Huberman Lab - The Science & Treatment of Bipolar Disorder

Welcome to the Huberman Lab Podcast,

where we discuss science

and science-based tools for everyday life.

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 the 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’re 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.

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 Interorgan 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 that 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 one,

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 one.

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 one stimulator.

So they stimulate the release of that,

or they are in fact a synthetic version

of glucagon-like peptide one.

What is glucagon-like peptide one?

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 two 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 one,

that’s going to be a much lower amount

of glucagon-like peptide one

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, I should also point out

that yerba mate comes in a bunch of different forms.

There is some concern about certain smoky 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 one, 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 one

acts on 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

intestinal fugal enteric neurons.

You don’t need to know the name,

but those neurons do two things.

First of all, they cause some gut distention.

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 distention, okay?

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 distention

because major gut distention would be uncomfortable.

So GLP-1 is acting at the level of gut

to increase gut distention

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 distention,

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.


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 sympathogastro 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 distention

to make you feel full and on the brain to increase satiety

or 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’re 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 bi-directional,

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 the sponsors of today’s podcast.

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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 experienced 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.

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 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 I and bipolar II.

So let’s just talk about bipolar I first.

Bipolar I 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 I in a little bit more depth.

One of the key clinical criteria

or diagnostic criteria for bipolar I

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.


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 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 will 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 distractible?

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, you know,

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, you know, 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 distractible, 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, you know, 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, right?

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 at purchasing.

It can be other things as well.

It could be booking, you know,

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 in 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, right?

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 president of the universe, right?

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

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

a 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, then they’re going to hit you

with another barrage or a paragraph of information

or of just speech that’s 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 one,

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 described 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 in 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, right?

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, right?

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.

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 one.

Now, bipolar one 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 two.

So BP two or bipolar disorder two is somewhat different

than bipolar disorder one.

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, okay?

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.

In fact, that’s one of the key criteria for bipolar two.

Bipolar two is often diagnosed on the basis

of the presence of manic episodes

that are lasting four days or even less.

So someone with BP two 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 two

is one that I had mentioned briefly a moment ago,

which is that it’s often associated

with the drops into the depressive episodes.

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 one

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 one and bipolar two

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 I and bipolar II

that can allow us to get better insight

into whether or not somebody has bipolar I or bipolar II.

And that’s the percentage of time

that people with bipolar I versus bipolar II

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 I or bipolar II

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.

It’s 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 of American Medical Association Psychiatry,

so JAMA Psychiatry is a superb journal.

And basically people who have bipolar I on average

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

that was eventually converged upon,

but about 50% of their time is symptom-free.

That’s interesting, right?

Somebody who has genuine bipolar I 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 II disorder

who are spending about half of their time

in a depressed state.

So that’s interesting.

People with bipolar II 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, you know, how’s work going?

How are 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 II 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 four or 5% of the time.

Again, the criteria for BP2, bipolar II

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 can 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 shortened bouts of a 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 a family member, et cetera,

might be suffering from bipolar I or bipolar II.

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

from bipolar I, 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 II, 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, well, 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 can 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 II 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 in normal life due to some disability.

So that disability could be cancer,

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 one

and even bipolar two 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 one

or bipolar two 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.

Okay, 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 it’s 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, right?

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 depression.

It’s 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 in one part of the world versus another,

or had a two-parent household versus one-parent household,

you know, 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%.

Okay, 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

in 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 I,

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 are 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 are 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 the 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

and 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 described 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 bi-directional,

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,

because again, not everybody with bipolar disorder,

one or two, suffers from depressive episodes.

Sometimes yes, sometimes no.

In particular in bipolar two, yes,

but people with bipolar one 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 stardust.

Yes, we are talking about stardust 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’s 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

as 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 just doesn’t actually ever become a clear liquid

that you can inject.

So in order to try injecting different strains

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, okay?

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, right?

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 and 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

as 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

because 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 he had to be confined to a single room during the day.

Right, 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 an 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 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

and 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

because 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, you know,

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 cellar 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 nootrophic


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 for instance, you were to weight train

and use a heavier than normal weight

and 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 will 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, you know, 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 neuronal activity,

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 to 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.

