Friday, December 15, 2017

The New Mind-Body Science of Depression

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Charles Raison, MD, is the Mary Sue and Mike Shannon Chair for Healthy Minds, Children & Families and Professor in the School of Human Ecology and the School of Medicine and Public Health at the University of Wisconsin–Madison. He also serves as Director of Clinical and Translational Research for Usona Institute, as Interim Director of Research in Spiritual Health for Emory Univer¬sity Healthcare, and as the Founding Director of the Center for Compassion Studies in the College of Social and Behavioral Sciences at the University of Arizona.

Dr. Raison is internationally recognized for his studies examining novel mechanisms involved in the development and treatment of major depression and other stress-re-lated emotional and physical conditions, as well as for his work examining the physical and behavioral effects of compassion training. Dr. Raison received the Raymond Pearl Memorial Award from the Human Biology Association “in recognition of his contribu-tions to our understanding of evolutionary biocultural origins of mental health and illness”.

Dr. Raison’s book The New Mind–Body Science of Depression was published by W.W. Norton in 2017. In addition to his other activities, Dr. Raison serves as the mental health expert for

Dr. Dave: Dr. Charles Raison, welcome to Shrink Rap Radio. You and your co-author, Vladimir Maletic have written the 2017 book The New Mind-Body Science of Depression. I must say it’s a real tour de force on the topic of depression.

Raison: Thank you. It took us five years to do it.

Dr. Dave: What led to the writing of this book?

Raison: Well, it’s interesting. Vlad and I are colleagues. We’ve been colleagues and friends for years. We do a lot of medical education stuff, a lot of lecturing to mental health people. Vlad is a walking encyclopedia of neurobiologic and clinical knowledge. I have been in awe of him for years. Back, six, seven years ago, we began to talk about the fact that we should try to get some of this down. We were wandering around talking about it and people seemed really, really interested. So we decided to capture this program of education we’ve been doing for years and put it in print form. That’s what really launched the book.

Dr. Dave: I think it’s a really important book, but it seems like things are moving so fast in the field that it may not be a classic because the information will change.

Raison: I’ve already thought about how if and when the time came that we did a second edition, it’d be a major rewrite. From when we started the book to when we finished it, we had to go back and rewrite part of it. There’s been a lot of interesting discovery in the last four to five years.

Dr. Dave: Well, I have to say your book is very carefully argued, is evidence-based, and it presents a complex picture which makes for challenging reading.

Raison: Yeah, I know. It’s hard. Parts of it are very dense, you know. The book runs a gamut. We have some case studies in the back that are very approachable. We’ve got some sections about the neurobiology—there’s a lot in there. Very dense and detailed.

Dr. Dave: Well, I’m going to try to lead you through much of the book. Can you give us the highlights to start? Your focus is on major depressive disorder as opposed to what? There’s major and there’s?

Raison: There’s minor, there’s all sorts. The manual of psychiatry, the DSM, that codifies diagnoses. It has a number of new disorders. We focus on major depression because it’s the sort of standard depression. But one of the key arguments we make in the book is that it’s not—even though it has a code and we call it an illness, it’s not a discrete thing. In fact, we explicitly say that we prefer to use the word depression because we recognize that depression far exceeds the more limited bounds of major depression and that depression, in almost all of its forms, is very, very painful and can be very problematic for people.

I’ve come to prefer the word depression better. It’s not as clinical, not as exacting, but it gets closer to the fact that there is a phenomenon out there that is not one thing. It’s more like a cloud of symptoms, and something that is very common. You see something like it all around the world. You can see it in hunter-gatherers. It’s a thing. It’s not a thing that has hard boundaries, but it is a thing, and it really is depression.

Dr. Dave: I was really struck by what you just said, going back to hunters and gatherers, because you make the point that it’s not a symptom of western culture which many people might assume, but it goes all the way back.

Raison: Yes, as far as we know. We know it is in historical times. There’s a couple of ancient papyri from about 3,000 BC from Egypt that articulate something that we would clearly recognize as major depression. Mood disorders were beautifully described in the ancient world. Hippocrates did a good job. There were others. There’s a famous guy from Turkey … his name escapes me … who laid out mood disorders beautifully and recognized bipolar disorder as a type of mood disorder. Beautiful descriptions of depression in the renaissance. But more recently, there’s been some interesting work, part of which was done to test one of the theories that we talk about in the book, having to deal with why depression may have evolved.

A group of anthropologists out at the University of New Mexico went down to one group that may not be fully hunter-gatherers, but they’re pretty close, and did very, very rigorous depression screening there. It found a number of interesting things. One of them was that the biology of depression there looks like the biology of depression here, and second, that the symptoms looks the same. The people had very much the same symptoms and they had the symptoms from many of the same reasons. There’s a little cadre of reasons for why humans tend to get depressed. I think the best evidence suggest that those reasons are very ancient. Depression evolved probably as a response in one way or another for coping with those reasons.

