I’ve dealt with depression in my life. My body temperature also seems to run hot; in fact my wife Kate has nicknamed me “the baked potato.”

My guest today says that there may be a connection between those two things. His name is Charles Raison, he’s a psychiatrist, professor of psychiatry, and the co-author of The New Mind-Body Science of Depression. We begin our conversation with why Charles thinks it’s important to ask the question, “Does Major Depression even exist?” and what we do and don’t know about what causes depression. We then turn to the emerging theory that physical inflammation may play a role in depression; Charles describes what inflammation is, and why the body may become inflamed and physically hotter not only in response to physical illness, but psychological stress as well. We then discuss the paradoxical finding that short-term exposure to inflammation in the form of exercise or sitting in a sauna can reduce long-term inflammation, and how hot you probably have to get in a sauna for it to have antidepressant effects. We also talk about how intermittent fasting may have a beneficial effect on inflammation, before turning to whether taking anti-inflammatory drugs could also help, and why you might want to get a blood test to see if your body’s inflamed. We end our conversation with Charles’ thoughts on how to figure out the right treatment for depression for each individual.

If reading this in an email, click the title of the post to listen to the show.

Show Highlights

Does major depression even exist? Why is this an important question to ask?

Does depression have the same biomarkers among all people?

What causes depression? What role do genes play? Environment? Bacteria?

The power of relationships

The mind-body connection of depression

What is inflammation? How could it be causing depression? What is its effect on the brain?

How could this explain the origins of depression?

The role of stress in inflammation

What about exercise? Doesn’t that cause inflammation?

Does intermittent fasting work as a depression treatment?

What are some ancient practices for depression that might work today?

So do anti-inflammatory medications work for depression?

An overview of anti-depressant medications and new ideas about them

With the complex nature of what causes depression, how should one go about treating it then?

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Read the Transcript

Brett McKay:

Brett McKay here, and welcome to another edition of the Art of Manliness podcast. I have dealt with depression in my life. My body temperature also seems to run hot. In fact, my wife, Kate, has nicknamed me the Baked Potato. My guest today says there may be a connection between those two things. His name is Charles Raison, he’s a psychiatrist, a professor of psychiatry and the coauthor of The New Mind-Body Science of Depression. We begin our conversation with why Charles thinks it’s important to ask the question, does major depression even exist? And what we do and don’t know about what causes depression.

We then turn to the emerging theory that physical inflammation may play a role in depression. Charles describes what inflammation is and why the body may become inflamed and physically hotter not only in response to physical illness, but psychological stress as well. We then discuss the paradoxical finding that short-term exposure to inflammation in the form of exercise or sitting in a sauna can reduce longterm inflammation, and how hot you probably have to get in a sauna for it to have antidepressant effects.

We also talk about how intermittent fasting may have a beneficial effect on inflammation before turning to whether taking anti-inflammatory drugs also help and why you might want to get a blood test to see if your body is inflamed. We end our conversation with Charles’s thoughts on how to figure out the right treatment for depression for each individual. After the show’s over, check for the show notes at aom.is/inflammationdepression.

All right. Dr. Charles Raison, welcome to the show.

Charles Raison:

Thank you for having me.

Brett McKay:

So, you are a psychiatrist. You’re at the University of Wisconsin, and you got this book out called The New Mind-Body Science of Depression. I really enjoyed it. It was basically having all the latest research about depression in one place. But tell us about your background, and what’s the approach you take at looking at depression and treating depression?

Charles Raison:

Yeah, so I am a psychiatrist, and I started life actually as a full-time clinician back in the ’90s, and I got more and more interested in doing research and was very interested, always sort of interested, in mind-body stuff and questions around consciousness and conscious experience, things that are sort of very au courant right now, that we’re a little bit more on the fringe, I think, when I was interested in these things. But I actually became a researcher to try to understand how bodily processes might be harnesses to enhance mental states. I was really interested in certain very advanced Buddhist meditation practices, so I became a researcher and spent a number of years looking at how inflammation produces depression and how inflammatory processes, how they alter the brain.

And I was always kind of a depression guy, but one of the implications to this was that if inflammation can cause depression, maybe if we used one of these really powerful anti-inflammatory cytokine blockers that are out now for treating things like psoriasis and such, that maybe if we did that we would discover a brand new antidepressant. And as it turned out, that wasn’t true. There’s an interesting story there. But that got me into the sort of business of trying to discover new treatments for depression in general, and especially old-new treatments.

So, a lot of the work I do these days is not just inflammation but looking at things I call ancient practices, things that humans discovered repeatedly across history, often used for spiritual purposes or healing purposes that I’m trying to retrofit and look at as antidepressant strategies. So, we’ve done work with heat, with hyperthermia, and I’m much involved in this movement currently to see if psychedelic medicines might have promise for the treatment of depression. So, long answer to a short question, but that’s pretty much who I am.

Brett McKay:

Yeah, that’s the way I discovered you, is your research about the connection between inflammation and depression. We’ll get into that in a bit, because it’s novel, it’s different. A lot of people don’t connect inflammation and depression, so we’ll look at that here in a bit. But let’s start off with this question. In the beginning of your book, The New Mind-Body Science of Depression, you start the book off with your coauthor with this provocative question, “Does major depression even exist?”

And I’m sure there’s people who are listening to this episode who have experienced major depression or know someone who has, so they’re probably thinking, “Well, this is a really silly question. Of course it does.” But why do you think it’s important as a depression researcher that you ask that basic question?

Charles Raison:

Yeah, it’s a key question, and I’ve been depressed myself so I’m right with them. So, my coauthor, Vlad Maletic, he’s also very eloquent about this, and there’s a couple of ways in which depression doesn’t exist. It doesn’t exist as a single thing, that’s for sure, right? So, we know, in fact, in the largest antidepressant study ever done, they went back and looked at sort of the different patterns of symptoms people could have, they had 4,000 people in the study and they had 2,000 different presentations, so in a 4,000-person group there were 2,000 sort of different depressions.

And if you look at how … There’s this thing called the DSM, which is the guidebook for mental health, and it lays out the criteria for depression. You’ve got to have five out of nine symptoms. Well, that means actually that two people could be depressed and share one symptom in common and have everything else different. So, that’s the first thing, is that it doesn’t exist as a single thing. The second thing is that there have a been a lot of studies that suggest, I think rightly, that on average depression tends to be associated with certain changes in the way the brain and the body function, but there’s no one thing that causes depression, right?