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 five 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 gonna 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, an 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 five 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,

you know, in one disease,

let’s just hypothesize here for a second

that for instance, in certain forms of schizophrenia,

there’s elevated dopamine,

and were 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 has it been since you 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 interoception,

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 a 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 game 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 are 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 red lining 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 of you listening, I just bumped the microphone.

Excuse me.

Those circuits are disrupted in people with bipolar

and the top-down control,

the kind of accelerator and brake

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 that by 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 Reuptake 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 Reuptake Inhibitor,

allows more of that serotonin

to sit within the synapse for longer, right?

It’s a reuptake inhibitor.

It prevents reuptake 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 oxase inhibitors, work a different way.

They inhibit the enzyme.

Anytime you hear A-S-E in biology,

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

So MAO inhibitors prevent the breakdown,

not the reuptake, 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 Tergiano.

She’s a professor at Brandeis University.

And what the Tergiano 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 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 conceptful, I don’t know if a conceptful 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 quadriceps 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, okay?

So the amount of neurotransmitter that’s vomited

onto a neuron is essentially kept constant

and then the response of the post-synaptic 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 post-synaptic 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 post-synaptic 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 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.

It 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, so-called homeostatic scaling.

It’s down-regulating 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 as a sedative in some cases

that allows people in manic episodes to sleep.

It’s classically described

as so-called dopamine receptor four 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 interoception,

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 I and bipolar II.

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 BP1 or BP2.

That’s just the reality of it.

You know, 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 because 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 in 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 has been sleeping or eating, et cetera.

So family-focused therapy involves other members

of the person suffering from bipolar disorders 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

is 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 did 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 BP1 and BP2 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,

I think 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 inducing a global seizure,

either low level or grand mal type seizure

in the patient’s brain and nervous system.

And 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 nootrophic 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

or electric convulsive therapy, ECT,

is the proper acronym and way it’s described,

is that it’s quite invasive, right?

This is something that you need to go to the hospital for.

And oftentimes there’s some inpatient care required

after the electric convulsive therapy.

It’s a fairly high cost,

especially for those that don’t have insurance.

And of course it requires anesthesia.

For most people, that’s not going to be a problem,

but for many people that could be a problem.

And there’s often some associated memory loss.

And so the memory loss,

the invasive nature of ECT and the cost

oftentimes rule out ECT for most patients.

And that’s why it’s sort of a late stage

or kind of last resort type thing

for treatment resistant depression.

Nowadays, ketamine type therapy is done repeatedly

or other treatments, for instance,

transcranial magnetic stimulation,

which is basically non-invasive.

It’s a coil that’s placed on the outside of the skull,

excuse me, and we can more accurately refer to it

as repetitive or RTMS,

repetitive transcranial magnetic stimulation.

Transcranial magnetic stimulation is a tool

that allows researchers and clinicians

to reduce the amount of activity in specific neural circuits

so they can actually target the magnetic field

to particular neural circuits

to reduce activity in those neural circuits.

Again, it’s minimally invasive.

It has been shown to be effective

in both increasing neuroplasticity in positive ways,

as well as reducing depressive episodes.

And in a few instances in reducing the amplitude

or the intensity of manic episodes

in people with bipolar disorder.

The problem is it’s still a very early technique.

There aren’t a lot of clinics and labs doing it.

I’m starting to see more advertisements,

literally commercial clinics

that are advertising RTMS or TMS.

I encourage you to approach those clinics with caution.

I’m of the mind that if those clinics

are not either closely

or maybe even distantly associated

with a research institution

that’s really up on the latest of RTMS,

you’d be wise to at least do your research, right?

And explore, talk to other patients

who’ve done these treatments.

But certainly in university hospitals

and in clinical settings and research settings,

RTMS is being used as a way to, for instance,

reduce the activity of certain limbic circuitries

so that people are just overall less excitable in manic

or to activate,

because it can also be used for activation now,

certain neural circuits,

activate, for instance, the parietal inputs,

the top-down control over the limbic system.

This is all happening right now.

So we have ECT, repetitive TMS or RTMS.

And then, as I mentioned earlier, ketamine therapies,

most of those are targeted

toward the depressive aspects of manic depression.

So for people with bipolar disorder

that doesn’t include depression,

those are going to be less effective.

