The Science & Treatment of Bipolar Disorder | Huberman Lab Podcast #82

- Welcome to the Huberman Lab Podcast,

where we discuss science and science-based tools

for everyday life.

[upbeat rock music]

I'm Andrew Huberman,

and I'm a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today we are going to be discussing bipolar disorder,

often called bipolar depression.

Bipolar depression is a condition

in which people undergo massive shifts

in their energy, their perception, and their mood.

However, it is very important to note

that these shifts in mood, energy, and perception

are all maladaptive.

They can often cause tremendous damage

to the person suffering from bipolar disorder

and tremendous damage to the people in their lives.

Today we are going to parse the biology

that leads to these shifts in mood, energy, and perception.

And we are going to talk

about the various treatments that exist.

Some of those treatments have been around

for a very long time,

and indeed one of those treatments, lithium,

has an incredible backstory about its discovery

and in understanding how lithium works

and some of the ways in which it does not work well,

it reveals a tremendous amount

about how the brain works normally in all individuals.

So that's a miraculous story that I look forward

to sharing with you.

As we go forward in this discussion about bipolar disorder,

I want everyone to keep in mind

that it is a very severe condition.

In fact, people suffering from bipolar disorder

are at 20 to 30 times greater risk of suicide.

So today is a serious discussion

and it's certainly one in which people

who are suffering from manic bipolar disorder

or who know people that are suffering

from manic bipolar disorder can benefit from.

However, for those of you that might know people

or who themselves suffer from major depression,

we will also be talking about important

treatment developments for major depression.

Major depression is a very common thing for many people.

In fact, most people will suffer from depression

of some sort at some point in their life,

although not necessarily a major depressive episode,

and yet major depression is very common.

So you'll soon learn up to 20% of people

will suffer from major depression.

So today's discussion will encompass all of that.

And it will also encompass basic brain mechanisms

of neuroplasticity, the brain's ability to change

in response to experience both for good and for worse.

And you'll learn a lot about the basic biology

of how the brain regulates mood, energy, and perception.

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Before we dive into the discussion

about manic bipolar disorder,

I want to highlight some recent findings

in an area totally separate from mental health

that I think are really important for everyone

to know about.

This is a paper published in the journal Cell,

which is a Cell Press Journal, an excellent journal.

In fact, one of the three apex journals.

So for those of you that are curious,

papers published in the journal Nature, Science and Cell

are considered the sort of Super Bowl,

Stanley Cup, and NBA championships of publishing.

And this paper entitled,

an inter-organ neural circuit

for appetite suppression illustrates

a very important principle that I think everyone

should know about,

and that's the principle of so-called parallel pathways.

Parallel pathways, as the name suggests,

are pathways, they could be neural pathways

or hormonal pathways or otherwise

that operate independently of one another

to accomplish a common goal.

And what this paper really shows

is that there's a set of peptides in the body

and the peptide that I'm referring to today

is called GLP-1, Glucagon-like peptide-1,

and some related peptides.

I've talked about these on the podcast before

for two reasons.

First of all, I'm a big proponent and consumer

of yerba mate.

Yerba mate is a tea that can promote the release

of glucagon-like peptide-1.

And there are also new prescription drugs

that are now hitting the market.

And for which there are really impressive clinical trials

for diabetes and obesity

that are essentially glucagon-like peptide-1 stimulator,

so they stimulate the release of that,

or they are in fact, a synthetic version

of glucagon-like peptide-1.

what is glucagon-like peptide-1?

It is a peptide, which is a small little protein,

that can dramatically suppress appetite.

So that's why these drugs are being explored

and are showing quite impressive results

for things like treatment of type 2 diabetes

and other forms of diabetes, as well as obesity.

So they lead to weight loss.

Now in terms of the yerba mate stimulation

of glucagon-like peptide-1,

that's going to be a much lower amount

of glucagon-like peptide-1 that's released

from drinking yerba mate as opposed to say,

taking a drug that stimulates GLP-1

or taking a drug that is GLP-1.

Nonetheless, should also point out

that yerba mate comes in a bunch of different forms.

There is some concern about certain smokey-flavored forms

of yerba mate being carcinogenic,

so that's why I avoid those forms of yerba mate.

But for me, yerba mate is one

of the preferred sources of caffeine.

For me, I like the way it tastes.

It does provide that sort of caffeine kick

that I like to have early in the day

for focus and for work and for exercise.

And yet I actively avoid the smoked varieties

of yerba mate because of the potential

carcinogenic effects of the smoked varieties.

Glucagon-like peptide-1, as I mentioned earlier,

can suppress appetite.

But what this paper shows is it does that

by at least two mechanisms through parallel pathways.

What this paper shows is that glucagon-like peptide-1

axon receptors in the body in a portion

of the nervous system called the enteric nervous system,

E-N-T-E-R-I-C, enteric nervous system.

This is a component of your nervous system

that you don't really have control over,

it's autonomic or automatic.

GLP-1 binds to what are called

intestinofugal enteric neurons,

you don't need to know the name,

but those neurons do two things.

First of all, they cause some gut distension,

so they actually make you feel full.

This is incredible, right?

A peptide, not actual physical food,

but a peptide that stimulates neurons

that cause changes in the so-called mechanoreceptors

of the gut, of the enteric nervous system

and make people feel full.

So it can lead to actually mild,

or I suppose if levels of GLP-1 are very high,

to major gut distension.

I think that the levels of GLP-1 that would come

from drinking yerba mate

and hopefully from appropriate dosaging of

the synthetic forms of GLP-1 or drugs that stimulate

GLP-1 would cause mild, not major, gut distension,

'cause major gut distension would be uncomfortable.

So GLP-1 is acting at the level of gut

to increase gut distension,

and by way of a pathway that goes from the gut

up to the hypothalamus, this little cluster of neurons

about the size of a marble that sits above

the roof of your mouth, is also suppressing appetite

through brain mechanisms.

So this is really beautiful, right?

You have a peptide, a small little protein

that's released in the gut

and that release within the gut causes gut distension,

which makes you feel full.

And by way of neural stimulation of the hypothalamus

also activates neural pathways within the brain

that trigger satiety, the feeling of having had enough food.

So to me, GLP-1 is both impressive and important.

Why?

Because this recent category of drugs

that's now hitting the market

seems to adjust obesity or can help people with weight loss

in order to help their health.

And it's doing so by at least two mechanisms.

One is within the brain, and the other is within the gut

and communication through the so-called gut brain access.

Because again, these enteric neurons

are communicating to the brain, the hypothalamus,

by way of this, what's called

the sympatho-gastro-spinal-reticular-hypothalamic pathway,

you absolutely do not need to know all of that.

That's a mouthful,

that's enough to make your mouth feel distended.

But at the same time, things like yerba mate,

and I'm sure there are other compounds out there as well,

but certainly yerba mate can stimulate the release of GLP-1.

So for those of you that are looking

for some mild appetite suppression

and want to accomplish that while also ingesting caffeine,

yerba mate might be a good option for that.

And just know that it's operating through two mechanisms,

on the body through mild gut distension

to make you feel full,

and on the brain to increase satiety

and make you feel less hungry.

And then for everybody, not just those

that are interested in appetite suppression,

I think it's important to understand

that these parallel pathways are fundamental

to how we are organized.

Another good example of this would be

when we are excited by something positive or negative,

so it could be stressful or we are positively aroused,

there is a parallel activation of epinephrine, adrenaline,

both from your adrenals and from an area in the brain

called the locus coeruleus.

So again and again, we see this in biology

and in neuroscience that your brain and your body

are acting in concert.

They're acting together through mechanisms

that either are independent, so separately in the brain

and separately in the body,

but directed towards a common goal,

or through communication between brain and body,

and almost always that communication

is going to be bidirectional,

body to brain and brain to body.

So I think these results are really interesting

and really important for sake of weight loss,

for sake of appetite suppression,

and just generally for the way that they illustrate

this very important theme

of the way that we are constructed

at a biological level which is parallel pathways.

Before we begin, I'd like to emphasize

that this podcast is separate from my teaching

and research roles at Stanford.

It is however part of my desire and effort

to bring zero cost to consumer information

about science and science-related tools

to the general public.

In keeping with that theme, I'd like to thank

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Let's talk about bipolar disorder.

And today I'm going to refer to bipolar disorder

interchangeably with bipolar depression,

although as you will soon learn,

not everyone with bipolar disorder

necessarily goes through highs and lows.

There is a subset of people who suffer

from bipolar disorder who experience the manic phases,

the highly elevated mood and energy,

and then drop down to so-called baseline,

so they don't necessarily go down into a depressive state.

They often will return to a somewhat normal state.

In fact, we will talk about the percentage of time

that people with bipolar disorder

tend to be symptom-free manic or depressed

in the context of the different categories

of bipolar disorder.

But as we wade into this topic that is bipolar disorder,

I just want to give you a little bit

of the background statistics

to anchor us in just how serious and prevalent

bipolar disorder is.

So bipolar disorder impacts about 1% of people,

that might seem like a small percentage,

but if you think about a room of a hundred people,

that means that at least one of them

is very likely to have bipolar disorder.

And as I mentioned earlier in the introduction,

bipolar disorder is very serious.

It has a 20 to 30% greater incidence of suicide

than the general population, which is,

first of all, extremely tragic

and extremely concerning.

So anyone that thinks they might have bipolar disorder

or who knows someone with bipolar disorder

should be especially vigilant about this.

And we'll talk about some of the,

or signs and risk factors, age of onset,

et cetera, as we move forward.

So 1% of people have bipolar disorder.

The typical age of onset is anywhere from 20

to 25 years old, although it can be much earlier.

And the earlier the onset of a bipolar episode,

which we will define in a few minutes,

the earlier the onset of that episode,

the higher likelihood that the bipolar disorder

is going to be a stable feature

of that person's psychology going forward.

And yet, I also want to point out

that there are some very good treatments

for bipolar disorder that those people

could still benefit from.

There are basically two kinds of bipolar disorder

referred to as bipolar 1 and bipolar 2.

So let's just talk about bipolar 1 first.

Bipolar 1 is characterized by

a fairly extended period of mania.

What is mania?

Mania is a period of very elevated mood,

energy, distractibility, impulsivity,

and some other symptomology that we'll talk about

going forward.

