Antidepressants Not Working? Here Is What Your Psychiatrist Missed with Dr. James Greenblatt

Mark Hyman, MD

Dr. Mark Hyman is leading a health revolution—one focused on using food as medicine to support longevity, energy, mental clarity, happiness, and so much more. Mark Hyman, MD is a practicing family physician and an internationally recognized leader, speaker, educator, and advocate in the field of Functional Medicine. He is the founder and director of The UltraWellness Center, Founder and Senior Advisor for the Cleveland Clinic Center for Functional Medicine, a sixteen-time New York Times best-selling author, and Board President for Clinical Affairs for The Institute for Functional Medicine. He is the founder and chairman of the Food Fix Campaign, dedicated to transforming our food and agriculture system through policy.

He is a co-founder and the Chief Medical Officer of Function Health. He is the host of one of the leading health podcasts, The Dr. Hyman Show with 150+ million downloads. Dr. Hyman is a regular medical contributor to several television shows and networks, including CBS This Morning, Today, Good Morning America, The View, Fox, and CNN.

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Full Transcript

Automatically generated. Please forgive any typos or errors in the following transcript. It was generated by a third party and has not been subsequently reviewed by our team.

Dr. Mark Hyman
Let's talk about antidepressants. What percent are they affected for? Who are affected for? And where are we failing with these medications?

Dr. James Greenblatt
For too many years, 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, well, 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 b twelve or the amino acids, we can safely withdraw someone from these antidepressants.

Dr. Mark Hyman
If you've been dealing with anxiety, low energy, or trouble focusing and still feel like you're missing something, you're not alone. And that's why I created the Brain Shaping Academy, a new program that looks in places most people never think to check. Like nutrient deficiencies, the health of your gut, metabolism, your immune system, and lots more. Doctor Greenblatt, welcome back to the podcast. It's so good to have you.

I'm assuming right now, it's estimated that eighteen percent of Americans suffer depression. One in four 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 who have committed suicide, I know many people who have been depressed. I've had that in 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 thirty, forty years. You and I are kind of in the same generation, and you know, we we came up going, wait a minute, what we learned in medical school, and what we learned in residency, and 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 into this topic with you and to help people with depression have hope where often they don't. Really have 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 impacting so many people. We have to get to those root causes. So, Ken, take us back to the origin story a little bit.

We had you on the podcast before, but just briefly talk about your inspirations. Because I think I think it matters. And I think you know, you 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 Abraham Hoffer and Roger Williams. So talk a little bit about how each of those people have helped you think about psychiatry differently.

Dr. James Greenblatt
Sure. I I think you you mentioned my my three kinda hero mentors that defined my career. So, you know, Linus Pauling, you mentioned two Nobel Prizes. It's a little frightening when I give talks and I ask people, you know, if anyone knows no one raises their hand anymore. Linus Pauling got a Nobel Prize in chemistry and peace, and he, wrote this article on orthomolecular psychiatry.

It was a title in Science Magazine in the sixties. And, basically, it 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 money micronutrients. And then Abraham Hopper 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 fifty years ago that were all 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.

Dr. Mark Hyman
I think that's absolutely true. And I I I actually got to meet Abraham Hoffer and also Linus Pauling, never Roger Williams, but I think he died for 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 Pauling was a biochemist, and he understood biochemistry in a way that most of us don't. I mean, 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 orthopedics means to straighten bones. So ortho to correct molecules. Orthomolecular. And he talked about different nutrient needs and it was a very I mean, read the paper.

It's super geeky. I could barely understand half of it. 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 but, you know, we we shouldn't sort of assume that that's the problem, and we should start to look for things that are actually treatable. And and in your work, you really you kind of also talked about Roger Williams, was the father of biochemical individuality. And I often say the same thing as you, that 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 medical categorization book called DSM-five. It's helpful for grouping people in categories, but it 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, know, always say this, you have depression, it's not a Prozac deficiency, it's something that is often treatable.

Take us through how you kind of unpack the fundamental root causes, the drivers, the biological drivers of depression. Because most people think it's a chemical imbalance, 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 these drugs are not much better than placebo and they often come with a lot of side effects. So take us through these major biological drivers that you talk about in your book.

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.

Dr. Mark Hyman
That that for people listening, that that's a that's a particular gene that regulates folate metabolism, is very involved in neurotransmitter function and mood. So even traditional psychiatrists understand that folate can be a treatment for some cases of depression. And this is a gene that makes us different. That's what that gene was.

