So I'm going to be talking
today about bipolar depression
in adults.
And I'm hopeful that I
can help you understand
more about bipolar disorder
in general through this talk,
and also provide an overview
about diagnosing this illness
and treating this
illness, particularly
during the depressed phase.
As Nora mentioned,
I have been here
at Stanford for quite some time.
Did my residency here and then
did a post-doctoral fellowship
doing research and clinical
work in bipolar disorder
under the mentorship
of Terence Ketter.
And for the past
couple of years,
have joined the faculty at
the Bipolar Disorder Clinic.
So I'm going to talk today
about first summarizing
clinical features of
bipolar disorder in general
for people who don't
have a lot of familiarity
with the illness.
And then talking about the
specific challenges and issues
that come up when diagnosing
bipolar depression in adults.
And then discussing some
of the other challenges
that come when you have to
approach treatment for bipolar
depression in adults.
So bipolar disorder is
a psychiatric illness
that involves basically what we
call in lay terms mood swings.
And more specifically
what we mean by that
is that people have fluctuating
periods of depression and mood
elevation.
And we call them mood elevation
episodes of mania or hypomania.
The illness can affect up
to 4% of the population,
depending on how
broadly you define it.
And one thing to remember
is that bipolar disorder
is a lethal illness.
It does have a risk of suicide
that's up to 20 to 30 times
greater compared to
the general population.
So it's an illness that
requires careful attention,
careful monitoring,
and treatment.
Bipolar disorder,
even if it doesn't
cause the more extreme
problems of suicide,
is also a leading
cause of disability.
And this is across the world.
Looking at the World Health
Organization's "Global Burden
of Disease Report," you
can see that globally
in males and females when we
look at a statistic called
Years Lost to Disability--
so basically looking
at the disability related
burden of bipolar disorder--
it is the seventh
leading cause in males
and the eighth leading
cause in females, which
is quite astounding given
that it only affects 1% to 4%
of the population.
So how do we diagnose
bipolar disorder?
These ideas and concepts may
be familiar to some of you,
but I wanted to make sure
that everyone understands
what bipolar disorder is.
So bipolar disorder has
two major mood states.
One is depression and the
other is mood elevation.
So you can diagnose
bipolar disorder
once someone has had a major
depressive episode as well
as a mood elevation episode.
And major depressive
episodes are characterized
by at least two consecutive
weeks of sadness or loss
of interest in your
usual activities or loss
of enjoyment of things
that would normally
be enjoyable to the person, and
in addition to those symptoms,
you need to have three or
four additional symptoms, some
of which are more physical,
like change in appetite, sleep,
and energy.
And some are more psychic,
like decreased self-esteem,
feelings of excessive
guilt, suicidal thoughts.
People are often also dealing
with difficulty concentrating,
indecisiveness when
they're depressed.
So there's some cognitive
changes as well.
And in addition to having
a major depressive episode,
what distinguishes
bipolar disorder
from unipolar
depression-- and we'll
talk more about that-- is the
presence of either a manic
or a hypomanic episode.
And for mania, you need
to have at least one week
of consecutive mood
elevation symptoms.
And for hypomania,
the requirement's
a little bit more lenient.
You only need four days in a
row of mood elevation symptoms.
And so what are the symptoms
that we're talking about?
There's a mood change.
So the mood becomes either more
euphoric, giddy, excitable,
or more irritable,
very easily frustrated,
losing their temper more easily
than they normally would.
Or those two mood states could
be occurring in combination
with one another,
and they often are.
And in addition, our recent
Diagnostic and Statistical
Manual of Mood Disorders,
DSM 5, was released,
and added the criteria that
in addition to these mood
symptoms, a person
also has to be
experiencing increased
energy or increased
goal-directed activity.
And beyond these
symptoms, one also needs
to be experiencing three or
four of these other elevations
symptoms like being more self
confident, more grandiose,
needing less sleep than usual.
This is a very common symptom
during an elevated state.
Being more talkative than usual.
Feeling like your
thoughts are racing.
Being more easily distracted.
For example, starting
one thing and suddenly
getting excited about something
else and forgetting the one
thing you were doing and
kind of moving around
multitasking, but often not
in a very productive way.
One probably would also
experience an increase
in their activity level.
Suddenly wanting to write
a novel, join 20 clubs,
stay up all night doing
some kind of new project
or cleaning the house.
So that's the kind
of thing that might
happen when someone's elevated.
They might also just
be physically restless,
needing to pace, walk around.
They can't sit still.
And impulsivity or risk taking
is also another common symptom
during an elevated state.
People will, for example, just
spend down their credit cards
or drive dangerously,
get into legal trouble
because they feel like
nothing could stop them
or they're not thinking
about consequences.
So mania, as opposed
to hypomania,
is really distinguished
by the severity level.
In addition to this
increased duration that's
required, in order to
qualify as a manic episode
the episode should be
pretty severe, enough
that it requires them to be
hospitalized for the episode.
They're psychotic
during the episode.
Or they're experiencing
really major problems
as a result of it.
For example, having
to declare bankruptcy
because they overspent too
much, losing their job, getting
divorced because they
created too many problems
in their marriage,
getting into jail.
These are the types
of severe consequences
that would accompany
a manic episode.
So putting that
all together, I've
talked about bipolar
disorder in terms
of major depressive episodes
and either manic or hypomanic
episodes.
And we divide bipolar disorder
into two key subtypes.
Bipolar I is someone who's
had at least one manic episode
in their lifetime.