But overall, it’s going to be the talk therapies

of the sort that we discussed earlier or a moment ago,

plus drug treatments,

almost always lithium will be explored,

plus some treatments for the depressive episodes

in particular, if those depressive episodes are present.

Nowadays, there’s a lot of excitement about psilocybin,

which is a psychedelic.

In the US, psilocybin is still illegal.

It is not legal,

meaning you can get in a lot of trouble for possessing it,

certainly for selling it, et cetera.

But psilocybin is being explored as a clinical therapy

in certain laboratory settings,

in particular at Johns Hopkins School of Medicine.

It’s being explored in human patients

for the treatment of major depression,

for OCD, I believe, as well,

but certainly for major depression and for eating disorders.

And it seems from the initial wave of publications

from that work done by the incredible Matthew Johnson

or Dr. Matthew Johnson,

who was a guest on this podcast before.

He’s also been on the Tim Ferriss podcast.

He’s been on the Lex Friedman podcast.

Dr. Matthew Johnson came on this podcast

and talked about some of the work with psilocybin

for the treatment of depression.

Very impressive results there.

And as you can imagine,

very impressive results for the major depressive episodes

for bipolar.

However, at least to my knowledge, again, to my knowledge,

there have not been any controlled clinical trials

exploring psilocybin for the mania

associated with bipolar disorder.

If someone out there is aware of those clinical trials,

please let me know.

I’ll do an update in a future podcast.

But right now, no knowledge from me

about psilocybin clinical trials

for the manic component of bipolar disorder.

A number of people are probably also going to wonder about

whether or not cannabis or medical marijuana

is useful for bipolar disorder.

To address this, I looked to some previous lectures

and some clinicians at Stanford Psychiatry.

This question was asked of them.

And as it turns out,

cannabis does not seem to be effective

for the treatment of the manic phases of bipolar disorder

or for the treatment of the major depressive component.

The only treatment perhaps,

or I should say the only situation perhaps

in which it might be useful,

and this is what was relayed to me,

is that it may help with sleep in certain people

that are having trouble with insomnia.

Although nowadays it’s far more common

for people in manic episodes to be prescribed things

like trazodone or other benzos, benzodiazepines,

in order to try and get sleep within the manic episodes.

And benzodiazepines and trazodone, et cetera,

work largely through the so-called GABA system.

This is a neurotransmitter

that causes reductions in excitability of neurons,

hence why it’s being used to try and calm people down

and allow them to sleep during their manic episodes.

So not a lot or essentially no data

supporting the use of cannabis

for the treatment of bipolar disorder per se,

nor data supporting the use of psilocybin

for the treatment of bipolar disorder per se.

But I realized as I say that,

that there are going to be a number of people

that may have had positive or negative experiences

with cannabis or psilocybin

as they relate to bipolar disorder.

So please, if you’re willing or comfortable,

put that if you’re comfortable

into the comment section on YouTube.

And of course, if you are aware of any studies

on cannabis or psilocybin showing positive outcomes

for the treatment of bipolar disorder,

please provide links or PubMed ideas to those.

I’d love to peruse those studies.

There are two naturopathic,

or I should say nutrition supplement-based approaches

to bipolar disorder.

They get talked about a lot.

And one of them shows some interesting promise

or effectiveness even in a limited context.

Before marching into this description

of these two compounds,

in fact, before even mentioning these two compounds,

I do want to emphasize what’s been said

and written about over and over again,

and what was relayed to me from expert psychiatrists.

It is not wise to rely purely on talk therapy

or on natural approaches to the treatment

of bipolar disorder, given the intensity of the disorder

and the high propensity for suicide risk

in people with bipolar disorder.

It is a chemical and neural circuit disruption,

and it needs to be dealt with head-on

through the appropriate chemistry

and prescription drug approaches

from a board-certified psychiatrist.

I don’t say this to protect me.

I say this truly to protect those who either suffer from

or think they may suffer from bipolar disorder,

or if you know someone who you think might suffer

from a bipolar disorder.

Now, all that is not to say

that there aren’t useful lifestyle interventions

that can support people with bipolar disorder.

So I just briefly want to mention those.

