- Welcome to the Huberman Lab Podcast, where we discuss science
and science-based tools for everyday life. [upbeat rock music] I'm Andrew Huberman, and I'm a professor of
neurobiology and ophthalmology at Stanford School of Medicine. Today we are going to be
discussing bipolar disorder, often called bipolar depression. Bipolar depression is a condition in which people undergo massive shifts in their energy, their
perception, and their mood. However, it is very important to note that these shifts in mood,
energy, and perception are all maladaptive. They can often cause tremendous damage to the person suffering
from bipolar disorder and tremendous damage to
the people in their lives. Today we are going to parse the biology that leads to these shifts in
mood, energy, and perception. And we are going to talk about the various treatments that exist. Some of those treatments have been around for a very long time, and indeed one of those
treatments, lithium, has an incredible backstory
about its discovery and in understanding how lithium works and some of the ways in
which it does not work well, it reveals a tremendous amount about how the brain works
normally in all individuals. So that's a miraculous
story that I look forward to sharing with you. As we go forward in this
discussion about bipolar disorder, I want everyone to keep in mind that it is a very severe condition. In fact, people suffering
from bipolar disorder are at 20 to 30 times
greater risk of suicide. So today is a serious discussion and it's certainly one in which people who are suffering from
manic bipolar disorder or who know people that are suffering from manic bipolar
disorder can benefit from. However, for those of you
that might know people or who themselves suffer
from major depression, we will also be talking about important treatment developments
for major depression. Major depression is a very
common thing for many people. In fact, most people will
suffer from depression of some sort at some point in their life, although not necessarily a
major depressive episode, and yet major depression is very common. So you'll soon learn up to 20% of people will suffer from major depression. So today's discussion will
encompass all of that. And it will also encompass
basic brain mechanisms of neuroplasticity, the
brain's ability to change in response to experience
both for good and for worse. And you'll learn a lot
about the basic biology of how the brain regulates
mood, energy, and perception. I'm pleased to announce that
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added to the inventory. Before we dive into the discussion about manic bipolar disorder, I want to highlight some recent findings in an area totally
separate from mental health that I think are really
important for everyone to know about. This is a paper published
in the journal Cell, which is a Cell Press
Journal, an excellent journal. In fact, one of the three apex journals. So for those of you that are curious, papers published in the journal
Nature, Science and Cell are considered the sort of Super Bowl, Stanley Cup, and NBA
championships of publishing. And this paper entitled, an inter-organ neural circuit for appetite suppression illustrates a very important principle
that I think everyone should know about, and that's the principle of
so-called parallel pathways. Parallel pathways, as the name suggests, are pathways, they
could be neural pathways or hormonal pathways or otherwise that operate independently of one another to accomplish a common goal. And what this paper really shows is that there's a set
of peptides in the body and the peptide that
I'm referring to today is called GLP-1, Glucagon-like peptide-1, and some related peptides. I've talked about these
on the podcast before for two reasons. First of all, I'm a big
proponent and consumer of yerba mate. Yerba mate is a tea that
can promote the release of glucagon-like peptide-1. And there are also new prescription drugs that are now hitting the market. And for which there are really
impressive clinical trials for diabetes and obesity that are essentially glucagon-like
peptide-1 stimulator, so they stimulate the release of that, or they are in fact, a synthetic version of glucagon-like peptide-1. what is glucagon-like peptide-1? It is a peptide, which is
a small little protein, that can dramatically suppress appetite. So that's why these
drugs are being explored and are showing quite impressive results for things like treatment
of type 2 diabetes and other forms of diabetes,
as well as obesity. So they lead to weight loss. Now in terms of the yerba mate stimulation of glucagon-like peptide-1, that's going to be a much lower amount of glucagon-like peptide-1 that's released from drinking yerba
mate as opposed to say, taking a drug that stimulates GLP-1 or taking a drug that is GLP-1. Nonetheless, should also point out that yerba mate comes in a
bunch of different forms. There is some concern about
certain smokey-flavored forms of yerba mate being carcinogenic, so that's why I avoid
those forms of yerba mate. But for me, yerba mate is one of the preferred sources of caffeine. For me, I like the way it tastes. It does provide that sort of caffeine kick that I like to have early in the day for focus and for work and for exercise. And yet I actively avoid
the smoked varieties of yerba mate because of the potential carcinogenic effects of
the smoked varieties. Glucagon-like peptide-1,
as I mentioned earlier, can suppress appetite. But what this paper shows is it does that by at least two mechanisms
through parallel pathways. What this paper shows is
that glucagon-like peptide-1 axon receptors in the body in a portion of the nervous system called
the enteric nervous system, E-N-T-E-R-I-C, enteric nervous system. This is a component of your nervous system that you don't really have control over, it's autonomic or automatic. GLP-1 binds to what are called intestinofugal enteric neurons, you don't need to know the name, but those neurons do two things. First of all, they cause
some gut distension, so they actually make you feel full. This is incredible, right? A peptide, not actual physical food, but a peptide that stimulates neurons that cause changes in the
so-called mechanoreceptors of the gut, of the enteric nervous system and make people feel full. So it can lead to actually mild, or I suppose if levels
of GLP-1 are very high, to major gut distension. I think that the levels
of GLP-1 that would come from drinking yerba mate and hopefully from appropriate dosaging of the synthetic forms of GLP-1
or drugs that stimulate GLP-1 would cause mild,
not major, gut distension, 'cause major gut distension
would be uncomfortable. So GLP-1 is acting at the level of gut to increase gut distension, and by way of a pathway
that goes from the gut up to the hypothalamus, this
little cluster of neurons about the size of a marble that sits above the roof of your mouth, is
also suppressing appetite through brain mechanisms. So this is really beautiful, right? You have a peptide, a small little protein that's released in the gut and that release within the
gut causes gut distension, which makes you feel full. And by way of neural
stimulation of the hypothalamus also activates neural
pathways within the brain that trigger satiety, the feeling
of having had enough food. So to me, GLP-1 is both
impressive and important. Why? Because this recent category of drugs that's now hitting the market seems to adjust obesity or can
help people with weight loss in order to help their health. And it's doing so by at
least two mechanisms. One is within the brain, and
the other is within the gut and communication through the
so-called gut brain access. Because again, these enteric neurons are communicating to the
brain, the hypothalamus, by way of this, what's called the
sympatho-gastro-spinal-reticular-hypothalamic
pathway, you absolutely do not
need to know all of that. That's a mouthful, that's enough to make
your mouth feel distended. But at the same time,
things like yerba mate, and I'm sure there are other
compounds out there as well, but certainly yerba mate can
stimulate the release of GLP-1. So for those of you that are looking for some mild appetite suppression and want to accomplish that
while also ingesting caffeine, yerba mate might be a
good option for that. And just know that it's
operating through two mechanisms, on the body through mild gut distension to make you feel full, and on the brain to increase satiety and make you feel less hungry. And then for everybody, not just those that are interested in
appetite suppression, I think it's important to understand that these parallel
pathways are fundamental to how we are organized. Another good example of this would be when we are excited by
something positive or negative, so it could be stressful or
we are positively aroused, there is a parallel activation
of epinephrine, adrenaline, both from your adrenals and
from an area in the brain called the locus coeruleus. So again and again, we see this in biology and in neuroscience that
your brain and your body are acting in concert. They're acting together through mechanisms that either are independent,
so separately in the brain and separately in the body, but directed towards a common goal, or through communication
between brain and body, and almost always that communication is going to be bidirectional, body to brain and brain to body. So I think these results
are really interesting and really important
for sake of weight loss, for sake of appetite suppression, and just generally for the
way that they illustrate this very important theme of the way that we are constructed at a biological level
which is parallel pathways. Before we begin, I'd like to emphasize that this podcast is
separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that
theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is InsideTracker. InsideTracker is a
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Blinkist premium membership. That's Blinkist spelled B-L-I-N-K-I-S-T, blinkist.com/huberman to get 25% off and a seven-day free trial. Let's talk about bipolar disorder. And today I'm going to
refer to bipolar disorder interchangeably with bipolar depression, although as you will soon learn, not everyone with bipolar disorder necessarily goes through highs and lows. There is a subset of people who suffer from bipolar disorder who
experience the manic phases, the highly elevated mood and energy, and then drop down to so-called baseline, so they don't necessarily go
down into a depressive state. They often will return to
a somewhat normal state. In fact, we will talk about
the percentage of time that people with bipolar disorder tend to be symptom-free manic or depressed in the context of the different categories of bipolar disorder. But as we wade into this topic
that is bipolar disorder, I just want to give you a little bit of the background statistics to anchor us in just how
serious and prevalent bipolar disorder is. So bipolar disorder
impacts about 1% of people, that might seem like a small percentage, but if you think about a
room of a hundred people, that means that at least one of them is very likely to have bipolar disorder. And as I mentioned earlier
in the introduction, bipolar disorder is very serious. It has a 20 to 30% greater
incidence of suicide than the general population, which is, first of all, extremely tragic and extremely concerning. So anyone that thinks they
might have bipolar disorder or who knows someone with bipolar disorder should be especially vigilant about this. And we'll talk about some of the, or signs and risk factors, age of onset, et cetera, as we move forward. So 1% of people have bipolar disorder. The typical age of onset
is anywhere from 20 to 25 years old, although
it can be much earlier. And the earlier the onset
of a bipolar episode, which we will define in a few minutes, the earlier the onset of that episode, the higher likelihood
that the bipolar disorder is going to be a stable feature of that person's psychology going forward. And yet, I also want to point out that there are some very good treatments for bipolar disorder that those people could still benefit from. There are basically two
kinds of bipolar disorder referred to as bipolar 1 and bipolar 2. So let's just talk about bipolar 1 first. Bipolar 1 is characterized by a fairly extended period of mania. What is mania? Mania is a period of very elevated mood, energy, distractibility, impulsivity, and some other symptomology
that we'll talk about going forward. But this manic episode is extreme. This is a condition in
which the energy lift, the mood lift, and the sort of impulsivity and actions and words of the person suffering from manic bipolar disorder are very noticeable and very extreme. Now a key thing, however, is that it's not always noticeable to the person suffering from it that they are in this mode. Sometimes they recognize
that, sometimes they don't, but it's always highly
recognizable to other people that the person suffering
from manic bipolar disorder is not like other people. So let's talk about bipolar
1 in a little bit more depth. One of the key clinical criteria or diagnostic criteria for bipolar 1 is that a person suffer
from these manic episodes or display these manic episodes for seven days or more. That turns out to be very key. The stability of that manic episode for seven days or more turns