Dr. James Greenblatt
In the inpatient psychiatry world for thirty 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 meds and, 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 described, b twelve, 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 Yeah.

I mean, everything you and I have been talking about thirty 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 the stunning research that's just been blossoming.

Dr. Mark Hyman
And everything oh, you know, people in America have plenty of food. They eat a lot. They're not malnourished. Nonsense. When you look at the the the NHANES data, which is the government survey, the National Health and Nutrition Examination Survey, they go and test thousands of people every year and they monitor history and their health conditions, they found over ninety percent of Americans have a deficiency in one or more nutrients at the minimal level to prevent a deficiency disease.

Like how much vitamin C do need to not get scurvy or vitamin D to not get rickets, right? And so it's omega-3s are probably ninety percent. Eighty percent lower in deficient vitamin D, forty five percent 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 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 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 brain?

And by the way, 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.

Dr. James Greenblatt
Yeah. I mean, sometimes, you know, I I make a joke that I I'm more of a gastroenterologist than a psychiatrist because, I mean, even from from the meltdown, like, you know, zinc deficiency is 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 Yeah. Because they don't have enough digestive enzymes. Yeah. And then that sets the whole dysbiosis. And it's clear that, now and, again, the research has just supported it.

Dysbiosis has been related to every major psychiatric illness. I mean, Alzheimer's, depression, anxiety, anorexia. It's pretty stunning.

Dr. Mark Hyman
It's true. I mean, I I've had a lot of patients with with gut issues that when you might my 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 the ADD would improve.

I was like, well, what's going on here, right? You know, and so I think behavioral issues would improve. But I saw this over and over, and I just that's why I wrote the book, Ultra Mind Solution, a decade and a half ago because I was like, oh, wait a minute. There's more to the story than just these psychiatric diagnoses and drugs, and there's something else going on here that's affecting the brain. And a lot of the common pathway of this is inflammation.

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. I want you to sort of touch on that because I think even without gut symptoms, 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.

Dr. James Greenblatt
When 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 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 for many years.

And inflammation is a 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 wanna 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. And literally complete remission and reversal of symptoms, And there are no GI symptoms when they sit in your office.

They'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.

Dr. Mark Hyman
It's true. I mean, I think gluten creates a leaky gut. That creates inflammation. Inflammation affects the brain. But also there's 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 glutamorphins, 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 full not celiac. It could be non celiac gluten sensitivity which may affect up to twenty percent of the population. And I think that's again often missed. And again, you don't go to the psychiatrist and get a gluten sensitivity test, right? So that's part of the problem.

Talk a little bit more about this whole inflammatory phenomenon because I've seen a lot of literature and I'm seeing the psychiatrists talk about treating depression with these major biologic drugs that are immune suppressants like the 10 alpha blockers that cost $50 a year and have cancer risk and increase infection risk. I just think we're kind of misguided with that. I think the question should be why is there inflammation? So can you talk more about the sort of neuroinflammatory phenomena and and how it's sort of linked to to depression and what the root causes of that are?

Dr. James Greenblatt
Yeah. No. No. You're absolutely right. The the you know, it's a little frustrating to me, and and partly the reason I read 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 gonna necessarily help. So, yeah, you hit it nail in the head. We gotta find the root cause. And 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 kinda sets up the immune system to be hyperactive.

So we're always digging deeper. Could be obesity. Could be ultra processed foods. I mean, the list is 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 a supplement without having a more personalized path is is not gonna be as effective.

Dr. Mark Hyman
Let's just touch on a few more things. Then when I I wanna 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 think you can't practice medicine or psychiatry without knowing your biomarkers and how they relate to different conditions. And you really dive deep into that.

But before we go on to that, wanna 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. We'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.

Dr. James Greenblatt
It it just adds to that list of, you know, what we wanna look for in an assessment for a depressed patient. So clearly, you know, hormones and for many, it could be thyroid. It's probably the most common. And, you know, when we're in medical school, you know, 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.

Dr. Mark Hyman
Yeah. So so doing a good hormonal assessment is key, looking at thyroid, looking at cortisol, sex hormones, and it varies. Mean, even 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, know, which always made me laugh. But you know, these things have to get looked at in-depth. 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 one of the biggest things affecting people is the 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 but even more more mood instability and depression can be can be a factor. So that's something easy to fix. Again, something often not looked at.