But this manic episode is extreme.

This is a condition in which the energy lift,

the mood lift, and the sort of impulsivity

and actions and words of the person

suffering from manic bipolar disorder

are very noticeable and very extreme.

Now a key thing, however,

is that it's not always noticeable

to the person suffering from it

that they are in this mode.

Sometimes they recognize that, sometimes they don't,

but it's always highly recognizable to other people

that the person suffering from manic bipolar disorder

is not like other people.

So let's talk about bipolar 1 in a little bit more depth.

One of the key clinical criteria

or diagnostic criteria for bipolar 1

is that a person suffer from these manic episodes

or display these manic episodes

for seven days or more.

That turns out to be very key.

The stability of that manic episode

for seven days or more turns out to be very important.

And for those seven days,

the person is in an elevated mood,

expansive thought all day, every day for those seven days.

Now there are a lot of reasons

why somebody could be in a manic mode.

It doesn't necessarily mean

that somebody has bipolar disorder.

In fact, someone could be in a manic mode

for seven days or more

and still not be diagnosed with bipolar disorder.

Why?

Well, there are other things that can create manic episodes,

things like traumatic brain injury, things like seizure,

things like various prescription drugs or illicit drugs,

things like amphetamine and cocaine,

that is not the same as bipolar disorder

even though from a symptomology perspective,

they might look even identical.

So let's think about these symptoms

and the diagnostic criteria that a psychiatrist would use

in order to ask whether or not someone is manic

because they have manic by bipolar disorder

or whether or not that person is manic

for some other reason, such as traumatic brain injury,

illicit drugs, et cetera.

So typically a person would be brought into a clinic

or a person would bring themselves to a clinic

or meet with a psychiatrist,

it seems more likely that they would be directed

toward a psychiatrist because oftentimes

people who are in a manic episode

just simply won't have the perspective

or the foresight to bring themselves into the clinic.

And the psychiatrist is going to start to evaluate

for a couple of different things.

But first of all, what they're going to try and figure out

is whether or not the person has at least three

of the following symptoms.

The first symptom is distractibility.

Is the person distractable?

Are they going from one thing to the next.

People who are in a manic episode

will be talking about a pen

and then they'll be talking about something they saw

the other day and then something they want to purchase

and then a place they're going to travel to, et cetera,

but they are also very prone to any stimulus

within the room.

Meaning a bell could go off

or there could be a sound out in the hallway

and they'll orient to that.

And then they'll orient to the clinician

and then they'll orient to something in their pocket,

so they're all over the place.

You could think of this a little bit like ADHD

or attention-deficit disorder, but it's very extreme.

So highly distractable,

highly impulsive, impulsivity relates to actions.

So the person might be fidgeting with something

and then they might try and leave the room

or the person might, if they were out in the real world,

somebody might notice that the person

is going and purchasing

multiples of something that would be unusual for someone

to purchase.

So for instance, I happen to know someone

whose ex-spouse had bipolar disorder

and their ex-spouse went out and bought

10 plus air fryers.

I mean, I think unless you're a restaurant

that's using a lot of air fryers,

the idea that you would need more than one

or two air fryers might just seem a little bit

out of the norm.

And so that impulsivity can be purchasing,

it can be other things as well.

It can be booking 12 international trips in one afternoon

or going and buying three cars, et cetera.

So impulsivity.

the other is grandiosity.

People who have manic bipolar disorder

who are in a manic episode will often display

words of or actions of grandiosity.

And keep in mind, these are not lies

in the sense that the person isn't lying

in order to try and pull one over on anybody,

these are actual beliefs that the person comes to have

about their grandiose position in the world

or grandiose opportunities or potential in the world.

Typical forms of grandiosity and manic episodes

would be that the person suddenly decides

that they are going to win a Pulitzer Prize.

They are the person selected to win a Pulitzer Prize.

They're going to write a novel that afternoon,

and they're going to win a Pulitzer Prize that year,

which is more or less a delusion of grandeur.

The idea that someone could do that in one afternoon,

I suppose it is possible in the realm of all possibilities,

but it's extremely unlikely.

Other forms of grandiosity that often present themselves

in people suffering from a manic episode

will be that they're going to run for president

or that they are the person that they believe

is selected by the citizens of a given country

or by the universe to be the president of that country

or to be present of the universe.

It sounds ridiculous, but those sorts of delusions

of grandiosity are one condition

that often presents itself,

or one set of symptoms that presents itself.

Flight of ideas are also typical of manic episodes.

So this is a little bit like distractibility,

but this would be people talking extensively

about one thing and then switching

and talking extensively about something else.

It would be as if I was doing this podcast

talking about manic bipolar disorder

and then suddenly switching to OCD

and then to deliberate cold exposure

and then to the role of sugar

and its impact on the brain, et cetera.

So essentially a random selection

of the different topics that exist in science,

all of which I happen to be very interested in

and curious about,

but just as we have episodes of the podcast

that are about one or two topics,

and we focus on those in a fairly narrow trench

of discussion,

somebody who has a flight of ideas

would be jumping between categories and topics

in a kind of pseudo random way.

So they might take off down a path of one thing

and then switch to another without any transition

or with transitions that that don't have

any logical structure to them.

The other aspect of manic bipolar disorder

that often presents itself in the manic episodes

are agitation.

People feeling extremely physically agitated,

so a lot of shaking and moving about.

This can venture into the realm of paranoia,

but a lot of agitation,

a difficulty sitting down and being still,

a difficulty in just looking, feeling and acting calm.

And then another condition is no sleep.

And when I say no sleep, I mean no sleep

or very minimal sleep.

As incredible as it sounds,

people who are in a manic episode

can often go seven days or more with zero sleep.

And a key feature of this zero sleep

is that they're not troubled by it.

They're not thinking, oh, I'm suffering from insomnia

and I really, really want to sleep.

Sometimes that's the case, but more often than not,

they are simply not sleeping.

They're staying up 24 hours then another 24 hours,

it just continues for an entire week.

Again, inconceivable to those of us

that don't suffer from manic episodes.

I can only imagine how pulled apart most of us would feel

under those conditions, and yet they are just going

and going and going with no sleep,

up all hours, shopping, talking, running,

doing all sorts of different things in the categories

of other symptoms that we talked about before.

And it doesn't bother them that they're not sleeping.

And then the last sort of category of symptoms

that the psychiatrist is evaluating for

and seeing if they present is rapid pressured speech.

The rapid pressured speech is something

that when you hear it, you recognize it.

This is somebody that almost seems to be hitting you

with speech like machine gun fire,

it's coming at you, coming at you, coming at you

and there's really no room for conversation.

They're not offering any opportunity

for a back and forth, or if there is a back and forth,

they might ask you how you feel about something

and then you started, well, I,

[speaking gibberish]

then they're going to hit you with another barrage

or a paragraph of information

or of just speech, that pseudo random.

So we've got distractibility, impulsivity,

grandiosity, flight of ideas, agitation,

no sleep, and rapid pressured speech.

For someone to be diagnosed as in a manic episode,

they do not have to be engaging in

or displaying all of those symptoms.

They do however need to present

at least three of those symptoms,

and then in order to meet the condition of bipolar 1,

they have to be presenting those three symptoms

for at least seven days.

It could be longer, but at least seven days.

Now, this seems pretty straightforward, right?

At one level, the way that I describe this

and the way that it exists in the clinical literature,

you could think, well,

this should be pretty easy to diagnose.

And yet there's a complication there

or a challenge there because the psychiatrist, again,

has to determine that these manic episodes

are not due to something other than bipolar disorder.

For instance, again, it could be TBI,

traumatic brain injury, it could be seizures,

or meds or other sorts of drugs.

Corticosteroids, which are often prescribed

for a number of immune conditions or for wound healing

can also cause manic episodes.

So they have to determine that everything

that's happening meets the criteria I described before,

three out of seven of these symptom categories

for seven days or more

and that it can't be better explained

by something else going on in that person's life

or immediate medical history.

That's very important.

Now, the other challenge,

and this is something that's going to come up

again and again today, not just in the description

of the biology of bipolar disorder,

but also the description of different treatments

and treatment approaches,

is that typically, when somebody is sitting

in front of a psychiatrist,

in particular for the first time

those two people are interacting,

the psychiatrist is just getting one snapshot

of the person at that moment.

So the person could be on day one of a manic episode,

the person might be on day six of a manic episode,

the person could be transitioning out of a manic episode,

or the person could be suffering from a combination

of manic episode where,

because of the impulsivity of bipolar disorder,

they went out and used illicit drugs.

They also used cocaine.

So the psychiatrist has a serious challenge.

The psychiatrist has to determine based on a conversation,

this isn't a blood test,

this isn't a measurement that you can take on a scale

or with a biomarker, they have to use language,

a conversation with somebody who, by all accounts,

is pretty impaired at conversation

to determine whether or not

they're suffering from a manic episode

that is the consequence of bipolar disorder.

You can imagine this in the real world,

as somebody says, well, how long has it been

since you slept?

And the person starts to answer,

oh, well, the other day I went down to the basement.

I was going to get something out of

the refrigerator and I thought I might take a nap.

And then all of a sudden they're talking

about something completely different.

So they might not even have an answer.

So the psychiatrist has to be a really good detective,

a benevolent detective,

but a detective nonetheless

in determining whether or not

these symptoms have existed for seven days or more,

and whether or not they meet the, at least three,

it could be more, but at least three

of the criteria of symptom categories

I talked about before.

Now, assuming that they do,

assuming that the patient meets those criteria,

they are likely to be diagnosed with bipolar 1.

Now bipolar 1 disorder

means they're having these extended manic episodes,

seven days or more,

but it does not necessarily mean

that they are dropping into a depressive episode as well.

This is a common misconception about bipolar disorder

because as it's often called,

bipolar disorder is referred to as bipolar depression,

and yet many people with bipolar disorder

don't necessarily experience the deep depressive episodes.

Many of them do, but many of them do not.

So somebody can truly be diagnosed accurately

with bipolar one,

even though they're only experiencing manic episodes

and then dropping down to baseline.

Manic episode, then dropping down to baseline.

That's very important to understand.

Now, the second category of bipolar disorder is bipolar 2.

So BP-II or bipolar disorder 2 is somewhat different

than bipolar disorder 1.

