The Science & Treatment of Bipolar Disorder

Andrew Huberman 0:00 (soft rock music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, we are going to be discussing bipolar disorder, often called bipolar depression. Bipolar depression is a condition in which people undergo massive shifts in their energy, their perception, and their mood. However, it is very important to note that these shifts in mood, energy, and perception are all maladaptive. They can often cause tremendous damage to the person suffering from bipolar disorder and tremendous damage to the people in their lives. Today, we are going to parse the biology that leads to these shifts in mood, energy, and perception, and we are going to talk about the various treatments that exist. Some of those treatments have been around for a very long time, and indeed, one of those treatments, lithium, has an incredible backstory about its discovery. And in understanding how lithium works and some of the ways in which it does not work well, it reveals a tremendous amount about how the brain works normally in all individuals. So that's a miraculous story that I look forward to sharing with you. As we go forward in this discussion about bipolar disorder, I want everyone to keep in mind that it is a very severe condition. In fact, people suffering from bipolar disorder are at 20 to 30 times greater risk of suicide. So today is a serious discussion, and it's certainly one in which people who are suffering from manic-bipolar disorder or who know people that are suffering from manic-bipolar disorder can benefit from. However, for those of you that might know people or who themselves suffer from major depression, we will also be talking about important treatment developments for major depression. Major depression is a very common thing for many people. In fact, most people will suffer from depression of some sort at some point in their life, although not necessarily a major depressive episode, and yet major depression is very common. As you'll soon learn, up to 20% of people will suffer from major depression. So today's discussion will encompass all of that, and it will also encompass basic brain mechanisms of neuroplasticity, the brain's ability to change in response to experience, both for good and for worse, and you'll learn a lot about the basic biology of how the brain regulates mood, energy, and perception.

Andrew Huberman 2:23 I'm pleased to announce that the Huberman Lab Podcast is now partnered with Momentous supplements. We often talk about supplements on the Huberman Lab Podcast, and while supplements aren't necessary for everybody, many people derive tremendous benefit from them, for things like enhancing the quality and speed with which you get into sleep, or for enhancing focus, or for hormone support. The reason we partnered with Momentous supplements is several-fold. First of all, their supplements are of the absolute highest quality. Second of all, they ship internationally, which is important because many of our podcast listeners reside outside the US. Third, many of the supplements that Momentous makes, and most all of the supplements that we partnered with them directly on, are single-ingredient formulations. This is important for a number of reasons. First of all, if you're going to create a supplement protocol that's customized for your needs, you want to be able to figure out which supplement ingredients are most essential and only use those, and supplements that combine lots of ingredients simply won't allow you to do that. If you'd like to see the supplements that we partnered with Momentous on, you can go to livemomentous.com/huberman, and there, you'll see many of the supplements that we've talked repeatedly about on the Huberman Lab Podcast episodes. I should mention that the catalog of supplements that are available at livemomentous.com/huberman is constantly being expanded, so you can check back there, livemomentous.com/huberman, to see what's currently available, and from time to time, you'll notice new supplements being added to the

Andrew Huberman 3:42 inventory. Before we dive into the discussion about manic-bipolar disorder, I want to highlight some recent findings in an area totally separate from mental health that I think are really important for everyone to know about. This is a paper published in the journal Cell, which is a Cell Press journal, an excellent journal, in fact, one of the three apex journals. So for those of you that are curious, papers published in the journal Nature, Science, and Cell are considered the sort of Super Bowl, Stanley Cup, and NBA championships of publishing. And this paper, entitled An inter-organ neural circuit for appetite suppression, illustrates a very important principle that I think everyone should know about, and that's the principle of so-called parallel pathways. Parallel pathways, as the name suggests, are pathways, they could be neural pathways or hormonal pathways or otherwise, that operate independently of one another to accomplish a common goal, and what this paper really shows is that there's a set of peptides in the body, and the peptide that I'm referring to today is called GLP-1, glucagon-like peptide 1, and some related peptides. I've talked about these on the podcast before for two reasons. First of all, I'm a big, uh, proponent and consumer of yerba mate. Yerba mate is a tea that can promote the release of glucagon-like peptide 1, and there are also new prescription drugs that are now hitting the market, and for which there are really impressive clinical trials for diabetes and obesity, that are essentially glucagon-like