So, for instance, if you get type one diabetes, the reason you got type one diabetes is because there’s these cells in your pancreas that make insulin called beta cells, and they get wiped out, right? And if you wipe out the beta cells, you got type one diabetes. That’s what it is. There’s nothing like that for depression, right? There’s no single abnormality that all depressed people have to have or is there an abnormality that causes depression in all people, so it’s not a disease state that way. It may be 1,000 different disease states, each one very specific and we just can’t find them, or it may be that there’s 1,000 little contributors on average to any given person’s depression, biological contributors.

So, if you say, “Well, so what is depression?” Well, I like the question, because it’s also not true that it just flat out doesn’t exist. It does exist and kind of just the way Buddhists think the world exists, which is sort of conventionally and provisionally. Depression is a set of symptoms and it’s a disorder that’s characterized by people demonstrating or reporting a series of symptoms, much the way most 19th century diseases were, right? So, you look at things like pleurisy and lumbago and things like this, they were symptom-based diseases, and that’s what depression is.

For instance, people often want to try to find a biomarker for depression, some kind of blood test, but even a little bit of thought shows that that’s kind of a fool’s errand, because if the biomarker was absolutely positive but you felt great, no doctor would say, “You’re horribly depressed, you just don’t know it.” And conversely, if the biomarker was normal but you’re suicidal and depressed, nobody would say, “Well, you can’t be depressed. The biomarker is off,” right? Depression is a phenomenological condition. It is as it does and as it says.

Now, having said that, like I said, it’s not nothing either. It is a tendency. It’s like a cloud. It’s like a quantum cloud, right? So, if you get really depressed, if your mood gets really down, you’re very likely to pull in the other symptoms of depression. That’s how they came to form the disorder, so almost always when humans get catastrophically depressed they get changes in their sleep, they get changes in their appetite, they start having trouble thinking, they often are exhausted, they begin to think about suicide, all over the world. Even in hunter-gatherer tribes, this is the case, right? So, what I sometimes say is, if people want my opinion, “So, what is depression?”

I like to say that it is the most standard, most common way that human beings break down under adversity, and that is why you see depression in every culture, that’s why depression tracks both with personal adversity and societal adversity, and why it tends to have the same symptoms all over the world. Because we have a genetic heritage that all of us to one degree or other makes us susceptible to developing this syndrome when bad things happen to us.

Brett McKay:

Let’s talk about the causes of depression, at least the common explanations that are put out there for the causes of depression. What are those?

Charles Raison:

Well, so it’s really interesting, the official line in the field is that we don’t know what causes depression, because we don’t know what causes any psychiatric illness, right? But that’s actually not true, and this is something we make much of in the book. Like other illnesses, like other psychiatric illnesses, actually like a lot of other medical illnesses, depression seems to arise usually from an interaction between a genetic vulnerability and an environmental circumstance. And so that being the case, there’s this idea that depression is just sort of a brain disorder or it’s a neurotransmitter deficiency or something. Well, those sorts of ideas suggest that there should be a gene, and if we knew what the gene was, then you have the answer, and we really have not been able to find genes very well.

It wasn’t until a couple of years ago, even maybe a year ago, that we actually finally had a study with enough people in it to find reliably a risk-factor gene for depression. I mean, there have been a lot of studies looking at genes for depression, but they were all very flawed, so we don’t really know very much genetically about what causes depression. But on the other hand, we know exactly what causes depression environmentally. It fascinates me. And it has to do with what we were talking about a minute ago, and that is adversity, right? So, if depression is a genetic, environmental interaction, it suggests that there’s some people that may be so genetically protected that there isn’t an environment in the world that would make them depressed, and other people are so genetically vulnerable, whatever those genes are, that the world is definitely going to make them depressed because the world’s a hard place, right?

But when it comes to environmental causes of depression, it’s really adversity. It’s psychosocial adversity, and the thing that we’ve studied a lot, it’s actually immunologic adversity, right? So, one of the things I often say is that at the end of the day, depression really seems to be about managing relationships. It certainly is about relationships. It is disturbances and threats in our relationships of all kinds that most reliably produce depression.

So, in the human realm, things that are powerful depressogenic factors are losing somebody upon whom your self-esteem, your self-vision, requires. It’s being shamed, it’s losing encounters when you’re up against somebody, what they call agonistic encounters, if you’re in a competition and you lose. All these things that essentially at the end of the day, anything that tells a person and they believe it, that they’re a failure, that they’re a loser, that they’re not as good as other people, that they’re alone, that they’re inadequate to life, anything in the environment that does that really reliably increases the risk for depression.

And then there’s this thing called entrapment, and entrapment is this sense that you’re powerless to change your circumstances, right? And so if you’re in a situation, say, where you have an abusive spouse and you’re getting beaten up, you’re very, very likely to be depressed, because interpersonal conflict is a very powerful depressive driver. If you feel that you could never escape the relationship, you will be depressed, right? So, that’s this sort of other ailment, so those factors are very, very powerful depressogens in our human-human interactions.

But we are just a small part of the interdependent world in which we live, and we have such a powerful and intimate relationship with the microbial world. Because it’s very small, we often miss it, but our relationship with the bugs, with bacteria, parasites, viruses, is as powerful a factor in our emotional and mental wellbeing as our relationships with other people. Because of course how we handle those microbial agents really sort of dictates whether we’re going to live or die, especially across human evolution where death from infection was by far the number one cause of sort of failing to survive and reproduce.

So, because of that of course, any genes that evolve that mutated to provide is with sort of an enhanced ability to fight dying of infection, especially early in life, were selected and it turns out, this is one of the things we’ve argued, that those genes or those behaviors actually appear to have some benefit in fighting infection. And then of course the other aspect of the microbial world has to do with the good bacteria, if I can put it that way, right?

So, we are largely composed of bacteria and we have one of the causes that some of us speculate may be driving the increased depression in the modern world is the fact that we’ve so disrupted our sort of co-evolved relationships with this huge microbial world upon which we depended for a number of things. That those disruptions, even though we don’t necessarily recognize them consciously, may also be contributing to what seems to be something of an epidemic of depression in the modern world.

Brett McKay:

All right, so there’s a lot to unpack there. I think he raises an interesting point. It sounds like the approach you take, again, it’s this mind-body approach. You’re unifying mind and body, because I think typically the way most people think about depression, it’s that Cartesian split.

