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Up Show is dedicated to the reality of depression. Each week our
hosts will talk with some of the world's top experts on depression,
as well as people who have been impacted by this illness. The reality
of depression is that it is a debilitating and potentially deadly
medical condition that affects more than 15 million Americans every
year. The other reality of depression is that there is hope.
Down & Up Show #43: The Genetics of Depression
DR. REEF KARIM:
Welcome to the Down and Up Show on Depression is Real.org, I'm your
host Dr. Reef Karim, psychiatrist, addiction specialist and relationship
therapist. Today we'll be talking with Dr. Francis McMahon, the
Chief of the Genetics Unit at the National Institute of Mental Health.
Dr. McMahon joined the Mood and Anxiety Disorders Program at the
National Institute of Mental Health in 2002 after serving as an
Associate Professor of Psychiatry and Medical Director of the Electro
Convulsive Therapy Clinic at the University of Chicago.
Dr. McMahon, thanks for taking the time to speak with us today.
DR. FRANCIS MCMAHON:
Thanks for having me today.
DR. REEF KARIM:
First off, genetics and depression. Is there a genetic reason for
why people experience depression?
DR. FRANCIS MCMAHON:
The short answer is yes, but it's not the whole story. What we know
fromÉ about 50 years worth of studies, primarily in twins, is that
about half of the individual variability and risk for depression
can be explained by genes. What that's mean, if you take aÉ a pair
of twins who are identical twins, that means theyÉ they are essentially
identical genetically, and one of those twins has depression, then
the chances that the other twin will have depression are higher
because of their genetic relationship.
In order to understand how much of that is due to the fact that
twins are siblings and grow up in the same environment, you can
contrast thatÉ the identical twins with so-calledÉ diazigotic twins,
that is fraternal twins who only share about half their genes on
average.
And when you do that, you find thatÉ if you do a little bit of math,
that about 50 percent of the risk of depression is what geneticists
call heritable which means that it can be explained by the genes.
It's certainly higher, but itÉ to put too fine a point on it I think
might be misleading.
DR. REEF KARIM:
I mean does it mean that depression is an inheritable illness?
DR. FRANCIS MCMAHON:
It does.
DR. REEF KARIM:
So far, what does the research say?
DR. FRANCIS MCMAHON:
What the research tells us is that like so many common illnesses,
heart disease, diabetes, that depression has a genetic component.
ButÉ that genetic component doesn't really predict who will develop
the illness, it really is more like a risk factor in the way that
we say, for example, that high blood pressure is a risk factor of
heart attacks and strokes.
We don't yet understand is which particular genes are involved in
increasing risk and there are someÉ exciting new kinds of studies
underway right now that are aimed at identifying those genes. If
we can identify the genes, they might give us a clue about the underlying
biology linking back to the statement that you made about the biochemical
changes that we know underlie depression.
DR. REEF KARIM:
Are there any specific genes you guys are looking at that you can
discuss?
DR. FRANCIS MCMAHON:
Well one that has gotten a fair amount of attention over the last
five years or so is a gene known as G72 or DAOA and this is a gene
that was initially identified on chromosome 13, in a study ofÉ of
families with schizophrenia, interestingly enough. Subsequent studies
have looked atÉ families with bi-polar disorder and families with
depression.
And in each case there's been some evidence thatÉ this geneÉ accounts
for some ofÉ the risk for illness in those families.
DR. REEF KARIM:
Well how is research in the genetics depression conducted? Is itÉ
is it all twin studies, is itÉ is it more (unint.) what else, how
is it generally done?
DR. FRANCIS MCMAHON:
Well twin studies and family studies have been the traditional way
to establish that genes are important in the disease and there's
still some important family and twin studies of depression going
onto this day. But in the last 20 years or so, there's been increasing
interest inÉ the kinds of studies that can actually identify the
particular genes involved.
For awhile, genetic linkage studies were used to do that and those
are the kind of studies whereÉ where a large family or kindred is
studied using a genetic markers, looking to see whether particular
segments of chromosomes are inherited along with the illness within
a large group of families.
In general the genetic linkage studies have not paid off very well
for the common complex illnesses such as depression probably because
the story is too complicated and the linkage method doesn't have
good power in that circumstance. The new and exciting methods that
are being instituted over the last year or two, are called genome-wide
association studies.
The way these studies work is they don't require families at all
but can actually look atÉ direct comparisons between people who
have an illness and people who do not and look throughout the entire
genome, all chromosomes, looking for differences in particular molecular
markers that canÉ point to nearby genes as being involved in the
illness.
A large genome-wide association study of depression is currently
being conducted under the auspices of the National Institutes of
Health as part of what's called the GAIN study, the genetic association
information network. And this study isÉ is now through the genotyping
phase in that all the laboratory work has been done.
And is now in the hands of the statisticians and data analysts to
try to figure out what the signals are and what they mean. This
will really be the first look we've had atÉ at across the entire
genome of four genetic markers that maybe associated with depression.
