Welcome to Huberman Lab Essentials,

[music] where we revisit past episodes

for the most potent and actionable

science-based [music] tools for mental

health, physical health, and

performance.

I'm Andrew Huberman and I'm a professor

of neurobiology and ophthalmology at

Stanford School of Medicine. Today we

are going to be discussing bipolar

disorder, often called bipolar

depression.

Bipolar depression is a condition in

which people undergo massive shifts in

their energy, their perception, and

their mood. However, it is very

important to note that these shifts in

mood, energy, and perception are all

maladaptive. They can often cause

tremendous damage to the person

suffering from bipolar disorder and

tremendous damage to the people in their

lives. 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. So,

bipolar disorder impacts about 1% of

people. That might seem like a small

percentage, but if you think about a

room of 100 people,

that means that at least one of them is

very likely to have bipolar disorder.

The typical age of onset is anywhere

from 20 to 25 years old, although it can

be much earlier. There are basically two

kinds of bipolar disorder, referred to

as bipolar 1 and bipolar 2. Bipolar 1 is

characterized by a fairly extended

period of mania. What is mania? Mania is

a period of very elevated mood, energy,

distractibility, impulsivity, and some

other symptomatology that we'll talk

about going forward. But, this manic

episode is extreme. One of the key

clinical criteria or diagnostic criteria

for bipolar 1 is that a person suffer

from these manic episodes or display

these manic episodes for 7 days or more.

Typically, a person will be brought into

a clinic or a person would bring

themselves to a clinic or meet with a

psychiatrist. 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.

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, etc.

But they are also very prone to any

stimulus within the room. 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. 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.

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.

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. 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. Um 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 7 days or more with

zero sleep. And a key feature of this

zero sleep is that they're not troubled

by it. 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. It's coming at you,

coming at you, coming at you, and

there's really no room for conversation.

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 7 days. It could

be longer, but at least 7 days. Now,

bipolar one disorder

means they're having these extended

manic episodes, 7 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. The second category

of bipolar disorder is bipolar two. So,

BP2, 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. Bipolar two is often

diagnosed on the basis of the presence

of manic episodes that are lasting 4

days or even less. So, someone with BP2

might have 4 days of this increased

energy, goal-directed activity, they're

irritable, they're euphoric, they're not

sleeping, etc., but it's only lasting

for about 4 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, etc.,

etc. The other aspect of bipolar 2 is

one that I mentioned briefly a moment

ago, which is that it's often associated

with the drops into the depressive

episodes. One person might go from very

high highs that last 7 days or more to

very low lows. Bouts of depression,

major depression that can last 2 weeks

or more.

Other people are rapid cycling by way

of, you know, 3 days manic, 3 days

normal, 3 days manic, and then dropping

into 3 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 a

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 4 days or less or whether or not

it's 7 days or more,

these manic episodes really are the the

defining criteria of bipolar disorder

aka bipolar depression. 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 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. The key player in

this story is a physician by the last

name Cade. Cade was an 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 build-up 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. Eventually, he got out of this

prison as we 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, right? The exact measures that

he was taking in these guinea pigs

wasn't exactly clear. This is um at a

time or an era in science when you could

uh just sort of report things a little

bit more subjectively. Although there

were still numbers and statistics, what

Cade 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

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 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 it

doesn't actually

uh ever

become a clear liquid that you can

inject. So in order to try injecting

different strengths of uric acid, he

ended up using lithium to assist in the

dilution. And lithium worked. So what he

basically was doing, again for you

chemists, is he was taking uric acid, he

was adding lithium, and making a

solution of lithium urate. 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, if you 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 the 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

scientist, 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 1940s style medicine, and

this you would not happen now, he very

quickly moved from that animal model

into human patients and started

injecting human patients with lithium or

providing lithium orally to those

patients. And lo and behold, found an

absolutely profound and positive effect

of lithium in reducing symptoms of

mania. And as all good physician

scientists do, he wrote up his results.

