[MUSIC]
It's a pleasure to be here today and it's
a pleasure to speak with you.
I can't tell you how flattered I am that
my good friend and mentor,
Dr. Dilip Jeste invited me to
participate in this symposium today.
Having been an undergraduate, a medical student,
a resident, and for a while
a faculty member at UC San Diego,
I really do consider it a home in many ways and
a place that I'm very grateful to for
the wonderful training and education I've gotten.
These are my recent conflicts of interests,
and these are my collaborators.
The best ideas come from working with many wonderful,
intelligent, talented, and generous
people and I do want to acknowledge them.
We're going to first talk a
little bit about inflammation.
Inflammation has become
a really important concept in health.
However, I think it's a concept
that at times is poorly understood.
By that, I mean the following.
We need inflammation.
We need normal inflammation,
acute responses to irritants, to frostbite,
to cuts, to trauma,
to allergic reactions,
to infections in order to
heal and to preserve the integrity of our body.
Where we run into difficulty is when we have
chronic inflammatory state such as
rheumatoid arthritis, auto-immune diseases.
There seems to be linkages to cardiovascular disease,
cancer, and Alzheimer's disease.
When you have a chronic inflammatory state,
there are a host of changes that occur in the body.
I just want to highlight a couple of those right now.
One is the presence of depressive symptoms and fatigue.
Others include problems with
the immune system and in particular,
real shifts in certain components of the immune system
that alter our stress hormones and
alter a lot of different responses in our body.
Another shift that occurs is that
we go from a normal balance between
parasympathetic and sympathetic tone to a balance where
our fight or flight where sympathetic tone is enhanced.
This all can lead to
really problematic concerns throughout the body,
but I want to focus on the brain for a minute.
In this slide, what you see on the left-hand side
is a brain scan of a person
who has Parkinson's disease and depression.
What the red there represents is
increased oscillatory burst activity
that is due to a decrease in
brain compound called dopamine in the brain.
What one sees on
the right-hand side is inflammatory depression.
In this case, it was induced
by a treatment used for hepatitis C
and for treating melanoma, interferon-alpha.
What again you see is the same type of
increased burst activity suggesting
a decrease in dopamine in the inflammatory depression.
In this slide, what we have are a group of
people that were recruited in with depression.
By measuring a certain stable,
more stable protein that is a marker of
inflammation called C-reactive protein or CRP.
What we see is that
some people with depression have low levels of CRP,
some have intermediate levels
and some have high levels of CRP.
The other thing that these two slides show us
is that in people with more inflammation and higher CRP,
they also have higher levels of
another neurotransmitter in the brain called glutamate.
We're seeing with inflammatory depression in
decreased dopamine levels and increased glutamate levels.
This increase in glutamate level is not only
associated in slide A with
worsening depression symptoms but in slide B,
it's associated with a decreased motor speed,
the ability to tap your finger rapidly.
In slide C what you're seeing is
that you have a decreased reaction time
associated with increased glutamate
in the basal ganglia, the brain.
In D, what we see is there's a decrease in
cognitive flexibility associated with it.
We're seeing with inflammatory depression,
changes in neurotransmitters and
changes in neuropsychological functioning.
What we also see is a dissociation
between the brain electrical activities
in different parts of the brain,
and in particular the frontal part of the brain,
which is really used for thinking
and controls other parts of the brain,
particularly more primitive parts of the brain.
In this case, the frontal part of the brain is
disassociated from the basal ganglia
where there's that increased glutamate.
Some people have inflammatory depression
and these people have changes in
the connectivity in their brain as well as
in discrete functions and neurotransmitters.
That's what this summary slide talks about there.
What I want to do is talk a
little bit about omega-3 fatty acids,
in particular, DHA and EPA or EPA.
Omega-3 fatty acids cannot be
synthesized de novo on the body.
You have to eat foods that are rich in
Omega-3s in order to have them in your body.
Omega-3 fatty acids are important because they're
part of the membrane of neurons and cells.
Also what we're going to focus on is that they
also are important for decreasing inflammation.
The first study I wanted to briefly discuss was
a study that we did with Mass General Hospital.
We looked at 177 people gotten a variety depression,
and they were treated with one gram of EPA omega-3,
one gram of DHA omega-3,
or placebo for eight weeks.
We had hypothesized that
if we were going to see a response to the omega-3s,
it was going to be in those people with
depression who also had chronic inflammation.
What we were able to show in this study
were a couple of important points.
One was that the more
your BMI increase the more access weight you had on you,
the more likely you were to have higher levels
of CRP and other inflammatory markers,
and the more likely you were to have dysregulation
in hormones that are
associated with fat, leptin and adiponectin.
What we also showed in this study is again,
there was a really tight correlation
between weight change and
the number of positive markers
that one had of inflammation.
It was highest in obese women.
It was a much stronger finding with 93 percent of
obese women having a minimum of one inflammatory marker,
and almost 50 percent having 4-5 inflammatory markers.
The same held in with men,
but the finding was not nearly as strong.