And again, I’m lifting the statements I’m about to make

from some excellent online lectures

from psychiatrists at Stanford and elsewhere,

which essentially say that, of course, of course, of course,

getting better sleep, getting adequate exercise,

getting proper nutrition,

having quality, healthy social interactions,

even getting regular sunlight in the day

and avoiding bright light at night,

all of those things are going to braid together

to support the nervous system and the psyche of somebody

with bipolar disorder.

But they braid together to support the psyche

and the neurochemistry and the neural circuits

of anybody and everybody.

So they have generally a modulatory effect.

That is, they’re indirectly shifting the likelihood

that somebody might have an episode

or the intensity of an episode,

in particular, the depressive episodes, right?

You can imagine how someone

who’s heading into a depressive episode,

maybe they’re on a lower amount of medication

or they haven’t yet medicated

for the depressive episode of bipolar.

And now they’re making sure,

or their family is making sure

that they’re getting exercise, sunshine,

eating correctly, social engagement, et cetera.

Of course, it makes perfect sense

why they would have perhaps a shallower drop

into depression or maybe an offset of depressive episode.

That said, most all, if not all people

with bipolar disorder are likely

to need some sort of drug therapy intervention

in order to help them.

So lifestyle factors are always important

in all individuals,

though suffering from psychiatric conditions or not.

But in some conditions of the mind and body,

those lifestyle interventions can have a greater effect

in offsetting symptoms,

whereas in bipolar disorder,

I think it’s naive and in fact wrong

to say that lifestyle interventions alone

are going to prevent especially the extreme forms

of mania and depression.

Again, bipolar disorder being so serious

and carrying such high suicide risk,

we just have to point this out again and again.

Now, with that said, there are two substances

generally found as supplements,

although there are other sources of them as well,

including within nutritional sources

that have been shown, at least in some studies,

to be pretty effective

in adjusting the symptoms of bipolar disorder.

And those two things are inositol and omega-3 fatty acids.

Now, inositol is a compound

that is taken for a variety of reasons.

It’s something we’ve talked about on the podcast before.

I personally take inositol

not because I have bipolar disorder.

In fact, I am quite lucky

that I don’t have bipolar disorder,

but I take inositol at 900 milligrams of myoinositol

every third night or so in order to improve my sleep.

It’s something that I’ve added to my sleep stack.

It’s something that I found greatly enhances

the depth and quality of my sleep.

And if I wake up in the middle of the night

to use the bathroom, et cetera,

it’s greatly enhanced my ability to fall back asleep

when I want to go back to sleep.

It also seems to have a fairly potent

anti-anxiety effect during the day.

And as I discussed in our episode

about obsessive compulsive disorder,

inositol has been used at high dosages.

Again, I should say myoinositol has been used

at high dosages, levels of even 10, 18 grams.

Those are massive dosages, by the way,

to deal with certain symptoms of OCD to limited success.

And I should mention that high dosages

of 10 or 18 grams of inositol

can cause a lot of gastric discomfort, et cetera.

If you want to learn more about inositol

and its various uses, I encourage you to go to

where there’s the so-called human effect matrix

and that human effects matrix will describe

the many places in which myoinositol

and other forms of inositol have been shown to be effective

in, for instance, reducing anxiety, enhancing sleep,

and on and on.

Myoinositol is important because myoinositol,

and we can just say inositol,

is related to so-called second messenger pathways.

I don’t want to get too deep

into second messenger pathways,

but when certain substances bind,

like neurotransmitters to a receptor on a cell surface,

oftentimes those receptors themselves will open

and allow the passage of ions and other things into a cell.

Oftentimes they will engage

what are called second messenger systems.

That is, they will trigger mechanisms within the cell

to then go do other things.

This is probably something we should get into

in real detail in a future episode

for those of you that really want to nerd out

on cell-cell signaling, which is a favorite topic of mine.

In any case, inositol is related

to a number of so-called second messenger systems,

this handoff or this kind of stimulating

of changes within a cell that can inspire changes

in what’s called the membrane fluidity,

can actually make the membranes of cells,

the outside fence around a cell,

which is made up of fatty stuff,

it can change the fluidity,

meaning how readily things can float around in the membrane.

