The Science & Treatment of Bipolar Disorder
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I'm Andrew huberman and i'm a professor of neutral logy and optimal gy at stanford school of medicine. Today, we are going to be discussing by polar disorder, often called by polar 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 they shifts in mood. Energy and perception are all the adaptive.

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 the 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 back story about its discovery and in understanding how lithium um works and some of the ways in which IT does not work well, IT reveals a tremendous amt about how the brain works Normally in all individuals. That's a maculate story that I look forward to sharing with you as we go forward in this discussion about bipolar disorder.

Want everyone to keep in mind that this is a very severe condition. In fact, people suffer from bipolar disorder are at twenty to thirty times greater risk of suicide. So today is a serious discussion, and it's certainly won in which people who are suffering from manic bipolar disorder or who know people that are suffering from men and pipa 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 soon learn up to twenty percent 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 brains ability to change in response to experience both for good and for worse.

And you will learn a lot about the basic biology of how the brain regulates mood, energy and perception. Before we dive into the discussion about men up by polar disorder, I want to highlight some recent findings in the 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 and excEllent journ, in fact, one of the three apex journals.

So for those of you they are curious, papers published in the journal nature, science and cell are considered the sort of superbowl stanly cop in NBA championships of publishing. And this paper, entitled an into organ neural circuit for appetite suppression, illustrated very important principal that I think everyone should know about. And that's the principle of so called parallel pathways.

Parallel pathways, as the name suggests, our pathways that could be neural pathways or for mono pathways or otherwise, that Operate independently of one another to accomplish a common goal. And what this paper really shows is that there is a set of peptides in the body, and the peptide then referring to today is called the G L P. One gluckman like peptide one and some related peptides.

I've talked about these on the broadcast before for two reasons. First of all, I made big a proponent and consumer of eba mote. Eba te is A T that can promote the release of glucosamine peptide one.

And there are also new prescription drugs that are now hitting the market and for which there are really impressive clinical trials for diabetes and obesity that are essentially glucagon like peptide one stimulator. So they stimulate the release of that. Or they are, in fact, a synthetic version of glucagon like peptide one.

What is glucagon like peptide one? IT is a peptide which is a smaller 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 typed to diabetes and other forms of diabetes as well as obesity.

So they lead to weight loss. Now in terms of the year about muti stimulation of glucagon like peptide one that's gonna a much lower amount of glucagon like peptide one that's released from drinking your robot as opposed to say, taking a drug that stimulates G L P. One or taking a drug that is G L P.

one. I should also point out that year b mote comes in a bunch of different forms. There is some concern about certain smoke flavor forms of year bom being carson.

So that's why I avoid those forms of uba mot. But for me, uba market is one of the preferred sources of caffeine for me. I like the weight taste.

IT does provide that sort of caffeine kick that I liked to have early in the day for focus on for work and for exercise. And yet I actively avoid the smoked varieties of year by market because of the potential carcinogenic effects of the smoked varieties. Google gone like peptide one, as I mentioned earlier, can suppress appetite.

But what this paper shows is IT does that by at least two mechanisms, through parallel pathways. What this paper shows is that gluchow like peptide one axon receptors in the body in a portion of the nervous system called the interact nervous system, E N T E R I C interact nervous system. This is a component of your nerve system that you don't really have control over its automatic or automatic gp one bines to what are called in testing o fugal interrex neurons.

You don't need to know the name, but those neurons do two things. First of all, they some gut distinction. So they actually make you feel for this is incredible, right? A peptide, not actual physical food, but a peptide that stimulate neurons, that cause changes in the so called mechano receptors of the gut of the interact nervous system and make people feel full. So I can lead to actually mild, or I suppose ve levels of G, L, P, one are very high to major gut detention.

Okay, I think that the levels are G, L, P one that would come from drinking your biot and hopefully from appropriate dosage ing of the synthetic forms of top one or drugs that stimulate J P one would cause mild, not major, got to tension. Cause major got to tension, would be uncomfortable. So G, L, P, one is acting the level of gut to increase gut detention.

And by way of a pathway that goes from the gut up to the hypothesis cluster of neurons about the size of a marble that sits above the roof, your mouth is also suppressing appetite through brain mechanisms. So this is really beautiful, right? You have a peptide, small little protein that's released in the gut.

And that released within the gut causes got detention, which makes you feel full. And by way of, neural stimulation of the hypothesis, also activates neural pathways within the brain that trigger the tidy, the feeling of having had enough food. So to me, G, L, P one is both impressive and important.

why? Because this recent category of drugs that's now hiding the market seems to adjust. Obesity 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 internews are communicating to the brain, the hypothalamus, by way of this, what's called the sympathy gastro spinal particular hypothermic path way.

You absolutely do not need to know all of that. That's a mouthful that's enough to make your mouth el extended. But at the same time, things like year but mote. And i'm sure there are other compounds out there as well. But certainly year by moi can stimulate the release of gp one.

So for those of you that are looking for some mild appetite suppression and want to accomplish that while also ingesting caffeine, year bermont might be a good option for that and just know that it's Operating through two mechanisms, on the body, through mile, get dimension to make you feel full and on the brain to increase the tide or make you feel less hungry. And then for everybody, not just those that are interested in appetite suppression, I think it's important to understand that these parallel pathways are fundamental to how we are organized. Another good example this would be when we are excited by something positive or negative, so we could be stressful or we're positively arouse.

There is a parallel activation of epinephrine, neal, in both from your dreams and from an area in the brain called the locust seul us. So again and again, we see this in biology and in neuroscience that your brain in 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 by directional body to brain and brain to body. So I think these results are really interesting and really important for sake of weight loss, for sake of appetite suppression, and just generally for the way that they illustrate this very important theme of the way that we are constructed at a biological level, which is parallel pathways. Before we begin, i'd like to emphasize that this podcast is separate from my teaching and research roles at stanford.

IT is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, i'd like to thank the sponsors of today's podcast. Our first sponsor is athletic Greens. Athletic Greens is in all in one of vitamin mineral probiotic c drink.

I've been taking athletic Greens since two thousand and twelve, so i'm delighted that their sponsor in the podcast, the reason I started taking athletic Greens and the reason I still take athletic gres once, twice a day, is that IT helps me cover all of my basic nutritional need to make up for any deficiencies that I might have. In addition, IT has probiotics, which are vital for microbial on health. I've done a couple of episodes now on the so called gut microbiome and the ways in which the microbiome interacts with your immune system, with your brain, to regulate mood, and essentially with every biological system relevant to health throughout your brain and body.

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Dog comes so huberman to claim the special offer of the five free travel packs and the ear supply of vitamin d three k two. Today's episode is also brought to us by element. Element is an electoral like drink that has everything you need and nothing you don't that means the exact ratios of electrolier ts are an element and those are sodium, magnesium and plastic um but IT has no sugar.

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Again, that's waking up dot com slashed huberman to access a free thirty day 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 experiences the manic faces, 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 weighed into this topic, that is, bipolar disorder, I just want to give you a little bit of the background statistics to anchor us and just have serious and prevalent bipolar disorder is.

So bipolar disorder impacts about one percent of people that might seem like a small percentage. If you think about a room of one 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 twenty to thirty percent grater incidents 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 will talk about some of the our signs and risk factors, age of onset at setter as we move forward.

So one percent of people had bipolar disorder. The typical age of onset is anywhere from twenty to twenty five 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 one and bipolar two. So let's just talk about bipolar one.

First, bipolar one is characterised by a fairly extended period of mania. What is mania? maia's? A period of very elevated mood energy distract ability in pulse vy and some other symptom logy that will talk about going forward.

But this manic episode is extreme. This is a condition in which the energy left, the mood left, and that sort of impulsivity and actions and words of the person suffer from manifields 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 suffered from. Many bipolar disorder is not like other people. So let's talk about bipolar one in a little bit more depth.

One of the key clinical criteria or diagnostic criteria for bipolar one 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 the ability of that manic episode for seven days or more turns out to be very important.

And for those seven days, the person is an an elevated mood, expensive thought all day, every day for those several 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 an a manic mode for seven days or more and still not be diagnosed with bipolar disorder. why? Well, 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 in federman and cocaine.

That is not the same as bipolar disorder, even though from a symptom logy perspective, they might look even identical. So let's think about these symptoms and the diagnostic criteria that a psychic st would use in order to ask whether not someone is manic because they have manic bipolar disorder, or whether not that person is manic for some other reason, such as traumatic brain injury as IT drugs at central. So typically a person will be brought into a clinic, or a person would bring themselves to a clinic or meet with a psychiatrist.

IT seems more likely that they would be directed toward psychiatrist because often times people who are in the 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 trying to figure out is whether not the person has at least three of the following symptoms.

The first symptom is distract ability. Is the person distracted bar? Are they going from one thing to the next? People who in the manic episode will be talking about a pen, and then they'll talking about something they saw the other day and then something they want to a purchase, and then in a place they're to travel to each other.