They don't even have
to have had depression.
As long as they've had one
mania, they are considered
Bipolar I. Bipolar II
disorder is characterized
by having depressive
episodes as well
as at least one hypomanic
episode in one's lifetime.
And unipolar depression or
major depressive disorder
is characterized by having
only major depressive episodes.
And so what you can see is that
all of these mood disorders
are characterized
by fluctuations
from a person's baseline.
So if that black line is where
the person is when they're
feeling normal or well, you
can see in Bipolar type I,
you're getting these wide
fluctuations up and down.
In Bipolar II, you're
getting the downs and maybe
more mild fluctuations
above the baseline.
That's the hypomanias.
And in unipolar
depression, you're
really just getting
the down fluctuations.
They're not getting elevated.
So what can be
difficult about when
you're sitting in
a doctor's office
and they're trying to
determine if you have bipolar
disorder or unipolar or
major depressive disorder,
the challenge is that depression
looks pretty much the same,
more or less, whether
you're bipolar or unipolar.
And as a result, 40% to 60% of
patients with bipolar disorder
will get misdiagnosed
with unipolar depression
and subsequently
get, perhaps, a delay
in the appropriate treatment
that they should be receiving.
So why does this happen?
Maybe the patient can't remember
or isn't aware that they've
ever had mania or hypomania.
Maybe the psychiatrist
doesn't ask about it
or they're focused
on the depression.
There could be a lot
of different reasons.
Another big reason
is that about half
of bipolar disorder patients
experience depression
as their very
first mood episode.
So they've never even
had a mania or hypomania.
That's not going to
happen until later
in their course of illness.
And at the time they're
sitting in the doctor's office,
nobody knows yet that they
have bipolar disorder.
Now, that being said,
there are certain clues
that a person might, if
they're sitting in your office,
they're depressed,
and they may never
have been manic or hypomanic,
that they might actually
have bipolar disorder.
So there are
certain risk factors
that have been established.
If your first major
depressive episode
occurred at under
25 years of age,
that increases the
likelihood that you're
bipolar by two-fold.
If you have a first degree
relative with bipolar
disorder-- this would
be a parent or a sibling
or a child-- you're
two and a half times
more likely to be bipolar.
If you've had a
history of psychosis,
whether the psychosis occurred
during depression or mania
or hypomania-- and
in this case, we're
talking about
someone who's maybe
been psychotic during
depression-- then that's
a three-fold increase
in the likelihood
that you actually
have bipolar disorder.
Another thing to bear in
mind is that bipolar disorder
is a heritable illness much
more so than major depressive
disorder.
So if you compare
the two illnesses,
major depressive disorder
is much more prevalent
in the population.
As many as 10% to
17% of individuals
will have an episode
of major depression.
Bipolar I disorder, having
had a manic episode,
only occurs in about
1% of the population.
If you have a first
degree relative with one
of these disorders--
major depressive disorder,
if you have a first degree
relative with major depression,
your odds of having
major depression
go up about three-fold.
If you have a first degree
relative with bipolar disorder,
your odds go up tenfold
of having bipolar illness.
The identical twin risk.
You can see if you
have an identical twin
with major depressive disorder,
the chances of the other twin
having it are 20% to 45%.
Whereas in Bipolar
I disorder, it's
significantly
higher, 40% to 70%.
Although it's not
100%, which suggests
that there's more than
just genes involved
in the cause of
bipolar disorder.
And we don't fully
understand this illness
and the causes of it.
But what we do know, from
estimates of large data sets,
is that the heritability
of bipolar disorder,
which means that the
amount of the risk that's
due to genetic factors, is about
85% compared to only 30% to 40%
of major depressive disorder.
So what we can say to distill
it down to the simplest terms
is that in major
depressive disorder,
genetics and
environment probably
have a similar level of impact
on your risk for the illness.
Whereas in bipolar
disorder, genetics
have a far greater
amount of impact
on your risk of getting the
illness than your environment.
But the environment
still probably matters.
So talking more now
about bipolar depression.
Depression does account for the
majority of the illness burden
amongst patients with
bipolar disorder.
So these are based on
some longitudinal studies
in the NIMH collaborative
depression study
where patients were
followed over time
with sequential interviews.
And they were able to
estimate how much percentage
of time they spent in
different mood states.
And they separated this out
by Bipolar I and Bipolar II
disorder.
And as you can see in both
types of bipolar disorder,
about half the time
people are actually
symptom-free on average.
In Bipolar I disorder,
then another third
of the time they're depressed
and about 15% of the time
they're manic or mixed.
In Bipolar II disorder, you
can see it's almost like 50/50.
They're either depressed
or they are symptom-free,
with a very small
proportion of the time being
spent in a hypomanic
or elevated state.
And so this is important,
as patients with Bipolar II
disorder might
question whether they
have bipolar disorder
because they're
just always either
OK or depressed
and not the high periods.
And this really emphasizes
that that's classic.
That's not out of the ordinary.
Patients with
Bipolar II disorder
will tend to have a greater
burden of depression
in their illness than Bipolar
I. But you can see here
that depression in both
types of bipolar disorder
does predominate the
course of the illness.
Another important
thing to know is
that if you look at studies of
functioning in bipolar disorder
and you look at the impact
of depression on functioning,
it really has a dramatic
impact on occupational and just
general life functioning.
And it seems to be more
pronounced than the impact
that mania or hypomania
would have on functioning.