First of all, it's characterized most often

by the presence of both manic episodes, mania,

and depressive episodes,

or what's referred to as hypomania.

Now, anytime in biology or in medicine you hear hypo,

it's the opposite of hyper.

So we've got normal hyper and hypo.

Hypomania is a somewhat suppressed level of mania.

So this is not going to be as extreme

as the mania that we typically think of.

And yet the hypo can be due to the duration,

not the intensity of mania.

That's right.

Hypomania can mean a lessened intensity of mania,

but it can also be used to refer to

a shorter duration of mania.

And in fact, that's one of the key criteria

for bipolar 2.

Bipolar 2 is often diagnosed

on the basis of the presence of manic episodes

that are lasting four days or even less.

So someone with BP-II might have four days

of this increased energy, goal-directed activity,

they're irritable, they're euphoric,

they're not sleeping, et cetera,

but it's only lasting for about four days.

Or they could be having longer extended periods of mania,

but they are hypomanic episodes.

They're not quite as intense

so the pressured speech isn't quite as pressured.

The impulsivity isn't quite as severe,

et cetera, et cetera.

The other aspect of bipolar 2

is one that I had mentioned briefly a moment ago,

which is that it's often associated

with the drops into the depressive episode.

So people are going from manic episodes

for four days or less,

then they're dropping into a depression,

going back to normal, manic again.

I do want to point out however

that people who have bipolar 1 can indeed go

from manic episodes to severe,

what we call major depression,

so they can oscillate like a sine wave,

really high highs, really low lows.

And very important to understand

in terms of understanding both bipolar 1 and bipolar 2

is that it's not always a sine wave.

This is really important

and it's something that frankly I did not know

until I started researching this episode

and talking to some psychiatrists.

I should mention, I've talked to several

board certified psychiatrists in preparation

for this episode,

I'll give some references to them.

And in fact, some of them are going to be coming

on the podcast as guests in the future

for more in-depth discussion about bipolar

and other psychiatric disorders.

But all the psychiatrists I spoke to confirmed

what the other was saying, which was that

the way that bipolar disorder can present

can vary tremendously between individuals.

One person might go from very high highs

that last seven days or more,

to very low lows.

Bouts of depression, major depression

that can last two weeks or more.

Other people are rapid cycling by way

of three days manic, three days normal,

three days manic, and then dropping

into three days depression.

So you want to erase that picture in your mind

that manic bipolar disorder is this sine wave,

this cycling up and down between mania and depression.

It can take a lot of different forms.

And again, this is a serious challenge

for the psychiatrist to diagnose people because of that

fact that they're only getting a snapshot

of the person unless they've known them for some time

and are working with them for some time.

But this is also especially important

for those of you that

either have bipolar depression or suspect that you might,

or that know someone with bipolar depression

or suspect somebody might have bipolar depression,

AKA bipolar disorder.

Because if you're noticing that somebody

is very manic and then normal, well,

that's a very different picture

than somebody who's going from very manic

to very deep bouts of depression.

The very manic to deep bouts of depression

is easier to recognize because of the extremes

of those highs and lows.

Now, this might seem somewhat obvious

to all of you as I describe it,

and yet it's very important as a, frankly,

a citizen of the planet

who knows other human beings

to keep an eye out for these manic episodes,

because again, whether or not it's four days or less,

or whether or not it's seven days or more,

these manic episodes really are the defining criteria

of bipolar disorder, AKA bipolar depression.

There are a couple other key features

about bipolar 1 and bipolar 2

that can allow us to get better insight

into whether or not somebody has bipolar 1 or bipolar 2,

and that's the percentage of time

that people with bipolar 1 versus bipolar 2 spend

in a manic state, a depressed state,

or a symptom-free state.

And this is also important to discuss

because it turns out that people

with genuine diagnosed bipolar 1

or bipolar 2 are often symptom-free,

which again can make it difficult

for us as people that know them

or for people that are treating people

with bipolar disorder to identify whether or not

somebody is in a manic episode

or a depressive episode,

or whether or not they are headed into a manic

or depressive episode.

So the numbers on this have been studied.

This from a paper, actually two papers,

first author, Judd, J-U-D-D et al.

published some years ago, 20 years ago,

but the data hold up really nicely over time.

These were both published

in Journal American Medical Association Psychiatry.

So JAMA Psychiatry is a superb journal.

And basically people who have bipolar 1 on average

spend about 50%, it's actually 53% was the number

that was eventually converged upon,

but about 50% of their time symptom-free.

That's interesting, right?

Somebody who has genuine bipolar 1 disorder

can spend as much as half of their life

symptom-free, sleeping normally,

speaking normally, et cetera.

About 32% of the time depressed,

And when we say depressed, we mean major depression.

So severe challenges with waking up

at two or three in the morning,

and having trouble falling back asleep.

That's one of the defining characteristics of depression,

or sleeping far too much,

having a hard time getting out of bed in the morning,

suppressed appetite, suppressed libido,

suppressed motivation,

all the general symptoms of major depression

which we'll talk about a little bit more later

and in an upcoming episode about major depression

in particular.

And then about 15% of their time

in this kind of manic state or mixed manic state,

where they are showing

long, again, seven days or more bouts

of sleeplessness, irritability,

pressured speech, grandiosity, et cetera.

Contrast that with people who have bipolar 2 disorder

who are spending about half of their time

in a depressed state.

So that's interesting, people with bipolar 2 disorder,

while not always displaying depressed states

or oscillations between mania or hypomania

and depressed states,

they tend to be in the depressed state more often.

And again, this is major depression.

This isn't just a little bit of a low,

this is a serious depression of their nervous system,

their mood, and as we say, their affect,

their outlook on life,

and that's one of the key distinguishing features

of major depression is that people's outlook on life

becomes very diminished in the sense

that they don't see a future.

You ask them about, how's work going?

How're your relationships?

And it's not just that they feel that that's going poorly,

they really feel as if there's no opportunity

for those things to improve.

Those people with bipolar 2

tend to be symptom-free about 45% of the time.

Again, these are averages,

so about 45% of the time,

that's a considerable amount of the time.

And they tend to be in these hypomanic states

only about 4 or 5% of the time.

Again, the criteria for BP-II, bipolar 2

is these four days or less

of mania or hypomania,

but only 4% of the time or 5% of the time

is a small enough sliver of the pie

that is these people's existence

that you could imagine why it would be

easy for them or other people

to overlook the fact that they have bipolar disorder

and not major depression.

Think about it.

This is a person who, or I should say

a collection of people who are spending

about half of their time depressed,

close to half, 45% of their time symptom-free,

and then about 5% of their time in a hypomanic state.

So either shorten bouts of

high intensity mania or hypomania

that is of reduced intensity.

One of the reasons that I mentioned these percentages

of time spent in a symptom-free, depressed manic

or hypomanic state is because one of my major goals

for today's episode is that it will increase awareness

of whether or not you or somebody you know,

could be a coworker, could be family member, et cetera,

might be suffering from bipolar 1 or bipolar 2.

I think it's fair to say that if somebody is suffering

from bipolar 1,

that is likely to be revealed

or to reveal itself

before too long, because of the fact

that people have these extended periods of mania

and mania is such an extreme state,

not just for the person who's experiencing it,

but the way that it presents is just so extreme

and out of the ordinary.

But bipolar 2, you can imagine

could really duck under the radar

of our awareness.

And you could imagine that we might just think

somebody is low or depressed,

especially if that person tends to self-medicate

with alcohol or other substances.

We might think, oh, they're drinking more than often

more than usual, excuse me,

or they're spending more time alone and isolating.

But then when they're in their hypomanic state,

that might actually present as normal to us

because they were in such a depressed state before.

So it's very important that we dial up our awareness,

that we have tune our antennae to the possibility

that people out there who might appear depressed

or that we haven't heard from in a while

might actually be suffering from bipolar 2 disorder.

Before we move into a in-depth discussion

about the different kinds of treatments

for bipolar disorder,

I'd like to touch on just a few additional aspects

of what bipolar disorder can do

in terms of its negative consequences.

And also talk about some of the inherited risk

that is the genetic factors

and the environmental factors that can contribute

to bipolar disorder.

In terms of the burden,

the very real, emotional, and occupational

and educational burden that can occur

for somebody with bipolar disorder,

that's actually been studied.

There's a measure of this, it's called global burden

which is defined as the years lost

in engaging a normal life due to some disability.

So that disability could be cancer

or that disability, in this case, is bipolar disorder.

And basically the way this sort of study is done

is that through questionnaires,

I should say quite in-depth questionnaires,

there's a probing for whether or not somebody has lost

two consecutive weeks or more

of interest in normal activities.

Now, for people who have depression,

that's a kind of straightforward thing to address, right?

You ask somebody, when was the last time you ate,

or when was the last time that you went a few days

without food or lost interest

in relationships or work or sex or things of that sort

and they answer and you can figure out

the amount of time that you've essentially

been withdrawn from normal levels of activity for them.

With bipolar disorder, What it turns out

is that the global burden of having bipolar 1

and even bipolar 2 is massive.

In fact, having bipolar disorder

sits as one of the highest risk factors

for being in the top 10

of all categories of disabilities

leading to global burden.

Put in plain English, what that means is

having bipolar 1 or bipolar 2 disorder

is extremely debilitating.

It really slows down one's life trajectory

unless it's treated properly.

Now, the other aspect of bipolar disorder

is its heritability.

And this gets into a little bit of some tricky science

related to inheritability versus

the genetic contribution of a given disease.

So that might sound like the same thing,

you think, okay, genes relate to heritability,

heritability relates to genes,

but of course, everything about the way

that our nervous system works and functions

and expresses itself, healthy or otherwise,

is an interaction between our genes

and our environment.

And so typically the way these studies are done

is you address what is the risk

of somebody having a given condition

in the general population?

We talked about that before, bipolar disorder

is a 1% of the world's population.

Compare that to people who have only major depression.

So this would be repeated bouts

of two weeks or more of serious depression,

not just low mood or something due to a life loss,

but major depression,

which is 10 to 17% of people have major depression.

They suffer from major depressive disorder,

compared to bipolar disorder which, again, is 1%.

Now, you can address how much of the 1%

of bipolar disorder that exists is due

to genes versus environment

in a somewhat exact way.