Dr. Dave: I was also surprised to learn that individuals who have experienced more than one major depression show lasting cognitive decline. I wasn’t aware of that. That’s rather alarming.

Raison: Very alarming. I mean, for those of us that have struggled with depression.

Dr. Dave: As I have.

Raison: Yeah, I have too. If you’ve had a depression, if you think about it, you probably recognize that it impairs your thinking, it makes you feel sluggish, you have a hard time remembering things. Then there’s this indecisive thinking that comes up, but we don’t sometimes think of that as cognitive, but you have a hard time making decisions, things seem overwhelming that way. There’s older data that those symptoms take longer to clear up than mood symptoms do. They’re not always as responsive to antidepressants, they linger, and they are a major source of morbidity in the disorder.

Part of what nails people with depression is it screws up their ability to think and remember. It’s a huge problem, and it’s a problem that we’re becoming more aware of in the last few years. Certainly, it’s become of more interest since we started writing the book because it’s become a focus of the pharmaceutical industry. There are a couple new antidepressants that target a serotonin receptor that has been associated with improved cognition, you know, so all of a sudden, people are very interested in this idea, “Oh, man. Maybe we can specifically do something about it.” Not so clear if that’s true, but anyway, it’s a big deal.

Dr. Dave: One of the things that you take on is the DSM-5 which has some coverage of depression. What is it that they’ve got wrong there?

Raison: Well, what they’ve got a couple of things wrong, but they’ve got a couple of things right. What they have wrong is that it’s built upon an idea that is extremely admirable and it was the idea of one of my main mentors. I went to a school in a place called Washington University in St. Louis. That was really one of the two primary founding sites for what became the DSM. The chairman of the department Samuel Guze along with Eli Robins felt and provided some evidence that psychiatric conditions were really diseases. That if you look at their symptoms and if you follow their symptoms over time, that it would be like discovering a bacteria and saying, “Oh, hey, that’s what causes tuberculosis.”

So, they thought that something like major depression was a disease state and that it was a disease state that differs, say, from something like bipolar disorder or differed from something like schizophrenia. Why did it differ? Because it had different symptoms and tend to have different outcome over time. It’s not that that’s exactly wrong, but it’s pretty clear now that it’s really not true. That in fact, as we have come to understand the mechanisms for these disorders, both genetic and systems within the body. There’s a huge overlap between many of these disorders. For instance, the genetic risk factors for depression are largely shared with something like bipolar disorder and even with schizophrenia.

When you look at the mechanisms that underlie these disorders, there’s some evidence that there’s some differences between them. But what strikes me is the fac that so many of the changes were reminiscent of each other. We look at brain changes or immune changes. What is emerging now in psychiatry, is that in ways we never would have guessed 30, 40 years ago, these disorders we label as being separate have powerful genetic and biological overlaps. We don’t know how to cleave nature at the joints. What we don’t know how to do though is to take these emerging scientific data and say, “Oh, well, let’s come up with a whole bunch of new disorders.” If two people with depression have got the same symptoms and one of them has a problem with their immune system, with TNF (tumour necrosis factor alpha), that’s a immune molecule then they’ve got a TNF disorder, so hey, what we used to call it major depression, we can now call it TNF disease.

Another person has got a problem with their cortisol, so we’re not going to call it major depression, we’re going to call it cortisol disorder. But that’s what we cannot do yet. Even though we’ve begun to understand that there are complex overlaps in the biology of these disorders and within each disorder, we have not yet come up with anything frankly, better than the DSM. That’s why in our book, and this eventually is what the National Institute of Mental Health has recently decided too, is to recognize that the DSM with its description of things like major depression is a useful clinical document that helps people use the same language. You and I can diagnose the same thing if we see somebody with something like major depression. But that these are not disorders like rheumatoid arthritis or pneumococcal pneumonia. The

Dr. Dave: In fact, you talk about the National Institute of Mental Health and IMH in the book. You say that for the purposes of funding research, they’re sort of ignoring the DSM-5 and requiring a different type of research. Can you briefly characterize what that different type of research is?

Raison: Another colleague of mine, a very famous guy named Tom Insel became the head of NIMH. He is no longer there, but about 15 years ago, this brilliant, bold controversial man came in and said, “When we look at research in general, if we look at cancer, we see a significant decline in deaths from cancer over the last 20 years. If we look at heart disease, even more impressive. We look at, say, depression, let’s say suicide as a proxy for depression. Rates haven’t dropped, they’ve gone up. We are failing.” More recently he said, “I don’t know what the number was, like $20 billion during my tenure in IMH. We did some really cool work, but I don’t think we accomplished anything.” So he decided to take the bull by the horns and say he thought part of the problem was that we’re trying to study these DSM disorders and they don’t exist. That they don’t exist that way. They don’t have a single mechanism.