And he wrote it up in a paper

entitled lithium salts in the treatment

of psychotic excitement. Okay, back then

they didn't call it mania, they called

it psychotic excitement. This is a paper

that was published September 3rd, 1949

in the Medical Journal of Australia, a

classic study in the field of

psychiatry. Lithium, I should mention,

has a number of important features, but

it also a number of important side

effects that need to be considered.

First of all, it does have

a certain toxicity, and so levels of

lithium in the blood need to be

monitored extremely carefully. So, it's

not the sort of thing that people can

just take it 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 3 months of lithium treatment.

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. 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. And only by understanding

how lithium works at the cellular level,

at the neural circuit level, etc., do we

really stand to find those new

discoveries. Lithium seems to be able to

suppress inflammation, and

importantly, it can suppress

inflammation in neural tissues and

within the brain in particular. The

other thing about lithium is that

lithium is neuroprotective.

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.

I've talked about this a little bit on

the Huberman Lab Podcast before, but

there are two modes of perception.

Exteroception is literally an attention

to things that are happening beyond the

confines of our skin. Then there's

interoception, which is perception of

things that are happening internally.

So, we are always existing in a balance

between exteroception and interoception.

But, as it turns out, people with

bipolar disorder, over time, and

especially into the second and third

decade of having bipolar disorder, seem

to have progressively diminished levels

of interoception. And that very likely

is important in their inability to

register, for instance, that wow, they

are talking at an excessive rate, or

they haven't slept in 5 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. 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 it 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. And it appears that

lithium very likely protects us against

some of that atrophy of those circuits

for interoception.

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. 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. And then

there's a category of therapy

called interpersonal and social rhythm

therapy. This is deserving of its own

entire

uh 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,

etc. 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 an 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. 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. 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. 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 uh

depression and bipolar disorder, but

nonetheless is used when drug treatments

don't work. Some of the negatives of

electric

shock therapy um or electroconvulsive

therapy ECT is the is the proper acronym

and and way it's described is that it's

quite invasive, right? This is something

that um you need to go to the hospital

for and often times there's some um

inpatient care required after the

electric shock uh 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 uh 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 often times

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. There

are two naturopathic, or I should say

nutrition supplement-based approaches to

bipolar disorder that 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. If you know someone who you

think might suffer from 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. 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 mg of myo-inositol

every third night or so in order to

improve my sleep. It also seems to have

a fairly potent anti-anxiety effect

during the day. So, the ability for fish

oil, and in particular the omega-3 fatty

acids, which come in varieties like EPA

and DHA, 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.

There are several studies that have

shown that supplementing with

fish oil or omega-3 fatty acids at

levels of, for instance, 9.6 g of fish

oil per day for 4 months 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. 9.6 g of fish oil per

day over 4 months is a lot of fish oil

to be ingesting on a given day. This was

a double-blind

uh 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. But I don't think I can

overemphasize enough that, especially

for bipolar disorder and the great risk

of suicide and suffering and, you know,

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 uh 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. 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,

in school, in 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.

It's been explored at a research level.

Really, there are data pointing 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 incidents 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 data set gleaned

from more than a thousand 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,

you know, 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, non-fiction writers, poetry,

etc. Turns out that if you were to look

at the profession, 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 were professional athletes,

didn't seem to have There was no

incidents 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

non-fiction writers,

well, there, especially for the poets,

you find that as many as 90%

of these very successful poets

had either depression or mania. Again,

associative correlative,

no causal relationship here.

But, it is really striking to see how

the creative occupations, poetry,

fiction, art, non-fiction writing, even

though non-fiction writing is about

non-fiction, it's still creative, music

composition, theater, much higher

incidence of things like mania. 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 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. 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. 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. So

once again, thank you for joining me

today for our discussion about the

biology and treatment of bipolar

disorder. And last but certainly not

least, thank you for your interest in

science.

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