But they are also very proud any stimulus within the room, meaning, you know, a bell could go off, that could be a sound out in the whole way. And they're only into that and then they're only into the clinton and then they into something in their pocket. So they are they're all over the place.

You can 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 fighting with something and then they might try to leave the room or um the person might if they were out in the real world, somebody might notice that the person is going and purchasing you know multiples of something that would be unusual for someone to purchase.

So in ces I have to know someone whose um x spouse had bipolar disorder and their expose went out in boat ten plus air fires, right? I mean, I think unless you're a restaurant that's using a lot of air fires, the idea that you would need more than one or two airfix um might just seem a little bit out of the norm. And so that impulsivity can be at purchasing IT can be other things as well.

I can be booking twelve international trips in one afternoon or going and buying three cars, IT said. So impulsivity, the other is grandiosity. People who have managed by polar 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 ground OS position in the world, or grandiose opportunities or potential in the world. Typical forms of grandiosity and manic episodes would be that the person sudenly decides that they are going to win a pull out surprise.

They are the person selected to in a pullet surprise, they're going going to write a novel that afternoon, and they onna win a pull that surprise that year, which is more less a delusion of granger, right? The idea that someone could do that in one afternoon, I suppose IT is possible in the realm of all possibilities, but it's extremely unlikely other forms of grandiosity that often present themself elves in people suffering from a manic episode will be that they are 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, right?

That sounds ridiculous, but those sorts of delusions of grand osi 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 distraction ability.

But this would be people talking extensively about one thing and then switching and talking extensively about something else. I would be as if I was doing this podcast talking about manic bipolar disorder, then suddenly switching to ocd and then to deliberate cold exposure, and then to now the role of sugar and its impact on the brain at set. So essentially a random selection of the different topics that exists in science, all of which I haven't be very interested in and curious about.

But just as we have episodes of the podcast that 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 um in a kind of suo random way so they might take off down a path of one thing and then switched to another without any transition or with transitions that that don't have any logical structure to them. The other aspect of manic biologist order that often presents itself in the manic episode agent people feeling extremely physically agitated or a lot of shaking and moving about. This can venture into the ROM of paranoia, but a lot of agita difficulty, sitting down and being still a difficulty, and 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, they're not thinking, oh, i'm suffered from in soma. I really, really want to sleep sometimes that's the case. But more often than not, they are simply not sleeping.

They are staying up twenty four hours than another twenty four hours and just continues for entire week. Again, inconceivable to those of us. They don't suffer from manic episodes. Can only imagine how pulled apart most of us would feel under those conditions in 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 that this is somebody that almost seems to be hitting you a speech like machine gun fire. It's coming at you, coming at you, coming at you. And there's really no room for conversation.

They're not offering any opportunity for a back and forth forth. There is a back and forth, I ask you how you feel about something, and then you started, well, they're going to hit you with another garage. Or a paragraph of of information, or of of just speech that suda random.

So we ve got distracted ly, impulsivity, grandiosity, flight of ideas, agitation, no sleep and rapid pressured speech for someone to be diagnosed as in a manic episode. They do not have to be engaging in or displaying all of those symptoms. They do, however, need to present at least three of those symptoms.

And then in order to meet the condition of bipolar one, they have to be presenting those three symptoms for at least seven days. IT could be longer, but at least seven days. Now this seems pretty strait forward, right at one level.

The way that I describe this in the way that that exist in the clinical literature, you can think, well, this should be pretty easy to diagnose. And yet there's a complication. There are a chAllenge there, because the psychiatrist, again, has to determine that these manic episodes are not due to something other than bipolar disorder.

For instinct, again, IT could be T, B, I, tormented, brain injury, could be seizure or meds or other to drugs. Critical steeds, which are often prescribed for a number of immune conditions or for won healing, can also cause manic episodes. So they have to determine that everything that's happening meets the criteria I describe before.

Three out of seven of these symptom categories for seven days or any 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 gonna 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 psychiatrist, in particularly for the first time, those two people are interacting, the psychiatrist st is just getting one snp APP shot of the person at that moment, right? So the person could be on day one of a manic episode, the person might be on day six of a manic episode, the person could be transitioning out of a manic episode, or the person could be suffering from a combination of manic episode, where, because of the impulsivity of bipolar disorder, they went out and use delicate drugs. They also used cocaine.

So the psychosis has a serious chAllenge. The psychiatrist st. Has to determine based on a conversation, right? The assistant blood test, this isn't to measures that you can take on a scale or with a biomass.

They have to use language, a conversation with somebody who, by all accounts, is pretty impaired 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 as IT been since you slept in?

The person starts to answer, oh, the other day I went down to the basement. I was gone to get something out of the the refrigerator. I thought I might take a nap and then all 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 not they meet that at least three could be more, but at least three of the criteria of symptom categories, ies I talked about before. Now, assuming that they do, assuming that the patient meets those criteria, they are likely to be diagnosed with bipolar one. Now, bipolar one disorder means they are having these extended manic episode seven days or more, but IT does not necessarily mean that they are dropping into a depress sive episode as well.

This is a common misconception about bipolar disorder because, as is 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 episodes and dropping down to baseline. That's very important. understand.

Now the second category of bipolar disorder is bipolar two. So B, P, two or bipolar disorder two is somewhat different than bipolar disorder one. First of all, it's characterised most often by the presence of both manic episodes, mania and depressive episodes, or what's refer to as hyo mania.

Now, any time in biology or in medicine, you hear hypo is the opposite of hyper. okay? So we ve got Normal hyper and hypo.

Hypo mania is a somewhat suppressed level of mania. So this is not going to be as extreme me as the mania that we typically think of. And yet the hyo can be due to the duration, not the intensity.

Armenia, that's right. Hyper mania can mean a lesser intensity of mania. But I can also be used to refer to a shorter duration of mania.

In fact, that's one of the key caterina for bipolar two. Bipolar two is often diagnosed on the basis of the presence of manic episodes that are lasting four days or even less. So someone with bp two might have four days of this increased energy goal directed activity.

They're irritable, their europe, they're not sleeping at sea, but it's only lasting for about four days or they could be having longer extended periods of mania. But they are hypothetic episode s they're not quite as intent. So the pressured speech isn't quite as pressured.

The impulsivity isn't quite as severe at at at a the other aspect, bipolar two is one that i've 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 one can indeed go for manic episodes to severe, what we call major depression.

So they can also ate like a sign wave, really high, highly low lows. And very important to understand in terms of understanding both bipolar one and polar two is that it's not always a sign wave. This is really important and something that, Frankly, I did not know until I started researching this episode and talking to some psychiatrists I should mention.

I talk to several board certified psychiatrist in preparation for the episode. I'll give some references to them, and in fact, some of them are going to be coming on the podcast as guess in the future for more in depth discussion about bipolar and other h psychiatry disorders. But all the psychiatrist I spoke to confirm what the other was saying, which was that the way that bipolar disorder can present can very tremendously between individuals.

One person might go from very high highs that last seven days are more to very low lows. Bouts of depression, major depression, that class, two weeks or more. Other people are rapid cycling by way of, you know, three days manic, three days Normal, three days manic, and then dropping into three days depression.

So you want to race that picture in your mind, that manic bipolar disorder is the sign wave, the 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 psychic st. To diagnose people because of that fact that they are only getting a snapshot of the person unless theyd know them for some time and 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, A K 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 belts of depression, the very many of deep belts of depression is easier to recognize because of the extremes of those highs and lows. Now this, my team, 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 not it's four days or last, or whether not it's seven days or more, these manic episodes really are the defining criteria of bipolar disorder. A K.

Bipolar depression. There are a couple other key features about bipolar, one in bipolar two that can allow us to get Better inside into whether not somebody has bipolar one or bipolar two. And that's the percentage of time that people with bipolar won versus bipolar to spend in a manic state, a depressed state or a symptom free state.

This is also important to discuss because IT turns out that people with genuine diagnosed by polar one or bipolar two are often symptom free, which again can make IT difficult for us as people that know them or for people are treating people with bipolar disorder to identify whether not somebody is in a manic episode or deep reserve episode, whether not they are headed into a manic or depressive episode. So the numbers on this have been studied from a paper, actually two papers for south or judge J U D D at all, published um some years ago, twenty years ago. But the data hold that really nicely over time.

These were both publishing journal, american medical association psychiatry to genome psychiatry, superb journal. And basic. People who have bipolar won on average spend about fifty percent.

Actually, fifty three percent was was the number that was eventually converged upon, but about fifty percent of their time symptom free. That's interesting, right? Somebody who has genuine bipolar one disorder can spend as much as half of their life symptom freep sleeping Normally, speaking Normally eeta.

About thirty two percent of the time depressed. And when we say depressed, we mean major depression. So severe chAllenges with waking up a, two or three in the morning and having trouble following back to sleep. 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 epos, suppressed lib to s, suppressed motivation, all the general symptoms of major depression, which will talk about little bit more later, and in an upcoming piso's about major depression in particular, and then about fifteen percent 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 sleepiness, ness, ira ability, pressured speech, grandiosity had set up. Contrast that with people bipolar two disorder who are spending about half of their time in a depressed state. So that's interesting.