out to be very important. And for those seven days, the person is in an elevated mood, expansive thought all day,
every day for those seven days. Now there are a lot of reasons why somebody could be in a manic mode. It doesn't necessarily mean that somebody has bipolar disorder. In fact, someone could be in a manic mode for seven days or more and still not be diagnosed
with bipolar disorder. Why? Well, there are other things
that can create manic episodes, things like traumatic brain
injury, things like seizure, things like various prescription
drugs or illicit drugs, things like amphetamine and cocaine, that is not the same as bipolar disorder even though from a
symptomology perspective, they might look even identical. So let's think about these symptoms and the diagnostic criteria
that a psychiatrist would use in order to ask whether
or not someone is manic because they have manic
by bipolar disorder or whether or not that person is manic for some other reason, such
as traumatic brain injury, illicit drugs, et cetera. So typically a person would
be brought into a clinic or a person would bring
themselves to a clinic or meet with a psychiatrist, it seems more likely that
they would be directed toward a psychiatrist because oftentimes people who are in a manic episode just simply won't have the perspective or the foresight to bring
themselves into the clinic. And the psychiatrist is
going to start to evaluate for a couple of different things. But first of all, what they're
going to try and figure out is whether or not the
person has at least three of the following symptoms. The first symptom is distractibility. Is the person distractable? Are they going from one thing to the next. People who are in a manic episode will be talking about a pen and then they'll be talking
about something they saw the other day and then
something they want to purchase and then a place they're
going to travel to, et cetera, but they are also very
prone to any stimulus within the room. Meaning a bell could go off or there could be a
sound out in the hallway and they'll orient to that. And then they'll orient to the clinician and then they'll orient to
something in their pocket, so they're all over the place. You could think of this
a little bit like ADHD or attention-deficit disorder,
but it's very extreme. So highly distractable, highly impulsive, impulsivity
relates to actions. So the person might be
fidgeting with something and then they might try and leave the room or the person might, if they
were out in the real world, somebody might notice that the person is going and purchasing multiples of something that
would be unusual for someone to purchase. So for instance, I happen to know someone whose ex-spouse had bipolar disorder and their ex-spouse went out and bought 10 plus air fryers. I mean, I think unless you're a restaurant that's using a lot of air fryers, the idea that you would need more than one or two air fryers might
just seem a little bit out of the norm. And so that impulsivity can be purchasing, it can be other things as well. It can be booking 12 international
trips in one afternoon or going and buying three cars, et cetera. So impulsivity. the other is grandiosity. People who have manic bipolar disorder who are in a manic
episode will often display words of or actions of grandiosity. And keep in mind, these are not lies in the sense that the person isn't lying in order to try and pull
one over on anybody, these are actual beliefs
that the person comes to have about their grandiose
position in the world or grandiose opportunities
or potential in the world. Typical forms of grandiosity
and manic episodes would be that the person suddenly decides that they are going to
win a Pulitzer Prize. They are the person selected
to win a Pulitzer Prize. They're going to write
a novel that afternoon, and they're going to win a
Pulitzer Prize that year, which is more or less
a delusion of grandeur. The idea that someone could
do that in one afternoon, I suppose it is possible in
the realm of all possibilities, but it's extremely unlikely. Other forms of grandiosity
that often present themselves in people suffering from a manic episode will be that they're
going to run for president or that they are the
person that they believe is selected by the
citizens of a given country or by the universe to be the
president of that country or to be present of the universe. It sounds ridiculous, but
those sorts of delusions of grandiosity are one condition that often presents itself, or one set of symptoms
that presents itself. Flight of ideas are also
typical of manic episodes. So this is a little bit
like distractibility, but this would be people
talking extensively about one thing and then switching and talking extensively
about something else. It would be as if I was doing this podcast talking about manic bipolar disorder and then suddenly switching to OCD and then to deliberate cold exposure and then to the role of sugar and its impact on the brain, et cetera. So essentially a random selection of the different topics
that exist in science, all of which I happen
to be very interested in and curious about, but just as we have
episodes of the podcast that are about one or two topics, and we focus on those in
a fairly narrow trench of discussion, somebody who has a flight of ideas would be jumping between
categories and topics in a kind of pseudo random way. So they might take off
down a path of one thing and then switch to another
without any transition or with transitions that that don't have any logical structure to them. The other aspect of manic bipolar disorder that often presents itself
in the manic episodes are agitation. People feeling extremely
physically agitated, so a lot of shaking and moving about. This can venture into
the realm of paranoia, but a lot of agitation, a difficulty sitting down and being still, a difficulty in just looking,
feeling and acting calm. And then another condition is no sleep. And when I say no sleep, I mean no sleep or very minimal sleep. As incredible as it sounds, people who are in a manic episode can often go seven days
or more with zero sleep. And a key feature of this zero sleep is that they're not troubled by it. They're not thinking, oh,
I'm suffering from insomnia and I really, really want to sleep. Sometimes that's the case,
but more often than not, they are simply not sleeping. They're staying up 24 hours
then another 24 hours, it just continues for an entire week. Again, inconceivable to those of us that don't suffer from manic episodes. I can only imagine how pulled
apart most of us would feel under those conditions,
and yet they are just going and going and going with no sleep, up all hours, shopping, talking, running, doing all sorts of different
things in the categories of other symptoms that
we talked about before. And it doesn't bother them
that they're not sleeping. And then the last sort
of category of symptoms that the psychiatrist is evaluating for and seeing if they present
is rapid pressured speech. The rapid pressured speech is something that when you hear it, you recognize it. This is somebody that almost
seems to be hitting you with speech like machine gun fire, it's coming at you, coming
at you, coming at you and there's really no
room for conversation. They're not offering any opportunity for a back and forth, or if
there is a back and forth, they might ask you how
you feel about something and then you started, well, I, [speaking gibberish] then they're going to hit
you with another barrage or a paragraph of information or of just speech, that pseudo random. So we've got distractibility, impulsivity, grandiosity, flight of ideas, agitation, no sleep, and rapid pressured speech. For someone to be diagnosed
as in a manic episode, they do not have to be engaging in or displaying all of those symptoms. They do however need to present at least three of those symptoms, and then in order to meet
the condition of bipolar 1, they have to be presenting
those three symptoms for at least seven days. It could be longer, but
at least seven days. Now, this seems pretty
straightforward, right? At one level, the way that I describe this and the way that it exists
in the clinical literature, you could think, well, this should be pretty easy to diagnose. And yet there's a complication there or a challenge there because
the psychiatrist, again, has to determine that these manic episodes are not due to something
other than bipolar disorder. For instance, again, it could be TBI, traumatic brain injury,
it could be seizures, or meds or other sorts of drugs. Corticosteroids, which
are often prescribed for a number of immune
conditions or for wound healing can also cause manic episodes. So they have to determine that everything that's happening meets the
criteria I described before, three out of seven of
these symptom categories for seven days or more and that it can't be better explained by something else going
on in that person's life or immediate medical history. That's very important. Now, the other challenge, and this is something
that's going to come up again and again today, not
just in the description of the biology of bipolar disorder, but also the description
of different treatments and treatment approaches, is that typically, when
somebody is sitting in front of a psychiatrist, in particular for the first time those two people are interacting, the psychiatrist is just
getting one snapshot of the person at that moment. So the person could be on
day one of a manic episode, the person might be on day
six of a manic episode, the person could be transitioning
out of a manic episode, or the person could be
suffering from a combination of manic episode where, because of the impulsivity
of bipolar disorder, they went out and used illicit drugs. They also used cocaine. So the psychiatrist has
a serious challenge. The psychiatrist has to determine
based on a conversation, this isn't a blood test, this isn't a measurement
that you can take on a scale or with a biomarker, they
have to use language, a conversation with somebody
who, by all accounts, is pretty impaired at conversation to determine whether or not they're suffering from a manic episode that is the consequence
of bipolar disorder. You can imagine this in the real world, as somebody says, well,
how long has it been since you slept? And the person starts to answer, oh, well, the other day I
went down to the basement. I was going to get something out of the refrigerator and I
thought I might take a nap. And then all of a sudden they're talking about something completely different. So they might not even have an answer. So the psychiatrist has to
be a really good detective, a benevolent detective, but a detective nonetheless in determining whether or not these symptoms have existed
for seven days or more, and whether or not they
meet the, at least three, it could be more, but at least three of the criteria of symptom categories I talked about before. Now, assuming that they do, assuming that the patient
meets those criteria, they are likely to be
diagnosed with bipolar 1. Now bipolar 1 disorder means they're having these
extended manic episodes, seven days or more, but it does not necessarily mean that they are dropping into
a depressive episode as well. This is a common misconception
about bipolar disorder because as it's often called, bipolar disorder is referred
to as bipolar depression, and yet many people with bipolar disorder don't necessarily experience
the deep depressive episodes. Many of them do, but many of them do not. So somebody can truly
be diagnosed accurately with bipolar one, even though they're only
experiencing manic episodes and then dropping down to baseline. Manic episode, then
dropping down to baseline. That's very important to understand. Now, the second category of
bipolar disorder is bipolar 2. So BP-II or bipolar disorder
2 is somewhat different than bipolar disorder 1. First of all, it's
characterized most often by the presence of both
manic episodes, mania, and depressive episodes, or what's referred to as hypomania. Now, anytime in biology or
in medicine you hear hypo, it's the opposite of hyper. So we've got normal hyper and hypo. Hypomania is a somewhat
suppressed level of mania. So this is not going to be as extreme as the mania that we typically think of. And yet the hypo can
be due to the duration, not the intensity of mania. That's right. Hypomania can mean a
lessened intensity of mania, but it can also be used to refer to a shorter duration of mania. And in fact, that's
one of the key criteria for bipolar 2. Bipolar 2 is often diagnosed on the basis of the
presence of manic episodes that are lasting four days or even less. So someone with BP-II might have four days of this increased energy,
goal-directed activity, they're irritable, they're euphoric, they're not sleeping, et cetera, but it's only lasting for about four days. Or they could be having longer
extended periods of mania, but they are hypomanic episodes. They're not quite as intense so the pressured speech
isn't quite as pressured. The impulsivity isn't quite as severe, et cetera, et cetera. The other aspect of bipolar 2 is one that I had mentioned
briefly a moment ago, which is that it's often associated with the drops into
the depressive episode. So people are going from manic episodes for four days or less, then they're dropping into a depression, going back to normal, manic again. I do want to point out however that people who have