peptide 1 stimulators, so they stimulate the release of that, or they are in fact a synthetic version of glucagon-like peptide 1. What is glucagon-like peptide 1? It is a peptide which is a small little protein that can dramatically suppress appetite, so that's why these drugs are being explored and are showing quite impressive results for things like treatment of type two diabetes and other forms of diabetes, as well as obesity, so they lead to weight loss. Now, in terms of the yerba mate stimulation of glucagon-like peptide 1, that's going to be a much lower amount of glucagon-like peptide 1 that's released from drinking yerba mate as opposed to, say, taking a drug that stimulates GLP-1 or taking a drug that is GLP-1. Nonetheless, I should also point out that yerba mate comes in a d- bunch of different forms. There is some concern about...... certain smokey flavored forms of yerba mate being carcinogenic, so that's why I avoid those forms of yerba mate. But for me, yerba mate is one of the preferred sources of caffeine for me. I like the way it tastes, it does provide the sort of caffeine kick that I like to have early in the day for focus and for work and for exercise, and yet I actively avoid the smoked varieties of yerba mate because of the potential carcinogenic effects of the smoked varieties. Glucagon-like peptide 1, as I mentioned earlier, can suppress appetite, but what this paper shows is it does that by at least two mechanisms through parallel pathways. What this paper shows is that glucagon-like peptide 1 acts on receptors in the body in a portion of the nervous system called the enteric nervous system, E-N-T-E-R-I-C, enteric nervous system. This is a component of your nervous system that you don't really have control over, it's autonomic or automatic. GLP-1 binds to what are called intestinofugal enteric neurons. You don't need to know the name, but those neurons do two things. First of all, they cause some gut distension, so they actually make you feel full. This is incredible, right? A peptide, not actual physical food, but a peptide that stimulates neurons that cause changes in the so-called mechanoreceptors of the gut of the enteric nervous system and make people feel full. So, it can lead to actually mild, or I suppose if levels of GLP-1 are very high, to major gut distension. Okay? I think that the levels of GLP-1 that would come from drinking yerba mate and hopefully from appropriate dosaging of the synthetic forms of GLP-1 or drugs that stimulate GLP-1 would cause mild, not major gut distension, 'cause major d- gut distension would be uncomfortable. So, GLP-1 is acting at the level of gut to increase gut distension, and by way of a pathway that goes from the gut up to the hypothalamus, this little cluster of neurons about the size of a marble that sits above the roof of your mouth, is also suppressing appetite through brain mechanisms. So, this is really beautiful, right? You have a peptide, a small little protein that's released in the gut, and that release within the gut causes gut distension, which makes you feel full, and by way of neural stimulation of the hypothalamus, also activates neural pathways within the brain that trigger satiety, the feeling of having had enough food. So to me, GLP-1 is both impressive and important. Why? Because this recent category of drugs that's now hitting the market seems to adjust obesity or can help people with weight loss in order to help their health, and it's doing so by at least two mechanisms. One is within the brain and the other is within the gut and communication through the so-called gut-brain axis, because again, these enteric neurons are communicating to the brain, the hypothalamus, by way of this what's called the sympathogastrospinal reticular hypothalamic pathway. You absolutely do not need to know all of that. That's a mouthful. That's enough to make your mouth feel distended. But at the same time, things like yerba mate, and I'm sure there are other compounds out there as well, but certainly yerba mate can stimulate the release of GLP-1. So, for those of you that are looking for some mild appetite suppression and want to accomplish that while also ingesting caffeine, yerba mate might be a good option for that. And just know that it's operating through two mechanisms, on the body through mild gut distension to make you feel full, and on the brain to increase satiety or make you feel less hungry. And then for everybody, not just those that are interested in appetite suppression, I think it's important to understand that these parallel pathways are fundamental to how we are organized. Another good example of this would be when we are excited by something, positive or negative, so it could be stressful or we're positively aroused, there is a parallel activation of epinephrine, adrenaline, both from your adrenals and from an area in the brain called the locus coeruleus. So again and again, we see this in biology and in neuroscience, that your brain and your body are acting in concert, they're acting together through mechanisms that either are independent, so separately in the brain and separately in the body, but directed towards a common goal, or through communication between brain and body. And almost always, that communication is going to be bidirectional, body to brain and brain to body. So, I think these results are really interesting and really important for sake of weight loss, for sake of appetite suppression, and just generally for the way that they illustrate this very important theme of the way that we are constructed at a biological level, which is parallel pathways.