People with bipolar two disorder, while not always displaying depressed states or asos tions between mania, hyper mania 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 law.

This is a serious depression of their nervous system, their mood. And as we say, they're affect their outlook on life. And that's one of the key distinguishing features of major depression, is that people's outlook on life becomes very diminished in the sense that they don't see a future.

You ask them about, you know, how's work going, how relationships. And it's not just that they feel that that's going poorly. They really feel as if there is no opportunity for those things to improve.

Those people would buy polar too, tend to be symptom free, about forty five percent of time. Again, these are averages. So about forty five percent of the time, it's a considerable amount of time. And they tend to be in these hyper manic states, only about four or five percent of the time.

Again, the criteria for bp two by polar two is these four days or less of mania hypotension, but only four percent of the time, or five percent the time, is a small enough sliver of the pie. That is, these people's existence that you can imagine why IT would be easy for them or other people to overlook the fact that they have bipolar disorder and not major depression. Think about IT.

This is a person who, or I should say, a collection of people who are spending about half of their time depressed, close to half, forty five percent their time symptom free, and then about five percent of their time in a hypothetic state, or either shorten belts of high intensity mania or hypo mania, that is a reduced intensity. One of the reasons that I mention these percentages of time spent in a symptom free depressed mechanic, a hypothetic state, is because one of my major goals for today's episode is that IT will increase awareness of whether not you or somebody you know could be a coworker, could be a family membered that that might be suffering from bipolar one or bipolar two. I think it's fair to say that if somebody e's suffering from bipolar, one 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.

A mania is such an extreme state, not just for the person who was experiences, but the way that IT presents is just so extreme and out of the ordinary. But by polar two, you can imagine, can really duck under the raydon of our awareness. And you could imagine that we might just think somebody is low or depressed, especially that person tends to self medicate with alcohol or other substances. We might think about whether drinking more than often, more than usual, excuse me, or they're spending more time alone in isolation. But then when they're hypomanic state, that might actually present as Normal to us because they were in such a depressed state before.

So it's very important that we dial up our awareness that we can tune and ten I 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 two disorder before we move into a indebt discussion about the different kinds of treatments for bipolar disorder, 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 the burden, the the very real emotional and occupational and educational burden that can occur for somebody with bipolar disorder that's actually been study. There's a measure of this is 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, that disability in this cases, by polar disorder. And basically, the way this sort of study is done is that through questionnaire, I should say quite in deep questionnaire, there is a pRobing for whether 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 straight forward thing to address, right?

You ask somebody, you know, when was last time you aid, or when was the last time that went a few days without food or lost interest in in relationships or work or sex or things that that sort in the answer. And you can figure out the amount of time that they've essentially been withdrawn from Normal levels of activity for them with bipolar disorder. What IT turns out is that the global burden of having bipolar one, and even by polar too, is massive.

In fact, having by polar disorder sits as one of the highest risk factors for being in the top ten of all categories of disabilities, leading to global burden. Put in plain english, what that means is having bipolar one or bipolar do disorder is extremely debilitating. IT really slows down one's life trajectory unless it's treated properly.

Now the other aspect, bipolar disorder is its, her itabhi. And this gets into a little bit of some tRicky science related to inherit ability versus the genetic contribution of a given disease. So that might sound like the same thing you think.

Okay, genes relate to heritability. Her itabhi relates to genes. But of course, everything about the way our nervous system works and functions and expresses itself healthier 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 by polar disorder, a one percent of the world's population compare that to people who have only major depressions.

So this would be repeated bout of two weeks or more of serious depression, not just low mood or something due to a life loss, but major depression, which is ten to seventeen percent of people have major depression. okay? They they suffer from major depressive disorder compared to by polar disorder, which again is one percent. Now you can address how much of the one percent of bipolar disorder that exists is due to genes versus environment in a somewhat exact way. This is never an exact science.

In 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 to further nal 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 identically for eternal 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 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 twenty to forty five percent chance that their identical twin will also have major depressive disorder.

Now that tells you right there that I can all be genes that is not a gene for major depression per sale. If IT is a gene that or a collection of genes, that those genes are also subject to environmental influences, either predator within the room or after children are born. Now, the large range there, of twenty to forty five percent could be due to any number of things.

IT could be experimental, meaning the techniques that we're used in experiments. IT could be due to um regional differences like different one part of the world of verse and another a lot of different factors right now. We probably deve into all that at some point, will probably do an episode, the genetics of nervous system heritability and heritability of features and mental health seta.

But we can compare major depression in the heritability or the genetic concordance between identical twins in major depression or by polar disorder, and ask if one twin of an identical twin pair has made bipolar depression, what is the likelihood that the other twin will have IT and IT? Turns out that number is much higher to forty to seventy percent. Likelihood of 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, one percent for bipolar versus ten to seventeen percent for major depression. But the genetic component is much higher, forty to seventy percent for bipolar disorder versus twenty to forty five percent for major depression.

I know i'm throwing a lot of numbers um 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. Asked questions like if two twins were raised separately or together and one part of the world versus another or had a two parent households versus one parent household, you know evaluate a lot of different variables, what they were able to discover. And this has been shown again and again, is that the genetic contribution to bipolar disorder is very, very high.

That is, the heritability of bipolar disorder is eighty five percent. okay. So again, I want to be really clear what this means. The total occurrence in the general population, fairly low, still serious one percent, but fairly low compared to other things like major depression.

However, if someone has bipolar disorder, it's very likely that they inherited some genes or sets of genes, or more accurately, a suspect ability within their genes to environmental influences that can trigger bipolar disorder. There are a lot of different ways to discuss and to conceptualize her itabhi. So I want to be very careful with the way that i'm working this.

What this means is that people with bipolar disorder very likely have gene, or more typically, it's going to be a set of genes that creates a suspect ability for bio disorder to present itself. Now, what environmental factors trigger or increase that superability is not entirely clear. This always seems to center back onto the same sets of things like early life stress trauma that are, certainly, those are going to exasperate the likelihood that someone who has a genetic propensity for bipolar disorder will express that bipolar disorder and its full array of some tommo's gy.

But eighty five percent, while very, very high, is not one hundred percent. Again, eighty five percent, while a very high number for her itabhi, is not one hundred percent. What that means is that there is no single gene or identify gene cluster for bipolar disorder. The reason I keep drilling into this over and over is that I think we can confidently say that someone has bipolar disorder, that there was something in their genetic in age that LED to that or that very likely LED to that. And yet it's not like ee color or some other physical feature, which we can actually do the the direct, it's called model an genetics and figure out whether or not somebody directly inheriting that gene from one parent or the other parent.

So the takeaway here is that if you have an certainly an identical twin or eternal twin or sibling or a parent or even a cousin or an uncle that has bipolar disorder, particularly by polar one, well, then you need to be on the look out 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, distinguished by polar disorder from a 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 by polar disorder, and vice versa. But there are some key distinctions that need to be made, because IT turns out that bipolar disorder and borderline personality disorder are quite distinct in terms of that are 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 hyper mania.

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, you know, there's something coming up this friday that's really exciting or lets, you know, enter a relationship together of one former 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, are other types of mood shifts that are dramatic and more adaptive in response to things that are coming in through the external environmental 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 borders line personality disorder is that they will feel that they absolutely adore you and want to spend all their time with you. Just think the world of you, you can do no wrong. And in fact, they genuinely can feel that way and can genuinely think that way about you. And then for whatever reason, IT could be a perception of something that you did or something that you said, or suspicion that you're thinking something about them.

They can suddenly shift or split their emotions and what's called movie from a good object, or I can do no wrong object to a bad object, they're 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 well being at that. And that can sign them down a pathway of being very angry, very depressed. At seta, as I described the contour of a person with borderline personality disorder as somebody who splits very suddenly in response to some environmental trigger, real or perceived, there is the risk, of course, that IT makes the person with borderline personality disorder sounds like a bad person.

You know, 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 and disorder, whether not their romantic relations are familiar or co workers, that said, can be very chAllenge, ed can be very high friction because of the good object, bad object shifts at at a, it's by directional, meaning the person with borderline personality disorder, as you can imagine, is also going through a lot of suffering.

At one moment, they feel as if someone is wonderful and can do no wrong to them, and they want to be so strongly affiliated with them. And then 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 is 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 is a fairly common disorder, but it's important that we distinguished borderline personality disorder from bipolar disorder, mostly on the basis of this need for a trigger. Again, in by polar disorder. There is no need for a trigger to create a manic episode or a major depressive epsom.

They just happen or they can just happen. Wherein butterine 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 bottle line personality disorder from one mode to the next. As we move in to our discussion about the treatments for and neural circuits underlying bipolar disorder, I wanted just nail down one more key point.

This is a very brief point, but it's perhaps the most important point, which is the highs and lows, or we should say the highs, these manic episodes and sometimes lows, because again, not everybody with bipolar disorder one or two suffers from depressive episodes. Sometimes yes, sometimes no. In particular bipolar two, yes.