bipolar 1 can indeed go from manic episodes to severe, what we call major depression, so they can oscillate like a sine wave, really high highs, really low lows. And very important to understand in terms of understanding
both bipolar 1 and bipolar 2 is that it's not always a sine wave. This is really important and it's something that
frankly I did not know until I started researching this episode and talking to some psychiatrists. I should mention, I've talked to several board certified
psychiatrists in preparation for this episode, I'll give some references to them. And in fact, some of them
are going to be coming on the podcast as guests in the future for more in-depth discussion about bipolar and other psychiatric disorders. But all the psychiatrists
I spoke to confirmed what the other was saying, which was that the way that bipolar disorder can present can vary tremendously between individuals. One person might go from very high highs that last seven days or more, to very low lows. Bouts of depression, major depression that can last two weeks or more. Other people are rapid cycling by way of three days manic, three days normal, three days manic, and then dropping into three days depression. So you want to erase
that picture in your mind that manic bipolar
disorder is this sine wave, this cycling up and down
between mania and depression. It can take a lot of different forms. And again, this is a serious challenge for the psychiatrist to
diagnose people because of that fact that they're only getting a snapshot of the person unless they've
known them for some time and are working with them for some time. But this is also especially important for those of you that either have bipolar depression
or suspect that you might, or that know someone
with bipolar depression or suspect somebody might
have bipolar depression, AKA bipolar disorder. Because if you're noticing that somebody is very manic and then normal, well, that's a very different picture than somebody who's going from very manic to very deep bouts of depression. The very manic to deep bouts of depression is easier to recognize
because of the extremes of those highs and lows. Now, this might seem somewhat obvious to all of you as I describe it, and yet it's very important as a, frankly, a citizen of the planet who knows other human beings to keep an eye out for
these manic episodes, because again, whether or
not it's four days or less, or whether or not it's seven days or more, these manic episodes really
are the defining criteria of bipolar disorder,
AKA bipolar depression. There are a couple other key features about bipolar 1 and bipolar 2 that can allow us to get better insight into whether or not somebody
has bipolar 1 or bipolar 2, and that's the percentage of time that people with bipolar
1 versus bipolar 2 spend in a manic state, a depressed state, or a symptom-free state. And this is also important to discuss because it turns out that people with genuine diagnosed bipolar 1 or bipolar 2 are often symptom-free, which again can make it difficult for us as people that know them or for people that are treating people with bipolar disorder to
identify whether or not somebody is in a manic episode or a depressive episode, or whether or not they
are headed into a manic or depressive episode. So the numbers on this have been studied. This from a paper, actually two papers, first author, Judd, J-U-D-D et al. published some years ago, 20 years ago, but the data hold up
really nicely over time. These were both published in Journal American Medical
Association Psychiatry. So JAMA Psychiatry is a superb journal. And basically people who
have bipolar 1 on average spend about 50%, it's
actually 53% was the number that was eventually converged upon, but about 50% of their time symptom-free. That's interesting, right? Somebody who has genuine
bipolar 1 disorder can spend as much as half of their life symptom-free, sleeping normally, speaking normally, et cetera. About 32% of the time depressed, And when we say depressed,
we mean major depression. So severe challenges with waking up at two or three in the morning, and having trouble falling back asleep. That's one of the defining
characteristics of depression, or sleeping far too much, having a hard time getting
out of bed in the morning, suppressed appetite, suppressed libido, suppressed motivation, all the general symptoms
of major depression which we'll talk about
a little bit more later and in an upcoming episode
about major depression in particular. And then about 15% of their time in this kind of manic
state or mixed manic state, where they are showing long, again, seven days or more bouts of sleeplessness, irritability, pressured speech, grandiosity, et cetera. Contrast that with people
who have bipolar 2 disorder who are spending about half of their time in a depressed state. So that's interesting, people
with bipolar 2 disorder, while not always
displaying depressed states or oscillations between mania or hypomania and depressed states, they tend to be in the
depressed state more often. And again, this is major depression. This isn't just a little bit of a low, this is a serious depression
of their nervous system, their mood, and as we say, their affect, their outlook on life, and that's one of the key
distinguishing features of major depression is that
people's outlook on life becomes very diminished in the sense that they don't see a future. You ask them about, how's work going? How're your relationships? And it's not just that they
feel that that's going poorly, they really feel as if
there's no opportunity for those things to improve. Those people with bipolar 2 tend to be symptom-free
about 45% of the time. Again, these are averages, so about 45% of the time, that's a considerable amount of the time. And they tend to be in
these hypomanic states only about 4 or 5% of the time. Again, the criteria for BP-II, bipolar 2 is these four days or less of mania or hypomania, but only 4% of the time or 5% of the time is a small enough sliver of the pie that is these people's existence that you could imagine why it would be easy for them or other people to overlook the fact that
they have bipolar disorder and not major depression. Think about it. This is a person who, or I should say a collection of people who are spending about half of their time depressed, close to half, 45% of
their time symptom-free, and then about 5% of their
time in a hypomanic state. So either shorten bouts of high intensity mania or hypomania that is of reduced intensity. One of the reasons that I
mentioned these percentages of time spent in a
symptom-free, depressed manic or hypomanic state is
because one of my major goals for today's episode is that
it will increase awareness of whether or not you
or somebody you know, could be a coworker, could
be family member, et cetera, might be suffering from
bipolar 1 or bipolar 2. I think it's fair to say
that if somebody is suffering from bipolar 1, that is likely to be revealed or to reveal itself before too long, because of the fact that people have these
extended periods of mania and mania is such an extreme state, not just for the person
who's experiencing it, but the way that it
presents is just so extreme and out of the ordinary. But bipolar 2, you can imagine could really duck under the radar of our awareness. And you could imagine
that we might just think somebody is low or depressed, especially if that person
tends to self-medicate with alcohol or other substances. We might think, oh, they're
drinking more than often more than usual, excuse me, or they're spending more
time alone and isolating. But then when they're in
their hypomanic state, that might actually
present as normal to us because they were in such
a depressed state before. So it's very important that
we dial up our awareness, that we have tune our
antennae to the possibility that people out there who
might appear depressed or that we haven't heard from in a while might actually be suffering
from bipolar 2 disorder. Before we move into a in-depth discussion about the different kinds of treatments for bipolar disorder, I'd like to touch on just
a few additional aspects of what bipolar disorder can do in terms of its negative consequences. And also talk about some
of the inherited risk that is the genetic factors and the environmental
factors that can contribute to bipolar disorder. In terms of the burden, the very real, emotional, and occupational and educational burden that can occur for somebody with bipolar disorder, that's actually been studied. There's a measure of this,
it's called global burden which is defined as the years lost in engaging a normal life
due to some disability. So that disability could be cancer or that disability, in this
case, is bipolar disorder. And basically the way
this sort of study is done is that through questionnaires, I should say quite
in-depth questionnaires, there's a probing for whether
or not somebody has lost two consecutive weeks or more of interest in normal activities. Now, for people who have depression, that's a kind of straightforward
thing to address, right? You ask somebody, when
was the last time you ate, or when was the last time
that you went a few days without food or lost interest in relationships or work or
sex or things of that sort and they answer and you can figure out the amount of time that you've essentially been withdrawn from normal
levels of activity for them. With bipolar disorder, What it turns out is that the global burden
of having bipolar 1 and even bipolar 2 is massive. In fact, having bipolar disorder sits as one of the highest risk factors for being in the top 10 of all categories of disabilities leading to global burden. Put in plain English, what that means is having bipolar 1 or bipolar 2 disorder is extremely debilitating. It really slows down one's life trajectory unless it's treated properly. Now, the other aspect of bipolar disorder is its heritability. And this gets into a little
bit of some tricky science related to inheritability versus the genetic contribution
of a given disease. So that might sound like the same thing, you think, okay, genes
relate to heritability, heritability relates to genes, but of course, everything about the way that our nervous system
works and functions and expresses itself,
healthy or otherwise, is an interaction between our genes and our environment. And so typically the way
these studies are done is you address what is the risk of somebody having a given condition in the general population? We talked about that
before, bipolar disorder is a 1% of the world's population. Compare that to people who
have only major depression. So this would be repeated bouts of two weeks or more
of serious depression, not just low mood or
something due to a life loss, but major depression, which is 10 to 17% of people
have major depression. They suffer from major
depressive disorder, compared to bipolar disorder
which, again, is 1%. Now, you can address how much of the 1% of bipolar disorder that exists is due to genes versus environment in a somewhat exact way. This is never an exact science. And the way that this is typically done is to look at concordance, that is the likelihood
that two identical twins will both have a given condition as opposed to two fraternal twins, which have more different genes than identical twins, of course. And then two siblings who
have similar genes, of course, but less similar than
identical or fraternal twins and so on and so forth. So what you basically do is you evaluate the
probability that two people in the general population
who are completely unrelated will have the same
condition, versus two people in the general population
who are very related, identical twins. And what you find is
that in identical twins, if one identical twin
has true major depression or major depressive disorder, there's a 20 to 45% chance that their identical twin will also have major depressive disorder. Now that tells you right there that it can't all be genes, that is not a gene for
major depression per se, or if it is a gene or
a collection of genes, that those genes are also subject to environmental influences, either prenatal, within the womb or after children are born. Now the large range there of 20 to 45% could be due to any number of things. It could be experimental, meaning the techniques that
were used in experiments, it could be due to regional differences, one part of the world versus another. There are a lot of different factors. Right now, we probably
shouldn't delve into all that. At some point, we'll
probably do an episode all about the genetics of
nervous system heritability and heritability of features
and mental health, et cetera. But we can compare major
depression and the heritability or the genetic concordance
between identical twins in major depression and
bipolar disorder and ask, if one twin of an identical twin pair has bipolar depression, what is the likelihood that
the other twin will have it? And it turns out that
number is much higher. It's 40 to 70% likelihood or probability that if one twin has bipolar disorder, that their identical twin will
also have bipolar disorder. So again, the total
incidence of bipolar disorder in the general population is much lower than it is for major depressions, 1% for bipolar versus 10 to