Dr. James Greenblatt
Yeah. I mean, think Chris Palmer's work and Georgia Eid and a number of other people have really kinda put this kind of understanding of insulin resistance as a factor in 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.

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 imbalances, to genetic factors. All these are really important to assess.

And one that 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 the how do we diagnose the root causes through through testing.

Dr. James Greenblatt
Yeah. It is is a frightening door to open, but but we have to assess. I mean, I think in a standard psychiatric practice, we the two most common things we see is is mercury and and copper. And 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 kinda 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.

Dr. Mark Hyman
I know. I mean, I I I've been 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 I actually figured out that it was mercury, I chelated myself and it went away. So I think 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 get people 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.

Dr. James Greenblatt
Yeah. No. It's really important. I I, you know, I I just read an article, a group of people figuring out the DSM six, the next version. Mhmm.

They commented on we're still not ready to include biomarkers. So we go twenty more years without a concept of biomarkers. And there's just 20, if not a 100, that you and I know contribute to depression. But the our colleagues who are kinda 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 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 and 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 and then in in a functional psychiatry practice, we like to add genetic testing, looking at MTHFR and a few other genes. We like to add look at amino acid levels and fatty acid levels and a molecule called cryptopyrrole, which has tremendous implications. So it 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.

Dr. Mark Hyman
Yeah. I think you're you're talking about things that we we do all the time. We look at all the nutrient levels, You know, homocysteine, methylmalonic acid, are b vitamin markers for b twelve, folate, b six, 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, lithium levels in places like the hair, and 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 a one c. So there's so many ways of looking at things.

And we can also look at all the hormonal issues, complete thyroid testing and sex hormone testing and cortisol testing, or you mentioned pregnenolone. These are all things that should be standard part of practice. Even gluten sensitivity, food sensitivities, these 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 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 Functional Health for basically a dollar a day, dollars $3.65 a year, you can get twice your testing, see what's going on, and then you can modify those risks and change things.

So I think it's really, really important. And the basic idea here is that depression and many mental illnesses are not just in your head, they're in your body. And you need to adjust those 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, you know, various factors just as to give you a flavor how you work through some of these problems with with patients?

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 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 so that's the challenge, and that's why, you know, you it's important to to see mental health professionals who know this work. But I but I think, you know, over the years, the the cases, you know, that kinda most traumatic to me are when I can use words like remission and recovery. The the the mood is completely gone.

So I've seen that in celiac disease, you know, from seven 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's nonverbal 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 b twelve 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, b six, b twelve, and folate, and have also been shown we've known for twenty 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 b six, b twelve, or folate, and then treat the underlying cause, and the depression completely disappears.

Dr. Mark Hyman
You see these miraculous recoveries of things that are, quote, you know, chronic illnesses. I think, you know, when you look at the 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 cost 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 have such a horrible mental health system that doesn't really address this, unfortunately.

And you've been doing this for decades and so have I. And we've just seen over and over some of these repeatable patterns that aren't just voodoo or 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 have any curiosity about why psychiatrists are so resistant to this. Is so it far outside the paradigm? 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, t three for some patients with depression, which is a thyroid hormone.

They'll they'll kinda play with the edges of it, but it's like they don't really even realize what they're doing.

Dr. James Greenblatt
It's challenging and and frustrating for me being, you know, kinda one foot in, one foot out. But I I'm 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 psyche and certainly lifestyle, sleep, and exercise.

So and 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, it is is so powerful.

And I think it empowers docs to think that they have a a cure. And and that's medicine is. Right? Surgery and drugs. I'm 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.

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 do once you get on them, you're kind of like in a pickle. One, because if you stop them, who knows if your depression's going to come back and how do you prevent that? And two, 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 they seem to help some people, but talk about their efficacy or effectiveness over broader population.

Are they effective? What percent are they effective for? Who are they effective for? And and where are we where are we failing with these medications?

Dr. James Greenblatt
We're failing in a lot of fronts. I mean, even in traditional psychiatry literature, you know, the word is treatment refractory depression, no no response to medicines is at least a third. And and those two thirds that, quote, got better, they still have symptoms. You know? They've only shown improvement.

And I 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 and probably 10, maybe fifteen years ago 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, what'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 b 12 or the amino acids, we can safely withdraw someone from these antidepressants.

Dr. Mark Hyman
So basically, what you're saying is 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.

Dr. James Greenblatt
Oh, absolutely. I've just seen it thousands of times. What these antidepressants do, you know, they kinda trick the brain, particularly SSRIs and SNRIs, the Prozac. And 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.