This is never an exact science.

And the way that this is typically done

is to look at concordance,

that is the likelihood that two identical twins

will both have a given condition

as opposed to two fraternal twins,

which have more different genes

than identical twins, of course.

And then two siblings who have similar genes, of course,

but less similar than identical or fraternal twins

and so on and so forth.

So what you basically do

is you evaluate the probability that two people

in the general population who are completely unrelated

will have the same condition, versus two people

in the general population who are very related,

identical twins.

And what you find is that in identical twins,

if one identical twin has true major depression

or major depressive disorder,

there's a 20 to 45% chance

that their identical twin will also have

major depressive disorder.

Now that tells you right there

that it can't all be genes,

that is not a gene for major depression per se,

or if it is a gene or a collection of genes,

that those genes are also subject

to environmental influences,

either prenatal, within the womb

or after children are born.

Now the large range there of 20 to 45%

could be due to any number of things.

It could be experimental,

meaning the techniques that were used in experiments,

it could be due to regional differences,

one part of the world versus another.

There are a lot of different factors.

Right now, we probably shouldn't delve into all that.

At some point, we'll probably do an episode

all about the genetics of nervous system heritability

and heritability of features and mental health, et cetera.

But we can compare major depression and the heritability

or the genetic concordance between identical twins

in major depression and bipolar disorder and ask,

if one twin of an identical twin pair

has bipolar depression,

what is the likelihood that the other twin will have it?

And it turns out that number is much higher.

It's 40 to 70% likelihood or probability

that if one twin has bipolar disorder,

that their identical twin will also have bipolar disorder.

So again, the total incidence of bipolar disorder

in the general population is much lower

than it is for major depressions,

1% for bipolar versus 10 to 17% for major depression.

But the genetic component is much higher,

40 to 70% for bipolar disorder

versus 20 to 45% for major depression.

I know I'm throwing a lot of numbers out there,

but basically what this means

is that researchers have been able to take those numbers

and filter them through a number of different risk factors

that are related to early development,

ask questions like if two twins were raised separately

or together, or in one part of the world versus another,

or had a two parent household versus one parent household,

evaluate a lot of different variables,

what they were able to discover,

and this has been shown again and again,

is that the genetic contribution to bipolar disorder

is very, very high.

That is the heritability of bipolar disorder is 85%.

So again, I want to be really clear what this means,

the total occurrence in the general population, fairly low,

still serious, 1%,

but fairly low compared to other things

like major depression.

However, if someone has bipolar disorder,

it's very likely that they inherited

some gene or sets of genes,

or more accurately, a susceptibility within their genes

to environmental influences

that can trigger bipolar disorder.

There are a lot of different ways to discuss

and to conceptualize heritability

so I want to be very careful with the way

that I'm wording this.

What this means is that people with bipolar disorder

very likely have a gene, or more typically

it's going to be a set of genes

that creates a susceptibility for bipolar disorder

to present itself.

Now, what environmental factors trigger

or increase that susceptibility is not entirely clear.

This always seems to center back

onto the same sets of things like

early life stress, trauma, et cetera,

certainly those are going to exacerbate the likelihood

that someone who has a genetic propensity

for bipolar disorder will express

that bipolar disorder

and its full array of symptomology,

but 85%, while very, very high, is not 100%.

Again, 85%, while a very high number

for heritability is not 100%.

What that means is that there is no single gene

or identified gene cluster for bipolar disorder.

The reason I keep drilling into this over and over

is that I think we can confidently say

that if someone has bipolar disorder,

that there was something in their genetic lineage

that led to that, or that very likely led to that,

and yet it's not like eye color

or some other physical feature,

which we can actually do the direct,

so it's called Mendelian genetics,

and figure out whether or not somebody

directly inherited that gene from one parent

or the other parent.

So the takeaway here is that if you have

certainly an identical twin, or a fraternal twin,

or a sibling or a parent,

or even a cousin or an uncle

that has bipolar disorder, in particular bipolar 1,

well, then you need to be on the lookout

for bipolar disorder, perhaps in yourself

and for the family members of that person.

My goal within this episode up until now

has been to provide a clear and detailed picture

of bipolar disorder and its various forms.

Before we start to talk about treatments

for bipolar disorder and some of the neural circuit basis

for bipolar disorder,

I want to make sure that I distinguish bipolar disorder

from borderline personality disorder.

We will do an entire episode

or maybe even several episodes

about borderline personality disorder.

Borderline personality disorder

can indeed present itself

in ways that resemble bipolar disorder and vice versa,

but there's some key distinctions that need to be made

because it turns out that bipolar disorder

and borderline personality disorder

are quite distinct in terms of their defining criteria.

The key distinction between somebody

with borderline personality disorder

and bipolar disorder

is that in borderline personality disorder,

there can be episodes that can resemble mania or hypomania.

So periods of flights of ideas,

or where people are spending money excessively

or sexually promiscuous in ways

that seem manic or could even be

a little bit manic or a lot manic,

and yet more often than not,

there is an environmental trigger

for those manic episodes.

That is distinctly different from bipolar disorder

where the person will have manic episodes

without any need for a trigger.

There doesn't need to be a call

from someone saying, hey, let's go on a vacation together,

or there's something coming up this Friday

that's really exciting,

or let's enter a relationship together

of one form or another.

The person with bipolar disorder will have episodes of mania

or episodes of major depression

without any need for an external stimulus

or environmental trigger.

But the person with borderline personality disorder,

almost always, again,

there's never an always in biology and psychiatry,

but almost always is going to exhibit flights of mania

or depressive episodes or other types of mood shifts

that are dramatic and maladaptive

in response to things that are coming in through

the external environment or relationships

of some kind.

In fact, one of the defining characteristics

of borderline personality disorder

is this thing that's referred to as splitting.

A good example of splitting in a person

with borderline personality disorder

is that they will feel that they absolutely adore you

and want to spend all their time with you

and just think the world of you.

You can do no wrong.

And in fact, they genuinely can feel that way

and can genuinely think that way about you.

And then for whatever reason,

it could be a perception of something

that you did or something that you said

or suspicion that you're thinking something about them,

they can suddenly shift or split their emotions

in what's called move you from a good object

or a can do no wrong object to a bad object.

They'll suddenly decide that you are cheating on them

or that you are being mean to them

or that you're insulting them

or that something that you're doing is in violation

to their self worth, their wellbeing, et cetera

and that can send them down a pathway

of being very angry, very depressed, et cetera.

As I describe the contour of a person

with borderline personality disorder

as somebody who splits very suddenly in response

to some environmental trigger, real or perceived,

there's the risk, of course,

that it makes the person with borderline

personality disorder sound like a bad person,

that they're very volatile.

And while they can be volatile,

I want to be very careful to point out

that the person with borderline personality disorder

is also suffering in this context.

So while those sorts of relationships

with people with borderline personality disorder,

whether or not they're romantic relationships

or familial or coworkers, et cetera,

can be very challenged, can be very high friction

because of the good object, bad object shifts, et cetera,

it's bidirectional, meaning the person

with borderline personality disorder,

as you can imagine, is also going through

a lot of suffering.

At one moment, they feel

as if someone is wonderful and can do no wrong

to them and they want to be so strongly affiliated

with them, and then in the next moment,

they feel as if that person is attacking them

through their actions or even through their non actions.

So again, we will return

to borderline personality disorder

in a separate episode, it's a serious disorder,

both for the person that has it

and for people around them.

Fortunately, there are some emerging treatments

that are showing promise

and it's a fairly common disorder,

but it's important that we distinguish

borderline personality disorder from bipolar disorder,

mostly on the basis of this need for a trigger.

Again, in bipolar disorder, there is no need

for a trigger to create a manic episode

or a major depressive episode,

they just happen or they can just happen.

Whereas in borderline personality disorder,

almost always there's an external trigger

or a perception that something happened

in the environment or that somebody is behaving

a certain way that dramatically shifts

the person with borderline personality disorder

from one mode to the next.

As we move into our discussion about the treatments for

and neural circuits underlying bipolar disorder,

I want to just nail down one more key point.

This is a very brief point

but it's perhaps the most important point, which is

the highs and lows, or we should say the highs,

these manic episodes, and sometimes lows,

'cause again, not everybody

with bipolar disorder 1 or 2

suffers from depressive episodes,

sometimes yes, sometimes no,

in particular in bipolar 2, yes,

but people with bipolar 1 can have extreme manic episodes

and then just return to normal as you recall.

Well, those extreme lows and or extreme highs

of people with bipolar disorder

impact their lives in very negative ways.

This is essential and it's something

that we're going to return to a little bit later

when we talk about the relationship

between bipolar disorder and creativity,

because it turns out that there's a quite

strong association there,

one that would almost lead you to believe

that being bipolar can be beneficial

in certain contexts, and yet,

on whole, having bipolar disorder

is extremely detrimental and challenging

to the person suffering from it.

And it's something that we want to keep in mind

as we think about treatments and the underlying biology.

Now I'd like to talk about some of the treatments

for bipolar disorder.

And in the discussion of those treatments,

there's an absolutely incredible history

of the discovery of one particular treatment

that still shows great success in many patients,

although some people can't take it for reasons

that we'll talk about.

And in the description of the discovery

of this treatment for bipolar disorder,

it also reveals to us that sometimes

treatments come to the profession of medicine

and through science in ways that precede

the discovery of the underlying biology.

That's right, every once in a while,

someone will discover a treatment for a disease

without any understanding

about the underlying biological basis

of that disease.

And in fact, that is the case for bipolar disorder

and the treatment that we are referring to

is lithium.

Lithium, as some of you know,

is on the periodic table of elements.

It is indeed a naturally occurring substance.

It actually arrived on earth by way of star dust.

Yes, we are talking about star dust on this podcast,

but if you'd like to learn more about the origins of lithium

and how lithium arrived here on earth

for its discovery and applications in psychiatry,

there's a beautiful talk that exists on YouTube

and we'll provide a link to this

in the show note captions that describes

the history of lithium in terms

of its interplanetary travels

and arrival on earth.

This is a talk delivered by a physicist

who is expert in quantum mechanics

and is expert in lithium.

And it's a just wonderful talk that I can refer you to,

less on the biology in that talk,

but certainly a lot about lithium as an element.