So theÉ the results of that study are being anticipatedÉ by the
field with great eagerness.
DR. REEF KARIM:
What are these genetic markers that appear to make a person more
susceptible to depression? What would you say it is right now?
DR. FRANCIS MCMAHON:
Well the genetic markers are mainly a tool that we use right now.
In most cases we don't expect them to actually directly represent
the genetic change, the mutation if you will, that's actually contributing
to the illness.
But they cast a light that reaches a certain distance from them
and within that light often the actual genetic change that matters,
the one that leads to a biochemical difference, can be found. So
the strategy so far has been actually to select markers based on
their location and how easily they can be worked with in the laboratory
and then to use the information that comes from studying those markers
to undertake the harder work of actually mapping and identifying
the mutations that lead to the illness itself.
It might seem a little far fetched but this approach has actually
worked quite well for a number of diseases using a marker first
as an indication of where the genetic change of interest may lie
and then zeroing in on that change within the laboratory as a second
step.
DR. REEF KARIM:
Right. In the field of research we always talk about bench research
and then eventually how that leads to the development of innovative
treatment or how that alters how we actuallyÑhow the clinicians
actually treat individuals. How does learning about the genetics
associated with depression and even other mood disorders help with
treatment? How could it alter how we treat people?
DR. FRANCIS MCMAHON:
Well let me say right now it hasn't helped much at all because we
don't yet have enough specific information to be able to make conclusions
that we feel confident taking into the clinic. But the goal of these
sort of studies and it's a goal that we could reach within the next
decade are two things.
One, to use genetic markers to identify the genes that are actually
contributing to the illness. If we understand how those genes work
maybe we can understand what's gone wrong and devise ways to treat
it directly.
The second goal which actually might even pay off in the shorter
term is to use these genetic markers to identify people who are
most likely to respond well to a particular medication. These markers
may take up some of the same genes as the studies aimed at finding
genes involved in the illness but it might actually pick up other
genes as well.
The nice thing about those kinds of studies is we don't really need
to thoroughly understand how the genes work to be able to use the
markers to pick out people who will do well with a given treatment.
We know for example that with anti-depressants that only about half
of people who are treated with anti-depressants will respond well
to the first treatment, and that even after three treatments are
tried you're still only up to about two-thirds of people who were
responding well.
And that can sometimes take four, five or six months to get to that
stage. So what we really would like are medications that will work
at a higher rate the first time and will work more quickly. Genetic
markers might help us identify people who will respond particularly
well to particular medications.
By the same token, the markers can be used to identify people who
might have side effects from the treatment that would make it hard
for them to take an adequate dose or might actually cause them problems
while they're taking the medication.
We've been involved with a couple of studies related to a study
known as the ÒStar DÓ, which is a large depression study where outpatients
were followed over a period ofÑofÑof many weeks while being treated
with antidepressants or seen every two weeks in the clinic, asked
how they were doing and also asked to report any side effects they
were having.
Fortunately, about half of the people in that study also gave us
a DNA sample. We've been able to look in their DNA and try to correlate
the genetic markers with some of theÑtheÑthe study outcomes, such
as who does well with particular medications and who doesn't, who
has side effects and who doesn't.
And we've had some interesting leads on that. We're still waiting
for confirmation in other samples, but it shows us that this approach
can pay off and might actually move us toward a more personalized
kind of treatment in psychiatry.
DR. REEF KARIM:
That's interesting, yes, but I think the concept of personalized
treatment is so (inaud.) on geneticÑ you know, whether it's genetic
mapping markers or whatever you wanna call it, the genetic (inaud.)
that.
DR. FRANCIS MCMAHON:
Absolutely. And it's possible thatÑthat's [sic] genetic could play
a big role in treatment even when they don't play so big a role
in causing the illness in the first place cause we know genetics
are involved with the way in which drugs are absorbed, the way in
which they're metabolized, and also differences in the way they
work in different individuals.
DR. REEF KARIM:
Any last thoughts for our listeners, you know?
DR. FRANCIS MCMAHON:
Well, the main thing would be to tell people is that although they
may be suffering from these illnesses and may not have found good
treatments right now, that things are changing very rapidly. And
there's really good reason to be optimistic and to be hopeful that
in the coming years some real advance is gonna be made that will
allow us to treat these illnesses better and maybe even come up
withÑwithÑwith curative treatments that will really relieve people
from these illnesses that can be so devastating to lives and families.
DR. REEF KARIM:
Well, thank you so much for speaking with us today, Dr. McMahon.
DR. FRANCIS MCMAHON:
Pleasure talking to you.
DR. REEF KARIM:
We hope to see great things from the investigators of the National
Institution of Mental Health Genetics Unit when it comes to the
genes involved in depression. And join us next time for another
segment of the Down and Up Show on depressionisreal.org. I'm Dr.
Reef Karim.