But people with bipolar one can have extremely episodes. And then just returned 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 context. And yet on whole, having bipolar disorder is extremely detrimental and chAllenging to the person suffering from IT, something that we want to keep in mind as we think about treatments and the underline biology. Now I would like to talk about some of the treatments for bipolar disorder.

And in the discussion of those treatments, there is 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 will 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 proceed, the discovery of the underlying biology. That's right.

Everyone's 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 um lithium um, as some of you know, is on the period table of elements. IT is indeed ding naturally occurring substance that actually arrived on earth by way of a stardust.

Yes, we are talking about stardust on this podcast, but if you like to learn more about the origins of lithium and how lithium m arrived here on earth for its discovery and applications in psychiatry, there is a beautiful talk that exist on youtube and will provide a link to this in the shown note captions that describes the history of living um in terms of its interplanetary travels and arrival on earth this is a talk delivered by a physicist whose expert in quantum mechanics and is expert in lyth yum. And it's a just wonderful talk that I can refer you to less on the biology and that talk, but certainly a lot about lithium is and elements. So for those of you nerds like me that love to know how things came to be here on the planet in one former another, i'll encourage you to take a brief listen to that talk.

We are going to discuss lithium um in the context of its applications for treatment of bipolar disorder and the discovery of lithium as a treatment for bipolar disorder. He is truly a miraculous story that I think everyone should know. The key player in this story is a physician by the lesson kid.

He was an australian position, and kid has a very interesting story in his own right. Kid was an australian psychiatrist, or australian psychiatrist, who also was a soldier. And during world war ii, after the follow single ported japan, he became a prisoner of war.

And he was a prisoner of war from one thousand and forty two until one thousand forty five. So he had some time for observation. And during his imprisonment, he observed some of his fellow inmates as going through pretty wild vacova in mood and energy, essentially going from manic episodes to depress episodes or romantic to Normal episodes.

And for one reason or another, we don't know why, because I can find any reporters to why he hypotheses this. But he hypothesized that there were some build up of some chemical in these people's brains that then they would urinate out, and that urinating out of whatever chemical was there would allow them to be more relaxed than not manic. In other words, kid hypothesize that there is a build up of chemical and certain people's brains that makes the manic and the urinate that chemical out.

So eventually he got out of this prisons, as we mentioned, in one thousand nine hundred and forty five, 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 libia mania and yearn from people who are not manic. And he took that urine and he would inject IT into gini pigs as an experimental model.

And his general observation was that there was something in the urine that was indeed making the ginny pigs more manic. If they were injected with your in from a manic patient, right, the exact measures that he was taking these gini pigs wasn't exactly clear. This is um at a timer and ear and science when you could uh the sort of report things a little bit more objectively, although there were still numbers and statistics was a little more of like case studies and and descriptions, but IT turns out that even though that all seems a little bit loose IT LED to some incredible and still important a discoveries for a psychiatric health.

So what he figured out was that the year n informant's. Patients seemed to be more toxic for the skinny pigs. And he also knew that there are two toxic substances in urine, urine in york acid.

So he was able to separate the era and european 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 namic patients. So he did not seem that urea was the compound that was creating these many episodes or related to manic epo des or held the toxic.

So instead he focused on the uric acid. Now, in order to put the erick acid into solution so that he could inject IT into these skinny pigs, he had to try a number of different compounds in order to dilute IT. Just so happens that, and you chemist will be familiar with this, but there are certain things that just don't go into solution easily.

You put the powder in the a vile, you add some water sAiling or another solution, you mixed IT up in the power they suspended in there and just doesn't doesn't actually ever become a clear liquid that you can inject. So in order to try in jacking different strength of your acid, he ended up using lytham to assist in the dilution. And litham worked.

So what he basically was doing again for you, chemist, as he was taking euro acid, he was adding lithium and making a solution of lithium. You're right. Okay, this is a lot of details, but this is important because what he eventually found is that when he diluted the york acid with lithium and created lithium, your lithium eua could actually calm down these ginny pigs that were injected with the toxic area.

He also found that lithium urate had a generally coming effect on these ginny pigs. So now we're really off in crazy territory were talking about you're in from patients that separating out ura and europe acid adding lithium um to the eurasia. We're injecting this in the gini pigs is getting pretty wild and pretty weird.

But this is medicine. And from time to time, this is medicine and science. Kid was a good scientist in addition to being a good physician. And by good scientist, I mean that he did control experiments here.

He was injecting lithium year rate into animals and senior effect, but he knew that that solution of the lithium urate contained not just the york acid, but he also contained lithium. And so he quite appropriately asked, maybe the lithium alone is having this coming effect on these ginny pix. And indeed, that was the case when he did the proper control experiment and injected only lithium solution into these skinning pigs.

They come down from there. He, in sort of nineteen and forty style medicine, would not happen now. He very quickly moved from the animal model into human patients and started injecting human patients with lithium, or providing lithium only to those patients.

And loan, behold, found an absolutely profound and positive effect of lithium in reducing symptoms of mania. And as all good physician science to do, he wrote up his results and he wrote IT up in a paper entitled lithium m sault in the treatment of psychotic excitement. Gay, back then they didn't all IT mania.

They call IT psychotic excitement. This is a paper that was published september third, one thousand hundred and forty nine, in the medical journal of australia. We will provide a link to the 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 clinical, to just take a quick look at the second page in this paper that would 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 release in detail now because they would take a lot of unnecessary time, but things like a case, seven MC age, forty years old, suffering manic, recurrent mania. And this episode, he had been excited, restless and violent for over two months, and was interfering so often that had been confined to a single room during the day.

right? This is very dilute what we now know to be bipolar depression. He commends, taking with him centrate twenty grains.

That's a measure of the amount lithium. Three times a day. In four days he was distinctly quieter. And by federal, three, thirteen, one thousand, thousand and forty nine appeared practically Normal. He continued well in on february twenty to nine hundred and forty nine, the dose of situate was reduced to ten grains at, at, at a, 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 is 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, kate really lays out the case for why lithium is such an important discovery in the treatment of what at that time they were calling psychotic, excited in what we now know to be manic by polar depression.

Lithium, I should mention, has a number of important features, but is 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 lifetime in the blood need to be monitored extremely carefully. So it's not the source thing that people can just take IT a given dose and every patient response 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 one thousand nine hundred and forty nine 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 the um in fact, still to this day is very low cost and still to this day no one really owns the pattern for lithium in its purest form. So that made IT unattractive IT IT turns out that the fda in the united states didn't allow the theme to be used as a treatment for manor bipolar disorder until one thousand and seventy.

So we're talking about a full twenty one years from the publication of this paper by kate in the medical journal australia, showing quite beautifully the great potential and use of latium for calling the symptoms of bipolar disorder until the first patients in the united states were starting to access live um regularly and nowadays of course clithering is available but still not able to be patented because it's element number three on the period tables naturally occurring. It's not literally falling down from the stars and started going into pill form but rather IT can be synthesized um in laboratories um 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 golden example of a treatment that works, at least in many individual, prior to an understanding of the biological basis of the disease for which that treatment is needed. Now with that said, scientific 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 excelling treatment for something, it's important. 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 that has any side affects 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 go well. There's this continued search for Better treatments for bipolar disorder, even though lithium works because lytham um 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 and said a 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 cellars level, at the neural circuit level at seta, do we really stand to fine those new discoveries.

If you were to do a literature search on the actions and mechanisms of lithium in terms of how I can calm people down and reduce the romantic 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 B D N F brain derived neutrophils factor b DNF is often talked about in the context of neural plasticity, the brain in neural stem ability to change in response to experience. And indeed, IT does seem that ingesting lithium increases B D N.

B D N F is what we call permissive for plasticity. 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 say.

What b DNF does is IT permits the nerves, the nerve cells and their connections in the brain to be more likely to change if the proper environmental conditions are met. That is, B D N F creates a kind of balancing to neural plasticity. IT opens the gates to neuroplasticity, so lithium does increase b DNF.

We will 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 poet anti in flam ory. Now inflation tion is one of those words that thrown around extensively nowaday, especially on social media and especially as IT relates to any health condition.

It's like inflation tion information. Information always seems to be discussed in the context of inflation tion being bad. But I do want to point out that inflation tion is a natural adaptive pose to physical injury to a seller, organ or tissue of any kind information is the basis by which adaptations occur to exercise.

So for instance, you were to weight train and use a heavier than Normal weight and to do a set to failure or create some little microtest rs in the muscle that are healthy in the sense that they would create adaptations and make that muscle stronger, maybe grow that there's an inflationary response associated with that, that is critical to the positive adaptation. So inflamed tion isn't always bad, although excessive or as we say, runaway inflation tion is bad. Lithium seems to be able to suppress inflation tion.

And importantly, I can suppress inflation tion in neural tissues, in within the brain in particular, that is important. And we returned 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? There are lot of reasons why neurons can die.

There can be a physical insult to the news. You can get hit really hard in the head. A bullet, got forbid, can enter the skull and kill neurons. A lot of reasons why neurons can die.