So for those of you nerds like me,

that love to know how things came to be here on the planet

in one form or another,

I'll encourage you to take a brief listen to that talk.

We are going to discuss lithium in the context

of its applications for treatment of bipolar disorder.

And the discovery of lithium as a treatment

for bipolar disorder is truly a miraculous story

that I think everyone should know.

The key player in this story is a physician

by the last name Cade, he was an Australian physician.

And Cade has a very interesting story in his own right.

Cade was an Australian psychiatrist

or Australian psychiatrist

who also was a soldier.

And during World War II,

after the fall of Singapore to Japan,

he became a prisoner of war

and he was a prisoner of war from 1942 until 1945.

So he had some time for observation

and during his imprisonment,

he observed some of his fellow inmates

is going through pretty wild vacillations

in mood and energy,

essentially going from manic episodes

to depressed episodes, or from manic to normal episodes.

And for one reason or another,

we don't know why because I couldn't find any report

as to why he hypothesized this,

but he hypothesized that there was some buildup

of some chemical in these people's brains

that then they would urinate out.

And that urinating out of whatever chemical

was in there would allow them to be more relaxed

and not manic.

In other words, Cade hypothesized

that there's a buildup of a chemical

in certain people's brains that makes them manic

and they urinate that chemical out.

So eventually he got out of this prison,

as we mentioned in 1945,

and he started doing experiments

in addition to seeing patients in his clinic.

And what he did is he started to take urine

from people who exhibited mania

and urine from people who were not manic,

and he took that urine and he would inject it

into guinea pigs as an experimental model.

And his general observation was that

there was something in the urine

that was indeed making the guinea pigs more manic

if they were injected with urine from a manic patient.

The exact measures that he was taking in these guinea pigs

wasn't exactly clear.

This is at a time or an era in science

when you could just sort of report things

a little bit more subjectively,

although there were still numbers and statistics,

it was a little bit more of like case studies

and descriptions, but it turns out

that even though that all seems a little bit loose,

it led to some incredible and still important discoveries

for psychiatric health.

So what he figured out was that the urine

from manic patients seemed to be more toxic

for these guinea pigs.

And he also knew that there are two toxic substances

in urine, urea and uric acid.

So he was able to separate the urea and uric acid

from people with mania

and patients that did not have mania.

And he figured out that the urea was the same in both

these mentally ill, manic patients

and the non manic patients.

So it did not seem that urea

was the compound that was creating these manic episodes

or related to manic episodes

or held the toxicity

so instead he focused on the uric acid.

Now in order to put the uric acid into solution

so that he could inject it into these guinea pigs,

he had to try a number of different compounds

in order to dilute it.

It just so happens that,

and you chemists will be familiar with this,

but there's certain things that just don't go

into solution easily.

You put the powder in a vial,

you add some water or a saline or another solution,

you mix it up and the powder stays suspended in there,

it doesn't actually ever become a clear liquid

that you can inject.

So in order to try injecting different strengths

of uric acid,

he ended up using lithium

to assist in the dilution, and lithium worked.

So what he basically was doing,

again for you chemists,

is he was taking uric acid, he was adding lithium,

and making a solution of lithium urate.

this is a lot of details, but this is important

because what he eventually found

is that when he diluted the uric acid

with lithium and created lithium urate,

lithium urate could actually

calm down these guinea pigs that were injected

with the toxic urea.

He also found that lithium urate

had a generally calming effect on these guinea pigs.

So now we're really off in crazy territory,

we're talking about urine from patients

that's separating out urea and uric acid,

we're adding lithium to the uric acid,

we're injecting this into guinea pigs,

this is getting pretty wild and pretty weird,

but this is medicine, and from time to time,

this is medicine and science.

Cade was a good scientist in addition

to being a good physician,

and by good scientists,

I mean that he did control experiments.

Here he was injecting lithium urate into animals

and seeing an effect,

but he knew that that solution of lithium urate

contained not just the uric acid,

but it also contained lithium.

And so he quite appropriately asked,

maybe the lithium alone is having this calming effect

on these guinea pigs.

And indeed, that was the case.

When he did the proper control experiment

and injected only lithium solution into these guinea pigs,

they calmed down.

From there, he in sort of 1940 style medicine,

this would not happen now,

he very quickly moved from that animal model

into human patients and started injecting human patients

with lithium or providing lithium orally to those patients.

And lo and behold, found an absolutely profound

and positive effect of lithium

in reducing symptoms of mania.

And as all good physician scientists do,

he wrote up his results.

And he wrote it up in a paper entitled,

Lithium Salts in the Treatment of Psychotic Excitement.

Okay, back then they didn't call it mania,

they called it psychotic excitement.

This is a paper that was published September 3rd, 1949

in the Medical Journal of Australia.

We will provide a link to this study,

is now a classic study in the field of psychiatry.

It's a really wonderful paper to read.

And actually I encourage people,

even if you're not a scientist or a clinician

to just take a quick look at the second page

in this paper that we've made available to you

where he describes each of the various case studies

or the individuals that he looked at.

I'm not going to read these in detail now,

'cause it would take a lot of unnecessary time,

but things like case seven, MC, aged 40-years-old,

suffering from manic recurrent mania.

In this episode, he'd been excited, restless,

and violent for over two months

and was interfering so often

that had to be confined to a single room

during the day.

So this is very debilitating,

what we now know to be bipolar depression.

He commenced taking lithium citrate, 20 grains,

that's a measure of the amount of lithium,

three times a day.

In four days, he was distinctly quieter

and by February 13th, 1949, appeared practically normal.

He continued well and on February 20th, 1949,

the dose of citrate was reduced to 10 grains,

et cetera, et cetera.

He left the hospital.

There are numerous descriptions

of this sort within this paper,

including some descriptions of patients

that did not see such success,

and including some descriptions of patients

that suffered from some negative side effects.

So that's important to point out as well,

but it's an absolutely wonderful paper

and it's an absolutely wonderful voyage

into the history of psychiatry

right down to the discussion where

in just three short paragraphs,

Cade really lays out the case for why

lithium is such a important discovery

in the treatment of what, at that time,

they were calling psychotic excitement

and what we now know to be manic bipolar depression.

Lithium, I should mention,

has a number of important features,

but it also a number of important side effects

that need to be considered.

First of all, it does have

a certain toxicity and so levels of lithium

in the blood need to be monitored extremely carefully.

So it's not the sort of thing that people

can just take at a given dose

and every patient responds the same,

there's a lot of oversight and a lot of blood tests

that have to be done,

especially in the first three months of lithium treatment.

I should mention that lithium treatment

is still used to some great degree of success in many,

not all people suffering from bipolar depression,

or bipolar disorder rather,

but there are a number of important things that happened

between 1949 and present day

that prevented lithium from reaching patients

that really needed it.

And that all can be summarized

in two or three short sentences.

Basically, by virtue of the fact that lithium

is a naturally occurring element, it could not be patented.

And as a consequence of that,

there wasn't a lot of potential profit

for drug companies to produce lithium.

In fact, still to this day, it's very low cost,

and still to this day, no one really owns the patent

for lithium in its purest form.

So that made it unattractive.

It turns out that the FDA in the United States

didn't allow lithium to be used as a treatment

for manic bipolar disorder until 1970.

So we're talking about a full 21 years

from the publication of this paper by Cade

in the Medical Journal of Australia

showing quite beautifully

the great potential in use of lithium

for quelling the symptoms of bipolar disorder

until the first patients in the United States

were starting to access lithium regularly.

And nowadays, of course, lithium is available,

but still not able to be patented

'cause it's element number three on the periodic table,

it's naturally occurring.

It's not literally falling down from the stars as stardust

and going into pill form,

but rather it can be synthesized

in laboratories, but it is available.

It does show not only great potential in many patients

but great application in many patients

despite its side effects.

So lithium really stands as this kind of golden example

of a treatment that works, at least in many individuals,

prior to an understanding of the biological basis

of the disease for which that treatment is needed.

Now with that said, scientists and clinicians

have been quite rigorous in trying to understand

why and how lithium works in order to understand

the why and how of bipolar disorder.

This is the way that proper medicine and science is done.

Even if there's an excellent treatment for something,

it's important to understand why that treatment works

because, first of all, not everyone

responds to that treatment.

Second of all, scientists and physicians understand

that just because we have one treatment that works,

if it has any side effects at all,

there is the possibility for better treatments.

So it's not just about trying to bypass a drug

that doesn't make much money for drug companies,

I know a lot of people think in those terms,

they think, oh, well,

there's this continued search for better treatments

for bipolar disorder even though lithium works

because lithium doesn't allow drug companies

to make much money.

That's not really the case.

The fact of the matter is is that the toxicity,

some of the other issues that are created with lithium,

the fact that people need

the ongoing blood testing, et cetera,

really stimulates the need, really an urgent need

for new and better treatments for bipolar disorder.

And only by understanding how lithium works

at the cellular level, at the neural circuit level,

et cetera, do we really stand to find

those new discoveries.

If you were to do a literature search on

the actions and mechanisms of lithium

in terms of how it can calm people down

and reduce their manic episodes,

you would find an enormous array of papers,

literally thousands of scientific studies

in animals and in humans,

which, for instance will tell you that lithium treatment

will increase so-called BDNF,

brain-derived neurotrophic factor.

BDNF is often talked about in the context

of neuroplasticity,

the brain and nervous system's ability

to change in response to experience.

And indeed it does seem that ingesting lithium

increases BDNF.

BDNF is what we call permissive for neuroplasticity.

It doesn't create specific changes in the brain,

meaning it's not going to make your memory better

or your coordination better,

or your emotional state better per se,

what BDNF does is it permits the neurons,

the nerve cells and their connections in the brain

to be more likely to change

if the proper environmental conditions are met.

That is BDNF creates a kind of buoyancy to neuroplasticity.

It opens the gates to neuroplasticity.

So lithium does increase BDNF,

we'll talk about why that's important in the context

of the neural circuits involved

with bipolar disorder in a few minutes.

It also seems to be a potent anti-inflammatory.

Now, inflammation is one of those words

that's thrown around extensively nowadays,

especially on social media and especially as it relates

to any health condition, it's like inflammation,

inflammation, inflammation, always seems to be discussed

in the context of inflammation being bad.