There’s the mind and then there’s the body, so sort of the people in the body camp would say, “Well, depression is just a biological thing. You’ve got something, a genetic that makes you have a propensity towards depression. You just have a chemical imbalance in your brain. Here, take this Prozac. It’ll make you feel better.”

And then on the mind side, they say, “Well, no, depression is just a matter of cognition. You’ve got faulty thinking. If you go to therapy, you can fix your thinking and fix your depression.”

It sounds like what you’re saying is that it’s both, both things are going on.

Charles Raison:

Yeah. I was going to say they’re both right. They’re both right, and both perspectives have significant clinical potential, and somehow neither one by itself is fully enough. I mean, that’s the crisis we’re at in mental health care, is that trying to find ways to marry those two things together, to leverage the strength of each perspective or each system of causality, if I can put it that way. Trying to find ways to marry these things together is something that a number of us working in the field are really, really interested in.

Brett McKay:

Okay, let’s kind of walk through an example of the mind affecting the body and the body affecting the mind. So, the mind affecting the body, you gave an example to say social stressors, you experience some sort of defeat and you think about it all the time. Everyone’s had that moment where they’ve had some sort of defeat in their life, they lost a job, they got rejected by somebody, and you just feel bad and you just think about it all the time. And that’s going to affect your body, correct?

Charles Raison:

Right.

Brett McKay:

Is that what you’re saying?

Charles Raison:

Yes.

Brett McKay:

Okay. And then the body part is the body can affect the mind by you get sick with some sort of something, some bacteria, and it caused you to feel sad and down in the dumps.

Charles Raison:

Yes, absolutely. That’s exactly right.

Brett McKay:

All right. Well, let’s talk about … It’s going to be hard to suss out, because this is really interesting, because all this stuff, it’s happening all at the same time possibly, right? So, it’s not like-

Charles Raison:

Yes, and in a loop, right?

Brett McKay:

Yeah, in a loop. Right.

Charles Raison:

That’s how things go, right? So, the mind affects the body, the body affects the mind, which then affects the body, so you can get these circles going and that’s part of what we think probably happens in depression where people … There’s a lot of evidence when you look at sort of patterns of brain functioning that on average depression kind of biologically one of its characteristics is that people have this sort of locked-in pattern of over-activation in areas that are sort of fixated on danger, fixated on the self. And then you kind of ruminate, just the same negative thoughts over and over and over again, so this being trapped in circles is one of the characteristics of clinical depression.

Brett McKay:

Okay, so let’s talk about this. Let’s get to your idea of cause of depression, not the only cause but a cause, and that’s inflammation, so I think first we’ve got to talk about what inflammation is. I think people have a sort of kind of basic understanding, if you cut yourself the wound becomes inflamed, it gets red around there.

Charles Raison:

Mm-hmm (affirmative).

Brett McKay:

So, let’s dig a little deeper. What happens when your body becomes inflamed?

Charles Raison:

Yeah. Okay, so right. When I went to med school in the ’80s and the immune system was really just beginning to be figured out, we thought inflammation was, what you say hot, red, painful, rubor, dolor, calor, is kind of localized phenomenon. It’s sort of how it’s seen just in popular culture. But I think a better way to think about inflammation is to step back and think about what happens when you get sick, so think about here you are and you’ve now just picked up an invading microorganism that the immune system thinks is really a threat. The red, hot and painful finger, when you got a splinter in it, is because it’s trying to kill that invading thing right there at the source, right?

But then let’s say that fails and now it’s in your body, so what are you going to do? Well, it turns out that mammalian immune systems, especially human immune systems, have two branches. They have a branch called the innate immune system and a branch called the acquired or adaptive immune system, and they serve different function. The innate immune system is what gets fired off first, so your body sees this dangerous thing and there’s a part of your immune system that recognizes it very generally. It just doesn’t like foreigners, basically, right? And seeing that the foreigner is there, it thinks the foreigner is dangerous enough, it pulls out a shotgun and starts firing. And what it fires are these very hot, angry, destructive chemicals called inflammatory cytokines, and they’re pretty good at killing dangerous foreign things.

But they have a lot of collateral damage, and this is why inflammation over time is associated with things like heart attacks and strokes, is because it tears up the tissues of the body also. It also makes you prone to diabetes and things like that, but you need this innate immune system. It’s sloppy, it’s imprecise, but it’s very fast. And there are unfortunate children born without functioning innate systems and they’re dead within a week or two, so you’ve got to have it, because otherwise you’re not fast enough off the draw to fight these dangerous pathogens.

But we’ve also evolved this other immune system, this acquired or adaptive immune system, and this is what people usually mean when they talk about the immune system, which is that antibodies and T cells and things like that, and this is really an amazing thing. Basically what it is, is that your body produces millions, billions of immune cells, B cells and T cells, each one of them just randomly has a slightly different pattern on its surface, and that pattern just randomly may or may not recognize a pattern on a bacteria or a virus. But these cells kind of float around in your body and when see that virus or bacteria, if it’s the right cell, it activates and the shotgun immune system, the innate immune system, plays a key role in presenting the dangerous bacteria cells to those antibody cells and those T cells.

So, when those guys get activated, they produce a ton of killer modalities that they’re like snipers. They only fire at cells that have that mark on them, and that mark generally is not on human cells. It’s generally only on that virus, only on that bacteria that’s invaded your body, so it’s able to completely kill the bacteria or the virus and not cause you any trouble. Now, every once in a while there’s a screw-up and the T cells or the B cells mistake something in your body for a bacteria or a virus, and when that happens you get an autoimmune condition like type one diabetes or multiple sclerosis or something like that. That’s why that happens.

But when things function well, what happens is you get this early shotgun immunity that is fast and sloppy and just shoots at everything, but it activates this sniper-like immune system that takes four to five days to operate, to come up to steam, but once that system is activated, the inflammation should die down and these very specific sniper cells should take out the pathogen. And then when they’re done doing that, instead of all vanishing, once your body has seen a particular virus or bacteria, the specific cells that multiplied by the millions and billions. They don’t all die. A little army of them stays in the body, they’re called memory T cells, and those cells patrol around and if they ever see that invading organism again, they can immediately ramp up a million times faster. That’s how vaccines work, right? They leave you with this little army of memory T cells for hopefully the flu, or for measles or whatever.

