays a lot of this out. And I think that for me, it's part of the reason that I co founded Function Health, which was to empower people to get this data on themselves and not have to wait for some doctor to hopefully figure out that this is the problem and they can be going on for years. I mean, thyroid issues often go on for years or even a decade before they get diagnosed because people just don't think about it or they don't do right diagnostic tests. So I think that the test not guess message is really important. And now with Function Health, for basically a dollar a day, $365 a year, you can get twice to your testing, see what's going on, and then you can modify those risks and, and change things. So really, I think it's really, really important. And the basic idea here is that, you know, depression and many mental illnesses are not just in your head, they're in your body. And do you need to adjust those fundamental, fundamental biological imbalances and test for those things and actually address those more systematically? So can you maybe share a little bit more about some cases and some stories of patients you've had that you've seen various factors just as to give you a flavor how you work through some of these problems with patients.
- [32:37]
Dr. James Greenblatt
The challenge, I think, for clinicians is all the tests that we've talked about. You know, how do you prioritize and how do you understand, you know, what's part of that depression? You know, some of these abnormal tests might not be affecting the mood. So that's the challenge and that's why, you know, it's important to see mental health professionals who know this work. But I think, you know, over the years, the cases, you know, that kind of most traumatic to me are when I can use words like remission and recovery, the mood is completely gone. So I've seen that in celiac disease, you know, from 7 year olds to 40 year olds, just completely eliminating gluten. I had someone in our training program presented a case last night of an autistic kid who was non verbal, who just took lithium orotate, a nutritional supplement that we, I talk about in the book and we use all the time and became verbal. So an autistic patient became verbal. And for our, you know, adults, the most common things we see are B12 deficiency. You mentioned homocysteine. I can't tell you how many patients that we've seen in the past year with these dramatically high homocysteine levels, which is a proven marker of deficiencies in B vitamins, B6, B12 and folate, and have also been shown, we've known for 20 years, a risk factor for depression as well as dementia. So it's a simple test where we then dig deeper to find out is it B6, B12 or folate, and then treat the underlying cause and the depression completely disappears.
- [34:34]
Dr. Mark Hyman
You see these miraculous recoveries of things that are, quote, you know, chronic illnesses. And I think, you know, when you look at the biggest burden on our society, we talk about chronic illness and diabetes and so forth and all the cardiometabolic diseases, and those are big. But when you talk about disability, quality of life, years lost, suffering, you know, the economic impact globally, not, not the direct cost, but the indirect costs on society from people who are depressed and can't function. It far exceeds all the rest of, of that and most put together. So it's, it's really the, one of the biggest drains on the whole society. And we, we have such a horrible mental health system that doesn't really address this, unfortunately. And, and you know, you've been doing this for decades and so have I. And we've just seen over and over some of these, these repeatable patterns that, that aren't just voodoo or, you know, kind of made up. But if you look at the scientific literature, it's there and if you put the pieces together, it's really there. And yet it just somehow hasn't gotten into traditional medicine and psychiatry. It's unfortunate. I wonder if you have a curiosity about why psychiatrists are so resistant to this. Is it just, is it just so far outside the paradigm or. It just seems like there's some areas where they kind of do this. Like they give Deplin, which is a very high dose folate, or they'll give, you know, T3 for some patients with depression, which is a thyroid hormone, although they'll kind of play with the edges of it. But it's like they don't really even realize what they're doing.
- [36:02]
Dr. James Greenblatt
It's challenging and frustrating for me being, you know, kind of one foot in, one foot out. But I'm hopeful. I mean, last year the American Psychiatric association, you know, 10,000 psychiatrists, the theme of the conference was nutrition and lifestyle. So it's pretty dramatic. So there were a lot of lectures on nutritional psych and certainly lifestyle, sleep and exercise. And then there's major psychopharm conferences. Actually the Harvard psychopharm conference this year, there was a little section on nutritional psychiatry. So I think there were five of us that gave half hour presentations. So things are changing. So, but not, not significant enough because the pharmaceutical hold is, is so powerful and I think it empowers docs to think that they have a cure. And that's medicine is right, surgery and drugs. I'm just hopeful that the younger generation of doctors and the limitations that's, you know, certainly hit with our just medication approach that things have, I think, changed dramatically in the past two years and will continue to change.
- [37:18]
Dr. Mark Hyman
Well, let's talk about the medication issue because you write about that in your book and you talk about, you know, how these drugs are often difficult to get off of and how they do you know, once you get on them, you're kind of like in a pickle. One, because if you stop them, who knows if your depression is going to come back and how do you prevent that? And two, you know, they're just hard to get off of because of the side effects of getting off of them. And so let's talk about antidepressants. And I think, you know, they seem to help some people, but talk about their efficacy or effectiveness over the broader population. Are they effective? What percent are they effective for? Who are they effective for? And where are we. Where are we failing with these medications?