So they came up with a system called RDoC, which stands for Research Domain Criteria, and, basically, instead of reaching into the DSM, they said, “We’re going to have these domains that we think characterize mental disturbance more generally, so a cognitive function domain, a stress resilience domain, a negative affect valence domain.” You’re only going to get grants if they propose to study those domains. But you can see you’re now setting up another set of these sort of criteria. So if you take something like stress resilience, there are probably a hundred ways to get stress resilience, right? Calling that a sort of a mechanism, it’s a step forward, but the problem is we don’t know the hundred ways.

The brain and the body in these regards are so complex that although we’ve learned a lot, really trying to zero in, is always the problem. But yes, NIMH has really changed things in very interesting ways in terms of they will now really only fund projects that use these sort of criteria and try to look at a mechanism. So, if I got a new treatment for depression, they’re not very interested in me just trying it on depressed people. What they want is for me to say, “I think it works by blocking inflammation.” So first show me that it blocks inflammation and then show me that people get less depressed. It’s a very logical idea, right? They’re really trying to get to be like the rest of medicine and try to find mechanisms.

Dr. Dave: I’m thinking of phenomenology as the experience, the inside experience of depression.

Raison: Yes. It’s often used to mean a “descriptor of symptoms”, like a description of what is it that people that have depression experience. There is no doubt that we need that, and there is no doubt that I have no idea what it is.

Dr. Dave: Okay.

Raison: We all have some ideas, but this is the huge challenge and … It depends on how you look at it. This is one of the things the book says too? If you try to go in up close and really hone in on details, it sort of is like a Buddhist feel in the world when you try to find solid objects, things just vanish into these complex interrelationships. If you try to be very specific about the phenomenology of something like depression, you cannot figure out where it starts, where it ends, what is what. But one of the things that Vlad and I realized in writing this book, was that if you step way back, you actually can get a sense of the phenomenology of depression. Then we can say some things.

One is that it’s remarkably common. Two is that it doesn’t really tend to come out of the blue. Most of the time it is in response to certain types of environmental adversities. It tends to hit men and women in different ages. In general, it tends to have a set of symptoms. Not everybody has all the symptoms, so if you go back, that turns out to be quite useful. It’s different than a simpler medical illness and it’s got a code. Because if you look at it this way, it has a narrative. It turns out that it has causes. It has effects too, but it has causes.

One of the arguments in the book is that the causes of depression are fairly stereotyped, suggesting that they’re ancient in human evolution, and they’re not random. That gives you a sense that we can call it a disease. Pragmatically, it might as well be a disease, it wrecks lives. But it’s not just a disease, it actually turns out to be an evolved response to adversity and that opens some really interesting doors for thinking about it and for thinking about its phenomenology.

Dr. Dave: Yeah. You mentioned bipolar, and I was wondering where does that fit in? Does that complicate the picture?

Raison: It does.

Dr. Dave: So is it more of its own thing or is it part of this thing?

Raison: Yeah. Oh, yeah. Well, so in the old days, in the way old days, people would kind of lump everything together. They thought everything ran together. There are modern people who think that all disorders of mood are bipolar. Most of us don’t believe that, but I admire that position. I don’t agree with it fully, but I really admire it. It’s old, it’s an ancient, it goes back to the ancient world to that guy whose name I’m not thinking of from Turkey. But more recently, and certainly in the DSM, there was this sharp distinction. Unipolar disorders, just depression, is one thing. Bipolar disorder is something else. That’s not true. We know that’s not true. They’re clearly not the same thing. Because to have bipolar disorder, you have to have a manic episode or hypomanic episode. Those can take various flavors, but when they’re extreme, people are psychotic, they’re hearing voices, they don’t sleep, they can’t stop talking, all the time. It looks like the opposite of depression.

Clearly, it’s not the same thing as depression, but bizarrely, it’s not altogether different either. Many of the biologic changes you see in mania, you can see in depression. It’s weird. Many people that seem to have depression, specially when it’s recurrent, when it happens to somebody a lot over the years, many of those people will eventually have something like a manic episode. As we’ve learned more, we’ve understood less in some ways. That’s one of the ways we’ve understood less. The clear demarkation of just regular old depression from a bipolar disorder has softened a little bit. Now I’ll tell you one way I think about the distinction is that depression tends to be response to certain types of adversity, largely social and often immune infectious related adversity. Bipolar disorder is often a response to the adversity of time. Most of us don’t think of time as an adversity, but it is. It’s quite an adversity, actually.

Dr. Dave: Getting older?