So, when we say inflammation, you can have inflammation from either arm of the immune system, but generally what we find in something like depression is hyperactivity of that shotgun immunity, right? So, let’s think about you getting the flu, right? So, what’s the first thing that happens? You start feeling weird, you start feeling freezing, you huddle up, you start getting a fever, maybe you throw up, you feel exhausted, you’ve got body aches, you want to sleep, you don’t want to do things, it’s hard to think about complicated stuff. Some people start feeling down emotionally. So, how does that happen? Does the flu virus, does it go up to your head and sort of sit in the driver’s seat and start kicking on your brain? No, it doesn’t do that.

What it does is it activates these inflammatory cytokines, these hot, inflammatory molecules. When that innate shotgun immune system recognizes the dangerous of the flu virus, it starts pumping out these inflammatory cytokines. They can make your finger hot and red, but they also go to the brain. And this is from some work we did with Andy Miller years ago. When they get to the brain, they basically cause every change in the brain that has been associated with depression, and that is why you get sick. The reason you get sick is not because the virus wants you to get sick. Oh, contrary, it’s the opposite. You get sick to fight the virus, because those cytokines, when they activate sickness behavior, which is sort of the classic expression of inflammatory activation when it’s intense, almost everything about sickness behavior has an antibiotic strategy. So, the reason you get a fever when you get sick is not because it feels bad, it’s because higher temperatures kill viruses and bacteria, and higher body temperatures sort of drive your immune system.

When you get sick, your body starts getting rid of all of its iron and it starts to try to hide away its iron, so you get anemic if it goes on long enough. So, why would you get anemic? Well, the answer is because a number of bacteria, they need the iron so badly that if you can deprive them of iron they’ll starve and die in your body, right? So, there’s a list of things like that, that all happen when people get sick. And by the way, when you get the flu you feel crappy for three or four or five days, that’s inflammation making you feel like that. And then one morning you wake up, you start feeling better, and the reason you’re feeling better is because that sniper-like adaptive immunity has come online and it’s killing the virus without doing anything to you, which is why you start feeling better, right?

So, the realization that inflammation maybe had something to do with depression, really it came from a couple of sources, but a primary source was this realization that inflammation produced a sickness. And in animal studies when you inflame a little animal and you inject it with one of these inflammatory cytokines in its body, it starts acting exactly the same way as if you’d put it in a terrible psychological stressor, so then people started looking around and they made a couple of interesting discoveries. They found out that as a group, people with depression tend to have higher levels of inflammation than people that are similar otherwise but not depressed, so it looked like there was this signal within the medically-healthy people that they had elevated inflammation. And this sort of realization that, “Oh my goodness, sickness looks a lot like depression,” or, “Depression looks a lot like sickness,” and it’s very interesting ways.

So, for instance, no surprise that when you get really sick you get a fever, not so well known that people with depression also have an elevated body temperature. They’re hyperthermic at least, and you treat them and their body temperature returns to normal. They tend to have the same iron deficiencies that you see in sickness, so we and others have actually argued that maybe depression evolved out of sickness as a way to help protect us from pathogens. So, anyway, it was this sort of line of reasoning that made many of us realize that, “Wow, if you inject people with inflammation, they get depressed. If you look at depressed people, they seem to as a group have increased inflammation.”

And then the coup de grace in this thing was, well, okay, it makes sense if you’re sick you get inflamed. If you get inflamed, you get depressed, so that’s probably partly why medical illness is such a risk factor for depression. But what about stress, especially younger people? They usually get depressed because of a psychological stressor, so starting in kind of the early-mid-2000s, people would take normal humans and stick them in a laboratory and give them a psychological stressor. We did hundreds of these back in the day. And you can show very clearly, and absolutely reliably, that all I have to do is take you, put you in a psychologically stressful situation and I can show that it activates your inflammation.

Within an hour, your inflammation is shooting up, and if you’re somebody who was neglected or abused or sort of traumatized as a kid, your inflammation is going to shoot up even higher, way higher in fact, because that early adverse experience has primed your body to respond to danger with increased inflammation. So, these pathways came together, and voila, that’s why it has now become this sort of widely thought about idea that depression and inflammation have something to do with each other.

Brett McKay:

Okay, so let’s talk … I want to backtrack about this idea that these cyto … Is it cyto kens?

Charles Raison:

Cytokines.

Brett McKay:

Cytokines.

Charles Raison:

Yeah.

Brett McKay:

So, you say they get to the brain and they cause all the things that we see in depressives, so we’re talking … Does it disrupt neurotransmitter stuff? Does it change the structure of the brain?

Charles Raison:

Yeah. Yep, yep. Oh, yeah.

Brett McKay:

Is that what’s going on?

Charles Raison:

Yeah, yeah. The inflammation wipes out a necessary co-factor for neurotransmitter production.

Brett McKay:

And does it change structures of the brain, so you’ve heard those things where people who are depressed have a sensitive amygdala, the almond-shaped thing. Does inflammation affect that?

Charles Raison:

Yep. Yep, it absolutely does. It also induces brain changes similar to those seen in depression, absolutely. Does it change the structure of the brain? That’s a good question. It’s like everything where there’s such a huge field now. I’ve never seen the study that it actually changes the size of the brain or something like that, but the activity of the brain, absolutely. And my old mentor, Andy Miller at Emory, who’s really I think the king of this field in so many ways, has shown that if you take just a big group of normal, medically-healthy depressed people and you measure their inflammation, the people that are depressed that have inflammation had very different patterns of brain function than the people that are depressed without inflammation.

Brett McKay:

Why does our body, when we experience psychological stress, why does it create inflammation? Because I think people, when they think of stress, they think of cortisol. They don’t think, “Oh, my body’s going to act like it’s sick and send out inflammation signals.”

Charles Raison:

Yeah. It’s truly interesting, isn’t it? I mean, you’d think, right? That when the going gets going, the tough would get going, and sometimes when I give lectures I will spend the whole beginning sort of trying to get people to marvel at this remarkable fact that we have this weird inflammatory bias. We think of inflammation making us tired and sick, and maybe not think straight. If you’re being chased by the saber-toothed cat, or God’s sakes, why would you want that? But I think the answer is, and a number of us sort of hit upon this at sort of the same time, that the evolutionary answer we believe is that if you think about what stress has meant across mammalian evolution, and even before the mammals but we’ll just stick to ourselves here, stress reliably meant usually one of three things, right?