Andrew Huberman 10:23 Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long-term health can only be assessed with a quality blood test. And nowadays, with the advent of modern DNA tests, you can also get insight into, for instance, what your biological age is and compare that to your chronological age. And of course, your biological age is the one that's important for your longevity and your understanding of your current health needs. One major problem with most blood tests and DNA tests out there, however, is that you get information back about levels of metabolic factors, levels of hormones and lipids and so forth, but you don't know exactly what to do with that information. InsideTracker solves that problem through their personalized platform, which can tell you, for instance, lifestyle factors like fitness or nutrition or supplementation that you can use to bring the numbers into the ranges that are ideal for your health needs. If you'd like to try InsideTracker, you can visit insidetracker.com/huberman to get 20% off any of InsideTracker's plans. That's insidetracker.com/huberman to get 20% off. Today's episode is also brought to us by ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two all-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were designed with performance in mind.I've spent a lifetime working on the biology of the visual system and I can tell you that your visual system has to contend with a number of very important challenges in order for you to see clearly. The designers of ROKA eyeglasses and sunglasses understand this, and for that reason, ROKA eyeglasses and sunglasses allow you, for instance, to move from a shady area to a bright area, or from a bright area to a shady area and still see everything with crystal clarity. Originally, their glasses and sunglasses were designed for performance, that is for running and cycling, and as a consequence, the eyeglasses and sunglasses stay on your face even if you get sweaty and they're extremely lightweight. In fact, most of the time, I don't even realize that they're on my face. I wear ROKA eyeglasses for reading and for driving at night, and I wear their sunglasses when I'm out during the day and it's really bright and I need to use sunglasses in order to be able to navigate in that bright sunlight. If you'd like to try ROKA glasses, you can go to roka.com, that's R-O-K-A dot-com, and enter the code Huberman to save 20% off your first order. Again, that's ROKA, R-O-K-A dot-com, enter the code Huberman at checkout. Today's episode is also brought to us by Blinkist. Blinkist is an app that has thousands of non-fiction books condensed down to just 15 minutes each, of key takeaways that you can read or listen to. I'm a big believer in reading physical books. I actually own a lot of hardcover books and paperback books, and I like holding them in my hand and flipping through the pages. I also like listening to audiobooks. But the reality is, I don't have a ton of time to read books and I don't have a lot of time to listen to entire audiobooks. There are also a lot of books that I've really enjoyed in the past that I have read in their entirety, but that I like to update myself on the information on every once in a while. Blinkist has terrific books available. For instance, I'm a big fan of Tim Ferriss's 4-Hour Body, gleaned so much knowledge from that book. Also from Nassim Taleb's book, The Black Swan, and the great Matt Walker's book, Why We Sleep, which is a book that I've read several times, and I actually listened to the synopsis of on Blinkist over and over because there's so many key takeaways. With Blinkist, you get unlimited access to read or listen to a massive library of condensed non-fiction books. Essentially all of the books that you ever wanted to listen to, and now you have time because they're condensed down to just 15 minutes each. Right now, Blinkist has a special offer just for Huberman Lab Podcast listeners. If you go to blinkist.com/huberman, you can get a free seven-day trial and you can get 20% off a Blinkist premium membership. That's Blinkist, spelled B-L-I-N-K-I-S-T, blinkist.com/huberman to get 25% off and a seven-day free trial. Let's talk about bipolar