Neuro protection is a situation in which a neuron is given some sort of chemical or physical resiliency that allows you to suffer an insult and yet bounce back. So it's very similar to the way that we think about psychological resiliency. No protection is an ability for neurons to be Better able to handle stress of different kinds, in particular exco toxic.

There's a phenomenon in bipolar disorder and a lot of other psychiatry 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 a certain brain circuits are too active for too long. Some of the chemicals associated with neuronal activity, things like calcium and neurotransmitter rs, like glue mate, 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 with bipolar disorder. Because if we are to take a step back and ask what is 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. And I saying Normal, I say that respectfully to the people with bipolar disorder by referring to people who do not suffer from manic episode, 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 in 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 register ring, their own internal state, in particular their emotional states and their thematic states. What we're referring to hear is something called into reception.

I've talked about this little bit on the huberman lab cast 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, honor within our body. Extra reception is literally an attention to things that are happening beyond the confines es of our skin.

So seeing that persons face over there, or seeing that color of leaf over there, or hearing a sound over to my left, that is exterior tion, perception of things beyond the confines of one skin. Then there's interaction tion, which is perception of things that are happening internally. My helpful, does my gut feel how? How fast is my heart beating? Some people can measure that quite accurately just by thinking about other people can't.

How happy am I? How sad am I? How energetic am I? How lyth's c am I eat set up. So we are always existing in a baLance between x terrell tion and interaction tion. 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 interaction tion.

And that very likely is important in their inability to register, for instance, that, wow, they are talking in an excessive rate, or they haven't slept in five or even ten days, or they haven't eaten in a long period time. This atrophy of neural circuits for international action 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. You're listening. The reality is that people with by polar 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, I mentioned earlier, sets in around the early twenty years, although sometimes that can be even earlier in the teens and so forth. But that hyperactivity, we think, leads to a toxicity and exco toxic of certain elements of the neural circuits that are responsible for interruption. In other words, the overuse of certain circuits can lead to a diminishing and nature phy, 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 B D N, very likely protects us against some of that atrophy of those circuits for interaction tion. So this is in the case in which people with bipolar have a neural circuit or lack a ual circuit, and people without bipolar are the opposite. This is the case in which everyone more less starts out the same.

But IT seems that there is 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 launch at udal 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 twenties and thirties, reveals just that, that there can be hyperactivity of circuits early on. But then hypos reduced activity of those very same circuits at a time, five or ten years later.

Again, this speaks to the complicated nature bipolar disorder and the complicated nature of psychiatry and linking specific psychiatric disorders to neural circuits in general. Because if you have a situation in which, you know, in one disease, let's just let's just hypothesize here for second that for instance, in certain forms of giza hernia, there's elevated doping and where we to just reduce the amount of mean that they would receive relief from those schizophrenic symptoms. Well, that's all pretty straight forward on the face of IT.

But in this situation with bipolar disorder, what we're talking about is hyperactivity, too much activity leading to hypo activity through death of those very circuits. And so now you can especially appreciate why when the patient shows up to the psychiatry rist 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, the fact that the very defining characteristic of bipolar disorders, that there are isolations 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 depress sive episodes. And they have to infer all that from discussions.

Again, just exchange of words depending on when that person walked into the office where they are in terms of manic episodes, no symptom logy or depressive symptoms, ology, and whether or not they've had that symptom logy for an extended period of time. And then just to make the situation even more complicated, the very circuits that atrophy, that start to win and disappear in people polar disorder are the circuits for interactive tion, for understanding what's going on in one zone body. So you can imagine if you sit down and ask somebody, well, you know, how long has a been sense you have slept?

That person may genuinely not know. Or if you ask the very depressed person, you know, 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 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 admitted a rather intense discussion about the symptom logy bipolar disorder so that you can have an understanding of the people around you and have an I in an year to whether not those people might be suffer from bipolar and if so, at what stage of the disease they might happen to be yet. Now I like to talk a little bit more about what is known about the neural circuits that lead to the manic states as well as IT the depressive states, but mainly the manic states of bipolar disorder. We already discussed the fact that into reception, register, ring 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. They're responsible for that lack of recognition. For that reason, i'd like to point out of paper.

This is a fairly recent paper just came out this year, but 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 large tunnel changes in structural connectivity in Young people at high genetic risk for bipolar disorder.

We will provide a link to the study in the shown out captions. There are a lot of data in this paper, in particular the imaging data, and it's quite extensive in terms of analyzing the so called iconic omics. You've ably heard of gene omics, which is the analysis of genes, and there display in different individuals or different animals.

And said a, you are proteomics, which is the display of where the existence of different proteins. So omics is a big thing. Now in scientist, you can throw omics behind anything, and IT becomes its own capet a, which, which means that becomes its own thing, so to speak. I said that only partially ingest none's conic omics is the analysis of connections between different neurons and neural circuit elements.

And what this paper really showed by analyzing the conic omics of neural circuits in the brains of many different people with different categories of an onset of and severity of bipolar disorder, as well as controls in different age groups at sara, is that people who are a particularly high risk for having bipolar disorder, or that have full blown by polar disorder, have deficits and actually reductions in the amount of connectivity between what I call the paradise brain regions and olympic system. Now, the limit 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 the 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 olympic system is intimately related to the so called automation ic nervous system, which regulate tes, our sleep wake cycles in the number of other things, like our digestion at sea, our level, hunger and on and on. So the limbic c system is really kind of like a volume control, or as nerd scientists like to say, a kind of game control on the overall level or amplitude of alertness or commonness. In fact, if we are very, very calm, we are sleep.

And 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 IT at a, or if we are very, very, very alert by way of olympic c auto omy interactions, well, then we can be in anxiety. We can be in for on 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 circuit tree are present in the olympics system, that doesn't necessarily mean that the limbic s system is at fault, because the way that neural circuit is work is that different brain areas are talking to one another through electrical, chemical signaling, and they are regulating one another.

And what this paper really tells us is that their elements within the pride or low, which is a kind of a section of the brain that sits off the side, it's not really off the side. But in neuron authorial nominal creature, the paradise lobe is connected in two ways by directionally. So prior lobe is connecting to limited system, and limit s system is connecting to pride.

O lobe, and in people with bipolar disorder, seems that the parade love is able to exert less top down control, that is, less suppression of certain elements of olympics system, which, at least right now, is leading researchers to hypothesize. That olympic system is sort of raving at higher levels, is going to rpm in your cars are going red lining at times, and ferries that are inappropriate, or at least abNormal. So we have two major sets of neutral 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 seat, a sensory cortex of the part of our cortex that registers how we feel, literally, sense of touch and internal state. So those circuits, excuse me, those for those of you listened, I just bumped the microphone.

Excuse me, those circuits are disrupted in people with bipolar and the top down control, the kind of accelerator and break on our overall levels of energy are also disrupted. Now that's all finding 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 he doesn't tell us how to moderate or change that circuitry. IT also does and 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 will talk about going forward, can benefit patients with bipolar. So IT a with him, is exerting its positive effects on by polar depression treatment, at least in part by preventing the loss of certain neural circuits, namely the neural circuits for the reception in the top down control over the limbic system.

Now turns out about examine lithium effects at a even more reductiones 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 transonic al magnet, existing lation, and even some of the more natural or so called neutral udal treatments, including things like hyo. So they get three supplementation, which we're going to talk about extensively. Now in order to understand what were 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 not one is talking about bipolar.

Depression, in fact, is 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 city 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 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 not a neural circuit and the neurons within IT become more active or less active in the context of homeostatic plastic largely depends on one mechanism. And its a beautiful mechanism that I make very clearly right now, even if you don't have a background in biology, neurons communicate with one another by releasing so called neurotransmitters ors, which are just chemicals.

Those newer transmittals are vomiting out. They're not actually vomit, but they're spit out into this called synaptic clap, often called the synapse. The synapse is just a little gap between neurons, and when they are released into the synapse, just stay there. They actually park or buying to receptors on what's called the post and optic neuron. And depending on how many receptors they buying to and how many recept tors are available at a, they can have a greater, lesser effect on the poston optic neuron.

This scenario of neurotransmitters being released into synapse is then binding to receptors on postnatal neuron and influencing the electrical excitability of those post and optic neurons sit central to not just the treatment of bipolar disorder, but to all treatment of all psychiatric conditions, and indeed to things like neuropathic pain as well. For example, the so called S S R S projects are loved, and others at a stands forth, selective serotonin reuptake inhibit. What does that mean? Well, serotonin is a neurotransmitter, actually neuromodulation, that's released into this in apps.

And then the S S R I, the selective serotonin reuptake inhibited allows more of that serotonin to sit within the synapse for longer, right? It's a reuptake inhibited prevents reuptake by the prison optic iron and that's a tone therefore can park in or dock in the receptors, as it's called of the post and optic neuron in greater numbers and have a greater impact on that post and optic neuron. So the drugs that are used to treat depression or other things that sort things like S S R ize work by changing the availability of neurotransmitter in the synapse, other things like mao inhibitors, mono, ami, ox and habitus work a different way.