And it's important to
see here in this graph
that as you get more
symptoms of depression,
your overall functional
impairment increases.
But you can start seeing
that increase even
at milder sub-syndromal
levels of depression.
And so what's
going on this scale
is a depression rating score.
The higher numbers
are more severe.
And as you go up on
the y-axis, you're
seeing percent of people
impaired in their functioning.
And even at sub-threshold
levels of depression,
you're seeing a dramatic
increase in how many people are
impaired in their functioning.
So treating even milder
sub-threshold depression
symptoms can be an
important target.
And bipolar depression,
as you might expect,
has a large impact
on risk of suicide.
Now, what the
table shows is just
the risk of suicide in
bipolar disorder in general.
Attempted suicide, estimated
annual rate of 3.9%.
And death by suicide, the
estimated annual rate is 1.4%.
While these numbers, they're
all less than 5% or so,
you can still see compared
to the general population
they're manifold higher.
And suicide attempts
in bipolar disorder
are far more likely to occur
when people are depressed
or in a mixed state with
some symptoms of depression
along with mood
elevation rather than
in a manic or hypomanic state.
And individuals who over time
have more of a depression
predominant illness
that experience
a lot more depression
than mood elevation
are more likely to
attempt suicide than those
who tend to have more manias.
And depression and
bipolar disorder
affects not only the patients,
but their caregivers,
the family and friends who take
care of them when they're ill.
Bipolar depressive
episodes appear
to be associated with
a greater caregiver
burden than manic or
hypomanic episodes.
And increased
caregiver burden is
associated with
even the caregivers
becoming more depressed and
having more health problems.
So it's an important
thing to remember
that treating the
bipolar depression,
it's about treating the patient
as well as people around them,
making sure everyone
has support.
There's a lot of
great support groups
out there, if you're familiar
with NAMI or the DBSA,
Depression Bipolar
Support Alliance.
If you're a family
member dealing
with bipolar disorder
in a loved one,
it's really important
to get support
that you need because
this illness affects
everyone who's in the
circle around the patient.
Now, how do we treat
bipolar depression?
I'm going to provide a little
bit of an overview of bipolar
treatment in general,
but then hone in
on what we do for depression.
This is a lot more detailed
than you need to understand,
but the key takeaway
points from this chart
are that when we approach
the treatment of bipolar
disorder as doctors,
we tend to approach it
based on what phase of the
illness the person is in.
So it's not like there's one
treatment for bipolar disorder
period and you just use it.
You have to think about
what state the patient's in.
And so a lot of
the drugs are meant
to target the acute phase
of bipolar disorder,
and that can either be acute
mania or acute depression
or it could be an
acute mixed state.
And so drugs that get
FDA approval will get
approved for one
of those states.
Either they're
approved for mania
or they're approved
for depression
because the clinical
trials specifically
went after that mood state.
Once you're recovered from the
acute phase, then what you do
is you shift into this
what we call maintenance
phase of treatment
where the goal is not
to get you out of
the illness phase,
but really to prevent
or delay recurrence
of the depression or the mania.
And so there are specific drugs
that are FDA approved just
for maintenance.
And often, it's
the same drugs that
are used for the acute
phase will get also used
in the maintenance phase.
So these are the different
FDA approved agents
for bipolar disorder separated
out by the phase of illness.
One of the things to notice
here is that in 1970,
all we had was lithium, really.
And then chlorpromazine
came along in '73
and got approval for mania.
And then there was
a really long lag
there where there was really
nothing else going on.
And then in the mid '90s,
we realized that Depakote
worked for acute mania.
And then a lot of
interest came about
after that to look at the
other anti-convulsants
and see whether they might
work in bipolar disorder.
A lot of that didn't
really pan out.
It did turn out
that lamotrigine,
which you can see on
the longer term list,
looked very promising initially
for bipolar depression,
but it didn't really
separate from placebo,
but ultimately got FDA approved
for longer term maintenance
treatment of bipolar disorder.
And then most of the action
really happened in the 2000s
when the anti-psychotics
started getting approvals one
after another for acute mania at
first and also for maintenance
treatments.
But what you can really see
here is under acute depression,
we only have three FDA
approved treatments.
This is really the huge
unmet need in pharmaceuticals
for bipolar disorder.
And it's not that they haven't
tried some of these agents
for depression.
It's a lot of them
haven't proven to be
more effective than placebo.
So what we have now is
three FDA approved agents
for bipolar disorder.
Only three, despite
the fact that this
is the most prominent illness
phase in bipolar disorder.
So what I talked about in this
slide is efficacy, really.
So what drugs work,
what drugs beat placebo
in the clinical trials.
But the other side of
the coin is tolerability,
and this is a huge challenge
in treating bipolar disorder.
A lot of the
medications that we use
have really bad side effects.
And so one way to think about
it is the schematic here.
There's a pyramid showing
you at the bottom what
are the medications that tend
to have the fewest side effects.
And these will be things
like antidepressants
or newer mood stabilizers
like Lamictal or lamotrigine.
As you start going
up the pyramid,
you get drugs that have a more
moderate level of side effects.
And this would be older mood
stabilizers like lithium,
divalproex, carbamazepine.
And some of the more recently
approved second generation
anti-psychotics like
aripiprazole, ziprasidone,
asenapine, and lurasidone.
And then at the
top here, that tend
to have the highest
liability for side effects
are the older second generation
anti-psychotics, risperidone,
olanzapine, quetiapine, and
clozapine are listed there.