Either you’re about to be eaten, or you are chasing down something to eat and that thing has got horns and hoofs, or you’re wanting to make a baby and you’re having to fight with the other guy with horns and hoofs. And so in all of those situations, because other than that most animals tend to kind of hang out, right? They sleep or they hang out, and so stress, the argument goes that stress was so reliably associated with a risk of wounding over evolutionary history that genes that evolved to prepotently and sort of jump the gun, activate inflammation in response to stress were selected because if you directly die from the stressful encounter from the wounding, well whatever, you’re dead. But many, many times organisms would survive and then they’d die of infection, because skin is the greatest of all immunologic organs and one of the absolute number one best ways to die before there were antidepressants was to get your skin opened up.

And of course, now we know with failure of antibiotics this is becoming more and more of a risk again, right? It’s terrifying. So, the reason that stress activates inflammation is stress has been a reliable signal that you’re in danger of having your skin opened up. If your skin gets opened up, you’re very likely to get an infection and that puts you at risk for dying, so rather than sitting around and waiting for it to happen, we are going to jump the gun, it’s called smoke alarm principle, right? And we’re going to turn on inflammation to be ahead of the game and to be ready for the immunologic damage, or the pathogen exposure that we think is going to happen, right?

And of course, if you do false alarms 1,000 times, yeah, you may incur some tissue cost from the inflammatory chemicals, but all you’ve got to do is not respond once and you’re dead, and so it’s this thing called the smoke alarm principle. So, what we’re looking at here of course is an evolutionary mismatch in the modern world, which is that for many of us, especially in first-world countries, stress does not very often anymore mean that you’re at risk for being wounded. Humans tend to make things sort of concrete abstract.

That’s one of the great things our brain does, and so now all these psychological stressors that are no longer associated with wounding still activate those ancient pathways, they still activate those ancient reactions and produce inflammation, even though the inflammation is of no value as far as we can tell and is actually detrimental. So, it’s a good case of an environmental mismatch that we are inheritors of, because the world has changed so fast in modern times, evolution hasn’t been able to catch up.

Brett McKay:

All right, so there’s psychological stress, but there’s also other kinds of stress too, like physical stress from exercise. That creates inflammation in the body as well, but also makes you feel good. So, what’s going on in the dynamic there?

Charles Raison:

So, this has been my little … It’s funny how we all have our little sort of areas that are fascinomas for us. That is true, that is a very fascinating observation. So, we know that exercise acutely activates inflammation. Early on when you asked me who I was and what I did, I said I kind of studied ancient practices, and one of the other antidepressant things we’ve studied is hyperthermia, heat, and we have shown, and now it’s been replicated by others, that in fact if you expose humans to a really heat stressor for a time-limited period, it produces an antidepressant effect. I mean, that’s why people go to saunas, right? Steam rooms and stuff.

So, we measured inflammation before and after taking depressed people and sticking them in this hyperthermia machine, and lo and behold it didn’t activate the whole inflammatory cascade, it activated something that looked a lot like what exercise does. And there was this signal in there that the more that inflammation got activated, the better people felt, the more undepressed they were a week later, so there’s a little bit of a mystery here. But some of us, including me, think that the answer actually can be seen in exercise. What does exercise do? Acutely, it raises inflammation. What does it do chronically? It lowers inflammation.

And so I think for many of these systems what happens is you can actually strengthen them or toughen them, or in some cases down-regulate them by certain types of acute repeated exposure, right? So, there may be cases in which brief exposure to stimuli that induce inflammation may actually have benefits for depression. Years ago, back in ’95 or ’96, there was a small study out of Germany published in Biological Psychiatry where they took a very small … They only took seven people, but these were really, really depressed inpatients. They were in the psychiatric hospital.

And they did something really cool, they shot them up with a bunch of inflammation into their veins and basically made the people sick, and every single one of them had a powerful antidepressant response. It didn’t last in most of them, but in several of them they actually continued to feel better for days and days afterwards. So, what we can say is that when you’re chronically inflamed, it’s a pretty powerful risk factor for depression. There may be some instances for reasons we don’t fully understand where an acute inflammatory stimuli might actually have mood protective effects.

Brett McKay:

It’s like the hair of the dog.

Charles Raison:

Sort of like the hair of the dog. Well said.

Brett McKay:

Yeah.

Charles Raison:

Yeah, that’s right.

Brett McKay:

So, this sauna research, have you guys figured out how long you need to stay in a sauna for it to have that effect? Is it five minutes, 10 minutes?

Charles Raison:

No, no, no, no. Well, so the short answer is no, we have not figured that out. My colleague, Ashley Mason, at the University of California in San Francisco is gearing up to do studies now that will really begin to try to look at that. We got into this, it was sort of interesting. I had two young colleagues who were graduate students of mine, in Austria of all places, I used to teach there episodically, and they worked at a sort of nontraditional psychiatric hospital that did mind-body treatments. And one of them was an engineer who found her old hyperthermia machine in the basement, rebuilt it, and we decided to stick depressed people in it, and we did. We cooked them up and we saw this really striking antidepressant response. You could see it five, six, seven days after a treatment.

I brought one of the guys to the United States and we got another fancy machine and we did it really well with a controlled condition and all of this stuff, and we saw exactly the same thing. Now, the thing was though, in Switzerland we had treated people to basically a core body temperature of 101.3 at 38.5 centigrade. It worked, and since it worked there, we did the same thing in the United States, but we never did a dose response study, so we never looked to see, “Well, what if we cooked you up more? Would it work even better?”

38.5 core body temperature, 101.3, is the upper end of what’s classified as mild hyperthermia. You get people much hotter than that and you start … The health risks begin to sort of increase significantly, so we think that that’s a good marker for a core body temperature that really seems to have an antidepressant response. Well, the study we did in Arizona was kind of cool, because we had this nice comparative condition where we put people into the same machine and we had fake lights, but we gave them a little bit of heat. There was some coils at the bottom of the box.

We wanted to fool them, and we did them. We fooled the majority of them, but it actually warmed them up too, and so people’s body temperature, the placebo condition wasn’t really a full placebo. They actually warmed up a little bit, but they didn’t have nearly as big an antidepressant response, so I think we can say, based on that, that the data at this point suggests that if you wanted to do it, you should get yourself a rectal thermometer and see if you … Seeing people, that’s usually the end of the discussion, but see if you can get yourself up to 101.3.