They inhibit the end time anytime you hear asc. And biology is very likely an enzyme which breaks things down. So mao inhibited prevent the breakdown, not the reuptake, but the breakdown of neurotransmitter, and therefore allow more neurotransmitter or to be available in the synapse, and influence the personal t cell homeostatic plasticity is a form of neuroplasticity, which overall circuits can become much more excitable or much less excited by the addition of more receptors in the postnatal neuron or by the removal of more receptors from the poston optic neon.

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. Classy, although there are several, is one by the name of gene turgeon o she's a professor at brand dice university. And what the turgeon to laboratory showed was that, for instance, if we are in the dark for a long period of time, literally when we're not seeing much for a long period time, there's an increase in the number of receptors in the poston optic neurons so that a smaller amount of light and excitability within the visual system can lead to greater amount of activity in the visual system.

Conversely, if there's an overactivity or an increase in activity in the visual system for some period of time, then a number of receptors in the post and optic iron are removed from that post and optic iron surface, making any newer transmitter or that's available only able to buy the receptors, they 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 well, that's a mouthful and a nearby and a concept for I don't know if the concept is a word, but in any case, that a lot to think about.

But all you need to know is that if a neural circuit 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 buy 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 quarter or stepping caves very much.

Well, when that cast comes off, sure, the muscle might be atrophy, 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 neil transmitter is released now has the opportunity to bind to more receptors, in that case in muscle, or in the case of brain circuits in post and optic irons. So homeostatic classic is is beautiful balancing mechanism that make sure that neural circuits are never too active nor too quiet for too long, and in a beautiful display of how treatment can lead to a Better understanding of biology, which can lead to the discovery of even Better treatments.

Lithium and another compound which will talk about kedem, seem to exert their actions largely through effects on homeostatic neuroplasticity. There's a wonderful paper that describes all the needy, greedy 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 tell deep into this, this paper was published in neon self external 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 described, ed, to you, in which measurements remain from neurons and the number of receptors in those neurons.

It's done somewhat indirectly through a method that's a detailed in neuroscience. Sts are familiar with basically what IT measures is how excited a given neuron is. Electrically excited to given neuron is to given amount of neurotransmitter.

Okay, so the the amount of neo transmitter that's vomited onto a neuron is essentially kept constant. And then the response of the position acting iron 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 personal tic. On, that is, neurons within the brain become a less excitable over time if lithium is present, where as kadee, which is now a common F D. A approved, at least in the us, is approved for the treatment of major depression, kadee does the opposite.

Cademy seems to increase the number of receptors in the personal tic neon and lead to greater levels of excitability and electrical activity within neural circuits to a given a fixed amount of neural transmitter. So this is super interesting because what IT means is that litham is causing circuits to be less active. Cademy is causing circuits to be more active.

And we know from excelling clinical data now that kadee 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 suppress mood, appetite, sleep issues at sea. Now the key thing about kadee that's often not discussed is that while its effects are very potent, they arent transient.

So one major drawback to academic therapy for depression is that 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, uh, cowl boy on your own.

I know that uh, and many of you are probably familiar with the fact academy also is abused recreationally. IT is a so called N M D A and method expert recept antagonist. So IT blocks the very receptor that's responsible for neural plasticity for changes in neutral circuits.

IT also changes excitability neurons, as I just described. So academy is a very potent chemical that has been shown over and over again, is an now fda approved for the treatment, major depression. But its effects seem to be transit ent.

Lithium, as I described earlier, seems to reduce the manic episodes, or the intensity of manic episodes and some tommo's gy and people with bipolar order doing that through neural protection. So protecting neutral circuits is from dying away that initially are overactive and that overactivity causing a pyo taxi blocks that excited toxic, 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 a bipolar disorder over activity of a given circuit eventually leads a neurological toxicity. Excuse me, lithium is preventing that neurotoxicity by reducing the number of receptors in certain elements within those circuits.

So so called homeostatic scaling. It's down, regulating the number of receptors leading to a less excitability and preventing, we think, excited, talk active. And in that sense, you can see exactly why it's important to get with theme treatment in their early for people with bipolar disorder, kedem in as a treatment for major depression seems to be effective.

But transients, and you can also see why you 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 treated both of the many and of the depressive episodes, if they're present.

And fortunately, there are excEllent drugs to do that. And I should mention that kadee and lithium are just too of the drugs within the kit that psychiatrists have access to. There are many things lanza pees and a number of different things, including close opening, close up as an anti I psychotic, which is commonly prescribed to as a sensitive, in some cases that allows people in manic episodes to sleep.

It's classically described as so called dopamine e receptor for antagonist. Although IT does other things as well, closer pee has a number of side effect features related to White blood cells and things 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 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, lyth, yum and kadee.

And we talked about why litham academy work, that they're work 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 symptom logy and the lack of interaction tion, why people can just persist and staying awake, awake, awake, not eating IT. Now you have in mind how all that is put together, and I think you have in mind some without 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 by polar one and bipolar two.

Now I would like to also talk about some of the not so typical therapeutic ics 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 online communities. And while it's not clear that any of them are particularly on their own, although some of them who Carry some hazards, I do think is important because of the critical time sensitive nature 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, were demonstrated to be ineffective treatments that they stand to combat by polar disorder much more successfully. First of all, a key point about drug therapies, adversus non drug therapies or talk therapies, without question, drug therapies are going to be most of went done also with talk therapies.

And we 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 are certainly the ones I spoken to have told me that talk therapy on its own is rarely, if ever, effective for bipolar depression and bipolar disorder with not bp one or bp two. That's just the reality of IT.

You know, contrast that with our discussion about obsessive compulsive disorder, which we talked about a few episodes ago. You haven't seen that episode of 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 initiated the right time and is 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 were turned 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 costa as another side effect. really.

There are both established and more novel forms of tok therapy being used again in concert with drug treatments for bipolar disorder. Codner behavioral therapy is the one that seems to be best, at least by way of the statistics in papers that exist. It's also the one that's been explored the most.

So one of the reasons why it's often consider the most popular effective is because it's also been around longer and it's been explored most. Podium behavioral therapy in general is a progressive exposure of the patient in a very controlled way in a clinical setting to some of the trigger or the conditions that would exacerbate bipolar disorder. Now earlier, I said multiple personality disorder has all these triggers and triggered elements from the extra an environment where as 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, some more stressful. So cold on behavioral therapy mean the discussion about and sometimes the direct exposure to uh, anxiety provoking elements of life can be very helpful for adJusting the responses to those otherwise triggered events and sometimes making the drug treatments more effective even at lower doses. There are also forms of therapy, including family focus 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 not somebody is doing well or poorly or veering toward or is emerging from a manic depressive episode, because they understand that person, they have a lot of data, could be purely subjective data, but they have a lot of exposure to how long or well somebody who's been sleeping, you're eating at sea. So family focus therapy involves other members of the person suffering from bipolar disorders, family, as well as conversations about family members in a way that helps patients with hypo disorder navigate not just three manic episodes, depressive episodes, but start to learn to predict what are the conditions, psychological, physical and otherwise, that can trigger by polar episodes.

And then there's a category of therapy called interpersonal and social rythm therapy. This is deserving of its own entire episode, really interpersonal and social rythm therapy, an expansion on family focus 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 at seta. And I should say that a overall theme that emerging in psychiatry and psychology is to start wherever possible, to incorporate more of the social aspects and the interpersonal aspects, in other words, not just talking to an examining a patient as one biological system, one nervous system, one set of chemicals and one life, but rather a set of chemicals, neural circuits and a life that's embedded in the chemicals, neural circuits and lives of other people um 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 have mentioned this earlier, but I should have forgive me that often times people who are in romantic epo 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 hangs I in the financial stress that results from those manic episodes of spending at sea.

And then of course, this Carries over to of sexual promise security, where people might be dealing with unwanted pregNancy or S T I. Or um you know very fractured interpersonal dynamics with existing or new relationships. I mean, you can imagine how these manics episodes as well as the depressive ve episodes can really wake out into an enormous amount of destruction.

Which brings us back to the initial criteria of bp one and bp two is that these manic episodes are not a good thing. These depressive episodes are not a good thing. They create a sense of euphoria, and the person experiencing mania, they create a sense that anything is possible.

But at the end of the day, and actually every day, these episodes are quite melted after they really destroy people's lives, and it's not just the life of the person that suffering from bipolar disorder. And so hence, cogent behavioral therapy, family focused therapy, and interpersonal and social rythm 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 that are not electric shock therapy. Electric shock erp y may sound barberry, and in fact, IT tends to look barberry, although this is done in the controlled setting of a hospital.