You know, we think of cells as very rigid,

like there’s a cell, there’s a neuron,

or there’s a immune cell,

but actually those cells have a fatty outside,

in particular, neurons have a fatty outside,

it’s a thin, fatty outside,

and it’s called the cell membrane,

and things are floating around in that cell membrane,

but it’s kind of like jello that hasn’t quite fixed,

and so things like receptors moving into the synapse

or moving out of the synapse for homeostatic plasticity,

things like the ability for certain genes

to be turned on in a cell or not turned on

can depend a lot on things that are happening

in that cell membrane and how readily things move around

in the cell membrane.

One way to think about

this whole picture of membrane fluidity

is that just imagine that every one of your cells

has this layer, it’s kind of a gelatinous-like layer,

and there are lots of little rafts floating around in there,

but those rafts are able to move more quickly

from one place to another

or get more stuck in one place or another,

depending on how set that jello is.

Inositol and lithium,

and as we’ll talk about next,

omega-3 fatty acids seem to change

the fluidity of those membranes.

In other words, they allow things to move in

and out of those membranes more readily or not,

and this is no surprise,

given that those membranes are made out of fatty stuff.

In particular, the membranes of neurons

are called a lipid bilayer.

It’s two layers of fat.

Okay, bi means two, lipid, fat,

and omega-3 fatty acids of the sort

that are found in certain fish,

and that fatty fish in particular,

and that are found in fish oil and cod liver oil, et cetera,

omega-3 fatty acids, when we ingest them,

are used for a lot of different things,

but they can be readily incorporated into pathways

or directly incorporated into cell membranes,

changing the way those cell membranes work,

and if those cell membranes

are the cell membranes of neurons,

changing the way that neurons work.

So the ability for fish oil,

and in particular, the omega-3 fatty acids,

which come in varieties like EPA and DHA,

we’ll talk about that in a moment,

have been explored at relatively high dosages

for their ability to offset some of the effects of mania

and to offset the effects of depressive episodes

in bipolar disorder,

and actually, the data there are pretty impressive,

although they are varied,

meaning you will find several studies,

and I’ll mention a few,

that found no effect of omega-3 supplementation

through fish oil.

Usually it’s capsuled fish oil,

although fish oil can also be taken in liquid form.

Oftentimes, taking in liquid form

is the more cost-efficient way to do it.

Taking in capsule form is the more palatable way to do it,

because fish oil, for a lot of people, doesn’t taste good,

but nonetheless, there are several studies

that have shown that supplementing with fish oil

or omega-3 fatty acids at levels of, for instance,

four grams per day for a period of time,

this is a study that we will link in the show notes,

this is Murphy et al. 2012,

this is a fatty acid supplementation of 70% EPA to DHA,

actually worsened symptoms of mania

over a period of about 16 weeks,

which on the face of it makes it seem like,

okay, omega-3 fatty acid supplementation,

very likely to not be good for bipolar disorder,

and yet, that was the manic phase.

When one looks at some of the other studies

of omega-3 fatty acid supplementation,

there is, for instance, a study published in 1999,

this is a much higher dosage supplementation

with omega-3 fatty acid,

this is a 9.6 grams of fish oil per day for four months,

and that actually greatly reduced symptoms

of bipolar depression compared to the control group,

which received olive oil,

olive oil is a different form of fat,

monounsaturated fat,

but doesn’t contain as much of the omega-3 fatty acids

and so forth.

So 9.6 grams of fish oil per day over four months

is a lot of fish oil to be ingesting on a given day.

This was a double-blind study,

this was only carried out, I should mention, in 30 subjects,

but it was males and females,

and the age range was pretty broad,

anywhere from 18 all the way up to 64 years of age,

which is important given the sort of longitudinal

or changes over time that one sees in bipolar disorder.

Here’s the major takeaway.

Supplementing with high-dose omega-3s

does seem to be beneficial for a good number of people

with bipolar disorder.

However, again, I want to highlight,

however, it should not be viewed

as the only treatment approach for bipolar disorder.

This goes back to what I was saying before

about the essential need in most every case

for high-potency prescription drug treatments

prescribed by a board-certified psychiatrist

for bipolar disorder.

However, omega-3 supplementation does seem to improve

or reduce the depressive symptoms

in the major depressive episodes of bipolar,

and there are a couple of studies,

and we’ll link to these in the show notes as well,

that show that it may even improve

some of the manic episodes as well,

meaning it reduces some of the manic symptoms.