And the way we did it in study was we got people up to 38.5 and the temperature was assessed with a rectal probe every, I think, 30 seconds, and when they had two or three 38.5, we turned the machine off and then we just sort of let them sit there for an hour, because the body temperature remained elevated. You’re not going to get to 101.3 by five minutes in the sauna. With this machine, it took people on average about 90 minutes, so more than an hour. The machine was designed to be more comfortable, so it wasn’t like a hellish sauna where your face is on fire and you’re dying, so yeah, we don’t know. Ashley, my colleague in California has been working with these infrared saunas. You’ve got to stay there for a while. You’re going to commit an hour to it probably at least to try to get up to that temperature.

Brett McKay:

And as you mentioned, you’ve been exploring other sort of ancient practices that humans have used that might have antidepressive benefits to it, so there’s saunas. People have been doing that for a long time. Exercise is one.

Charles Raison:

Absolutely.

Brett McKay:

Any other practices that you’ve found that may have an anti-inflammatory, antidepressive benefit?

Charles Raison:

Well, yes, and so there’s one that I am personally fascinated by and I just don’t have the bandwidth to study it, it’s interesting, and that is intermittent fasting, and I bet you’ve talked about that a lot on your program probably.

Brett McKay:

We have, yeah.

Charles Raison:

Yeah, because it’s one of these things that’s sort of hip right now, but there’s some really interesting data … I’m thinking of one study in particular where they took a bunch of kind of normal dudes and fasted them and measured the activity of this thing called the inflammasome, which is sort of the initiating biological mechanism within cells that turns on inflammation. And you fast them, and man, the activity that thing drops, drops, drops, and then they fed them and up, up, up, right? Which makes sense, right? Because you think about it, inflammation like the brain is charged with this large task of trying to figure out what is the self and what are its boundaries, and how do I maintain the integrity of the self, especially when that integrity requires that I let foreign things in, right?

So, food is a massive danger, and still to this day there’s a bunch of people that die every year from food poisoning at restaurants in the United States. I mean, food is a foreign object, it often carries organisms that can be dangerous, so of course it makes sense that when you eat, you are putting an inflammatory stressor on your body. You’re also putting a thermal stressor on your body, so every time you eat, you kind of run a little fever. It’s called diet-induced thermogenesis. You kind of got to burn it off. So, yeah, I mean, it is probably the case that fasting has anti-inflammatory properties. I know from my buddy, Robert Knight, who’s one of the kings of the microbiome, that fasting is also probably the fastest way to alter your microbiome in ways that we think of as being positive.

And so it’s interesting, there’s a couple small studies now suggesting that fasting, intermittent fasting, has antidepressant properties, and there’s a larger database where they fasted people, and sometimes much more than this sort of 18 hours or 12 hours without eating. People go for a couple days in some of these studies, but man, pretty reliably people’s mood really increases. The first day kind of stinks, there’s a hump, but when people get over the hump, they often develop this sort of really elevated mood.

Brett McKay:

Well, so you’ve been researching these ancient practices, but someone might be listening, “Okay, depression, inflammation’s involved. Can I just pop an Advil or get a steroid shot and reduce inflammation and reduce my depression?”

Charles Raison:

Yeah, that’s such a great question and I’m so glad you asked it, because there’s really something important to say about that based on the literature we’ve seen so far. That is this. Well, okay, so let me back up, so we did a study where we decided we were going to really test whether depression was an inflammatory condition. We were going to give depressed people a really powerful anti-inflammatory agent, not like Advil or a steroid shot, but I mean one of these things that used to be marketed as Remicade, it’s called infliximab. It has no other effects other than completely wiping out one of the two primary pro-inflammatory cytokines. It kills inflammation, which is why these drugs are so good for Crohn’s disease and rheumatoid arthritis and psoriasis and stuff like that.

So, we took 60 depressed people, we gave half of them three infusions of this infliximab to block their inflammatory cytokine, we gave the other half three infusions of salt water and nobody who was getting what. And then we followed them for 12 weeks, and the results were quite striking. The salt water worked a little better than the anti-inflammatory agent. It wasn’t significant, but the salt water had a very powerful antidepressant effect, and you talk about the power of placebo, because these were people that have failed other antidepressants. But we saw something really interesting, and this is the important point. The placebo and the anti-inflammatory cytokine blocker, if you looked at the two groups, their effect on depression was almost identical, but it wasn’t because they were the same. They were actually opposite.

And so before we gave people the first shot, we measured their inflammation and we found that if you were depressed and had high inflammation, the infliximab, the cytokine antagonist, worked significantly better than the placebo. But if you were just as depressed and had lower inflammation, and this was two-thirds of this study population, you did so much better with salt water than infliximab, that the only conclusion we could draw is that if you’re really depressed but your inflammation is not elevated, blocking it further is doing something bad for you. At the very least, it’s making you not able to respond to placebo, so it’s interfering with your ability to hope and to trust and to whatever placebo response is.

And there have been a number of studies, several studies after this, that have sort of shown the same thing. One in particular from Mark Rapaport, who’s the chair down at Emory, he did what will forever be probably the world’s largest study of omega-3 fatty acids just as a single treatment for depression, no anti-depressants, just placebo or omega-3 fatty acids. And the fatty acids didn’t work for squat, they don’t have general antidepressant effects. But he took a page from our lesson book and looked at their inflammation levels before they started the omega-3s.

He saw exactly the same thing, that if you are depressed with elevated inflammation, the omega-3s worked better than placebo, but if you were just as depressed and had lower inflammation, you want a placebo, you don’t want to be taking omega-3 fatty acids. So, if those are true results, omega-3 fatty acids may help your heart, but if you’re really depressed and you’re one of the at least half or maybe two-thirds of people that do not have elevated inflammation, take an omega-3 fatty acid you’re probably not doing yourself any favors, so no, we, me, I do not suggest that people routinely try anti-inflammatories for depression at this point.

Caveat, there is a good study from a guy named Jonathan Savitz at the Laureate Brain Institute where he looked at low-dose aspirin versus something called minocycline, which is an antibiotic, which is an anti-inflammatory versus a placebo. The minocycline only worked in people with elevated inflammation, just what you’d predict, but the aspirin worked in everybody, and it’s not because it’s an anti-inflammatory at that low dose. It’s doing something else. We don’t know what. So, there’s a little bit of evidence if you’re going to do something off the grid, that taking low-dose aspirin may have some antidepressant benefit. So, then of course the next question everybody asked is, “Okay. Well, shoot. Should I go get my inflammation measured?”