But I do want to point out that inflammation

is a natural adaptive response to physical injury

to a cell or organ or tissue of any kind.

Inflammation is the basis by which

adaptations occur to exercise.

So if, for instance,

you were to weight train and use a heavier

than normal weight kind,

do a set to failure or create some little micro tears

in the muscle that are healthy

in the sense that they would create adaptations

and make that muscle stronger, maybe even grow that muscle,

there's an inflammatory response associated with that

that is critical to the positive adaptation.

So inflammation isn't always bad,

although excessive, or as we say,

runaway inflammation is bad.

Lithium seems to be able to suppress inflammation and,

importantly, it can suppress inflammation

in neural tissues and within the brain in particular.

That is important.

And we return to that and why it's important

in a little bit.

The other thing about lithium

is that lithium is neuroprotective,

that is it can prevent neurons from dying

under certain conditions.

Why would neurons die?

Well, there are a lot of reasons why neurons can die.

There can be a physical insult to the neurons.

You can get hit really hard in the head, a bullet,

God forbid, can enter the skull and kill neurons,

there are a lot of reasons why neurons can die.

Neuroprotection is a situation in which a neuron

is given some sort of chemical or physical resiliency

that allows it to suffer an insult

and yet bounce back.

So it's very similar to the way that we think

about psychological resiliency,

neuroprotection is an ability for neurons

to be better able to handle stress

of different kinds, in particular, excitotoxicity.

There's a phenomenon in bipolar disorder

and a lot of other psychiatric conditions

in which hyperactivity of certain brain areas

actually starts to kill off neurons.

Hyperactivity doesn't always do this,

but it turns out that if certain brain circuits

are too active for too long,

some of the chemicals associated with neuroactivity,

things like calcium and neurotransmitters

like glutamate can actually kill the very neurons

that are active.

So it seems that lithium can prevent

some of that neurotoxicity.

Now, this turns out to be particularly important

for this discussion about bipolar disorder

and the neural circuit basis of bipolar disorder

because if we are just take a step back and ask,

what's different in the brains of people

with bipolar disorder?

There are some very interesting answers

that start to emerge.

There are basically two main neural circuits

that are present in normal individuals,

I say normal, I say that respectfully

to the people with bipolar disorder

by referring to people who do not suffer

from manic episodes or from manic depression.

There are circuits that are present

in people with bipolar disorder

and in people that do not suffer

from bipolar disorder,

both of those circuits do the same thing

in both sets of individuals,

and yet in people with bipolar disorder,

there seems to be an atrophy or a removal

of certain neural connections over time

that leads to a situation in which people

with bipolar disorder become very poor

at registering their own internal state,

in particular, their emotional states

and their somatic states.

What we're referring to here

is something called interoception.

I've talked about this a little bit

on the Huberman Lab Podcast before,

but there are two modes of perception.

Perception, of course, is a attention

to something that's happening in our environment

or to us on or within our body.

Exteroception is literally an attention to things

that are happening beyond the confines of our skin.

So seeing that person's face over there,

or seeing that color of leaf over there,

or hearing a sound over to my left,

that is exteroception, perception of things

beyond the confines of one's skin.

Then there's interoception

which is perception of things that are happening internally

like, how full does my gut feel?

How fast is my heart beating?

Some people can measure that quite accurately

just by thinking about it, other people can't.

How happy am I, how sad am I, how energetic am I,

how lethargic am I, et cetera, et cetera.

So we are always existing in a balance

between exteroception and interoception,

but as it turns out, people with bipolar disorder

over time, and especially into the second

and third decade of having bipolar disorder

seem to have progressively diminished levels

of interoception.

And that very likely is important

in their inability to register, for instance,

that, wow, they are talking at an excessive rate

or they haven't slept in 5 or even 10 days,

or they haven't eaten in a long period of time.

This atrophy of neural circuits for interoception

is starting to emerge as one of the defining

neural circuit characteristics

or underpinnings of bipolar.

Now I bridge to this conversation about neural circuits

from the statement that lithium can protect

against some of the neurotoxic effects

of neural circuits being very active.

Now this can get a little bit complicated,

but I promise I'm going to make it clear

for any of you that are watching and or listening.

The reality is

that people with bipolar depression

very likely have a hyperactivity,

that is an increased level of activity

in certain circuits within the brain

early in the expression of their disease.

And that typically, as I mentioned earlier,

sets in around the early 20s, although sometimes

that can be even earlier, in the teens and so forth.

But that hyperactivity, we think,

leads to a toxicity and excitotoxicity

of certain elements of the neural circuits

that are responsible for interoception.

In other words,

the overuse of certain circuits can lead to a

diminishing, an atrophy, or even a death

of certain elements within those circuits

and it appears that lithium,

through its anti-inflammatory and neuroprotective effects

and through its ability to increase BDNF,

very likely protects us against some

of that atrophy of those circuits for interoception.

So this isn't a case in which

people with bipolar have a neural circuit

or lack a neural circuit

and people without bipolar are the opposite.

This is a case in which everyone more or less

starts out the same,

but it seems that there's a hyperactivity

of certain neural circuits in people

with bipolar disorder that over time

actually causes those circuits to diminish.

Now, this is very important because some

of the more recent longitudinal studies

doing brain imaging on people

with bipolar disorder and those without,

and doing that over time in patients

starting as early as their teens,

but into their 20s and 30s reveals just that,

that there can be hyperactivity of circuits early on,

but then hypo, reduced activity of those very same circuits

at a time 5 or 10 years later.

Again, this speaks to the complicated nature

of bipolar disorder and the complicated nature

of psychiatry and linking specific psychiatric disorders

to neural circuits in general.

Because if you have a situation in which

in one disease, let's just,

hypothesize here for a second

that for instance, in certain forms of schizophrenia,

there's elevated dopamine and where we to just reduce

the amount of dopamine, that they would receive relief

from those schizophrenic symptoms,

well, that's all pretty straightforward on the face of it,

but in this situation with bipolar disorder,

what we're talking about is hyperactivity,

too much activity leading to hypoactivity

through death of those very circuits.

And so now you can especially appreciate why

when the patient shows up to the psychiatrist

or when the psychiatrist shows up to the patient

in the total course of their disease

is going to be very important.

And then layer on top of that

the complexity of the fact

that the very defining characteristic

of bipolar disorder is that there are oscillations in mood.

So now we need to think about treatments,

not just for the manic episodes,

but also treatments for the depressive episodes.

And that's, in fact, what psychiatrists do.

Turns out that they apply different treatments

or combinations of treatments for patients

that are in manic episodes versus depressive episodes

and they have to infer all that from discussions,

again, just exchange of words

depending on when that person walked into their office,

where they are in terms of manic episodes,

no symptomology or depressive symptomology,

and whether or not they've had that symptomology

for an extended period of time.

And then just to make the situation even more complicated,

the very circuits that atrophy that start to wane

and disappear in people with bipolar disorder

are the circuits for interoception,

for understanding of what's going on in one's own body.

So you can imagine if you sit down and ask somebody,

well, how long have, has it been

since you've slept, that person may genuinely not know.

Or if you ask the very depressed person,

how depressed are you?

That person may not be able to articulate that.

So fortunately there are solutions to this

and the solution is that more often than not,

the accurate understanding of whether or not someone

has bipolar depression or not,

and what stage of the illness they might be in or not

is going to depend on the reports of people around them

and not the patient themselves,

hence the importance of having a rather detailed

and admittedly a rather intense discussion

about the symptomology of bipolar disorder,

so that you can have an understanding

of the people around you and have an eye and an ear

to whether or not those people might be suffering

from bipolar, and if so, at what stage of the disease

they might happen to be at.

Now I'd like to talk a little bit more

about what is known about the neural circuits

that lead to the manic states,

as well as the depressive states,

but mainly the manic states of bipolar disorder.

We already discussed the fact that interception,

registering of one's own internal emotions

and bodily states is diminished in people

with bipolar disorder.

But we haven't really talked about the neural circuits

that are responsible for that lack of recognition.

For that reason, I'd like to point out a paper.

This is a fairly recent paper, just came out this year,

but it's an excellent one,

Looking at the changes over time in neural circuitry

in people with high genetic risk for bipolar disorder,

and in particular in young people.

And studies of this sort are rare,

but are exceedingly important because of the fact

that they track individuals over time.

The title of this paper is,

Longitudinal Changes in Structural Connectivity

in Young People at High Genetic Risk for Bipolar Disorder.

We will provide a link to this study

in the show note captions.

There are a lot of data in this paper,

in particular, neuroimaging data,

and it's quite extensive in terms of analyzing

the so-called connectomics.

You've probably heard of genomics,

which is the analysis of genes and their display

in different individuals or different animals, et cetera.

You have proteomics, which is the display of,

or the existence of different proteins.

So omics is a big thing now in science,

you kind of throw omics behind anything

and it becomes its own Wikipedia page,

which means it becomes its own thing,

so to speak, I say that only partially in jest.

Nonetheless, connectomics

is the analysis of connections

between different neurons and neural circuit elements.

And what this paper really showed

by analyzing the connectomics of neural circuits

in the brains of many different people

with different categories of, and onset of,

and severity of

bipolar disorder,

as well as controls in different age groups, et cetera,

is that people who are of particularly high risk

for having bipolar disorder

or that have full blown bipolar disorder,

have deficits and actually reductions

in the amount of connectivity between

what are called the parietal brain regions

and the limbic system.

Now, the limbic system I've talked about before

in this podcast, if you're not familiar with it,

I'll explain what it is in a moment,

it's simply a collection of brain structures,

not one brain structure,

but a collection of brain structures

that generally are responsible

for shifting the overall state that we're in

from states of more relaxed and calm

to states of more alert and focused.

The limbic system is intimately related

to the so-called autonomic nervous system,

which regulates our sleep wake cycles

and a number of other things like our digestion, et cetera,

our level of hunger and on and on.

So the limbic system is really kind of like a volume control

or as nerd scientists like to say,

a kind of gain control on the overall level

or amplitude of alertness or calmness.

In fact, if we're very, very calm,

we are asleep or even more calm, we can be in a coma.

If we are very alert, we can be wide awake

and ready to work and run, et cetera.