- [38:01]
Dr. James Greenblatt
We're failing on a lot of fronts. I mean, even in traditional psychiatry literature, you know, the word is treatment. Refractory depression, no response to medicines is at least a third. And those two thirds that quote got better. They still have symptoms. You know, they've only shown improvement. And I think that the limitations are it's just symptomatic based treatment without looking at the cause. But what has happened for too many years is the psychiatric community completely ignored what happens when you stop these medications. And, you know, I call it withdrawal. They call it discontinuation syndrome. Either way, it's pretty significant for some individuals. And this is where I think functional medicine can play a unique role in the field of psychiatry. Because I'm quite convinced if we do these functional medicine tests before someone stops their medication, we can completely eliminate those withdrawal symptoms. And it was just kind of eye opening probably 10, maybe 15 years ago when I had two people stopped the same medicine. It was Celexa. And one person did it fine and the next one had these intractable, you know, brain zaps and suicidal thoughts. And I realized it's not the medicine, it's what's going on in that individual. And once we do the functional testing, we replete the D and the B12 or the Amino acids, we can safely withdraw someone from these antidepressants.
- [39:37]
Dr. Mark Hyman
So basically what you're saying is get all the fundamental imbalances and dysfunctions sorted, test for them, address them, correct them. Kind of like the orthomolecular concept of correcting the molecular dysfunctions, and then you'll find an easier way of tapering off the medication.
- [39:55]
Dr. James Greenblatt
Oh, absolutely. I've just seen it thousands of times what these antidepressants do. You know, they kind of trick the brain, particularly the SSRIs and SNRIs, the Prozac. And the brain adapts to this medication, which means there's a functional serotonin deficiency. So there's less serotonin being produced. So if you have deficiencies in any of the cofactors, in serotonin synthesis, that you pull this drug and your brain just goes crazy and doesn't know what to do. But if you can replete that process, then it becomes much more manageable and we can eliminate those side effects.
- [40:36]
Dr. Mark Hyman
Do you try to mostly get people off of these drugs?
- [40:38]
Dr. James Greenblatt
Most of my work now is people who have struggled with inability to come off their antidepressants. They've been feeling okay or just side effects, whether it's weight gain, sexual side effects. So that's why a big part of what I've been doing is supporting people coming off the medications.
- [40:56]
Dr. Mark Hyman
And where do you find, like, resistance to the effects of actually working with patients with this model? Where are the ones you find are treatment resistant to using a functional medicine, sort of more holistic psychiatry approach in
- [41:14]
Dr. James Greenblatt
terms of the patients?
- [41:15]
Dr. Mark Hyman
Yeah, like, you know, some people do better, but some people, you know, don't necessarily.
- [41:20]
Dr. James Greenblatt
There are patients who want the quick fix, and that's what they're used to, and they want the medication, and we need to kind of respect that. And then what our role is, that these micronutrients will just minimize side effects and support, you know, their recovery. You know, other patients, you know, are interested in digging deeper and looking at the root cause as you described.
- [41:46]
Dr. Mark Hyman
Most time I'm looking at the literature. The psychiatric drugs, you know, do sometimes help people with major depression. But. But if you look at the literature objectively, at least what I've seen, and there's some big trials that looked at this, that for mild to moderate depression, it's not much better than placebo. They might work, but so does placebo. Right. So does a sugar pill. And so they're much better than placebo. Then why are we prescribing them, given they have all these side effects?
- [42:11]
Dr. James Greenblatt
Yeah, no, I used to have a picture of M&Ms. And, you know, because some of the research, you know, the best research may be 60% or, you know, and other people coming up with 50%. And that's what placebo will help. I mean, placebo has a powerful effect on depression, and we've known that for years. That's why there was a lag in drug development, because they couldn't beat the placebo. So that's why, you know, we haven't given up our skills and training in therapy. And part of the reason, you know, the name of the book is kind of hopeful, because that therapeutic alliance and our ability to instill hope in our Patients is just, you know, the first step.