Dr. Mark Hyman
Do you try to mostly get people off of these drugs?

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.

Dr. Mark Hyman
And 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?

Dr. James Greenblatt
In terms of the patients?

Dr. Mark Hyman
Yeah. Like, you know, you know, some people do better, but some people, you know, don't necessarily.

Dr. James Greenblatt
There are patients who want the quick fix, and that's what they're used to, and and they want the medication, and and we need to kinda respect that. And then what our role is that these micronutrients will just minimize side effects and and support, you know, their recovery. You know, other patients, you know, are interested in in digging deeper and looking at the root cause as you described.

Dr. Mark Hyman
Most of time I'm looking at the literature and the psychiatric drugs do sometimes help people with major depression. But if you look at the literature objectively, at least what I've seen, and there's some big trials that look at this, that for mild amount of 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?

Dr. James Greenblatt
Yeah. No. I used to have a picture of M and M's and you know you know, because some of the research you know, the the best research may be sixty percent or, you know, and other people coming up with fifty percent, and and that's what placebo will help. I mean, placebo has a powerful effect on depression, and we we've known that for years. That's why there was a 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 in in therapy. And and part of the reason, you know, the name of the book is kinda hopeful because that therapeutic alliance and our ability to instill hope in our patients is just, you know, the first step.

Dr. Mark Hyman
Yeah. I mean, the the name of your book is is quite good. It's it's Finally Hopeful, the personalized whole body plan to find and fix the root causes of depression. And 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 do we actually think about getting the root causes and treating the body of the system and then looking at the things we can actually measure and test. We did talk about this a little bit on your last podcast with me, but it might be worth sort of touching base at again because I think you know, you've been to one 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 and and talk to us about the role of nutritional lithium and how how you use it in clinical practice and how you assess it.

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 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. Oh, wow. 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 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 I think you can appreciate this.

Dr. Mark Hyman
I saw that paper.

Dr. James Greenblatt
Yeah. We 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 and we've been prescribing it for thirty years.

So it just kinda 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 two to five milligrams of lithium has been some of the most dramatic changes we've seen in depression and other mental health problem.

Dr. Mark Hyman
And how do you how do you know if someone needs that?

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.

Dr. Mark Hyman
And and you measure, like, lithium levels in the hair, or how do you sort of assess?

Dr. James Greenblatt
Yeah. Yeah. Blood levels won't help because the blood levels only pick up pharmaceutical lithium. So I 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 would use it as a nutritional supplement.

Dr. Mark Hyman
So I think one of the things that we get into medicine is binary thinking. It's either it is or that. It's either only holistic or only medicine or and truth is we need an approach that integrates all modalities. Whether it's 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 to mental health.

Dr. James Greenblatt
Sure. I I think many, both the doctors and patients, are 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 and, you know, having 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.

Dr. Mark Hyman
That's right. 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 b twelve is low, your thyroid's not working, 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 from development issues or life stresses, but often people mislabel the problem. And they go, you have depression, it's just 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 what 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 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 impressive. We've been doing this for a long time. You see these patterns. And I think 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 Doctor 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 Doctor Greenblatt at jamesgreenblattmd.com. He's got many courses for professionals and he's training a lot of doctors and psychiatrists how to do this thankfully. But he also, you've launched a new online platform which is a functional psychiatry clinic.

It's focused on delivering personalized root cause mental health for people of all ages called Finding a 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 they might might benefit from.

Dr. James Greenblatt
You know, we've been training doctors for a long time, and I think we wanted to kinda work as a group to provide a consultation model to offer, you know, functional psychiatry to 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.

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 with 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 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 and the kind of incredible amount of people who are struggling with these issues. Think Colin, I mean the data is sort of staggering, know, like when you look at globally, it's I think like over three hundred million people suffer from severe depression. And it's worse than older adults. Know, 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.

I think you've laid it out so beautifully and you've been doing this work for so long. So thank you for keeping at it. You could be retired and playing golf, you know. So I really appreciate your work.

Dr. James Greenblatt
To be done. Yes.

Dr. Mark Hyman
There is. A 100%. So thanks so much for being on the podcast and helping us understand the deeper level of how to think about mental health and equally depression and and all options there are for both assessing and and treating these people.

Dr. James Greenblatt
Great. Thanks for having me. Nice seeing you, Mark.

Dr. Mark Hyman
My pleasure. If you love that last video, you're gonna love the next one. Check it out here.