And if we were to put an
arrow showing efficacy,
it might go in the
opposite direction.
You tend to get the most
robust efficacy up at the top
and it tends to
get a little weaker
as you get to the bottom.
So we're always doing
this balancing act
of how to get efficacy
balanced with tolerability
with the medications
that we use.
And so that's really
one of the challenges
in treating this illness.
So what I'm showing you
here are the three FDA
approved treatments
for bipolar depression.
Olanzapine fluoxetine
combination, quetiapine,
and lurasidone.
And I've listed the most
common adverse effects.
And cost is also a
concern for many people.
Olanzapine fluoxetine
combination
was the first treatment
to get FDA approval
for bipolar depression.
Olanzapine alone
and fluoxetine alone
didn't seem to really cut it.
The combination of the
two synergistically
worked very well.
The downside, though,
is that olanzapine--
I don't know if you're
familiar with it--
has a huge risk of weight gain.
Upwards of half the people
who take it, maybe even more,
will experience significant
weight gain on this medication.
Metabolic side effects
go along with that.
Dyslipidemia, insulin
resistance, diabetes risk.
And it can be sedating as well.
Cost-wise, it's kind
of in the middle.
If you had to pay out of
pocket, it might be a little bit
difficult. But usually,
it's covered by insurance
because it is generic.
Quetiapine or
Seroquel is well known
for its sedating effects, which
sometimes is not a bad thing.
If you're having a lot of
insomnia or a lot of anxiety,
it can be calming.
But many people find that
it's just too sedating
to be able to tolerate.
And it can also cause
some weight gain and some
of the metabolic side effects.
Not as pronounced as olanzapine,
but the risk is still there.
And cost-wise, it's also
available in generics
and it's usually
covered by insurance.
Lurasidone was the most
recently FDA approved agent
for bipolar depression.
It's looking promising
in terms of tolerability
because it seems
more weight neutral.
Some people will gain weight
on it, but it's not common.
And it's not
particularly sedating.
The downside of lurasidone is it
can cause a side effect called
akathisia which is really
a feeling of restlessness,
an agitation.
And so people with
anxiety may not
like this medication so much.
It can also cause nausea.
And if your insurance
covers it, that's great.
Even if it does, you may
have a very high co-pay.
It's still pretty expensive.
It's not available in generic.
If you have to
pay out of pocket,
it's probably a deal
breaker for that medicine.
So these are our three options.
As you can see, they're
not by any means perfect.
They did prove their efficacy
in the clinical trials.
I have seen them
work in my patients.
But they have some
side effect liabilities
and/or cost liabilities.
So as clinicians, we
often start moving
to the non-FDA approved
medications as alternatives.
And I've listed the most common
ones here that you might see.
Lamictal or
lamotrigine, lithium,
and the antidepressants.
And lamotrigine gets commonly
used because, as I said,
in the earlier
clinical trials it
looked like there
was a signal there
where it was going to be
placebo for treating depression
in the acute phase.
And then when they
looked at more studies,
it wasn't replicated.
But because of that and
because of the maintenance
trials which show that it has
a good depression prevention
benefit-- meaning
once you're stable,
it seems to delay recurrence of
depression-- it's commonly used
to treat bipolar depression.
It's not an actual
antidepressant.
It's an anti-convulsant,
which maybe helps in
that it's not as likely to
cause a treatment related mania.
There is this rare
risk of a serious rash.
Very rare, but it's
life threatening.
So we go up very
slowly on the dose
so it takes longer to get you to
a therapeutic dose of Lamictal
or lamotrigine.
But it is quite inexpensive.
It's been available in
generic for quite some time,
and it's almost always
covered by insurance.
So you might see doctors
prescribing lamotrigine often
for bipolar depression.
Lithium is tried and
true first line treatment
for bipolar disorder.
There is some
modest efficacy data
suggesting it's better than
placebo for bipolar depression.
It's not as robustly effective
as the FDA approved ones
that I've already described.
Lithium has a laundry list
of potential side effects
that not everyone
will experience.
But the most common ones being
tremor, really excessive thirst
and urination, and
potential complications
for the kidney and the thyroid
that require monitoring.
It's very inexpensive and
almost universally covered
by insurance.
antidepressants.
Now, this is somewhat
more controversial.
They are amongst the most
commonly prescribed treatments
for bipolar disorder still.
They have some liabilities.
They tend to be
pretty well tolerated
in terms of side effects.
And this is probably
why they're commonly
used, in addition to
the fact that we just
have a lack of adequate
treatments for bipolar
depression.
There has in the past been
a lot of fear and concern
that giving an antidepressant
to a bipolar disorder patient
will make them manic.
This does happen.
It doesn't happen quite as
often as we thought it did.
And so we actually
have started thinking
this is more of a rare
potential adverse effect
of antidepressants, but not the
top of our list of concerns.
And particularly if you take an
antidepressant with something
that is anti-manic like
lithium or an anti-psychotic,
that risk seems
to be fairly low.
Most antidepressants
are pretty cheap
except for some of the brand
new ones that have recently
come out.
Most are covered by insurance.
So I want to spend
a little more time
on the antidepressant
thing because they
are so commonly prescribed.
They are a topic of
a lot of controversy.
The real problem
with antidepressants
is not that they're
going to make you manic
or there is the suicide
risk in younger people,
but that also is controversial.
What's really demonstrated
time and time again
in large studies, meta analyses,
is that they really just
don't work for bipolar disorder.