Or if we are very, very, very alert

by way of limbic autonomic interactions,

well, then we can be in anxiety.

We can be in full blown panic attack,

or we can be in mania.

We can have so much energy

that we feel like we don't need to sleep.

And in fact, disruptions in the circuitry

really seems to be what's going on

in people who have bipolar disorder.

Now, if disruptions in the circuitry

are present in the limbic system,

that doesn't necessarily mean that the limbic system

is at fault because the way that neural circuits work

is that different brain areas are talking

to one another through electrical-chemical signaling,

and they're regulating one another.

And what this paper really tells us

is that there are elements within the parietal lobe,

which is a kind of a section of the brain

that sits off to the side,

it's not really off to the side,

but in neuroanatomical nomenclature,

the parietal lobe is connected in two ways, bidirectionally.

So parietal lobe is connecting to limbic system

and limbic system is connecting to parietal lobe.

And in people with bipolar disorder,

it seems that the parietal lobe

is able to exert less top down control,

that is less suppression of certain elements

of the limbic system, which, at least right now,

is leading researchers to hypothesize

that the limbic system is sort of revving at higher levels.

It's kind of like RPM in your cars

or kind of redlining at times and for durations

that are inappropriate or at least abnormal.

So we have two major sets of neural circuit deficits

or changes in people with bipolar.

Their lack of internal awareness is reduced,

and that turns out to be, by way of neural structures,

like the insula which is a brain region

that is connected in a very direct way

to our somatosensory cortex,

so the part of our cortex that

registers how we feel,

literally, sense of touch and internal state.

So those circuits, excuse me,

for those for those of you listening

I just bumped the microphone, excuse me.

Those circuits are disrupted in people with bipolar

and the top down control,

that kind of accelerator and break

on our overall levels of energy are also disrupted.

Now that's all fine and good because, well, it's true,

at least according to what the data

at this point in time tell us,

there may be new discoveries to come,

but that all seems to be the case,

but it doesn't tell us how to modulate

or change that circuitry.

It also doesn't tell us how something like lithium

can actually benefit a large number of patients

or how a good number of the other treatments

for bipolar disorder, which we'll talk about going forward

can benefit patients with bipolar.

So it appears that lithium is exerting

its positive effects on bipolar depression treatment,

at least in part by preventing the loss

of certain neural circuits,

namely the neural circuits for interoception

and the top down control over the limbic system.

Now it turns out to be examining lithium's effects

at an even more reductionist level,

we can gain really important insight into what's going on

in bipolar depression and some of the other treatments

for bipolar depression, including behavioral treatments,

things like transcranial magnetic stimulation,

and even some of the more natural

or so-called nutraceutical treatments

including things like high dose omega-3 supplementation,

which we're going to talk about extensively.

Now, in order to understand what we're going

to talk about next, it's important

that everybody understand a key concept of neuroplasticity.

And this is a key concept regardless of whether or not

one is talking about bipolar depression.

In fact, it's something I think everybody,

every citizen of earth should know about,

and that's called homeostatic plasticity.

Homeostatic plasticity is a particular form

of neuroplasticity in which if a neural circuit

is overactive for a period of time,

there are changes that occur at the cellular level

that lead to a balance or a homeostatic regulation

of that circuit so that it's no longer overactive.

Conversely, if a neural circuit is underactive

for a period of time,

certain changes happen within the cells of that circuit

to ramp up their activity or make them more likely

to be active.

And whether or not a neural circuit

and the neurons within it become more active

or less active in the context of homeostatic plasticity

largely depends on one mechanism,

and it's a beautiful mechanism that I'll make

very clear to you right now,

even if you don't have a background in biology.

Neurons communicate with one another

by releasing so-called neurotransmitters,

which are just chemicals.

Those neurotransmitters are vomited out,

they're not actually vomited,

but they're spit out into the so-called synaptic cleft,

often called the synapse.

The synapse is just a little gap between neurons.

And when they are released into the synapse,

they don't just stay there,

they actually park or bind to receptors

on what's called the postsynaptic neuron.

And depending on how many receptors they bind to

and how many receptors are available, et cetera,

they can have a greater or lesser effect

on the postsynaptic neuron.

This scenario of neurotransmitters being released

into synapses then binding to receptors

on postsynaptic neurons and influencing

the electrical excitability of those postsynaptic neurons

sits central to not just the treatment of bipolar disorder,

but to all treatments of all psychiatric conditions

and indeed to things like neuropathic pain as well.

For example, the so-called SSRIs,

Prozac, Zoloft and others, et cetera,

stands for selective serotonin re-uptake inhibitor.

What does that mean?

Well, serotonin is a neurotransmitter.

It's actually a neuromodulator that's released

into the synapse, and then the SSRI,

the selective serotonin re-uptake inhibitor

allows more of that serotonin to sit within the synapse

for longer, it's a re-uptake inhibitor,

it prevents re-uptake by the presynaptic neuron.

and that serotonin therefore can park in

or dock in the receptors, as it's called,

of the postsynaptic neuron in greater numbers,

and have a greater impact on that postsynaptic neuron.

So the drugs that are used to treat depression

or other things of that sort, things like SSRIs,

work by changing the availability of neurotransmitter

in the synapse.

Other things like MAO inhibitors,

Monoamine oxidase inhibitors, work a different way.

They inhibit the enzyme.

Anytime you hear ase in biology,

it's very likely an enzyme which breaks things down.

so MAO inhibitors prevent the breakdown, not the re-uptake,

but the breakdown of neurotransmitter

and therefore allow more neurotransmitter

to be available in the synapse

and influence the postsynaptic cell.

Homeostatic plasticity is a form of neuroplasticity

in which overall circuits can become much more excitable

or much less excitable by the addition

of more receptors in the postsynaptic neuron

or by the removal of more receptors

from the postsynaptic neuron.

And the way this happens is just beautiful.

It was first discovered in the visual system

and the person primarily responsible

for the discovery of homeostatic plasticity,

although there are several,

is a woman by the name of Gina Turrigiano,

she's a professor at Brandeis University.

And what the Turrigiano Laboratory showed

was that for instance, if we

are in the dark for a long period of time, literally,

and we're not seeing much for a long period of time,

there's an increase in the number of receptors

in the postsynaptic neurons

so that a smaller amount of light and excitability

within the visual system can lead

to greater amounts of activity in the visual system.

Conversely, if there's an overactivity

or an increase in that activity in the visual system

for some period of time,

then a number of receptors in the postsynaptic neuron

are removed from that postsynaptic neuron surface,

making any neurotransmitter that's available

only able to bind the receptors that are left

and have less of an influence on those cells.

In other words, keeping a circuit

in so-called homeostatic balance

in a particular range of excitability.

Now, while that's a mouthful and an earful

and a concept-full, I don't know

if a concept-full is a word, but in any case,

that's a lot to think about,

but all you need to know is that if a neural circuit

is very active for a period of time,

in normal individuals, there will be a reduction

in the amount of activity by way of removing

receptors that bind neurotransmitter.

Whereas, if a neural circuit is very quiet,

it's not activated for a period of time,

maybe your leg is in a cast for instance,

and you're not activating your quadricep and calves

very much, well when that cast comes off,

sure, the muscle might be atrophied

but the nerves that connect to that muscle

are actually in a position to influence that muscle

even more once you start using that muscle or those muscles,

because whatever neurotransmitter is released

now has the opportunity to bind to more receptors,

in that case in muscle,

or in the case of brain circuits, in postsynaptic neurons.

So homeostatic plasticity is this beautiful,

balancing mechanism that makes sure that neural circuits

are never too active nor too quiet for too long.

And in a beautiful display of how

treatments can lead to a better understanding of biology,

which can lead to the discovery

of even better treatments, lithium and

another compound, which we'll talk about, ketamine

seem to exert their actions largely

through effects on homeostatic neuroplasticity.

There's a wonderful paper that describes

all the nitty-gritty of this.

Certainly most people listening, I'm guessing,

are not going to be interested in all this detail,

but for those of you that you are

and you want to delve deep into this,

this paper was published in Neuron Cell Press journal,

excellent journal,

it's titled, Targeting Homeostatic Plasticity

for the Treatment of Mood Disorders.

And there's one particular figure in this paper

that I'll just describe to you

in which measurements were made from neurons

and the number of receptors in those neurons,

it's done somewhat indirectly through a method

that's detailed and neuroscientists are familiar with.

Basically what it measures is how excited

a given neuron is, electrically excited a given neuron is

to a given amount of neurotransmitter.

So that the amount of neurotransmitter that's vomited

onto a neuron is essentially kept constant,

and then the response

of the postsynaptic neuron is measured.

So it can be of one level or higher or lower

depending on homeostatic plasticity.

And what this paper shows and what's been shown

over and over again, is that when neurons are exposed

to lithium for a period of time,

there is a reduction in the excitability

of the postsynaptic neuron, that is neurons within the brain

become less excitable over time if lithium is present,

whereas ketamine, which is now a common FDA-approved,

at least in the US, it's approved for the treatment

of major depression, ketamine does the opposite.

Ketamine seems to increase the number of receptors

in the postsynaptic neuron and lead to greater levels

of excitability and electrical activity

within neural circuits to a given fixed amount

of neurotransmitter.

So this is super interesting because what it means

is that lithium is causing circuits to be less active,

ketamine is causing circuits to be more active.

And we know from excellent clinical data now

that ketamine seems to be a very effective treatment

for major depression, and for the major depressive episodes

of people that suffer from bipolar depression,

that includes these major depressive episodes

of two weeks or longer of suppressed mood, appetite,

sleep issues, et cetera.

Now, the key thing about ketamine

that's often not discussed is that while its effects

are very potent, they are transient.

So one major drawback to ketamine therapy for depression

is that it has to be done repeatedly,

and how repeatedly, or how often, rather,

depends, of course, on a discussion

between the psychiatrist and the patient.

This is not something to cowboy on your own.

I know that, and many of you are probably familiar

with the fact that ketamine also is abused recreationally.

It is a so-called NMDA,

N-methyl-D-aspartate receptor antagonist,

so it blocks the very receptor that's responsible

for neuroplasticity for changes in neural circuits.

It also changes excitability in neurons as I just described.

So ketamine is a very potent chemical

that has been shown over and over again

and is now FDA approved for the treatment

of major depression, but its effects seem to be transient.