Any of you seen one floor of the cooker? Sss, the final scene or near final scene in that movie was jack nicolson in with the sof bite protector in his mouth and you know, getting electric shock therapy is as the um the name suggested I been ducking a global season either low level or grand mall type seure in the patients brain and nervous system might ask school, why? Why would one want to do that? Well, 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 resistance depressions, 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 and in discriminate release of things like serotonin, dopamine, a seat of calling, you know, a huge variety of neuro delatour, as well as things like b DNF brain derived in a trophic factor, which then allows neuroplasticity ity to take place again, be an upping permissive for neuroplasticity. The problem with uc t is that it's really only used for treatment resistance depression IT doesn't actually target the manic aspects of bipolar depression and bipolar disorder but non thesis used when drug treatments don't work.

Some of the negatives of electric shock therapy um electric convulsive therapy E C T is the is the proper acronym and way it's described is that is quite invasive right this is something that um you need to go to hospital for and often times there are some impatient care required after the electronic conversible. It's a fairly high cost, especially for those that don't have insurance. And of course, IT requires anesthesia.

For most people, that not can be a problem, but for many people, that could be a problem. And there is often some associated memory loss. And so the memory lost the invasive nature of E C T in the cost often times rule out E C T for most patients. And that's why it's of a late stage or kind of last resort type thing for a treatment resistance depression nowaday cademy ine type therapies done repeatedly or other treatments, for instance, transaction inie magnetic stimulation, which is basically non invasive. It's a coil is placed on the outside of the at skull, excuse me.

And we can more accurately refer to IT as repetitive, or r tms repetitive trans croning on my next stimulation, transmedia exim lation is a tool that allows researchers and clinic to reduce the amount of activity and 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 neural plasticity 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, is 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 A R T M S or T M S. I encourage you to approach those clinics with caution.

I'm of the mind that if those clinics or not, either closely or maybe even distantly associated with a research institution that really up on the latest of R T M S um you be wise to at least do your research right and um explore talk to other patients who done these treatments but certainly in university hospitals and clinical settings and research settings, r tms is being used as a way to, for instance, reduce the activity of certain limbic circuitry so that people are just overall less excitable in manic or two activate because I can also be used for activation certain world circuit activate for insincerely adil inputs that top down control over the olympics system. This is all happening right now. So we have ec t repetitive tms or r tms.

And then as I mentioned earlier, academy and 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, that we discussed earlier for a moment ago.

Plus drug treatments, almost always lithium will be explored plus some treatments for the depressive episode in particular, if those depressive episodes are present. Now that is, there is a lot of excitement about solicited on, which is a psychiatric uh, in the U. S.

Suicide on is still illegal. IT is not legal, meaning you can get in a lot of trouble for possessing IT, certainly for selling IT at sea. But Sullivan is being explored as a clinical therapy in certain laboratory settings, in particular a john hopkins school of medicine.

It's being explored in human patients for the treatment of major depression for uh O C D, 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 doctor Matthew Johnson, who was a guest on this podcast before, is also been on the temps podcast.

He's been on the lex freman and podcast. Doctor Matthew Johnson came on this podcasts, talked about some of the work of suicide and 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, solve and for the mania associated with bipolar disorder. If someone out there is aware of those clinical trials, please let me know.

I'll do IT data in future podcast. But right now, no knowledge from me about suicide and clinical trials for the manic component of bipolar disorder. A number of people are probably also going to wonder about whether not cannabis or medical marijuana is useful for bipolar disorder.

To address this, I looked to some um previous lectures and some clinicians at stanford psychiatry this question was asked of them. And as IT turns out, kenna iz 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, this is what was relate to me, is that IT may help with sleep in certain people that are having trouble within somalia, although nowadays is far more common.

Four people in manic pisos to be prescribed things like treasure, one or other benzo benzo. Do I, as a peans, in order trying get sleep within the manic episodes? And benza asians and treason is set to a work largely through the so called gaba system.

This is a neurotransmitter that causes reductions in excitability of neurons, hence wides being used to try and calm people down and allow them to sleep in their manic episodes. So not a lot or essentially no data supporting the use of cannabis for the treatment of bipolar disorder per say, nor data supporting the use of solicitation on for the treatment of bipolar disorder per say. But I realized as as I say that there are going to be a number of people that may have had positive or negative experiences with canada are sulfide as they related by polar disorder.

So please, um if you're willing, are comfortable put that if you're comfortable into. The comments section on youtube and of course if you are aware of any studies on cannabis suicide bon showing positive outcomes for the treatment by polar disorder um please um provide links or partment ideas to those i'd love to prove those studies. There are two natural paths, 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 effectively, even in a limited context, before marching into the 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 relate to me from expert psychiatrist 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 hypertension ity for suicide risk and 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 aboard certified psychiatrist, I don't say this to protect me.

I say this truly to protect those who either suffered from or think they may suffer from bipolar disorder if you know someone who you think might suffered from bipolar disorder. Now all that is not to say that there aren't useful lifestyle interventions that can support people with bipolar disorder. So I just briefly want to mention those.

And again, i'm lifting the statement 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 break together to support the nervous system and the size of somebody with bipolar disorder. But they brake together to port the psychic, the neurochemistry and the neuroscience. Its of anybody and everybody.

So they have generally a modulator effect, that is, they're indirectly shifting the likelihood that somebody might have an episode or the intensity of an episode in particularly with the depressive episode, right? You can imagine on someone who's heading into a depressive episode, maybe they are 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 families making sure that they are getting exercise, sunshine, eating correctly, social engagement, that, 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 factories are always important in all individuals those suffered from psychiatric conditions or not. But in some conditions of the mining body, those listy le interventions can have a greater effect in offsetting symptoms wherein bipolar disorder, I think it's not even, in fact, wrong to say that listy le of interventions alone are going to prevent, especially the extreme forms of mania and depression again, by polar disorder being so serious and caring such high suicide risk.

We just have to point this out again and again. Now, with that said, there two substances generally found as supplements, although the other sources of them as well, including with a nutritional sources that have been shown, lessening some studies to be pretty effective in adJusting the symptoms of hypo disorder. And those two things are innocent.

And omega fatty assets, now inox at all, is a compound that is taken for a variety of reasons, is something we talked about the podcast before. I personally take a hospital, not because I had by polar disorder infected quite lucky that I don't have bipolar disorder, but I take in hospital in one hundred milligrams of my own hospital every third nighter. So in order to improve my sleep, it's something i've added to my sleeping ack is something I found greatly enhances the depth quality of my sleep.

And if I wake up in the mill the night to use the bathroom and said, it's greatly enhances my ability to fall back asleep when I want to go back to sleep. IT also seems to have a fairly poor anti anxious effect during the day. And I discussed in our episode about obsessive compulsive disorder in, as at all, has been used at high dosages.

Again, I should say, mo, and after all, has been used at high dosages and levels of, know, even ten eighteen grams s so those are massive dosages, by the way, to deal with certain symptoms of ocd to limited success. And I should mention that hydrates of ten or eighteen grams of innocent can cause a lot of gastro discomfort eeta, if you want to learn more about innocente and its various users, I encourage you to go to examine dot com, where there is the so called human effect matrix. And that human effects matrix will describe the many places in which my own article and other forms of an arcade have been show, shown to be effective inferences, reducing anxiety, enhancing sleep and on and on.

Mile oscitation is important because my my own osa all, and we can just say in oslo, all is related to so called second message or pathways. I don't want to get too deep in their second message or pathways, but when certain substances bine like no transmit yers to expect on a cell surface, often times those receptors themselves will open and allow the passage of ions and other things into a cell. Often times they will engage what I called second messenger systems, that is, they will trigger mechanisms within the cell to then go do other things.

This is probably ly 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 part of mine, in any case in oita, is related to a number of so called second messenger systems. This hand off for this kind of stimulating of changes within a cell that can inspire changes in what's called the membrane fluidity, can actually make the membranes of cells, the outside fence around the cell, which is made up of fatty stuff.

You can change the fluidity, meaning how readily things can float around in the membership. And know, we think of cells is 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, partial neurons have a fati outside, it's a thin fati outside and called the sell and things are floating around in that same member e, but it's kind of like yellow that hasn't quite fixed. And so things like receptors moving into the synapse or moving out of the synapse for homeostatic plasticity, things like um 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 e fluidity is that just imagine that everyone of yours cells has this layer is kind of a glatt ness like layer. And there are lots of little rafts floating around in there. But those rafts or able to move more quickly from one place to another, or get more stuck in one place to another, depending on how set that yellow is, inas, atall and lithium.

And I will talk about next, omega fati assets 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 membrane s are made out of fatty stuff. In particular, the memories of neurons are called a lipid bi layers. It's two layers of fat. Okay, bye means to lipid fat and omega three fatty asses of the sort that are found in certain fish, and that fatty fish in particular, and that are found in fish oil, cod liver oil and sea omega fatty assets, when we adjust 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 membrane s work.

And if those cell membranes are the sell memories of neurons, changing the way that neurons work, so the ability for fishel, and in particular, the omega three fatty acids, which come in varieties like E P A N D H, A talk about that, have been explored at relatively hy 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 in, I mention a few that found no effect of mega three supplementation through fishel. Usually its capsule fishel, although official, can also be take taken, excuse me, in liquid form, often times taking liquid form mis, the more cost efficient way to do IT, taking a capable form is the more palatable for way to do IT.