So what you can see
here is a meta analysis
of antidepressants in
acute bipolar depression.
Antidepressants
compared to placebo
yielded very similar
rates of response
in remission from depression.
And just to go back to
my earlier point here,
this is showing rates
of switch to mania.
So how often people
on these medicines
in these clinical
trials became manic.
And you can see they're
almost identical rates
in the antidepressant
and the placebo.
So there really
doesn't seem to be
this dramatically increased
risk with antidepressants
of getting manic.
But the main problem is really
that they're not effective.
We use them a lot because
certain patients do respond.
Do we know whether
they're really responding
or whether it's
a placebo effect?
No.
We'll never know that.
Do we know whether
they're responding
or if their depression was just
going to get better anyways?
We don't know.
But we do know that
antidepressants
are easy to tolerate.
They're cheap.
They're something to try when
the other medications are
either not feasible
or don't work.
We often add them to
other medications.
We do use these medicines.
I have seen them work.
But if you look at
large data sets,
it's just not supportive
of these medications
for bipolar disorder.
So something to bear in mind.
I wanted to touch on
adjunct of psychotherapy
in bipolar disorder.
It's not recommended that
someone with bipolar disorder
have psychotherapy alone
without medications.
It hasn't proven to
be effective enough.
You tend to need medications
plus psychotherapy,
and adding psychotherapy
to medications
is highly recommended.
It can be very helpful.
A few particular
types of psychotherapy
have been studied
in bipolar disorder.
That would be
family-focused therapy,
cognitive behavioral
therapy, and interpersonal
and social rhythms therapy.
And what some
studies have shown is
that outcomes are better if
you receive psychotherapy
plus medications as
opposed to meds alone.
It seems to be
that psychotherapy
is more effective for
relapse prevention rather
than the acute episodes.
So again, in that maintenance
phase of treatments,
adding psychotherapy can
prolong wellness and keep people
well longer than
just meds alone.
If you're actually in an
acute episode of depression,
it hasn't really panned out
that adding psychotherapy
speeds recovery.
There are some other
treatment modalities aside
from medications that we
might turn to if medications
aren't working.
The one at the top,
electroconvulsive therapy--
this might be
something you might
be more familiar with, it's
been around for a long time--
can be very effective
for treatment resistant
depression in unipolar
and bipolar disorder.
It is highly invasive.
Requires you often to be in
the hospital for the beginning
of the treatment.
You do need general
anesthesia to undergo
electroconvulsive therapy.
There are some
cognitive side effects
that some people just don't
want to have to deal with.
You can get memory loss.
You can get anesthesia
related adverse effects.
So you go to ECT when the
medications aren't working
and the depression
is severe enough
that both the doctor
and the patient
agree that this is
what needs to happen.
But it can work when
everything else has not worked.
I've listed here repetitive
transcranial magnetic
stimulation, rTMS.
This is a newer treatment.
It's not so new anymore.
It's now gotten FDA
approval for treating
treatment resistant depression.
It's a lot less invasive
and time intensive than ECT.
You can do it entirely
as an outpatient
and you don't need anesthesia.
You basically receive
local magnetic stimulation
to the scalp.
And it's unclear how
effective this is going
to be for bipolar depression.
There really isn't a
lot of data out there.
More data has been available
for unipolar depression.
But it might be
something to try if you
want to go the route of a
more intense intervention
but don't want to do the ECT.
It's probably going
to be expensive
because it's hard
to get insurance
to cover this treatment.
Ketamine is something that's
very novel, very experimental.
It's being studied.
Not available commercially
as a treatment.
But it's shown in studies to
have very rapid antidepressant
effects.
Now, most of the treatments
we have for depression
take six weeks, sometimes
eight weeks to work.
Well, ketamine
works immediately.
What they've been
looking at it in
is people who are very
depressed and suicidal.
They'll get the
ketamine IV infusion.
And almost immediately, the
suicidal ideation resolves.
Their depression lifts.
They're feeling better.
Unfortunately, the effect seems
to only last a few days, maybe
a week or two at most.
And then it goes away.
And they haven't yet
been able to find a way
to sustain the effect
without additional infusion.
So it's not a very practical
treatment at this point.
It's still pretty experimental.
The actual mechanism
is still in question,
whether this is something that's
really going to be sustainable.
But I list it here as
something that's exciting,
a new inroad into treating
difficult to treat depressions.
I wanted to end on a
positive note here.
I've done some
research in this area.
My mentor, Dr. Ketter, has done
a lot of research in this area.
Bipolar disorder is,
as I've mentioned,
a very disabling and
disturbing illness.
But there are some
things about it
that there could be a little
bit of a silver lining
here, that there is a link
between bipolar disorder
and increased creativity.
And we can see here,
many eminent individuals
who have suffered from
bipolar disorder, some of whom
have been public about it.
This is a study that
was done by Ludwig
who looked at over
1,000 biographies
of eminent individuals and
looked at rates of mood
disorders-- so not
just bipolar disorder,
but also unipolar depression--
in these individuals.
You can see clustered at the
top are the more creative arts.
Poetry, fiction, theater, music.
You can see that the
rates of depression
are quite a bit higher up
there than you see down
at the bottom where we
get the military, science,
public office type people.
And then also the
rates of mania seem
to be a little bit more
prevalent as you go up
into these more creative arts.
There's been a lot of
studies on this topic,
and this is just one example.
But it does seem to be
that bipolar disorder is
over-represented in
creative individuals,
and creativity may be
over-represented amongst people
with bipolar disorder.