Now, I say all this from a place of great caution

because I know, especially for listeners of this podcast,

there’s a lot of interest in the behavioral tools,

the supplement-based tools, the nutrition tools

that can support bipolar disorder,

but I don’t think I can overemphasize enough

that especially for bipolar disorder

and the great risk of suicide and suffering

and inappropriate spending,

or I should say maladaptive spending and impulsivity

that’s associated with bipolar disorder,

that it’s hard to imagine a scenario

in which just talk therapy and fish oil

and lifestyle interventions are going to completely suppress

or treat bipolar disorder.

People with bipolar disorder really need to consider

the full picture of treatments, the drug treatments,

the talk therapy treatments and lifestyle treatments

and nutraceutical, or we can say supplement-based treatments

such as omega-3 supplementation,

as a full and necessary picture

for dealing with their illness.

I’d be remiss, however, if I didn’t emphasize

that the omega-3 fatty acid supplementation

is very interesting,

not just in terms of the subjective effects,

people saying they feel less depressed

or able to sleep better,

or maybe even some reduction in manic symptoms.

There’s actually been some really good brain imaging

to try and understand how omega-3 fatty acid treatments

are actually changing the brains and neural circuits

of people with bipolar.

And I will put a reference to this.

This is a paper that was published

in the American Journal of Psychiatry.

It’s entitled Omega-3 Fatty Acid Treatment

and T2 Whole Brain Relaxation Times in Bipolar Disorder.

I don’t have the opportunity

to go into a lot of detail right now

about what T2 whole brain relaxation times are,

but basically when people go into a MRI

or f-functional MRI scanner,

magnetic resonant imaging scanner,

what they’re getting essentially

is pulses of magnetic fields.

And the way that brain structures

and neural activity can be evaluated

has a lot to do with the sort of spinning,

or not sort of, it has to do with the spinning

and the relaxation times of different elements,

literally the protons and electrons within the neurons.

So it gets really detailed there.

And the relaxation time is essentially looking

at how quickly some of that spinning returns to rest.

And in particular, the fact that the relaxation times

are different for aqueous, that is liquid,

versus lipid, fatty,

versus other components of brain tissue.

And basically what this study shows

is that the membranes of neurons within the brains

of these people with bipolar disorder

showed more fluidity, more ability of things

to move in and around the membranes,

which we know is an important component of neuroplasticity

in bipolar subjects that were treated

with omega-3 fatty acids,

as compared to bipolar subjects

that did not receive omega-3 fatty acids.

And fortunately, this study also include

a healthy comparison group

where they could essentially find

that people with bipolar disorder

who supplemented with omega-3s

had changes at the cellular level

and the neural circuit level

that brought their brains and neural circuits

closer to that of the healthy comparison subjects.

So while I don’t want to point

to omega-3 fatty acid supplementation

as the be-all end-all of treatment for bipolar disorder,

certainly it is not,

it does have a strong mechanistic basis

for its possible support of neural circuitry,

of neuroplasticity,

and in particular, the ability to make changes

in cell membranes that are very reminiscent

of some of the neural circuit changes

and changes in membrane fluidity

that are seen with lithium treatment

and other known prescription drug treatments

that have been established now for decades

to be very effective for bipolar disorder.

So what that says is that omega-3 supplementation,

while not the only intervention that one should consider,

is something to consider and talk about with your doctor,

and it’s operating in powerful ways.

It’s not just that it’s changing, for instance,

your gut microbiome, which is powerful,

but is indirect to the brain.

It does seem to be having direct effects

on neurons and neural circuits.

Before we begin to conclude our discussion

about bipolar disorder,

I want to talk a little bit about this word disorder.

And this is a theme that doesn’t just relate

to bipolar disorder,

but other psychiatric disorders as well.

And when we think of a disorder,

we think of something that is really detrimental to us,

something that really impairs our ability

to function in work and school and relationships

and really starts to pull down our health status

in a variety of ways.

And certainly, bipolar disorder meets those criteria.

However, there is this idea

that things like bipolar disorder,

even things like schizophrenia in some cases,

are responsible for some of the creative aspects

or the creative works that have been observed

and carried out by human beings for many centuries.