And my answer these days is, “Well, maybe.” Five years ago, I’d say, “No, it’s too preliminary,” but there’s a thing called C-reactive protein, or CRP. You can get it easily done in a standard lab test, it’s standardized, and it’ll give you a pretty good readout on your inflammation. If it’s elevated, you’re more likely to die of a heart attack and a stroke, and you’re more likely to get diabetes and depression or dementia, and it tends to be elevated in depressed people. Another reason why it’s an interesting inflammatory biomarker is there’s now a couple of studies, including some work that I have done, showing that it can predict whether you’re going to respond to Prozac or not, right?

And so there are now a couple of studies, one of them fairly large actually, suggesting that if you just get the simple inflammatory measures, C-reactive protein, or CRP, if it’s elevated, elevated here is like a level greater than one, one milligram per liter, you don’t tend to respond to SSRIs, the serotonin antidepressants like Prozac, Paxil, Zoloft, Lexapro, Celexa. Those are the brand names. But if your CRP is elevated, you’re more likely to respond to something that has dopamine properties, something like, for instance, Wellbutrin, which the generic of this is bupropion. Or in one study it was nortriptyline, which is more of a norepinephrine drug, but it’s complicated but it fits the pattern, right?

But I think the key here is that almost all of us get depressed, get stuck on a drug where the primary mechanism of action is blocking the serotonin reuptake site, and there is now this gathering data to suggest that if your inflammation is elevated, you’re not as likely to respond to those. And then we’ve shown recently, working with actually a large pharmaceutical company, that CRP can predict people who do don’t respond to a very different kind of drug that’s used to treat bipolar disorder when people are depressed. It’s a drug called lurasidone, and it’s marketed as Latuda. It’s an atypical antipsychotic, it’s a dopamine-modulating agent, and we measured CRP before people started treatment with it versus placebo.

And man, if your CRP is low, the antipsychotic, Latuda, was no better than placebo, but if your CRP was high, it worked like gangbusters as an antidepressant. And we’ve replicated that not perfectly, but we’ve about three-quarters of the way replicated it in another large population of children with bipolar depression. So, this is sort of interesting, right? That it’s not quite ready for primetime, but it’s ready enough and the only risk is a blood stick, that I now often say, “Yeah, I think this is actually something worth doing. Look at the CRP levels if you’re trying to decide what antidepressant to use. We need larger studies, a lot of caveats, but you’re going to pick one eeny, meeny, miny, moe anyway, just randomly anyway. Take a look. If your inflammation is elevated, reach for something other than an SSRI.”

In general, I’m not hugely overwhelmed with anti-inflammatory agents as antidepressants, even in our big study. Yeah, it beat placebo, but it was not a miracle cure. Inflammation is a widespread ancient process, and it sets in motion a lot of downstream changes, and almost certainly those downstream changes are going to be more directly involved in the production of depression, and those pathways probably make better targets than inflammation itself.

Brett McKay:

Well, and I think it’s an important point to make, to bring out as you were talking about those studies about the effectiveness of antidepressants based on your CRP levels, is that you can be depressed but not inflamed.

Charles Raison:

Mm-hmm (affirmative).

Brett McKay:

Or inflamed and not depressed, right?

Charles Raison:

Absolutely. Both are very true.

Brett McKay:

Because I think people could hear this, “Oh, inflammation and depression. I’d just go to my doctor, “Hey, doctor, I’m inflamed. I’m going to sit in a sauna and that’s going to cure it,” but you might not be inflamed but still can be depressed.

Charles Raison:

Absolutely. Most depressed people are not inflamed.

Brett McKay:

So, why is that? Why do some people get inflamed when they’re depressed and some people get depressed but not inflamed?

Charles Raison:

Don’t know.

Brett McKay:

So, this conversation, what this research shows is that, okay, again, there’s no single cause for depression.

Charles Raison:

Right.

Brett McKay:

But it’s all these different things working together, so as a doctor, or maybe someone who’s got depression, how do you figure out the best approach to help a patient? I think at the end of the book you gave some case studies, which was really interesting, walking through.

Charles Raison:

Yeah.

Brett McKay:

But is it just a matter of trying different things to see what sticks, or have you kind of figured out a systematic way where you can find the thing or things that will help?

Charles Raison:

No. No, unfortunately. So, my opinion, but I know the field pretty well, whenever you hear anybody talking in depression, that they’re going to treat you with a brain scan, or they’re going to do a brain scan and tell you what to take, or that they’ve got an algorithm that is guaranteed to work, no. That’s BS. Now, it works sometimes because it induces a great deal of hope and trust and optimism, and those are very powerful effects, but the biology of it is always just really shaky. So, the truth of the matter still is that we don’t know ahead of time really who’s going to respond to what. The little CRP is a little caveat there. If it really gets replicated, it would be ironic that our first reliable predictive biomarker is not a brain thing but an immune system thing.

But no, the real question these days for me is whether you start somebody on an antidepressant and send them down that path. Because I think that the continental divide in the treatment of depression really is around this issue of, do you do something that sort of helps people build up resiliency within their own mind-body-brain complex that’s not dependent on a constant presence of an external substance, or do you go the other route where you fortify people with a drug that is kind of always on the brain and always there? These are things I never would have thought of 15, 20 years ago. 20 years ago I thought antidepressants were like brain food, I thought they were like fertilizer for the brain.

Unfortunately, we now know that when antidepressants really help people, which they do, no doubt about it, and they’re lifesavers, no doubt about that, but in our time and place many, many people, once they’ve kind of gone down the antidepressant path, find that they don’t do very well if they go off the antidepressants, that they … There are really convincing data that starting an antidepressant and stopping it is more likely to make you depressed in the future than having never started it in the first place. Oddly, placebo responses are more durable than antidepressant responses when you take away the placebo or the antidepressant.

Psychotherapy responses, while not perfect, are also more durable. One of my huge interests in psychedelics is not just the fact that they have a different mechanism of action in terms of inducing psychedelic states, but they seem to … One treatment lasts six, seven, eight hours, and then in certain populations, especially now, there’s a study out from NYU, people report being undepressed three, four years later. It’s like it was a reset, right? And that of course is what we should be looking for, because any drug that you take every day that operates on the brain seems to induce what’s been called oppositional tolerance, which is that the brain begins pushing back against the drug.