And what it seems to be is there
is some kind of an interaction
here where bipolar disorder is
associated with a specific type
of personality or temperament.
And that, in turn, interacts
with the bipolar illness
to fuel greater creativity.
And so if you look at
creative individuals who
have no mental illness and
patients with bipolar disorder,
you can find a lot of
crossover in their personality
and temperamental traits.
It's just food for thought.
But it's something to feel
good about, that there might
be some strengths
despite the suffering
of the different illness phases.
So to summarize,
bipolar disorder
is a chronic and
recurrent illness.
It affects up to 4%
of the population,
is a leading cause of
disability around the world.
Depression really does account
for the majority of the illness
burden of bipolar disorder in
terms of both time spent ill
and amount of
functional impairment.
There's an unmet need for
effective and well-tolerated
treatments for
bipolar depression.
Creativity and
creative achievements
may be increased in people
with bipolar disorder.
This is potentially mediated
by personality and temperament.
Wanted to post some of
our current studies,
if you're interested.
We are doing a study right
now of a medicine called
Suvorexant, a recently
FDA approved treatment
for insomnia that we're
looking at in bipolar disorder
patients who have insomnia.
And that's for patients
ages 18 and older
who have bipolar
disorder, are currently
experiencing insomnia.
I've listed the
phone number there
you can contact if you're
interested in that.
Infliximab for
bipolar depression
is another study for
patients ages 18 to 65
diagnosed with Bipolar
I or II disorder
currently experiencing
symptoms of depression.
Please note that's a
different phone number.
There's two different phone
numbers for these studies.
And I'm happy to take any
questions at this point.
Go ahead.
Me?
Yeah.
Is it fair to say that there
is no quantitative diagnostic
technique for bipolar disorder
as well as other kinds
of mental disorders?
Is it fair to say that?
So the question is,
is it fair to say
there is no quantitative
diagnostic technique
for bipolar disorder as well
as mental disorders in general.
I would say at this point in
time it is fair to say yes,
that we lack that type
of quantitative data.
We're making great strides
in looking at genetics,
looking at other
types of bio-markers,
neuro-imaging that might help
us at some point in the future
be able to tell
what a person has.
At this point, we
are still, what we
might say, in the "dark ages."
We're really relying on what
the patient sits in front of us
and tells us.
We're relying on what their
family members tell us
about their behavior.
It's very clinically driven
interview and history based
diagnoses at this point.
And the folks at the National
Institute of Mental Health
are very unhappy
with the situation
and really want to
drive forth research
that looks at more
quantitative ways
to diagnose and understand
these illnesses.
A follow-up question to that
is that if that is the case,
then it makes your job, to
treat bipolar disorder with any
of those medications
and then try to assess
the efficacy of any treatment.
So the point was made, it
makes it very challenging, yes,
to diagnose and
treat the illness.
And as I've suggested,
it can be challenging.
We do look for certain
clinical markers
that suggest a risk of bipolar.
Back there.
I'm wondering if
you could comment
on the link between ADHD
and bipolar disorder.
How often do you see it?
Are they related in some way?
And with respect to ADHD in
a person that has bipolar,
can you prescribe Adderall?
Should they be using Adderall?
Good question.
So I was asked about the
link between ADHD and bipolar
disorder and how do you
treat-- specifically you're
asking how do you treat ADHD
in someone who has co-morbid
bipolar disorder.
So this is an issue
that comes up very often
amongst pediatric populations.
There does appear to be
some link and an increased
co-morbidity of
these two illnesses,
particularly in children.
What it seems to be is that
patients with bipolar disorder
have a higher rate of ADHD than
kids without bipolar disorder.
But if you look at
people with ADHD,
there doesn't seem
to be an increased
rate of bipolar disorder
amongst those patients.
But some people
would beg to differ.
But in general, it
seems to be the case.
So there is a link.
In adults, ADHD tends to not
be as commonly diagnosed.
There is some thought that
it burns out in adulthood.
So it comes up more and it's
better studied in children.
Can you treat the ADHD?
What is ADHD?
Sorry.
Attention deficit
hyperactivity disorder.
Yeah.
And can you treat it?
From what I've seen,
the risk is there
that the stimulant medication
can exacerbate the mood
symptoms and potentially
trigger mood elevation
if you start one of these
medicines in someone
with bipolar disorder.
But there have been
other researchers
who have argued that if you
adequately treat the bipolar
disorder with mood stabilizers,
anti-psychotics, et cetera,
that you can then
safely treat the ADHD
with careful
monitoring to make sure
that they're not experiencing
destabilization of their mood.
It's still tricky.
You got to make sure,
because these stimulants can
cause insomnia.
Insomnia is a big problem
in bipolar disorder,
and you don't want
to make it worse.
But I would say
it's controversial,
but there's an argument to be
made that if you adequately
treat the bipolar
disorder first then
you can start going on to
start treating the ADHD.
Are there any new medications
or treatment strategies,
maybe with less
medication, that you're
aware of that look promising?
So the question is are there
new treatment strategies
that maybe are non-medication
oriented that look promising.
So some of the ones
that I brought up here,
I don't know how promising they
are because that the data just
isn't there in bipolar disorder.
For rTMS, for example.
But this might be a treatment
that can be helpful.
It's a non-medication
treatment for people
who have failed to
respond to medications.
Ketamine, I know there was a
study in bipolar depression
that looked good.
But again, this has
its own limitations.