And believe it or not,

there are good data to support the fact

that certain aspects of mania

are associated with creativity.

Now, we are long overdue for an episode about creativity,

its neural circuit basis, its chemical basis

here on the Huberman Lab Podcast.

And certainly, we will have that conversation.

But in the meantime,

I’d like to just briefly touch upon this idea

that certain occupations are associated

with a higher incidence of bipolar depression.

And in fact, it’s been explored at a research level.

Really, there are data pointed to the fact

that certain individuals of certain occupations

tend to be more creative

and that creativity is associated with,

again, associated, this isn’t causal,

it’s associated or correlated with higher levels

or incidence of bipolar depression

and maybe even other forms of depression.

So this is a study looking at mood disorders

in eminent individuals.

So these are people that are not just good at what they do,

but are exceptional at what they do

and explored the percentage of people in given professions

with either depression or mania.

And this was actually a dataset gleaned

from more than 1,000 20th century Westerners

based on their biographies that were reviewed

by other people.

So it’s a bit of an indirect measurement.

This isn’t psychiatrist data.

This is data, or I should say, these are data

that were compiled from self-reports

or from reads of self-reports.

And they explored a number of different professions.

So for instance, they looked at people in the military

or people who were professional athletes

or natural scientists or social scientists,

people who occupied positions in public office

or were musical performers, artists,

nonfiction writers, poetry, et cetera.

There are a lot of professions here.

I will post this or I’ll post a link to it

in the show note captions for you to peruse,

but I’ll just give you a sense of the extremes

on this graph because they’re very interesting.

Turns out that if you were to look at the profession,

or I should say among the professions they looked at

in this study, because they didn’t look at all professions,

those in the military and those who are professional

athletes or had jobs in the social or natural sciences

had the, of those, there was a lower percentage

of those that had depression or mania.

In some cases, like those who are professional athletes

didn’t seem to have, there was no incidence of mania,

at least in this data set.

Whereas at the opposite extreme of the graph,

those that were poets, so these are eminent individuals,

people that were exceptional poets,

exceptional fiction writers, exceptional artists

or nonfiction writers, well, there,

especially for the poets, you find that as many as 90%

of these very successful poets had either depression

or mania, as high as 90%, that’s incredible.

Contrast that with military where it’s as few as 10%

or professional athletes where it’s as few as 20%.

And for the professional athletes, as I mentioned before,

none of them had mania.

So does this mean that being a poet will make you manic

or depressed?

Well, first of all, let’s look at the poetry category.

It turns out that 75% of these eminent poets,

these highly accomplished poets had major depression.

Whereas only about 20% of those poets had manic episodes.

So again, it’s not that being a poet

is going to give you mania.

Certainly we’re not saying that.

It’s not that being a poet is going to give you depression,

but it turns out that people with depression

and people with depression and mania

seem to gravitate towards poetry

or at least are very successful at poetry.

Again, associative, correlative, no causal relationship here

but it is really striking to see how

the creative occupations, poetry, fiction, art,

nonfiction writing, even though nonfiction writing

is about nonfiction, it’s still creative,

music, composition, theater,

much higher incidence of things like mania.

And in fact, for the people in theater, the actors,

even though the overall occurrence of depression and mania

is lower than that in poets,

the fraction of those individuals that have mania

is exceedingly high.

It’s about 30% of those that they looked at

who are actors have manic episodes or have full-blown mania.

So I’m referring to these data because first of all,

I find them incredibly interesting, right?

Up until now, we’ve been talking about bipolar disorder

and other mood disorders for their maladaptive effects.

And again, they’re extremely maladaptive,

much, much higher incidence of suicide, et cetera.

But we’d be wrong to say that certain aspects

of manic episodes don’t lend themselves well to creativity

or that certain aspects of major depression

don’t lend themselves well to creativity

or to the performing arts or to poetry.

That said, in no way, shape or form,

do I believe that being depressed is a good thing

or that being manic is a good thing.

Again, we return to the basic foundational criteria

for bipolar disorder and major depression,

which is that the pressured speech, the not sleeping,

the incredible increases in energy and the flights of ideas

are generally not going to lead,

or I think it’s fair to say

are not going to lead to good places.