What we also showed in that study,
and this is a complicated slide,
but what you see with the 4-5 marker group is
that if you had 4-5 markers
of inflammation and you were treated with EPA,
you had a really large decrease
in your symptoms of depression,
more than 11 points.
This was associated with
what we call a really large effect size.
An effect size is a measure of
really how different the changes are from,
in this case, either placebo,
or if even from
the other active treatment DHA and in this case,
EPA at one gram a day cost
a really profound decrease
in these symptoms of depression.
However, if you had no markers of inflammation,
you did worse with EPA than you did with placebo.
We think this talks about the fact that you want to use
the right treatment with the right person and
that if you use treatment shot gun with everybody,
they're going to be some people wear that
treatment doesn't work,
and in fact makes people worse.
This study led us to an additional study that
was the first experimental therapeutic study
actually funded at NIH,
and the first experimental therapeutic study
funded by the National
Center for Complementary and Integrative Health.
This involved our colleagues at
Mass General and my team at Emory at the time,
we looked at three different doses of
omega-3 fatty acids of one gram a day of EPA,
two grams a day of EPA,
four grams a day of EPA or placebo.
What we were trying to see is,
is there a certain dose that was better than other doses?
What we found when we were looking at
a sustained effect over 12 weeks,
which dose of EPA had most people get better,
have at least a 50 percent reduction in symptoms.
What we found was that
four grams of EPA a day had a profound effect
on the number of people who got better with
a significant reduction in depressive symptoms.
What we also showed was
that fur gram a day that was associated with
decreasing depressive symptoms was also associated
with decreasing inflammation as measured by CRP.
We were really interested
in omega-3s for the following reason.
What you see here is what happens
acutely if you get inflammation going on.
Well, most of the treatments that we use,
you see all those ads on TV for infliximab.
You see these ads for all of these different biologics.
What these biologics are
doing is forming monoclonal antibodies
that then bind to and
inhibit the production of pro-inflammatory cytokines.
What they're doing is inhibiting somebody
from having a normal immune response,
or in certain cases,
an exaggerated immune response.
But what that means though,
is that it may make you more susceptible to getting
ill if you get an infection or something else happened.
We were interested in omega-3s because what omega-3s work
on is resolving inflammation.
They're not inhibiting an inflammatory response,
they are working on the other part.
If you have inflammation,
how does the body normally resolve it?
As it turns out,
the major mediators of the resolution of inflammation
are synthesized in the body
from omega-3 fatty acids, EPA and DHA.
We're really interested in that resolving of it.
If one looks at our bodies and biosynthesis,
the Western diet is very high in omega-6 fatty acids.
It's high in processed foods,
it's high in a lot of the meat products that we eat.
Omega-6 fatty acids tend
to predispose our body to produce
compounds that are called leukotrienes and things
that enhance
inflammation and then stimulate inflammation.
All that work on the Mediterranean diet and the idea
of vegetarian diets.
What those tend to do are those are diets
that tend to shift you away from
omega-6 foods and towards omega-3 rich foods,
like flaxseed, fish, seaweed.
In particular, EPA and DHA produce
these anti-inflammatory compounds that are
called resolvents and [inaudible].
We were interested to see if you increase the amount
of EPA a lot as we did with four grams a day.
What does it do to these pathways?
The reason why we're interested in
the resolvents is that an animal models,
they have antidepressant effects,
particularly in animal models of inflammatory depression.
Lo and behold, here you see that baseline placebo,
the one gram group,
the two gram group,
and then the four gram group.
What you see is that once you add the omega-3s,
you'd get a dose-dependent increase
in these precursors of the resolvents,
like 18-HEPE,
which also has anti-inflammatory properties.
But what you really see is
a dose-dependent increase in these resolvents.
In fact, if you look at RvE3,
you go from essentially none to
a large number of these resolvents being present.
Conversely, if we look at that inflammatory pathway,
the arachidonic acid pathway,
what happens is the four grams a day of EPA ends up being
a competitive substrate for the enzymes that are
normally shifted towards
producing inflammatory molecules.
The four gram swamps that pathway and pushes it towards
an anti-inflammatory pathway that's called LOX B4.
We're seeing that the omega-3 supplementation
at high doses in
inflamed individuals are shifting
a host of metabolic pathways towards anti-inflammation.
When we looked at folks that were responders
in that four gram group because not everybody got well,
but what we saw in those people
that did respond was there was
a massive increase in this pro resolving molecule,
18-HEPE, significant increases in resolvents E2 and E3,
and a really large decrease in
hs-CRP when you contrast
it to the folks that didn't get better.
Where are we going? One of the things I'm really
excited about is that
with Dr. Justin and his team at UCSD,
we're engaged in a foresight grant application
with the University of Utah,
UC San Diego and the Stein Institute,
Mass General Hospital, and Emory University.
Then in another study
I have going on with Mass General and Emory,
we're looking at augmenting
with omega-3s in treatment resistant depression,
people that don't respond to anything else.
I really want to thank you for
your patience with me today
and for taking the time to listen to my talk.
[MUSIC]