So there's other advances
being made in TMS
looking at specific parts
of the brain to target,
looking at different
modalities of TMS.
That's the new horizon of
what people are looking at.
But right now, I
think we're really
dealing with medications.
And most of the
development has been
in anti-psychotics,
which unfortunately
do carry a lot of side effects.
So we do have a great need for
more discovery in this area.
The answer to this
question is yes, please.
Is there any hope for food,
nutrition, foods or supplements
and exercise going with
the person's strengths
and lessening the medication?
So the question is can food,
dietary changes, or exercise,
more natural approaches, be
effective in bipolar disorder.
So there are some what we
call nutraceuticals that
have gained some attention.
These are things like
inositol, deplin--
which is involved in
folic acid, processing it,
somewhere along the
pathway of serotonin.
There's been some
excitement about these.
They haven't really
gone that far
or proven themselves that well.
But there are some doctors
out there who prescribe these.
And patients will say they
have maybe a mild or moderate
effect.
Food, I'm not as familiar with.
I know that maintaining
a healthy diet
and healthy exercise regimen
is always a good thing.
And exercise, in particular,
can be a mood lifter,
can be very helpful
in depression.
If you're dealing with bipolar
depression, unless it's mild
I would say that you're not
going to get much mileage out
of just doing these
natural things.
You are going to need
something more intensive.
But if you're on good
medicine and you're
getting a little bit of mild
depression, then certainly
I always recommend that my
patients get more active.
They start doing more social
things, being more involved.
And exercise, of course,
to maybe get themselves out
of it without having to
increase or add more medicine.
So there's some room for that.
It's not going to be really that
helpful in a very severe case
of depression.
But yes, good question,
thanks, In the back.
Has there been any history of
treating bipolar depression
with EMDR?
So the question is has there
been experience treating
bipolar depression with EMDR?
EMDR is a form of
psychotherapy that
has gained a lot of momentum in
the treatment of particularly
trauma related mental
illnesses like PTSD.
And I am not aware
of any studies
looking at this particular
modality in bipolar disorder.
Just speaking
anecdotally, I have
a number of patients who do
pursue that type of therapy.
They find it helpful
and therapeutic.
What we do know about
psychotherapy in general
is that the key
factor supporting
the success of the
therapy is the alliance
between the patient
and their therapist.
So there are these
evidence-based treatments
like CBT.
They are very good
for clinical trials
because they're manual based.
They're very regimented.
So you can study them in
these controlled fashions.
But I would say that if
you feel a good connection
with your therapist
and you're responding
well to whatever
their approach is,
it's probably going to help you.
Yes?
Once of your slides mentioned
interpersonal and social rhythm
therapy.
What is that?
What is that?
And what is the role?
In what phase of the
illness is it useful?
So I mentioned interpersonal
and social rhythm psychotherapy.
And what is that?
Where does it help?
So this was developed
out of Pittsburgh.
There is already a type
of psychotherapy called
interpersonal
psychotherapy that's
widely used in manual based.
Interpersonal
psychotherapy focuses
in on an interpersonal problem
in one's life and really hones
in on that as the source
of a person's distress
and tries to break that
down and work on it
over a number of sessions.
Interpersonal and
social rhythms therapy
is building on that model.
They're adding
into it a component
that was felt to be
particularly relevant
for bipolar disorder,
which is social rhythms.
The idea that your social
rhythm, your social routine,
your interpersonal patterns are
very important in maintaining
your mood stability.
So they will focus on aspects of
routine, medication adherence,
sleep, hygiene.
Things like that
are very important.
And what phase of illness?
Again, as I mentioned,
these therapies
have mostly proven to be
effective in the maintenance
phase, in delaying the
recurrence of mood episodes
when somebody's
achieved stability
rather than getting someone
out of an acute episode.
Yes?
What are options are there for
insomnia in bipolar disorder?
Well, one of them,
we're looking at here
in our study, Suvorexant.
But that aside.
So the question is what are the
treatment options for insomnia
in bipolar disorder?
The same treatment
options that you
would see for
anyone with insomnia
are often used in
bipolar disorder.
So the benzodiazepine,
sometimes we use.
The benzodiazepine-like
hypnotics, like zolpidem.
Or trazodone is commonly used.
Now, with bipolar disorder, we
often give very sedating mood
stabilizing medications anyway.
So sometimes we will
leverage that to try
to help someone sleep.
So quetiapine, for
example, if we're giving it
for a mood stabilizing
medication,
will often help treat
insomnia as well.
If somebody can't handle the
high enough dose of quetiapine
to get the mood
benefit out of it,
sometimes we'll use a low
dose of quetiapine just
to get sleep better on track.
Dr. Ketter likes to
use clozapine for sleep
in patients with very
refractory insomnia who
have taken boatloads
of other medicines
and aren't responding.
So clozapine's an
anti-psychotic that
requires a lot of monitoring
with blood levels.
And you check your
white count once a week.
But it's a very
sedating medicine.
It can help people with
refractory insomnia.
So I would say using
the standard sleep
medicines that are out there.
And if those fail,
then trying to go
to the anti-psychotics
which have sedating effects
is a common strategy.
Yes?
Is there any
information out there
regarding the use
of medical marijuana
in treating bipolar at all?
So the question was raised
as to any data or information
on medical marijuana
for bipolar disorder.
To my knowledge, there aren't
any really big studies on this.
I tend to think if
someone's using it,
it's probably
going to help them,
if anything, with sleep, maybe
a little bit with anxiety.