17% for major depression. But the genetic component is much higher, 40 to 70% for bipolar disorder versus 20 to 45% for major depression. I know I'm throwing a
lot of numbers out there, but basically what this means is that researchers have been
able to take those numbers and filter them through a
number of different risk factors that are related to early development, ask questions like if two
twins were raised separately or together, or in one part
of the world versus another, or had a two parent household
versus one parent household, evaluate a lot of different variables, what they were able to discover, and this has been shown again and again, is that the genetic
contribution to bipolar disorder is very, very high. That is the heritability
of bipolar disorder is 85%. So again, I want to be
really clear what this means, the total occurrence in the
general population, fairly low, still serious, 1%, but fairly low compared to other things like major depression. However, if someone has bipolar disorder, it's very likely that they inherited some gene or sets of genes, or more accurately, a
susceptibility within their genes to environmental influences that can trigger bipolar disorder. There are a lot of
different ways to discuss and to conceptualize heritability so I want to be very careful with the way that I'm wording this. What this means is that
people with bipolar disorder very likely have a gene, or more typically it's going to be a set of genes that creates a susceptibility
for bipolar disorder to present itself. Now, what environmental factors trigger or increase that susceptibility
is not entirely clear. This always seems to center back onto the same sets of things like early life stress, trauma, et cetera, certainly those are going
to exacerbate the likelihood that someone who has a genetic propensity for bipolar disorder will express that bipolar disorder and its full array of symptomology, but 85%, while very,
very high, is not 100%. Again, 85%, while a very high number for heritability is not 100%. What that means is that
there is no single gene or identified gene cluster
for bipolar disorder. The reason I keep drilling
into this over and over is that I think we can confidently say that if someone has bipolar disorder, that there was something
in their genetic lineage that led to that, or that
very likely led to that, and yet it's not like eye color or some other physical feature, which we can actually do the direct, so it's called Mendelian genetics, and figure out whether or not somebody directly inherited that
gene from one parent or the other parent. So the takeaway here is that if you have certainly an identical
twin, or a fraternal twin, or a sibling or a parent, or even a cousin or an uncle that has bipolar disorder,
in particular bipolar 1, well, then you need to be on the lookout for bipolar disorder, perhaps in yourself and for the family members of that person. My goal within this episode up until now has been to provide a
clear and detailed picture of bipolar disorder and its various forms. Before we start to talk about treatments for bipolar disorder and some
of the neural circuit basis for bipolar disorder, I want to make sure that I
distinguish bipolar disorder from borderline personality disorder. We will do an entire episode or maybe even several episodes about borderline personality disorder. Borderline personality disorder can indeed present itself in ways that resemble bipolar
disorder and vice versa, but there's some key
distinctions that need to be made because it turns out that bipolar disorder and borderline personality disorder are quite distinct in terms
of their defining criteria. The key distinction between somebody with borderline personality disorder and bipolar disorder is that in borderline
personality disorder, there can be episodes that can
resemble mania or hypomania. So periods of flights of ideas, or where people are
spending money excessively or sexually promiscuous in ways that seem manic or could even be a little bit manic or a lot manic, and yet more often than not, there is an environmental trigger for those manic episodes. That is distinctly different
from bipolar disorder where the person will have manic episodes without any need for a trigger. There doesn't need to be a call from someone saying, hey, let's
go on a vacation together, or there's something coming up this Friday that's really exciting, or let's enter a relationship together of one form or another. The person with bipolar disorder
will have episodes of mania or episodes of major depression without any need for an external stimulus or environmental trigger. But the person with borderline
personality disorder, almost always, again, there's never an always
in biology and psychiatry, but almost always is going
to exhibit flights of mania or depressive episodes or
other types of mood shifts that are dramatic and maladaptive in response to things
that are coming in through the external environment or relationships of some kind. In fact, one of the
defining characteristics of borderline personality disorder is this thing that's
referred to as splitting. A good example of splitting in a person with borderline personality disorder is that they will feel that
they absolutely adore you and want to spend all their time with you and just think the world of you. You can do no wrong. And in fact, they
genuinely can feel that way and can genuinely think
that way about you. And then for whatever reason, it could be a perception of something that you did or something that you said or suspicion that you're
thinking something about them, they can suddenly shift
or split their emotions in what's called move
you from a good object or a can do no wrong
object to a bad object. They'll suddenly decide that
you are cheating on them or that you are being mean to them or that you're insulting them or that something that
you're doing is in violation to their self worth,
their wellbeing, et cetera and that can send them down a pathway of being very angry, very
depressed, et cetera. As I describe the contour of a person with borderline personality disorder as somebody who splits
very suddenly in response to some environmental
trigger, real or perceived, there's the risk, of course, that it makes the person with borderline personality disorder
sound like a bad person, that they're very volatile. And while they can be volatile, I want to be very careful to point out that the person with
borderline personality disorder is also suffering in this context. So while those sorts of relationships with people with borderline
personality disorder, whether or not they're
romantic relationships or familial or coworkers, et cetera, can be very challenged,
can be very high friction because of the good object,
bad object shifts, et cetera, it's bidirectional, meaning the person with borderline personality disorder, as you can imagine, is also going through a lot of suffering. At one moment, they feel as if someone is wonderful
and can do no wrong to them and they want to
be so strongly affiliated with them, and then in the next moment, they feel as if that
person is attacking them through their actions or even
through their non actions. So again, we will return to borderline personality disorder in a separate episode,
it's a serious disorder, both for the person that has it and for people around them. Fortunately, there are
some emerging treatments that are showing promise and it's a fairly common disorder, but it's important that we distinguish borderline personality
disorder from bipolar disorder, mostly on the basis of
this need for a trigger. Again, in bipolar
disorder, there is no need for a trigger to create a manic episode or a major depressive episode, they just happen or they can just happen. Whereas in borderline
personality disorder, almost always there's an external trigger or a perception that something happened in the environment or
that somebody is behaving a certain way that dramatically shifts the person with borderline
personality disorder from one mode to the next. As we move into our discussion
about the treatments for and neural circuits
underlying bipolar disorder, I want to just nail
down one more key point. This is a very brief point but it's perhaps the most
important point, which is the highs and lows, or
we should say the highs, these manic episodes, and sometimes lows, 'cause again, not everybody with bipolar disorder 1 or 2 suffers from depressive episodes, sometimes yes, sometimes no, in particular in bipolar 2, yes, but people with bipolar 1 can
have extreme manic episodes and then just return to
normal as you recall. Well, those extreme lows
and or extreme highs of people with bipolar disorder impact their lives in very negative ways. This is essential and it's something that we're going to return
to a little bit later when we talk about the relationship between bipolar disorder and creativity, because it turns out that there's a quite strong association there, one that would almost lead you to believe that being bipolar can be beneficial in certain contexts, and yet, on whole, having bipolar disorder is extremely detrimental and challenging to the person suffering from it. And it's something that
we want to keep in mind as we think about treatments
and the underlying biology. Now I'd like to talk about
some of the treatments for bipolar disorder. And in the discussion of those treatments, there's an absolutely incredible history of the discovery of one
particular treatment that still shows great
success in many patients, although some people
can't take it for reasons that we'll talk about. And in the description of the discovery of this treatment for bipolar disorder, it also reveals to us that sometimes treatments come to the
profession of medicine and through science in ways that precede the discovery of the underlying biology. That's right, every once in a while, someone will discover a
treatment for a disease without any understanding about the underlying biological basis of that disease. And in fact, that is the
case for bipolar disorder and the treatment that we are referring to is lithium. Lithium, as some of you know, is on the periodic table of elements. It is indeed a naturally
occurring substance. It actually arrived on
earth by way of star dust. Yes, we are talking about
star dust on this podcast, but if you'd like to learn more
about the origins of lithium and how lithium arrived here on earth for its discovery and
applications in psychiatry, there's a beautiful talk
that exists on YouTube and we'll provide a link to this in the show note captions that describes the history of lithium in terms of its interplanetary travels and arrival on earth. This is a talk delivered by a physicist who is expert in quantum mechanics and is expert in lithium. And it's a just wonderful
talk that I can refer you to, less on the biology in that talk, but certainly a lot about
lithium as an element. So for those of you nerds like me, that love to know how things
came to be here on the planet in one form or another, I'll encourage you to take
a brief listen to that talk. We are going to discuss
lithium in the context of its applications for
treatment of bipolar disorder. And the discovery of
lithium as a treatment for bipolar disorder is
truly a miraculous story that I think everyone should know. The key player in this
story is a physician by the last name Cade, he
was an Australian physician. And Cade has a very interesting
story in his own right. Cade was an Australian psychiatrist or Australian psychiatrist who also was a soldier. And during World War II, after the fall of Singapore to Japan, he became a prisoner of war and he was a prisoner of
war from 1942 until 1945. So he had some time for observation and during his imprisonment, he observed some of his fellow inmates is going through pretty wild vacillations in mood and energy, essentially going from manic episodes to depressed episodes, or
from manic to normal episodes. And for one reason or another, we don't know why because
I couldn't find any report as to why he hypothesized this, but he hypothesized that
there was some buildup of some chemical in these people's brains that then they would urinate out. And that urinating out
of whatever chemical was in there would allow
them to be more relaxed and not manic. In other words, Cade hypothesized that there's a buildup of a chemical in certain people's brains
that makes them manic and they urinate that chemical out. So eventually he got out of this prison, as we mentioned in 1945, and he started doing experiments in addition to seeing
patients in his clinic. And what he did is he
started to take urine from people who exhibited mania and urine from people who were not manic, and he took that urine
and he would inject it into guinea pigs as an experimental model. And his general observation was that there was something in the urine that was indeed making
the guinea pigs more manic if they were injected with
urine from a manic patient. The exact measures that he was
taking in these guinea pigs wasn't exactly clear. This is at a time or an era in science when you could just sort of report things a little bit more subjectively, although there were still
numbers and statistics, it was a little bit more
of like case studies and descriptions, but it turns out that even though that all
seems a little bit loose, it led to some incredible and
