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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 CNN.com.
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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