It's probably not
going to do anything
for depression or mania.
And so that's just based
on clinical experience.
Studies need to be done.
I haven't seen any
big studies on that.
Yes?
You didn't mention this,
but what is rapid cycling?
What is rapid cycling,
is the question.
Rapid cycling is defined
as having four or more mood
episodes within a
12 month period.
I didn't talk about
it specifically.
It's kind of a whole
other area of discussion.
It does affect what
sort of treatment
you may want to choose.
If you have rapid
cycling depression,
you may be having lots
of episodes of depression
in the same year or
you may have depression
alternating with mania or
hypomania throughout the year.
We tend to think that
anti-convulsants like Depakote
or lamotrigine might be better
for rapid cycling bipolar
disorder.
But you can still try lithium.
You can still try
the anti-psychotics.
There aren't a lot of
great studies on treatments
for rapid cycling.
But the common
thinking is that you'd
want to switch to an
anti-convulsant to try
to get that under control.
You want to avoid
antidepressants
in rapid cycling.
That's another thing, because
they might exacerbate it.
Are there any injectables
medications for bipolar?
The question is are there
any injectable medications
for bipolar disorder.
Yes.
Particularly for the
maintenance phase of treatment.
Risperidone
long-acting injectable
is FDA approved
for the maintenance
treatment of bipolar disorder.
Injectable medicines, much more
commonly used in schizophrenia.
But they can be very helpful for
patients who are having trouble
sticking with their meds,
who go off their meds,
but they have good family
support and good provider
support and they're able to
get into their doctor's office
once every month or every two
weeks to get the injection.
So risperidone is
the only one that
is approved for
bipolar specifically.
But any of the other ones--
aripiprazole or paliperidone--
could also potentially be used.
Yes?
How do you distinguish between
schizoaffective disorder
and a psychosis
associated with mania?
Those are two separate
things, I think,
and how do you
distinguish those?
The question was
asked how do you
distinguish between
schizoaffective disorder
and psychotic mania.
That's a good question.
And if you're in the hospital
with a psychotic episode
where you're also manic, it's
hard to know at that moment
whether there is
a schizoaffective
or a bipolar disorder.
And the difference being
schizoaffective disorder
is a much more predominately
psychotic illness
where the patients would
be psychotic even when
they're not in a mood episode.
Whereas bipolar disorder, if
you're going to be psychotic
it has to be limited to
the actual mood episode.
And the psychosis
won't occur outside
of the depression or the mania.
So it's a tough one to call
if you're in the hospital
and you just see a
snapshot of that patient
in a moment in time.
You really need the
longitudinal follow-up
to understand if the
psychosis persists even when
the mood episode resolves.
And that would lean towards
a schizoaffective diagnosis.
Yeah.
Does the intensity of
an individual's bipolar
change over their lifetime,
or does it stay steady,
or is there a lot of
individual variation
when you look at one
individual over time.
I'm sorry, what was the
first part of your question?
Does the what?
The intensity of--
The intensity.
--bipolar or the degree
of the bipolar condition,
does it change over
time on one individual,
or is there a lot of
variation on that?
Is that a predictable path?
Does the intensity
of the illness
change over time
within individuals
in a predictable way?
So there are
theories about this.
There is an argument
of something
called kindling theory.
Robert Post came up
with this theory,
that it's like a
seizure disorder
where one seizure
begets more seizures.
And epilepsy kind of
progresses in that manner.
So he likened bipolar
disorder to epilepsy,
saying episodes
beget more episodes.
So as the illness wears on,
episodes come more frequently,
they're more spontaneous,
less related to stressors.
So that's a model of illness
progression suggesting
the illness gets more
intense over time.
What we have seen in reality,
actuality, doesn't necessarily
support that.
We do see a lot of variability
across individuals,
that some will do
better over time,
will get the memo that they
need to take their meds,
and they'll stay
on them and they'll
function better and be OK.
Other people, you do see
the progressive pattern
where they'll get
worse over time
despite how much you treat them.
So I think there isn't really
an easy answer to that.
There's a lot of heterogeneity.
And now even with
introducing these subtypes
of bipolar disorder,
Bipolar I and II,
you're going to see even more
variability in how the illness
course proceeds.
We have enough time,
one more question.
Someone I haven't heard from.
You.
Good.
Say a little bit more
about the heritability.
I have trouble interpreting
the 85% statistic you quotes.
Yeah.
OK.
So do you want me to
go back to that slide?
Not necessarily.
All right.
So the question was asked
as far as heritability,
how do you interpret the
85% heritability of bipolar
disorder.
Those heritability
estimates come
from family and twin
studies, looking
at how much the illness hangs
together within a family,
for example.
And you guesstimate from
that how much of the illness
is due to genetics.
So the 85% heritability is a
way of saying that about 85%
of your risk of the illness
is due to genetic factors
rather than other factors such
as environmental stressors,
geography, things like that.
So the 85% suggests
that bipolar disorder
is a very heritable illness.
And we could see
that in family trees.
You could see it with
this increased risk
with first degree relatives.
That's really the
take home message,
that bipolar
disorder is something
that runs in families.
There are genetic aspects of it.
We haven't yet
discovered the gene.
There's no gene,
apparently, that
causes bipolar disorder,
which has been disappointing.
But we can't really
say where that risk
is coming from in terms
of specific genes.
But we do know there's a
large, large genetic component
to the illness.
Thank you, Dr. Miller.
You're welcome.
[APPLAUSE]