still important discoveries for psychiatric health. So what he figured out was that the urine from manic patients
seemed to be more toxic for these guinea pigs. And he also knew that there
are two toxic substances in urine, urea and uric acid. So he was able to separate
the urea and uric acid from people with mania and patients that did not have mania. And he figured out that the
urea was the same in both these mentally ill, manic patients and the non manic patients. So it did not seem that urea was the compound that was
creating these manic episodes or related to manic episodes or held the toxicity so instead he focused on the uric acid. Now in order to put the
uric acid into solution so that he could inject
it into these guinea pigs, he had to try a number
of different compounds in order to dilute it. It just so happens that, and you chemists will
be familiar with this, but there's certain
things that just don't go into solution easily. You put the powder in a vial, you add some water or a
saline or another solution, you mix it up and the powder
stays suspended in there, it doesn't actually ever
become a clear liquid that you can inject. So in order to try injecting
different strengths of uric acid, he ended up using lithium to assist in the dilution,
and lithium worked. So what he basically was doing, again for you chemists, is he was taking uric acid,
he was adding lithium, and making a solution of lithium urate. this is a lot of details,
but this is important because what he eventually found is that when he diluted the uric acid with lithium and created lithium urate, lithium urate could actually calm down these guinea
pigs that were injected with the toxic urea. He also found that lithium urate had a generally calming
effect on these guinea pigs. So now we're really
off in crazy territory, we're talking about urine from patients that's separating out urea and uric acid, we're adding lithium to the uric acid, we're injecting this into guinea pigs, this is getting pretty
wild and pretty weird, but this is medicine,
and from time to time, this is medicine and science. Cade was a good scientist in addition to being a good physician, and by good scientists, I mean that he did control experiments. Here he was injecting
lithium urate into animals and seeing an effect, but he knew that that
solution of lithium urate contained not just the uric acid, but it also contained lithium. And so he quite appropriately asked, maybe the lithium alone is
having this calming effect on these guinea pigs. And indeed, that was the case. When he did the proper control experiment and injected only lithium
solution into these guinea pigs, they calmed down. From there, he in sort
of 1940 style medicine, this would not happen now, he very quickly moved
from that animal model into human patients and started
injecting human patients with lithium or providing
lithium orally to those patients. And lo and behold, found
an absolutely profound and positive effect of lithium in reducing symptoms of mania. And as all good physician scientists do, he wrote up his results. And he wrote it up in a paper entitled, Lithium Salts in the Treatment
of Psychotic Excitement. Okay, back then they didn't call it mania, they called it psychotic excitement. This is a paper that was
published September 3rd, 1949 in the Medical Journal of Australia. We will provide a link to this study, is now a classic study in
the field of psychiatry. It's a really wonderful paper to read. And actually I encourage people, even if you're not a
scientist or a clinician to just take a quick
look at the second page in this paper that we've
made available to you where he describes each of
the various case studies or the individuals that he looked at. I'm not going to read these in detail now, 'cause it would take a
lot of unnecessary time, but things like case seven,
MC, aged 40-years-old, suffering from manic recurrent mania. In this episode, he'd
been excited, restless, and violent for over two months and was interfering so often that had to be confined to a single room during the day. So this is very debilitating, what we now know to be bipolar depression. He commenced taking
lithium citrate, 20 grains, that's a measure of the amount of lithium, three times a day. In four days, he was distinctly quieter and by February 13th, 1949,
appeared practically normal. He continued well and
on February 20th, 1949, the dose of citrate was
reduced to 10 grains, et cetera, et cetera. He left the hospital. There are numerous descriptions of this sort within this paper, including some descriptions of patients that did not see such success, and including some
descriptions of patients that suffered from some
negative side effects. So that's important to point out as well, but it's an absolutely wonderful paper and it's an absolutely wonderful voyage into the history of psychiatry right down to the discussion where in just three short paragraphs, Cade really lays out the case for why lithium is such a important discovery in the treatment of what, at that time, they were calling psychotic excitement and what we now know to be
manic bipolar depression. Lithium, I should mention, has a number of important features, but it also a number of
important side effects that need to be considered. First of all, it does have a certain toxicity and
so levels of lithium in the blood need to be
monitored extremely carefully. So it's not the sort of thing that people can just take at a given dose and every patient responds the same, there's a lot of oversight
and a lot of blood tests that have to be done, especially in the first three
months of lithium treatment. I should mention that lithium treatment is still used to some great
degree of success in many, not all people suffering
from bipolar depression, or bipolar disorder rather, but there are a number of
important things that happened between 1949 and present day that prevented lithium
from reaching patients that really needed it. And that all can be summarized in two or three short sentences. Basically, by virtue of
the fact that lithium is a naturally occurring element,
it could not be patented. And as a consequence of that, there wasn't a lot of potential profit for drug companies to produce lithium. In fact, still to this
day, it's very low cost, and still to this day, no
one really owns the patent for lithium in its purest form. So that made it unattractive. It turns out that the
FDA in the United States didn't allow lithium to
be used as a treatment for manic bipolar disorder until 1970. So we're talking about a full 21 years from the publication of this paper by Cade in the Medical Journal of Australia showing quite beautifully the great potential in use of lithium for quelling the symptoms
of bipolar disorder until the first patients
in the United States were starting to access lithium regularly. And nowadays, of course,
lithium is available, but still not able to be patented 'cause it's element number
three on the periodic table, it's naturally occurring. It's not literally falling
down from the stars as stardust and going into pill form, but rather it can be synthesized in laboratories, but it is available. It does show not only great
potential in many patients but great application in many patients despite its side effects. So lithium really stands as
this kind of golden example of a treatment that works,
at least in many individuals, prior to an understanding
of the biological basis of the disease for which
that treatment is needed. Now with that said,
scientists and clinicians have been quite rigorous
in trying to understand why and how lithium works
in order to understand the why and how of bipolar disorder. This is the way that proper
medicine and science is done. Even if there's an excellent
treatment for something, it's important to understand
why that treatment works because, first of all, not everyone responds to that treatment. Second of all, scientists
and physicians understand that just because we have
one treatment that works, if it has any side effects at all, there is the possibility
for better treatments. So it's not just about
trying to bypass a drug that doesn't make much
money for drug companies, I know a lot of people
think in those terms, they think, oh, well, there's this continued
search for better treatments for bipolar disorder
even though lithium works because lithium doesn't
allow drug companies to make much money. That's not really the case. The fact of the matter
is is that the toxicity, some of the other issues that
are created with lithium, the fact that people need the ongoing blood testing, et cetera, really stimulates the
need, really an urgent need for new and better treatments
for bipolar disorder. And only by understanding
how lithium works at the cellular level, at
the neural circuit level, et cetera, do we really stand to find those new discoveries. If you were to do a literature search on the actions and mechanisms of lithium in terms of how it can calm people down and reduce their manic episodes, you would find an
enormous array of papers, literally thousands of scientific studies in animals and in humans, which, for instance will tell
you that lithium treatment will increase so-called BDNF, brain-derived neurotrophic factor. BDNF is often talked about in the context of neuroplasticity, the brain and nervous system's ability to change in response to experience. And indeed it does seem
that ingesting lithium increases BDNF. BDNF is what we call
permissive for neuroplasticity. It doesn't create specific
changes in the brain, meaning it's not going to
make your memory better or your coordination better, or your emotional state better per se, what BDNF does is it permits the neurons, the nerve cells and their
connections in the brain to be more likely to change if the proper environmental
conditions are met. That is BDNF creates a kind of
buoyancy to neuroplasticity. It opens the gates to neuroplasticity. So lithium does increase BDNF, we'll talk about why that's
important in the context of the neural circuits involved with bipolar disorder in a few minutes. It also seems to be a
potent anti-inflammatory. Now, inflammation is one of those words that's thrown around extensively nowadays, especially on social media
and especially as it relates to any health condition,
it's like inflammation, inflammation, inflammation,
always seems to be discussed in the context of inflammation being bad. But I do want to point
out that inflammation is a natural adaptive
response to physical injury to a cell or organ or tissue of any kind. Inflammation is the basis by which adaptations occur to exercise. So if, for instance, you were to weight train and use a heavier than normal weight kind, do a set to failure or create
some little micro tears in the muscle that are healthy in the sense that they
would create adaptations and make that muscle stronger,
maybe even grow that muscle, there's an inflammatory
response associated with that that is critical to the
positive adaptation. So inflammation isn't always bad, although excessive, or as we say, runaway inflammation is bad. Lithium seems to be able to
suppress inflammation and, importantly, it can suppress inflammation in neural tissues and within
the brain in particular. That is important. And we return to that
and why it's important in a little bit. The other thing about lithium is that lithium is neuroprotective, that is it can prevent neurons from dying under certain conditions. Why would neurons die? Well, there are a lot of
reasons why neurons can die. There can be a physical
insult to the neurons. You can get hit really
hard in the head, a bullet, God forbid, can enter the
skull and kill neurons, there are a lot of reasons
why neurons can die. Neuroprotection is a
situation in which a neuron is given some sort of chemical
or physical resiliency that allows it to suffer an insult and yet bounce back. So it's very similar to
the way that we think about psychological resiliency, neuroprotection is an ability for neurons to be better able to handle stress of different kinds, in
particular, excitotoxicity. There's a phenomenon in bipolar disorder and a lot of other psychiatric conditions in which hyperactivity
of certain brain areas actually starts to kill off neurons. Hyperactivity doesn't always do this, but it turns out that if
certain brain circuits are too active for too long, some of the chemicals
associated with neuroactivity, things like calcium and neurotransmitters like glutamate can actually
kill the very neurons that are active. So it seems that lithium can prevent some of that neurotoxicity. Now, this turns out to
be particularly important for this discussion about bipolar disorder and the neural circuit
basis of bipolar disorder because if we are just
take a step back and ask, what's different in the brains of people with bipolar disorder? There are some very interesting answers that start to emerge. There are basically two
main neural circuits that are present in normal individuals, I say normal, I say that respectfully to the people with bipolar disorder by referring to people who do not suffer from manic episodes or