Because visual, for a lot of you, doesn't taste good. But nonetheless, there are several studies that have shown that supplementing with visual or mega family assets at levels up, 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 all two thousand twelve. This is a fat aid supplementation of seventy percent E P. A. To DHA. Actually worsening symptoms of mania over a period of about sixteen weeks, which on the face of IT, makes a team like, okay, a mega three family assets of lemon ation very likely do not be good for bipolar disorder.

And yet that was the manic face when one looks at some of the other studies that would make a three fat acid supplementation. There is, for instance, a study question, one thousand and ninety nine. This is a much higher dosage supplementation with a mega family ask.

This is in nine point six grams official per day for four months, and then actually greatly reduced symptoms of bipolar depression compared to the control group which receive olio. Il olios is a different form of fat mono and actually fat, but doesn't contain as much of the omega three 的 accepts and so forth。 So nine point, nine point six grams of official per day over four months.

A lot of social, to be interesting on a given day. This was a double line study. This was only Carried out, as I mentioned, in thirty subjects. But IT was males and females.

And the age range was pretty broad, anywhere from eighteen all the way up to sixty four years of age, which is important, given this of lodge and tutor or changes over time that one season by polar disorder. Here's the major take away supplementing with hindus. Omega's es 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 potently prescription drug treatments. Proscribed bywords sort tif ed psychiatrist for bipolar disorder.

However, omega supplementation does seem to improve or reduced the depressive symptoms in the major depressive episodes of bipolar, and there are a couple studies and will linked to these in the shown notes as well. They 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 podcasts, is a lot of interest in the behavioral tools, the supplement based tools and nutrition tools that can support by polar disorder.

But I don't think I can over emphasize enough that especially for bipolar disorder, in the great risk of suicide and suffering and appropriate spending, I should say, maladaptive spending and impulsivity that's associated with bipolar disorder, that it's hard to imagine that in which just talk therapy and fishel and listy le interventions are going to completely h 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 neutral udal, or, we can say, supplement based treatment such as our megory supplementation, as a full and necessary picture for dealing with the illness. I'd be remiss, however, if I didn't emphasize that the omega fatty acid supplementation is very interesting, not just in terms of the subjective effects, you know, people saying they feel less depressed are able to sleep Better, and even some reduction in manic symptoms.

That actually means a really good brain imaging to try and understand how mega fat 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 psychic.

It's entitled a megory fat acid treatment and t two whole brain relaxation times in bytes AR disorder. I don't have the opportunity to go into a lot of detail right now about what tea to hobin relaxation times are. But basically, when people go into A M R I or f functional M R I scanner, magnetic remy, excuse me, magnetic resonance imaging scanner, what they're getting essentially a pulses of magnetic fields.

And the way that brain structures in neural activity can be evaluated has a lot to do with the sort of spinning, or sort of has to do with the the spinning in 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 fatti versus other components of brain tissue. And basically, what the study shows is that the membranes of neurons within the brains of these people with biologist order showed more fluidity, more ability of things to move in and around the membrane es, which we know is an important component of neural plasticity in bipolar subjects that were treated with mega three fati assets as compared to bipolar subjects that did not receive omega fati assets. And fortunately, the study also include a healthy comparison group, where they could essentially find that people with bipolar disorder who supplemented with her megatheria changes at the cellar level and the neural circuit level that brought their brains and newer circuits closer to that of the healthy comparison subjects.

So well, I don't want to point to omega file asic supplementation as the ball and and all of treatment for bipolar disorder certainly is not IT does have a strong mechanistic basis for it's possible support of neural circuitry of neuroplasticity and in particularly the ability of make changes in cell membranes that are very reminiscent of some of the neural circuit changes and changes in membership fluidity that are seen with lithium treatment and other known prescription drug treatments that have been establishing now for decades to be very effective for bipolar disorder. So what that says is that omega 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 is changing. For instance, you got microbial, 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, 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.

When we think of a disorder, we think of something that is really detrimental to us, something that really empires our ability to function in work and school and relationships, and really starts to pull down our health status in a variety of ways. And certainly by polar 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 a 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 have just briefly touch upon this idea that certain are associated with a higher incidence of bipolar depression. And in fact, it's been explored at a research level. Really, there are data pointed in the fact that certain individuals of certain occupations tend to be more creative, and that creativity is associated with, again, associated.

This is in causing its 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 imminent 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 Green from more than a thousand twenty century western based on their biography that were reviewed by other people. So it's a bit of an indirect measures. This isn't psychiatry data. This is data, or I like, these are data that were compiled from self reports or from reads of self reports.

And they export a number of different professionals so far, instances they looked at people in the military, or people who were profession athletes, or natural scientists or social scientists, people who occupyed positions in public office, or were musical performers of artists, non vict writers, poetry. Etta, there are a lot of professionals here. Uh, I will post this or i'll post a link to IT in the showed te captions for you to prove.

But i'll just give you a sense of the extremes on this graph because they're very interesting. Turns out that if you were to look at the profession, or I should say, among the professions they looked at in this study, because they didn't look at all professions, those in the military and those who are professional athletes or had jobs in the social or natural sciences, had the of those. There was a lower percentage, those that had depression or mania, in some cases, like those were professional athletes, didn't seem to have.

There was no incidents of mania, at least in this data set. Whereas at the opposite extreme of the graph, those that were poets. So these are imminent individuals, people that were exceptional poets, exceptional fiction writers, exceptional artist or non fiction writers, will.

They are, especially for the poets. You find that as many as ninety percent of these very successful poets had either depression or mania as as ninety percent. That's incredible.

Contrast that with military, where it's as few as ten percent, or professional athletes, where it's as few as twenty percent for the professional athletes as I made before, or none of them had mania. So does this mean that being a poet will make you manager depressed? Well, first of all, let's look at the poetry category.

IT turns out that seventy five percent of these eminent poets, these highly accomplished poets, had major depression, whereas only about twenty percent of those poets had manic episodes. okay. So again, it's not that being a poet is gonna romania. Certainly, we're not saying that's not that being a poet is going to give you depression, but IT turns out that people with depression and people's pression in 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 nonfiction writing about non fiction, and is still creative music, composition, theater, much higher incidents of things like manian. In fact, for the people in theater, the actors, even though the overall occurrence of depression, armenia is lower than that in poets, the fraction of those individuals that have mania is exceedingly high. It's about thirty percent of those that they looked at who are actors have manic episodes or have full blown mania.

So i'm referred to this data because, first, while I find them incredibly interesting, right up until now, we've been talking about by polar disorder and other mood disorders, their maladaptive effects. And again, they're extremely more adaptive, much, much or incense of of suicide, IT said. But we'd be wrong to say that certain aspects of manic episodes 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 caterina 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 thirty minutes a day of composing a writing poetry, maybe even some of the laws that we feel, right, some of the sadness, some of the grief, some of the nostalgia we feel. Provided that it's not pathologic that is not persistent for the four or seven days that are diagnostic of bipolar two and bipolar one disorder, respectively.

Well, then we can start to view emotional states as something that can actually lend themselves to positive outcomes. And you may be even to creativity and to improve occupations. So it's important that we have a nuances view of what sadness versus depression, versus major depression are.

It's important that we distinguished between being erratic, being very energized and full blown by police disorder and a raises for another reason as well. Nowadays, very common to hear people saying, uh, 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, a huberman lab 点 com。 In that episode, I pointed out that ocd, obsessive compulsive disorder is very small adaptive, right? I think it's number seven, as I recall, on the list of debilitating diseases, all diseases in terms of lost time at work, suffering relationships inside of us.

So it's a really serious condition. And yet we often hear all 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 o they're all over the place. They're bipolar. Well, that's a very subjective and and label that people give one another in passing.

More and more often i'm hearing this. And yet, bipolar disorder, when they are not bp one or bp two, are extremely more adaptive and extremely associated with high suicide risk. So well, i'm not here to police people.

I'm not certainly the word police or the nomenclature police. I do think that whether not you refer to people as O C D or as bipolar, it's that's up to you. It's not my place to say. But I do think it's important that all us understand that these psychiatric conditions Carry with them tremendous more adaptive 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 were 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 by disorder, in particular homeostatic scaling or homeostatic plasticity. All of that, of course, is relevant to bipolar disorder.

And I hope you will be useful in your understanding and maybe even in in your pursuit of treatments for bipolar depression, bipolar disorder for you or other people. I also hope that you 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 of adi layers on the outside of neurons and the movement of receptors in other net that is present in all of us.

The influence of megory fati assets is central to that discussion, as is the discussion about various drug treatment. 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 serota levels, your dopamine levels, your seto colling level, 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 neo modulators and tools to adjust those neuromodulators under more standard non disease conditions, we did an episode on newer chemicals and how to control them.

You can find that at huberman lab dot com, along with all other episodes of the human life podcast, should mention everything is time stamp, 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 or enjoying this podcast, please subscribe our youtube channel. That's a terrific zero cost way to support us. In addition, please subscribe to the podcast on spotify and apple.

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