- [42:54]
Dr. Mark Hyman
Yeah. I mean, the name of your book is quite good. It's finally helpful. The personalized whole body plan to find and fix the root causes of depression. And honestly, James, medicine is really not focused on root causes. It's focused on describing the disease, the symptoms, and then trying to suppress those symptoms with a medication or modify some downstream pathway, rather than dealing with the upstream root cause. And that's really what you and I have been doing for so long is actually how to. How do we actually think about getting the root causes and treating the body, the system, and then looking at the things we can actually measure and test. We did talk about this a little bit on your. On your last podcast with me, but it might be worth sort of touching base again because I think, you know, you've been some of the leaders in nutritional lithium supplementation. Low doses of lithium, not the massive doses you get for people with bipolar disorder or manic depressive disorder. But you're saying it's often missing. And it's, It's. There's a lot of kind of research globally on how it may be linked to suicide and, and genetics, how they play a role. And talk to us about the role of nutritional lithium and how, how you use it in clinical practice and how you assess it.
- [44:06]
Dr. James Greenblatt
I mean, I think lithium orotate, nutritional lithium, is one of the most important tools in my toolbox as a psychiatrist. And again, 2025, the year of research, just a stunning paper came out of Harvard, published in Nature, where they demonstrated that, one, lithium was low in the brains of Alzheimer's patients. So it was one of 50 elements tested.
- [44:32]
Dr. Mark Hyman
Wow.
- [44:33]
Dr. James Greenblatt
And then two, that lithium orotate, in these mice models that develop Alzheimer's pathology, lithium orotate was able to prevent and reverse the neuropathology of Alzheimer's. So it was one of the most stunning things. And it was, you know, not lithium carbonate. So the other forms of lithium did not reverse the plaques and tangles, but only lithium orotate. And I think you can appreciate this.
- [45:05]
Dr. Mark Hyman
I saw that paper.
- [45:06]
Dr. James Greenblatt
Yeah, we've been talking about lithium orotate, but everyone who, you know, commented on the study said, brilliant, great. But we need more research because we've never used lithium orotate, and we've been prescribing it for 30 years. So it just kind of helped us as clinicians. But lithium is an essential element for brain health. And I'm quite convinced there are some individuals that just have a little higher need based on family histories, particularly addiction or bipolar, and sometimes 2 to 5 milligrams of lithium has been some of the most dramatic changes we've seen in depression and other mental health problems.
- [45:49]
Dr. Mark Hyman
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- [46:49]
And how do you, how do you know if someone needs that?
- [46:52]
Dr. James Greenblatt
Good question. So symptoms. I look at irritability and impulsivity. So moodiness, irritability, and that could be in an ADHD kid or depressed person. And then, and then family history is important to me as well. So family history of depression, addiction, bipolar or suicide.
- [47:14]
Dr. Mark Hyman
And do you measure like lithium levels in the hair or how do you sort of assess.
- [47:19]
Dr. James Greenblatt
Yeah, yeah. Blood levels won't help because the blood levels only pick up. Pharmaceutical lithium. So I do look at a trace mineral hair test on everyone and oftentimes we can see now undetectable lithium. But even if there's lithium in the hair, sometimes we'd use it as a nutritional supplement.
- [47:37]
Dr. Mark Hyman
So I think, you know, one of the things that we get into medicine is binary thinking. It's either this or that. It's either only, you know, holistic or only medicine. Or, and truth is we need an approach that integrates all modalities, whether it's, you know, functional medicine, psychiatry, and root cause analysis and addressing the imbalances in the system combined with talk therapy, combined with other trauma related therapies, combined with medication. So it's really a spectrum of things that we have to choose from. It's just that there's a whole toolbox that we never addressed, which is the toolbox that you and I use that gets ignored by traditional medicine. So talk to us about how you think about an more of an integrated approach to mental health.
- [48:17]
Dr. James Greenblatt
Sure. I think many, both the doctors and patients are struggling with, you know, do I take supplements or do I take medications? And everything that we talk about in the book can be utilized, you know, with medications. And oftentimes looking at these functional tests, utilizing the supplements while someone's on medications is a path to help someone taper off the medications. But, but I think depression is complicated for some individuals and, you know, haven't given up my prescription pad if needed. And certainly the role of psychotherapy, whether it's couples therapy, family therapy, you know, or trauma therapy, can be incorporated into treatment models. So we don't have to pick one or the other, but we have to embrace all that's right.