Raison: No, not that. Getting up everyday, going through the day, going to sleep. The literal passage of circadian rhythms is a powerful stressor, right? The most stressful thing you do most days that aren’t terrible is get up in the morning and your body prepares for it a couple of hours. It activates the stress system. That’s why there’s a surfeit of death rate at dawn. The reason people die at dawn is because it’s really rough to get up. Ask any teenager, they know that. But it turns out to be true, right?
Dr. Dave: I was thinking of teenagers.

Raison: Most of us manage that. In bipolar disorder, one of the classic things that induces episodes in bipolar disorder is disruption of circadian functioning, so missing sleep. For people with a bipolar disorder, all you need do is keep them up for a night and they’ll frequently go fully manic. If you put them asleep for 12 hours … When I used to do a lot of clinical work I ran a large inpatient service in California. Several times we took people that were doing things like running around naked in public, screaming, and stuff like that. Put them to sleep for 12 hours and, literally, when the people woke up the next morning and said, “Oh my God. Where am I? What happened?”, they were perfectly normal.
Some manic people have outbreaks when they get on a plane and fly to Europe. Bipolar disorder is more of a brain disorder. When it’s really severe, it really looks like there’s something wrong with people’s brains. But it’s not just that, we also know that the episodes of bipolar disorder are sparked by the environment, but they’re also sparked by the stress of time, circadian time, in a way that depression, regular old depression is not.

Dr. Dave: Now one of the things that you emphasized in the book is that depression is not a unitary disorder, and that there’s a complex interaction between genetics and environment.

Raison: That’s right. Although, that’s not novel. I think the whole field now recognizes that psychiatric disorders arise at the interface of genetic vulnerability and environmental conditions. The conditions that produce depression are often conditions of adversity. It’s a continual model and a simple way to think about it is that there’s some people whose essential makeup is largely driven by genes and the way those genes are expressed through epigenetic changes. There’s other people that take a lot of grief to get unhappy and get depressed. There’s a famous story from ancient Athens about a king who had everything until the end of his life when he lost his wife, he lost his children, he lost his kingdom. On his deathbed he said, “Call no man be happy until he dies.” Meaning that there are things that can happen that can probably upset everybody, but some people need a lot of push from the environment.

Other people are genetically vulnerable. They’re more sensitive to environmental perturbations. They need much less push from the environment. Because life is difficult, as the Buddhist said, “All life is suffering,” you are going to suffer in life. The more you’re vulnerable to that, the more likely you are to get depressed because the world is just not … it’s not a bowl of cherries, right? Most of us fall somewhere in the middle, but that’s a way of thinking about a continuum where the genes and the environment talk to each other that way. One of the things we do in the book that’s really interesting is we raise the point that even the dichotomy of genes and the environment is in many ways false. Because if you think about what a gene is, it’s a chemical structure, but it’s really an encoding of information.

If you say, “Well, what’s that information?” It really isn’t encoding. It’s information about past environments. Because those genes are there mostly, not always, but mostly because they were selected by past environments. From a genes point of view, everything outside the gene is environment, right? If you’re a gene and you wanted to survive and reproduce, your body is outside environment. If you’re a human, then there’s a lot more on the inside. You think your guts are on the inside, and your genes are on the inside, and the environment starts with your skin. But it really turns out that there’s another continuum which is genes and environments. They’re also married to each other and they’re ciphers for each other. One element to environment is a new element to a gene.

Think about an individual gene. Its environment includes the chromosome. It includes the entire genome because it’s fighting with those other genes. They get along but they also fight. Then if you look at a chromosome, well, its environment is the cell. You look at the cell, its environment is the body. When you really get into it, you begin to realize that although it’s very difficult to model these things, what really is going on is that all these levels are in constant interaction with each other, and the interactions are largely bidirectional. You get these extreme, complex systems. When you get complex systems it’s hard to make simple predictions. That’s why we can’t accurately forecast the weather. They become so complex that actually finding what they’re doing becomes either intractable, meaning you don’t have enough computer power to do it, or nearly impossible. That’s one of the challenges for thinking about why depression is so difficult. The simplest thing to say, and when I started with this, we know the genes and environments interact with each other.

Dr. Dave: Are we talking about multiple causal pathways.

Raison: Yes. Multiple causal pathways that are also interacting with each other in ascending levels. You get 12 pathways and these 12 pathways interact with each other, then those interactions can interact with each other. Some levels are going to be much more important for intervention than others. That’s how we can do anything in life. But still, in this way, it’s a like a quantum understanding in that it’s a cloud of causes. Some of them are more important than others, but it’s very complicated. In some circumstances, a cause that wasn’t so relevant in another circumstance becomes very important. That’s another complication. I think one of the things writing the book did for me was making me realize, with a certain humility, that we’re learning a lot. What I’m saying to you now, wouldn’t have been said 20 years ago. Even the articulation of our ignorance has become more knowing, but it’s a very humbling thing.

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