from manic depression. There are circuits that are present in people with bipolar disorder and in people that do not suffer from bipolar disorder, both of those circuits do the same thing in both sets of individuals, and yet in people with bipolar disorder, there seems to be an atrophy or a removal of certain neural connections over time that leads to a situation in which people with bipolar disorder become very poor at registering their own internal state, in particular, their emotional states and their somatic states. What we're referring to here is something called interoception. I've talked about this a little bit on the Huberman Lab Podcast before, but there are two modes of perception. Perception, of course, is a attention to something that's
happening in our environment or to us on or within our body. Exteroception is literally
an attention to things that are happening beyond
the confines of our skin. So seeing that person's face over there, or seeing that color of leaf over there, or hearing a sound over to my left, that is exteroception,
perception of things beyond the confines of one's skin. Then there's interoception which is perception of things
that are happening internally like, how full does my gut feel? How fast is my heart beating? Some people can measure
that quite accurately just by thinking about
it, other people can't. How happy am I, how sad
am I, how energetic am I, how lethargic am I, et cetera, et cetera. So we are always existing in a balance between exteroception and interoception, but as it turns out, people
with bipolar disorder over time, and especially into the second and third decade of
having bipolar disorder seem to have progressively
diminished levels of interoception. And that very likely is important in their inability to
register, for instance, that, wow, they are talking
at an excessive rate or they haven't slept
in 5 or even 10 days, or they haven't eaten in
a long period of time. This atrophy of neural
circuits for interoception is starting to emerge
as one of the defining neural circuit characteristics or underpinnings of bipolar. Now I bridge to this conversation
about neural circuits from the statement that
lithium can protect against some of the neurotoxic effects of neural circuits being very active. Now this can get a little bit complicated, but I promise I'm going to make it clear for any of you that are
watching and or listening. The reality is that people with bipolar depression very likely have a hyperactivity, that is an increased level of activity in certain circuits within the brain early in the expression of their disease. And that typically, as
I mentioned earlier, sets in around the early
20s, although sometimes that can be even earlier,
in the teens and so forth. But that hyperactivity, we think, leads to a toxicity and excitotoxicity of certain elements of the neural circuits that are responsible for interoception. In other words, the overuse of certain
circuits can lead to a diminishing, an atrophy, or even a death of certain elements within those circuits and it appears that lithium, through its anti-inflammatory
and neuroprotective effects and through its ability to increase BDNF, very likely protects us against some of that atrophy of those
circuits for interoception. So this isn't a case in which people with bipolar have a neural circuit or lack a neural circuit and people without
bipolar are the opposite. This is a case in which
everyone more or less starts out the same, but it seems that there's a hyperactivity of certain neural circuits in people with bipolar disorder that over time actually causes those
circuits to diminish. Now, this is very important because some of the more recent longitudinal studies doing brain imaging on people with bipolar disorder and those without, and doing that over time in patients starting as early as their teens, but into their 20s and
30s reveals just that, that there can be hyperactivity
of circuits early on, but then hypo, reduced activity
of those very same circuits at a time 5 or 10 years later. Again, this speaks to
the complicated nature of bipolar disorder and
the complicated nature of psychiatry and linking
specific psychiatric disorders to neural circuits in general. Because if you have a situation in which in one disease, let's just, hypothesize here for a second that for instance, in certain
forms of schizophrenia, there's elevated dopamine
and where we to just reduce the amount of dopamine, that
they would receive relief from those schizophrenic symptoms, well, that's all pretty
straightforward on the face of it, but in this situation
with bipolar disorder, what we're talking about is hyperactivity, too much activity leading to hypoactivity through death of those very circuits. And so now you can
especially appreciate why when the patient shows
up to the psychiatrist or when the psychiatrist
shows up to the patient in the total course of their disease is going to be very important. And then layer on top of that the complexity of the fact that the very defining characteristic of bipolar disorder is that
there are oscillations in mood. So now we need to think about treatments, not just for the manic episodes, but also treatments for
the depressive episodes. And that's, in fact,
what psychiatrists do. Turns out that they apply
different treatments or combinations of treatments for patients that are in manic episodes
versus depressive episodes and they have to infer
all that from discussions, again, just exchange of words depending on when that person
walked into their office, where they are in terms of manic episodes, no symptomology or
depressive symptomology, and whether or not they've
had that symptomology for an extended period of time. And then just to make the
situation even more complicated, the very circuits that
atrophy that start to wane and disappear in people
with bipolar disorder are the circuits for interoception, for understanding of what's
going on in one's own body. So you can imagine if you
sit down and ask somebody, well, how long have, has it been since you've slept, that
person may genuinely not know. Or if you ask the very depressed person, how depressed are you? That person may not be
able to articulate that. So fortunately there are solutions to this and the solution is that
more often than not, the accurate understanding
of whether or not someone has bipolar depression or not, and what stage of the illness
they might be in or not is going to depend on the
reports of people around them and not the patient themselves, hence the importance of
having a rather detailed and admittedly a rather intense discussion about the symptomology
of bipolar disorder, so that you can have an understanding of the people around you
and have an eye and an ear to whether or not those
people might be suffering from bipolar, and if so, at
what stage of the disease they might happen to be at. Now I'd like to talk a little bit more about what is known
about the neural circuits that lead to the manic states, as well as the depressive states, but mainly the manic
states of bipolar disorder. We already discussed the
fact that interception, registering of one's own internal emotions and bodily states is diminished in people with bipolar disorder. But we haven't really talked
about the neural circuits that are responsible for
that lack of recognition. For that reason, I'd like
to point out a paper. This is a fairly recent paper,
just came out this year, but it's an excellent one, Looking at the changes over
time in neural circuitry in people with high genetic
risk for bipolar disorder, and in particular in young people. And studies of this sort are rare, but are exceedingly
important because of the fact that they track individuals over time. The title of this paper is, Longitudinal Changes in
Structural Connectivity in Young People at High Genetic
Risk for Bipolar Disorder. We will provide a link to this study in the show note captions. There are a lot of data in this paper, in particular, neuroimaging data, and it's quite extensive
in terms of analyzing the so-called connectomics. You've probably heard of genomics, which is the analysis of
genes and their display in different individuals or
different animals, et cetera. You have proteomics,
which is the display of, or the existence of different proteins. So omics is a big thing now in science, you kind of throw omics behind anything and it becomes its own Wikipedia page, which means it becomes its own thing, so to speak, I say that
only partially in jest. Nonetheless, connectomics is the analysis of connections between different neurons
and neural circuit elements. And what this paper really showed by analyzing the connectomics
of neural circuits in the brains of many different people with different categories
of, and onset of, and severity of bipolar disorder, as well as controls in
different age groups, et cetera, is that people who are
of particularly high risk for having bipolar disorder or that have full blown bipolar disorder, have deficits and actually reductions in the amount of connectivity between what are called the parietal brain regions and the limbic system. Now, the limbic system
I've talked about before in this podcast, if you're
not familiar with it, I'll explain what it is in a moment, it's simply a collection
of brain structures, not one brain structure, but a collection of brain structures that generally are responsible for shifting the overall
state that we're in from states of more relaxed and calm to states of more alert and focused. The limbic system is intimately related to the so-called autonomic nervous system, which regulates our sleep wake cycles and a number of other things
like our digestion, et cetera, our level of hunger and on and on. So the limbic system is really
kind of like a volume control or as nerd scientists like to say, a kind of gain control
on the overall level or amplitude of alertness or calmness. In fact, if we're very, very calm, we are asleep or even more
calm, we can be in a coma. If we are very alert, we can be wide awake and ready to work and run, et cetera. Or if we are very, very, very alert by way of limbic autonomic interactions, well, then we can be in anxiety. We can be in full blown panic attack, or we can be in mania. We can have so much energy that we feel like we don't need to sleep. And in fact, disruptions in the circuitry really seems to be what's going on in people who have bipolar disorder. Now, if disruptions in the circuitry are present in the limbic system, that doesn't necessarily
mean that the limbic system is at fault because the way
that neural circuits work is that different brain areas are talking to one another through
electrical-chemical signaling, and they're regulating one another. And what this paper really tells us is that there are elements
within the parietal lobe, which is a kind of a section of the brain that sits off to the side, it's not really off to the side, but in neuroanatomical nomenclature, the parietal lobe is connected
in two ways, bidirectionally. So parietal lobe is
connecting to limbic system and limbic system is
connecting to parietal lobe. And in people with bipolar disorder, it seems that the parietal lobe is able to exert less top down control, that is less suppression
of certain elements of the limbic system,
which, at least right now, is leading researchers to hypothesize that the limbic system is sort
of revving at higher levels. It's kind of like RPM in your cars or kind of redlining at
times and for durations that are inappropriate
or at least abnormal. So we have two major sets
of neural circuit deficits or changes in people with bipolar. Their lack of internal
awareness is reduced, and that turns out to be,
by way of neural structures, like the insula which is a brain region that is connected in a very direct way to our somatosensory cortex, so the part of our cortex that registers how we feel, literally, sense of
touch and internal state. So those circuits, excuse me, for those for those of you listening I just bumped the microphone, excuse me. Those circuits are disrupted
in people with bipolar and the top down control, that kind of accelerator and break on our overall levels of
energy are also disrupted. Now that's all fine and good
because, well, it's true, at least according to what the data at this point in time tell us, there may be new discoveries to come, but that all seems to be the case, but it doesn't tell us how to modulate or change that circuitry. It also doesn't tell us
how something like lithium can actually benefit a
large number of patients or how a good number
of the other treatments for bipolar disorder, which
we'll talk about going forward can benefit patients with bipolar. So it appears that lithium is exerting its positive effects on
bipolar depression treatment, at least in part by preventing the loss of certain neural circuits, namely the neural
circuits for interoception and the top down control
over the limbic system. Now it turns out to be
examining lithium's effects at an even more reductionist level, we can gain really important
insight into what's going on in bipolar depression and
some of the other treatments for bipolar depression,
including behavioral treatments, things like transcranial
magnetic stimulation, and even some of the more natural or so-called nutraceutical treatments including things like high
dose omega-3 supplementation, which we're going to
talk about extensively. Now, in order to
understand what we're going to talk about next, it's important that everybody understand a
key concept of neuroplasticity. And this is a key concept