- [49:11]
Dr. Mark Hyman
I mean, I always, I always jokingly say, you know, it's a lot harder to be, you know, happy or enlightened if you're mercury poisoned or your B12 is low, your thyroid's not working, or you have a lot of gut issues. Fix those things and then you see what's left. And then there may be issues that are more from your childhood or more, you know, from development issues or life stresses, but often people mis. Label the problem and, and they go, you have depression. It's just a totally a mental issue. It's all in your head. So we have to do things that affect your brain chemistry or your talking, your therapy, which doesn't really address the root causes. So I think root cause medicine is sort of where it's at. I think it's something that's coming up. And also the whole idea of treating the system, not just individual symptoms, which we do in psychiatry. And I think when you're, when you're doing, is really a more comprehensive approach and you're doing things that most psychiatrists don't do, which is you're doing blood tests, you're doing stool tests, you're doing, you know, urinary tests for toxin testing, hormonal testing. I mean, these are things that are just so outside the scope of what most psychiatrists actually look at. So, I mean, I think it's, it's impressive. We've been doing this for a long time. You see these patterns. And I think your, your book Finding Hope is really a great summary of a lot of these things you've learned over your lifetime that help can provide actual hope for people who are struggling with this. So I Think anybody listening, anybody struggling with depression, anybody having a hard time, for sure you should get Dr. Greenblatt's book the Personalized Whole Body Plan to find and fix the root cause of depression. It's out now. You can get anywhere you get books. You can find out more about Dr. Greenblatt. James greenblattmd.com he's got many courses for professionals and he's training a lot of doctors and psychiatrists how to do this thing, thankfully. But he also. You've launched a new, a new online platform which is a functional psychiatry clinic that's focused on delivering personalized root cause mental health for people of all ages called Finally Living. Can you talk more about that? I think that's really kind of an interesting model and I think for people listening and struggling it might be something that might benefit from.
- [51:21]
Dr. James Greenblatt
You know, we've been training doctors for a long time and I think we wanted to kind of work as a group to provide a consultation model to offer, you know, functional psychiatry to more individuals. So I think in the next month we should have clinicians licensed in all 50 states to not take over treatment but to really do the testing, provide the consultation and help people get on that path to recovery for those struggling with depression.
- [51:52]
Dr. Mark Hyman
Thank you for doing this. It's so important. I think, you know, it's much needed because people are struggling out there. So I think for people listening, just realize that, you know, if you're depressed or you struggle from mental health issues, you have someone you love who is that. There is a roadmap to thinking about this. There is a systematic way of assessing somebody through deep root cause testing, through comprehensive, you know, history taking to find out what's going on. And through that we often find the clues that help us really solve these patients problems and relieve a lot of suffering, which is so necessary given the scope of and the kind of incredible amount of people who are struggling with these issues. I think, I mean the data is sort of staggering when you look at globally it's. I think over 300 million people suffer from severe depression and it's worse in older adults. It's tremendous amounts of suicide, almost third leading cause of death in ages 15 to 29. So I think we need to kind of revise our framework, revise our thinking and actually help people with a new model. And I think you've laid it out so beautifully and you've been doing this work for so long. So thank you for keep it at it. You could be retired and playing golf, you know.
- [53:08]
Dr. James Greenblatt
So I really appreciate your work to be done.
- [53:10]
Dr. Mark Hyman
Yeah, there is. 100%. So thanks so much for being on the Pod Ask and helping us understand the deeper level of how to think about mental health, particularly depression and all the options there are for both assessing and treating these people.
- [53:24]
Dr. James Greenblatt
Great. Thanks for having me. Nice seeing you, Mark.
- [53:26]
Dr. Mark Hyman
My pleasure.
- [53:28]
If you love this podcast, please share it with someone else you think would also enjoy it. You can find me on all social media channels at Dr. Mark Hyman.
- [53:35]
Please reach out.
- [53:36]
I'd love to hear your comments and questions. Don't forget to rate, review and subscribe to the Dr. Hyman show wherever you get your podcasts. And don't forget to check out my YouTube channel at Dr. Mark Hyman for video versions of this podcast and more.
- [53:47]
Thank you so much again for tuning in.
- [53:49]
We'll see you next time on the Dr. Hyman Show. This podcast is separate from my clinical practice at the Ultra Wellness center, my work at Cleveland Clinic, and Function Health where I am Chief Medical Officer. This podcast represents my opinions and my guests opinions. Neither myself nor the podcast endorses the
- [54:04]
views or statements of my guests.
- [54:05]
This podcast is for educational purposes only and is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided with the understanding that it does not constitute medical or
- [54:17]
other professional advice or services.
- [54:19]
If you're looking for help in your journey, please seek out a qualified medical practitioner. And if you're looking for a functional medicine practitioner, visit my clinic, the Ultra Wellness center at ultrawellnesscenter.com and request to become a patient.
- [54:31]
It's important to have someone in your corner who is a trained, licensed healthcare
- [54:35]
practitioner and can help you make changes,
- [54:37]
especially when it comes to your health. This podcast is free as part of my mission to bring practical ways of improving health to the public. So I'd like to express gratitude to sponsors that made today's podcast possible. Thanks so much again for listening. Thanks.