This is why you get withdrawal reactions, right? If you take Valium every day for … If you take that for a long period of time and you stop it suddenly, you’ll have a seizure, because what’s Valium doing? It’s constantly pushing on the brain to calm it down. Well, the brain begins to kind of fight back. It kind of gears up, right? And so then you get this sort of compromise between the pushing down of the Valium and the pushing back the brain, and then you take away the Valium real suddenly and the pushing back of the brain is unopposed, and it goes hyper-excitable and you get seizures and stuff like that, right?

Antidepressants is not as dramatic, but lots of people have withdrawal reactions and what that tells you is that the brain, you could say it’s become dependent on it, but I like better this idea that the brain has begun to come to some sort of balance with the antidepressant that puts the brain in a place where it’s trying to overcome the antidepressant effects on most. You take away the antidepressant, and that overcoming thing is unopposed and people have a very, very high rate of crashing back into depression. One of the surest way to make people depressed if they’re not depressed is to suddenly stop their antidepressant, so this is a thing.

I’m a pharmaceutical … I’m a drug doctor. I mean, the only real expertise I have clinically is writing prescriptions for psychotropic agents, and I’ve seen a lot of patients over the years and I can promise you that, God, man, damn, some people these agents really work great for. Another problem is that they probably don’t work optimally for at least 50% of the people, but there’s a lot of people that get a huge benefit. But I worry increasingly about anything that the human side becomes utterly dependent on. It tends to weaken the human element, and then this is where you see this increased risk of relapse and such.

So, I’ve gotten more and more interested in how we can begin to find premature depression, that instead of inducing some sort of state of dependency where the human is now joined almost like a cyborg to the technology, say the antidepressant, then what we’ve done is found a technology that actually strengthens people, stimulates them so that this intervention drops away. But the person is now in a self-sustaining state of enhanced wellness, and it’s promising. It looks like there are ways of doing this. I mean, the hyperthermia, the heat, showed a little bit of that signal. People felt better for weeks afterwards. But again, another very long answer to say that no, we do not as a field have a magic formula. If you come to see me, you’re depressed, I listen to you, I think about what the situation is, I wonder about what to do, but there’s not a cookbook that gives me all the answers.

Brett McKay:

But you’re going to do things like I thought you said maybe … Well, you’re going to ask more things about, “Do you have any sort of sickness?”

That’s another doctors typically don’t ask whenever a patient comes in saying, “I’m depressed.”

They never ask about, “Well, are you inflamed? Have you been sick?” That might be a thing they might start thinking about now.

Charles Raison:

Absolutely.

Brett McKay:

And it might not be the thing that determines it, but it’s another factor they might want to consider.

Charles Raison:

Well, so I’ll give you a quick story. One of my partners and closest friends has a mom who’s had a history of very, very difficult bipolar disorder, lots of depressions and manias. She’s older, she’s probably 78, she develops a cataclysmic depression about two months ago. I mean, the woman becomes catatonic, she’s not eating, she’s not talking. When she does talk, she says, “Please put the pillow over my head and kill me. I want to die.” They tried antidepressants, they were going to go for shock therapy, but she failed that in the past, and they started giving her ketamine, this new treatment. And then somebody gets an X-ray and her lungs are riddled with cancer and she’s dying, right? So, there’s a classic example of that.

Now, you can’t do anything about it particularly, but it would have helped the family back in time. They could have been spared months of this sort of, “Oh my God, our mom has such horrible depression. It’s terrible. Should we let her die?” All this stuff. When yes, she had horrible depression, so she had a vulnerability and it was launched by the fact that she was having massive inflammatory response to the cancer. So, I’ve literally just lived through what you’re talking about, and so absolutely yes, that’s absolutely something they should ask about.

The other thing that they should ask about, but good luck because the doctor only has four or five minutes to see you, just economically, but they should also ask you, “What’s gone wrong in your life?” Because depression can come out of the blue, that definitely happens, but most of the time, especially if people haven’t been depressed a bunch of times before, there’s a story there and people won’t tell you the story right away. I used to call it the, “Oh, by the way,” phenomenon, they bury the lead. Depression is often a narrative disorder. There’s often a story that’s driving it, and helping people with that can be profoundly powerful as a treatment, actually, so it’s the same thing of ask about the sickness. Well, yeah, ask if there’s immunological adversity, a sickness, and intersex social adversity, and they both are the powerful drivers of depression.

Brett McKay:

Well, Charles, this has been a great conversation. Is there some place people can go to learn more about your work?

Charles Raison:

Yes. They can go … I’m going to give you a couple of just names. If people Google this, they can find it. They can go to what’s called the Center for Healthy Minds at the University of Wisconsin-Madison. They can go to the School of Human Ecology at the University of Wisconsin-Madison. They can go to the Center for the Study of Human Health and Emory University in Atlanta, Georgia. And then if they’re interested in the psychedelics, they can go to the website for Usona, that’s U-S-O-N-A, Institute. You can find out about me at all of those sites, and if you just Google me, you’ll find me pretty quickly. You can listen to me ad nauseam say a lot of this, but yeah, I mean, I’m pretty easy to find.

Brett McKay:

Okay. Well, Charles, thanks so much for your time. It’s been a pleasure.

Charles Raison:

Thanks, Brett. Yeah, great questions, man.

Brett McKay:

My guest today was Dr. Charles Raison. He is a psychiatrist and the coauthor of the book, The New Mind-Body Science of Depression. It’s available on Amazon.com. Also, just Google his name like he said and you can find out more of the work that he does and the research he’s done on the topic of inflammation and depression. Also, check out our show notes at aom.is/inflammationdepression where you can find links to resources where you can delve deeper into this topic.

Well, that wraps up another edition of the AoM podcast. Check out our website at artofmanliness.com where you can find our podcast archives as well as thousands of articles we’ve written over the years. We’ve got a whole series about depression in men on the site, so go check that out. And if you’d like to enjoy ad-free episodes of the AoM podcast, you can do so on Stitcher Premium. Head over to stitcherpremium.com to sign up. Use code “manliness” for a free month trial. Once you’re signed up, you can download the Stitcher app on Android or iOS to start enjoying new episodes of the AoM podcast at free.

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