regardless of whether or not one is talking about bipolar depression. In fact, it's something I think everybody, every citizen of earth should know about, and that's called homeostatic plasticity. Homeostatic plasticity
is a particular form of neuroplasticity in
which if a neural circuit is overactive for a period of time, there are changes that
occur at the cellular level that lead to a balance or
a homeostatic regulation of that circuit so that
it's no longer overactive. Conversely, if a neural
circuit is underactive for a period of time, certain changes happen within
the cells of that circuit to ramp up their activity
or make them more likely to be active. And whether or not a neural circuit and the neurons within
it become more active or less active in the context
of homeostatic plasticity largely depends on one mechanism, and it's a beautiful
mechanism that I'll make very clear to you right now, even if you don't have
a background in biology. Neurons communicate with one another by releasing so-called neurotransmitters, which are just chemicals. Those neurotransmitters are vomited out, they're not actually vomited, but they're spit out into
the so-called synaptic cleft, often called the synapse. The synapse is just a
little gap between neurons. And when they are
released into the synapse, they don't just stay there, they actually park or bind to receptors on what's called the postsynaptic neuron. And depending on how many
receptors they bind to and how many receptors
are available, et cetera, they can have a greater or lesser effect on the postsynaptic neuron. This scenario of
neurotransmitters being released into synapses then binding to receptors on postsynaptic neurons and influencing the electrical excitability
of those postsynaptic neurons sits central to not just the
treatment of bipolar disorder, but to all treatments of
all psychiatric conditions and indeed to things like
neuropathic pain as well. For example, the so-called SSRIs, Prozac, Zoloft and others, et cetera, stands for selective
serotonin re-uptake inhibitor. What does that mean? Well, serotonin is a neurotransmitter. It's actually a
neuromodulator that's released into the synapse, and then the SSRI, the selective serotonin
re-uptake inhibitor allows more of that serotonin
to sit within the synapse for longer, it's a re-uptake inhibitor, it prevents re-uptake by
the presynaptic neuron. and that serotonin therefore can park in or dock in the receptors, as it's called, of the postsynaptic
neuron in greater numbers, and have a greater impact
on that postsynaptic neuron. So the drugs that are
used to treat depression or other things of that
sort, things like SSRIs, work by changing the
availability of neurotransmitter in the synapse. Other things like MAO inhibitors, Monoamine oxidase inhibitors,
work a different way. They inhibit the enzyme. Anytime you hear ase in biology, it's very likely an enzyme
which breaks things down. so MAO inhibitors prevent the
breakdown, not the re-uptake, but the breakdown of neurotransmitter and therefore allow more neurotransmitter to be available in the synapse and influence the postsynaptic cell. Homeostatic plasticity is
a form of neuroplasticity in which overall circuits can
become much more excitable or much less excitable by the addition of more receptors in
the postsynaptic neuron or by the removal of more receptors from the postsynaptic neuron. And the way this happens
is just beautiful. It was first discovered
in the visual system and the person primarily responsible for the discovery of
homeostatic plasticity, although there are several, is a woman by the name of Gina Turrigiano, she's a professor at Brandeis University. And what the Turrigiano Laboratory showed was that for instance, if we are in the dark for a long
period of time, literally, and we're not seeing much
for a long period of time, there's an increase in
the number of receptors in the postsynaptic neurons so that a smaller amount
of light and excitability within the visual system can lead to greater amounts of
activity in the visual system. Conversely, if there's an overactivity or an increase in that
activity in the visual system for some period of time, then a number of receptors
in the postsynaptic neuron are removed from that
postsynaptic neuron surface, making any neurotransmitter
that's available only able to bind the
receptors that are left and have less of an
influence on those cells. In other words, keeping a circuit in so-called homeostatic balance in a particular range of excitability. Now, while that's a mouthful and an earful and a concept-full, I don't know if a concept-full is a
word, but in any case, that's a lot to think about, but all you need to know
is that if a neural circuit is very active for a period of time, in normal individuals,
there will be a reduction in the amount of activity
by way of removing receptors that bind neurotransmitter. Whereas, if a neural
circuit is very quiet, it's not activated for a period of time, maybe your leg is in a cast for instance, and you're not activating
your quadricep and calves very much, well when that cast comes off, sure, the muscle might be atrophied but the nerves that connect to that muscle are actually in a position
to influence that muscle even more once you start using
that muscle or those muscles, because whatever
neurotransmitter is released now has the opportunity
to bind to more receptors, in that case in muscle, or in the case of brain circuits,
in postsynaptic neurons. So homeostatic plasticity
is this beautiful, balancing mechanism that makes
sure that neural circuits are never too active nor
too quiet for too long. And in a beautiful display of how treatments can lead to a better
understanding of biology, which can lead to the discovery of even better treatments, lithium and another compound, which
we'll talk about, ketamine seem to exert their actions largely through effects on
homeostatic neuroplasticity. There's a wonderful paper that describes all the nitty-gritty of this. Certainly most people
listening, I'm guessing, are not going to be
interested in all this detail, but for those of you that you are and you want to delve deep into this, this paper was published in
Neuron Cell Press journal, excellent journal, it's titled, Targeting
Homeostatic Plasticity for the Treatment of Mood Disorders. And there's one particular
figure in this paper that I'll just describe to you in which measurements
were made from neurons and the number of
receptors in those neurons, it's done somewhat
indirectly through a method that's detailed and
neuroscientists are familiar with. Basically what it measures is how excited a given neuron is, electrically
excited a given neuron is to a given amount of neurotransmitter. So that the amount of
neurotransmitter that's vomited onto a neuron is
essentially kept constant, and then the response of the postsynaptic neuron is measured. So it can be of one
level or higher or lower depending on homeostatic plasticity. And what this paper shows
and what's been shown over and over again, is that
when neurons are exposed to lithium for a period of time, there is a reduction in the excitability of the postsynaptic neuron,
that is neurons within the brain become less excitable over
time if lithium is present, whereas ketamine, which is
now a common FDA-approved, at least in the US, it's
approved for the treatment of major depression,
ketamine does the opposite. Ketamine seems to increase
the number of receptors in the postsynaptic neuron
and lead to greater levels of excitability and electrical activity within neural circuits
to a given fixed amount of neurotransmitter. So this is super interesting
because what it means is that lithium is causing
circuits to be less active, ketamine is causing
circuits to be more active. And we know from excellent
clinical data now that ketamine seems to be
a very effective treatment for major depression, and for
the major depressive episodes of people that suffer
from bipolar depression, that includes these
major depressive episodes of two weeks or longer of
suppressed mood, appetite, sleep issues, et cetera. Now, the key thing about ketamine that's often not discussed
is that while its effects are very potent, they are transient. So one major drawback to
ketamine therapy for depression is that it has to be done repeatedly, and how repeatedly, or how often, rather, depends, of course, on a discussion between the psychiatrist and the patient. This is not something
to cowboy on your own. I know that, and many of
you are probably familiar with the fact that ketamine
also is abused recreationally. It is a so-called NMDA, N-methyl-D-aspartate receptor antagonist, so it blocks the very
receptor that's responsible for neuroplasticity for
changes in neural circuits. It also changes excitability
in neurons as I just described. So ketamine is a very potent chemical that has been shown over and over again and is now FDA approved for the treatment of major depression, but its
effects seem to be transient. Lithium, as I described earlier, seems to reduce the manic episodes or the intensity of manic
episodes in symptomology, in people with bipolar disorder, it's doing that through neuroprotection. So protecting neural
circuits from dying away that initially are overactive and that overactivity
causing excitotoxicity, blocks that excitotoxicity, we believe. And it seems to do that in part by diminishing the amount of
activity in those circuits. So this is a beautiful mechanistic story, and it's the sort of story
that you'd love to have for a great number of
psychiatric illnesses. And fortunately we have
for bipolar disorder. Overactivity of a given circuit eventually leads to
neurotoxicity, excuse me, lithium is preventing that
neurotoxicity by reducing the number of receptors
in certain elements within those circuits, so
called homeostatic scaling, it's downregulating
the number of receptors leading to less
excitability and preventing, we think, excitotoxicity. And in that sense, you can see exactly why it's important to get lithium treatment in there early for people
with bipolar disorder. Ketamine as a treatment
for major depression seems to be effective but transient. And you can also see why
it would be important, not just to reduce the manic episodes for people with bipolar disorder, but to also treat the depressive episodes. So this is a key feature of the treatment for bipolar depression
and for bipolar disorder. there needs to be
treatment both of the mania and of the depressive
episodes if they're present. And fortunately, there are
excellent drugs to do that. And I should mention
that ketamine and lithium are just two of the drugs within the kit that psychiatrists have access to. There are many things, olanzapines and a number of different,
including Clozapine. Clozapine is an antipsychotic which is commonly prescribed to as a sedative in some
cases that allows people in manic episodes to sleep. It's classically described as so called dopamine
receptor 4 antagonist, although it does other things as well. Clozapine has a number
of side effect features related to white blood cell and things of that sort that
require careful monitoring. So there are an enormous number now, literally dozens and
dozens of different drugs, each designed to target
either the manic phase, the depressive phase, or
some what we call acute sort of early phases
versus ongoing treatments. This is a vast galaxy of drug treatments that really should be navigated, I should say, absolutely
should be navigated by a board certified psychiatrist. And of course in close discussion with both the person suffering
from bipolar disorder, but also ideally the family members of the person suffering
from bipolar disorder. But I think, at least up until now, we've focused on the two major pathways for treatment, lithium and ketamine. And we've talked about why
lithium and ketamine work, that they're working on opposite ends of this homeostatic scaling. We talked a bit about the
circuits that are involved in generating what we think are the manic symptomology
and the lack of interception. Why people can just
persist in staying awake, awake, awake, not eating, et cetera. Now you have in mind how
all that is put together. And I think you have in mind, some of the well-demonstrated treatments for the different component
parts of bipolar disorder, which now I'm hoping
you're also well versed in based on our early, early discussion of what constitutes
bipolar 1 and bipolar 2. Now I would like to also talk about some of the not so typical therapeutics for bipolar disorder and
also point to the things that have been tried and failed for successful treatment
of bipolar disorder, because some of those things are often talked about and suggested, especially in online communities, and while it's not clear that any of them are particularly hazardous on their own, although some of them
do carry some hazards, I do think it's important
because of the critical time sensitive nature of bipolar disorder and the urgency of
getting treatments early to try and prevent some
of the longer lasting neural circuit changes
that if people can avoid some of the less effective or demonstrated to be ineffective treatments, that they stand to combat bipolar disorder much more successfully. First of all, a key point
about drug therapies versus non-drug therapies
or talk therapies, without question, drug therapies are going to be most effective when done also with talk therapies. And we'll talk about which talk therapies have been demonstrated