Lithium, as I described earlier,

seems to reduce the manic episodes

or the intensity of manic episodes in symptomology,

in people with bipolar disorder,

it's doing that through neuroprotection.

So protecting neural circuits from dying away

that initially are overactive

and that overactivity causing excitotoxicity,

blocks that excitotoxicity, we believe.

And it seems to do that in part

by diminishing the amount of activity in those circuits.

So this is a beautiful mechanistic story,

and it's the sort of story that you'd love to have

for a great number of psychiatric illnesses.

And fortunately we have for bipolar disorder.

Overactivity of a given circuit

eventually leads to neurotoxicity, excuse me,

lithium is preventing that neurotoxicity by reducing

the number of receptors in certain elements

within those circuits, so called homeostatic scaling,

it's downregulating the number of receptors

leading to less excitability and preventing,

we think, excitotoxicity.

And in that sense, you can see exactly why

it's important to get lithium treatment

in there early for people with bipolar disorder.

Ketamine as a treatment for major depression

seems to be effective but transient.

And you can also see why it would be important,

not just to reduce the manic episodes

for people with bipolar disorder,

but to also treat the depressive episodes.

So this is a key feature of the treatment

for bipolar depression and for bipolar disorder.

there needs to be treatment both of the mania

and of the depressive episodes if they're present.

And fortunately, there are excellent drugs to do that.

And I should mention that ketamine and lithium

are just two of the drugs within the kit

that psychiatrists have access to.

There are many things, olanzapines

and a number of different, including Clozapine.

Clozapine is an antipsychotic

which is commonly prescribed to

as a sedative in some cases that allows people

in manic episodes to sleep.

It's classically described

as so called dopamine receptor 4 antagonist,

although it does other things as well.

Clozapine has a number of side effect features

related to white blood cell

and things of that sort that require careful monitoring.

So there are an enormous number now,

literally dozens and dozens of different drugs,

each designed to target either the manic phase,

the depressive phase, or some what we call acute

sort of early phases versus ongoing treatments.

This is a vast galaxy of drug treatments

that really should be navigated,

I should say, absolutely should be navigated

by a board certified psychiatrist.

And of course in close discussion

with both the person suffering from bipolar disorder,

but also ideally the family members

of the person suffering from bipolar disorder.

But I think, at least up until now,

we've focused on the two major pathways

for treatment, lithium and ketamine.

And we've talked about why lithium and ketamine work,

that they're working on opposite ends

of this homeostatic scaling.

We talked a bit about the circuits that are involved

in generating what we think

are the manic symptomology and the lack of interception.

Why people can just persist in staying awake,

awake, awake, not eating, et cetera.

Now you have in mind how all that is put together.

And I think you have in mind,

some of the well-demonstrated treatments

for the different component parts of bipolar disorder,

which now I'm hoping you're also well versed in

based on our early, early discussion

of what constitutes bipolar 1 and bipolar 2.

Now I would like to also talk about

some of the not so typical therapeutics

for bipolar disorder and also point to the things

that have been tried and failed

for successful treatment of bipolar disorder,

because some of those things

are often talked about and suggested,

especially in online communities,

and while it's not clear that any of them

are particularly hazardous on their own,

although some of them do carry some hazards,

I do think it's important because of the critical

time sensitive nature of bipolar disorder

and the urgency of getting treatments early

to try and prevent some of the longer lasting

neural circuit changes that if people can avoid

some of the less effective or demonstrated

to be ineffective treatments,

that they stand to combat bipolar disorder

much more successfully.

First of all, a key point about drug therapies

versus non-drug therapies or talk therapies,

without question, drug therapies

are going to be most effective

when done also with talk therapies.

And we'll talk about which talk therapies

have been demonstrated to be most effective.

There is some argument about what I'm about to say next,

but in general, most psychiatrists will tell you,

or certainly the ones I've spoken to have told me,

that talk therapy on its own

is rarely, if ever effective for bipolar depression

and bipolar disorder, whether or not it's BP-I or BP-II.

That's just the reality of it.

Contrast that with our discussion

about obsessive-compulsive disorder,

which we talked about a few episodes ago,

if you haven't seen that episode,

We have an in-depth episode all about OCD

and obsessive-compulsive personality disorder.

There it seems that drug therapies and talk therapies

can be done independently or in combination.

As expected, combined drug and talk therapies

are more effective there than either one alone,

but there are pretty impressive effects

of talk therapy alone provided

that they're initiated at the right time,

and it's the right form of talk therapy.

That's OCD, but in terms of bipolar disorder,

it really seems that the drug therapies are necessary,

at least in most all cases.

That said, talk therapies are terrific augment

or support for those drug therapies

and sometimes can allow people

to take lower doses of those drug therapies,

which turns out to be important

because of the side effect profiles of a lot

of drug therapies and sometimes the cost as well.

I guess we can think of cost

just as another side effect really.

There are both established and more novel forms

of talk therapy being used, again,

in concert with drug treatments for bipolar disorder.

Cognitive behavioral therapy is the one

that seems to be best,

at least by way of the statistics and papers that exist.

It's also the one that's been explored the most.

So one of the reasons why it's often considered

the most popular or effective

is 'cause it's also been around longer

and it's been explored the most.

Cognitive behavioral therapy in general

is a progressive exposure of the patient

in a very controlled way, in a clinical setting,

to some of the triggers or the conditions

that would exacerbate bipolar disorder.

Now, earlier I said borderline personality disorder

has all these triggers and triggered elements

from the external environment,

whereas bipolar disorder does not.

And that's still true, but

it is the case that somebody with bipolar

can have worse symptoms if life conditions

get worse or more stressful.

So cognitive behavioral therapy,

I mean the discussion about

and sometimes the direct exposure to

anxiety provoking elements of life

can be very helpful for adjusting the responses

to those otherwise triggering events

and sometimes making the drug treatments

more effective even at lower doses.

There are also forms of therapy

including family-focused therapy,

which is especially important in terms

of bipolar disorder because

family members, provided that they are not themselves

in a manic episode due to the

close heritability of bipolar disorder,

but family members can often be excellent windows

into whether or not somebody is doing well or poorly,

or is veering toward or is emerging from

a manic or depressive episode

because they understand that person,

they have a lot of data,

it could be purely subjective data,

but they have a lot of exposure to how long

or well somebody's been sleeping or eating, et cetera.

So family-focused therapy involves other members

of the person suffering from bipolar disorder's family,

as well as conversations about family members

in a way that helps patients

with bipolar disorder navigate,

not just through manic episodes and depressive episodes,

but start to learn to predict what are the conditions

psychological, physical, and otherwise

that can trigger bipolar episodes.

And then there's a category of therapy

called interpersonal and social rhythm therapy.

This is deserving of its own entire episode really.

Interpersonal and social rhythm therapy,

it's sort of an expansion on family-focused therapy,

although it's distinct in certain ways as well,

and really focuses on how people are relating to others

in their life, and in the workplace,

and in the school environment,

and also within the family, et cetera.

And I should say that a overall theme

that's emerging in psychiatry and psychology

is to start wherever possible to incorporate

more of the social aspects

and the interpersonal aspects.

In other words, not just talking to

and examining a patient as one biological system,

one nervous system, one set of chemicals, and one life,

but rather a set of chemicals, neural circuits,

and a life that's embedded in the chemicals

and neural circuits and lives of other people.

Just by way of example, you can imagine

that if somebody is in a very healthy relationship

or a very abusive relationship,

that that's going to strongly impact

the outcomes of manic episodes.

You can imagine that if the financial situation

is one in which people can recover from manic episodes,

I didn't mention this earlier, but I should have,

forgive me, that oftentimes people

who are in a manic episode will go out

and spend immense amounts of money

that they simply cannot afford to lose.

And then the depressive episodes that, in many cases,

follow are made far worse by the financial anxiety

and the financial stress that results

from those manic episodes of spending, et cetera.

And then of course, this carries over

to sexual promiscuity where people might be dealing

with unwanted pregnancy or STIs, or

very fractured interpersonal dynamics

with existing or new relationships.

I mean, you can imagine how these manic episodes,

as well as the depressive episodes

can really wick out into an enormous amount of destruction,

which brings us back to the initial criteria

of BP-1 and BP-2 is that these manic episodes

are not a good thing.

These depressive episodes are not a good thing.

They create this sense of euphoria

in the person experiencing mania,

or they create this sense that anything is possible.

But at the end of the day, and actually every day,

these episodes are quite maladaptive.

They really destroy people's lives.

And it's not just the life of the person

that's suffering from bipolar disorder.

And so hence cognitive behavioral therapy,

family-focused therapy and interpersonal

and social rhythm therapies are the primary

three talk therapies that are most often combined

with drug therapies in order to try

and really reduce the harm.

It's really all about harm reduction

from manic episodes and depressive episodes.

One very exciting and emerging treatment

that does show great promise,

and in some cases, great outcomes,

for bipolar disorder is, believe it or not

electric shock therapy.

Electric shock therapy may sound barbaric,

and in fact, it tends to look barbaric,

although this is done in the controlled setting

of a hospital.

If any of you have seen One Flew Over the Cuckoo's Nest,

the final scene or near final scene in that movie

was Jack Nicholson with the sort of bite protector

in his mouth and getting electric shock therapy,

and it's as the name suggests, it's a kind of inducing

a global seizure, either low level or grand mal type seizure

in the patient's brain and nervous system.

You might ask, well, why would one want to do that?

Well, it turns out that this is a well-established,

and in many cases, very effective treatment

for major depression.

Electric shock therapy is generally used

for treatment-resistant depression.

So these are people that have no positive response

or ongoing positive response to drug therapies

or other therapies.

Electric shock therapy is thought to work

primarily by stimulating the massive kind

of indiscriminate release of things

like serotonin, dopamine, acetylcholine,

a huge variety of neuromodulators,

as well as things like BDNF,

brain-derived neurotrophic factor

which then allows neuroplasticity to take place.

Again, BDNF being permissive for neuroplasticity.

The problem with ECT is that it's really only useful

for treatment-resistant depression,

it doesn't actually target the manic aspects

of bipolar depression and bipolar disorder,

but nonetheless, is used when drug treatments don't work.

Some of the negatives of electric shock therapy