In fact, often lead to bad places.

But we would also be wrong if we didn’t consider the fact

that there is a somewhat inextricable relationship

between mania and creativity.

And it could be that hypomania or brief periods of mania,

maybe even an hour a day or 30 minutes a day

of composing or writing poetry,

maybe even some of the lows that we feel, right?

Some of the sadness, some of the grief,

some of the nostalgia that we feel,

provided that it’s not pathologic,

that it’s not persistent for the four or seven days

that are diagnostic of bipolar two

and bipolar one disorder respectively.

Well, then we can start to view emotional states

as something that can actually lend themselves

to positive outcomes and maybe even to creativity

and to improved occupations.

So it’s important that we have a nuanced view

of what sadness versus depression

versus major depression are.

It’s important that we distinguish between being erratic,

being very energized and full-blown bipolar disorder.

And I raise this for another reason as well.

Nowadays, it’s very common to hear people saying,

oh, you know, that person is OCD.

Well, on the episode about OCD that I did a few weeks back,

that you can find if you like at,

in that episode, I pointed out

that OCD, obsessive compulsive disorder,

is very maladaptive, right?

I think it’s number seven, as I recall,

on the list of debilitating diseases,

all diseases in terms of lost time at work,

suffering relationships, et cetera.

So it’s a really serious condition.

And yet we often hear, oh, that person is obsessive.

And as I pointed out,

there is obsessive compulsive personality disorder.

And then there is obsessive compulsive tendencies,

which actually benefit people.

But that is distinct from obsessive compulsive disorder

as a clinically diagnosed thing.

Similarly, we hear that, oh, somebody is being bipolar,

or, you know, they’re all over the place, they’re bipolar.

Well, that’s a very subjective

kind of label that people give one another in passing.

More and more often I’m hearing this.

And yet bipolar disorder, whether or not it’s BP1 or BP2,

are extremely maladaptive

and extremely associated with high suicide risk.

So while I’m not here to police people,

I’m certainly not the word police

or the nomenclature police,

I do think that whether or not you refer to people as OCD

or as bipolar, et cetera, that’s up to you, all right?

It’s not my place to say.

But I do think it’s important that all of us understand

that these psychiatric conditions

carry with them tremendous maladaptive weight.

So today we’ve really done a deep dive

into bipolar disorder and to both the manic

and the depressive components that are present

or can be present in bipolar disorder

and the different forms of bipolar disorder

and some of the major treatments for bipolar disorder,

in particular lithium and its underlying mechanisms

and some of the neural circuit and chemical basis

and neuroplasticity basis

of the treatments for bipolar disorder,

in particular homeostatic scaling or homeostatic plasticity.

All of that, of course, is relevant to bipolar disorder

and I hope will be useful in your understanding

and maybe even in your pursuit of treatments

for bipolar depression,

bipolar disorder for you or other people.

I also hope that it will be useful in your understanding

of how brain circuits work in normal conditions

or in conditions where there is no disease state

or maladaptive conditions.

Homeostatic plasticity is present in all of us.

Membrane fluidity due to how easily things move around

in the surface, the fatty layers on the outside of neurons

and the movement of receptors in and out of neurons,

that is present in all of us.

The influence of omega-3 fatty acids

is central to that discussion,

as is the discussion about various drug treatments

because even if you’re not somebody

who’s taking a drug treatment

or who is pursuing a drug treatment for bipolar disorder

or another psychiatric condition,

your serotonin levels, your dopamine levels,

your acetylcholine levels,

all of these play into what we call your mental

and physical health.

In fact, if any of you are interested

in the various categories of neuromodulators

and tools to adjust those neuromodulators

under more standard non-disease conditions,

we did an episode on neurochemicals

and how to control them.

You can find that at

along with all other episodes of the Huberman Lab Podcast.

Should mention everything is timestamped

so you can navigate to the specific topics

and tools of interest to you.

And meanwhile, I just want to thank all of you

for joining me on this voyage through the biology

and the treatments for bipolar disorder.

I do hope you found it beneficial

both for yourself and for others.

I just want to remind people that bipolar disorder

is an extremely serious condition.

If you suspect that you have bipolar disorder

or you know somebody who does,

please make sure that you or they talk

to a qualified health professional.

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