to be most effective. There is some argument about
what I'm about to say next, but in general, most
psychiatrists will tell you, or certainly the ones I've
spoken to have told me, that talk therapy on its own is rarely, if ever effective
for bipolar depression and bipolar disorder, whether
or not it's BP-I or BP-II. That's just the reality of it. Contrast that with our discussion about obsessive-compulsive disorder, which we talked about a few episodes ago, if you haven't seen that episode, We have an in-depth episode all about OCD and obsessive-compulsive
personality disorder. There it seems that drug
therapies and talk therapies can be done independently
or in combination. As expected, combined
drug and talk therapies are more effective there
than either one alone, but there are pretty impressive effects of talk therapy alone provided that they're initiated at the right time, and it's the right form of talk therapy. That's OCD, but in terms
of bipolar disorder, it really seems that the
drug therapies are necessary, at least in most all cases. That said, talk therapies
are terrific augment or support for those drug therapies and sometimes can allow people to take lower doses of
those drug therapies, which turns out to be important because of the side
effect profiles of a lot of drug therapies and
sometimes the cost as well. I guess we can think of cost just as another side effect really. There are both established
and more novel forms of talk therapy being used, again, in concert with drug treatments
for bipolar disorder. Cognitive behavioral therapy is the one that seems to be best, at least by way of the
statistics and papers that exist. It's also the one that's
been explored the most. So one of the reasons
why it's often considered the most popular or effective is 'cause it's also been around longer and it's been explored the most. Cognitive behavioral therapy in general is a progressive exposure of the patient in a very controlled way,
in a clinical setting, to some of the triggers or the conditions that would exacerbate bipolar disorder. Now, earlier I said borderline
personality disorder has all these triggers
and triggered elements from the external environment, whereas bipolar disorder does not. And that's still true, but it is the case that somebody with bipolar can have worse symptoms if life conditions get worse or more stressful. So cognitive behavioral therapy, I mean the discussion about and sometimes the direct exposure to anxiety provoking elements of life can be very helpful for
adjusting the responses to those otherwise triggering events and sometimes making the drug treatments more effective even at lower doses. There are also forms of therapy including family-focused therapy, which is especially important in terms of bipolar disorder because family members, provided
that they are not themselves in a manic episode due to the close heritability of bipolar disorder, but family members can
often be excellent windows into whether or not somebody
is doing well or poorly, or is veering toward or is emerging from a manic or depressive episode because they understand that person, they have a lot of data, it could be purely subjective data, but they have a lot of
exposure to how long or well somebody's been
sleeping or eating, et cetera. So family-focused therapy
involves other members of the person suffering from
bipolar disorder's family, as well as conversations
about family members in a way that helps patients with bipolar disorder navigate, not just through manic episodes
and depressive episodes, but start to learn to predict
what are the conditions psychological, physical, and otherwise that can trigger bipolar episodes. And then there's a category of therapy called interpersonal and
social rhythm therapy. This is deserving of its
own entire episode really. Interpersonal and social rhythm therapy, it's sort of an expansion
on family-focused therapy, although it's distinct
in certain ways as well, and really focuses on how
people are relating to others in their life, and in the workplace, and in the school environment, and also within the family, et cetera. And I should say that a overall theme that's emerging in
psychiatry and psychology is to start wherever
possible to incorporate more of the social aspects and the interpersonal aspects. In other words, not just talking to and examining a patient
as one biological system, one nervous system, one set
of chemicals, and one life, but rather a set of
chemicals, neural circuits, and a life that's
embedded in the chemicals and neural circuits and
lives of other people. Just by way of example, you can imagine that if somebody is in a
very healthy relationship or a very abusive relationship, that that's going to strongly impact the outcomes of manic episodes. You can imagine that if
the financial situation is one in which people can
recover from manic episodes, I didn't mention this
earlier, but I should have, forgive me, that oftentimes people who are in a manic episode will go out and spend immense amounts of money that they simply cannot afford to lose. And then the depressive
episodes that, in many cases, follow are made far worse
by the financial anxiety and the financial stress that results from those manic episodes
of spending, et cetera. And then of course, this carries over to sexual promiscuity where
people might be dealing with unwanted pregnancy or STIs, or very fractured interpersonal dynamics with existing or new relationships. I mean, you can imagine
how these manic episodes, as well as the depressive episodes can really wick out into an
enormous amount of destruction, which brings us back
to the initial criteria of BP-1 and BP-2 is that
these manic episodes are not a good thing. These depressive episodes
are not a good thing. They create this sense of euphoria in the person experiencing mania, or they create this sense
that anything is possible. But at the end of the day,
and actually every day, these episodes are quite maladaptive. They really destroy people's lives. And it's not just the life of the person that's suffering from bipolar disorder. And so hence cognitive behavioral therapy, family-focused therapy and interpersonal and social rhythm
therapies are the primary three talk therapies that
are most often combined with drug therapies in order to try and really reduce the harm. It's really all about harm reduction from manic episodes and
depressive episodes. One very exciting and emerging treatment that does show great promise, and in some cases, great outcomes, for bipolar disorder is, believe it or not electric shock therapy. Electric shock therapy may sound barbaric, and in fact, it tends to look barbaric, although this is done in
the controlled setting of a hospital. If any of you have seen One
Flew Over the Cuckoo's Nest, the final scene or near
final scene in that movie was Jack Nicholson with
the sort of bite protector in his mouth and getting
electric shock therapy, and it's as the name suggests,
it's a kind of inducing a global seizure, either low
level or grand mal type seizure in the patient's brain and nervous system. You might ask, well, why
would one want to do that? Well, it turns out that
this is a well-established, and in many cases, very
effective treatment for major depression. Electric shock therapy is generally used for treatment-resistant depression. So these are people that
have no positive response or ongoing positive
response to drug therapies or other therapies. Electric shock therapy is thought to work primarily by stimulating the massive kind of indiscriminate release of things like serotonin, dopamine, acetylcholine, a huge variety of neuromodulators, as well as things like BDNF, brain-derived neurotrophic factor which then allows
neuroplasticity to take place. Again, BDNF being permissive
for neuroplasticity. The problem with ECT is
that it's really only useful for treatment-resistant depression, it doesn't actually
target the manic aspects of bipolar depression
and bipolar disorder, but nonetheless, is used when
drug treatments don't work. Some of the negatives of
electric shock therapy 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, 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 and manic or to activate because it can also be used for activation now of
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 Ferris Podcast, he's been on the Lex Fridman Podcast. Dr. Matthew Johnson came on this podcast, he's 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, though 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 realize, 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 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. 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, those 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, a 900
milligrams of myo-inositol 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
myo-inositol has been used at high dosages, at 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 examine.com where there's the so-called
Human Effect Matrix, and that Human Effects
Matrix will describe the many places in which myo-inositol
and other forms of inositol have been show shown to be effective in, for instance, reducing anxiety, enhancing sleep and on and on. Myo-inositol is important
because myo-inositol, 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 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,
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 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 everyone 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 at 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 what called a lipid bilayer, it's two layers of fat,
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, 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, excuse me, 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 at al. 2012. This is a fatty acid
supplementation of 70% EPA to DHA actually worsen 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 then 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 board
certified psychiatrists 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 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 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, excuse me, magnetic resonance 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-3 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, 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. 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. 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, 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 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, 'cause 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, 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 incidence of mania, at least in this dataset, 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. 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, non-fiction writing, even though non-fiction
writing is about non-fiction, it's still creative, music
composition, theater, much higher incidents
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 instance
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, 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, 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 2 and bipolar 1 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, ah, 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 hubermanlab.com, in that episode, I pointed out that OCD, obsessive-compulsive
disorder is very maladaptive. 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's being bipolar. You know, they're all over the place. They're bipolar. Well, that's a very subjective 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 BP-1 or BP-2 are extremely maladaptive
and extremely associated with high suicide risk. So while I'm not here to police people, I'm not 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, 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 hubermanlab.com along with all other episodes
of the Huberman Lab Podcast. I 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. If you're learning from and
are enjoying this podcast, please subscribe to our YouTube channel, that's a terrific, zero
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is happy to announce that we partnered with
Momentous Supplements. If you'd like to see our supplements and the ones that we designed
in concert with Momentous, you can go to livemomentous.com/huberman. Please also check out
Huberman Lab on social media. We are hubermanlab on both
Twitter and Instagram. In both places, I cover science
and science-related tools, some of which overlaps with the content of the Huberman Lab Podcast, but much of which is distinct from the information covered
on the Huberman Lab Podcast. We also have a newsletter, it's called the Neural Network Newsletter. It's completely zero cost and it contains summaries of podcasts and some actionable
protocols from each podcast. You can sign up for it by
going to hubermanlab.com, go to the menu and click on
Neural Network Newsletter. You can also see some examples of previous newsletters there. I should mention that by signing up, you do provide your email, but we do not share
your email with anybody. And again, it is completely zero cost. 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. [upbeat rock music]
