Understanding Bipolar Depression

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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


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


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


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


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


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.


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


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?


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


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.



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?


Attention deficit hyperactivity disorder.


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


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.


Once of your slides mentioned interpersonal and social rhythm


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.


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.


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.


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


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.


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.


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.


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.



Say a little bit more about the heritability.

I have trouble interpreting the 85% statistic you quotes.



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


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.