Andrew Huberman 14:24 disorder, and today I'm going to refer to bipolar disorder interchangeably with bipolar depression, although as you will soon learn, not everyone with bipolar disorder necessarily goes through highs and lows. There is a subset of people who suffer from bipolar disorder who experience the manic phases, the highly elevated mood and energy, and then drop down to so-called baseline, so they don't necessarily go down into a depressive state. They often will return to a somewhat normal state. In fact, we will talk about the percentage of time that people with bipolar disorder tend to be symptom-free manic or depressed in the context of the different categories of bipolar disorder. But as we wade into this topic that is bipolar disorder, I just want to give you a little bit of the background statistics to anchor us in just how serious and prevalent bipolar disorder is. So, bipolar disorder impacts about 1% of people. That might seem like a small percentage. If you think about a room of 100 people, that means that at least one of them is very likely to have bipolar disorder. And as I mentioned earlier in the introduction, bipolar disorder is very serious. It has a 20 to 30% greater incidence of suicide than the general population, which is, first of all, extremely tragic and extremely concerning. So, anyone that thinks they might have bipolar disorder or who knows someone with bipolar disorder should be especially vigilant about this, and we'll talk about some of the, um, sort of signs and risk factors, age of onset, et cetera as we move forward. So 1% of people have bipolar disorder. The typical age of onset is anywhere from 20 to 25 years old, although it can be much earlier, and the earlier the onset of a bipolar episode, which we will define in a few minutes, the earlier the onset of that episode, the higher likelihood that the bipolar disorder is going to be a stable feature of that person's psychology going forward, and yet I also want to point out that there are some very good treatments for bipolar disorder that those people could still benefit from.

Andrew Huberman 16:30 There are basically two kinds of bipolar disorder, referred to as bipolar I and bipolar II. So let's just talk about bipolar I first. Bipolar I is characterized by a fairly extended period of mania. What is mania? Mania is a period of very elevated mood, energy, distractibility, impulsivity, and some other symptomatology that we'll talk about going forward, but this manic episode is extreme. This is a condition in which the energy lift, the mood lift, and the sort of impulsivity and actions and words of the person suffering from manic bipolar disorder are very noticeable and very extreme. Now, a key thing, however, is that it's not always noticeable to the person suffering from it that they are in this mode. Sometimes they recognize that, sometimes they don't, but it's always highly recognizable to other people that the person suffering from manic bipolar disorder is not like other people. So let's talk about bipolar I in a little bit more depth. One of the key clinical criteria or diagnostic criteria for bipolar I is that a person suffer from these manic episodes or display these manic episodes for seven days or more. That turns out to be very key. The stability of that manic episode for seven days or more turns out to be very important, and for those seven days, the person is in an elevated mood, expansive thought all day every day for those seven days. Now, there are a lot of reasons why somebody could be in a manic mode. It doesn't necessarily mean that somebody has bipolar disorder. In fact, someone could be in a manic mode for... seven days or more and still not be diagnosed with bipolar disorder. Why? Well, there are other things that can create manic episodes, things like traumatic brain injury, things like seizure, things like various prescription drugs or illicit drugs, things like amphetamine and cocaine. That is not the same as bipolar disorder, even though from a symptomatology perspective, they might look even identical. So, let's think about these symptoms and the diagnostic criteria that a psychiatrist would use in order to ask whether or not someone is manic because they have manic bipolar disorder or whether or not that person is manic for some other reason, such as traumatic brain injury, illicit drugs, et cetera. (smacks lips) So, typically a person will be brought into a clinic or a person would bring themselves to a clinic or meet with a psychiatrist. It seems more likely that they would be directed toward a psychiatrist because oftentimes people who are in a manic episode just simply won't have the perspective or the foresight to bring themselves into the clinic. And the psychiatrist is going to start to evaluate for a couple of different things. But first of all, what they're going to try and figure out is whether or not the person has at least three of the following symptoms. The first symptom is distractibility. Is the person distractible? Are they going from one thing to the next? People who are in a manic episode will be talking about a pen, and then they'll be talking about, you know, something they saw the other day, and then something they want to purchase, and then a place they're going to travel to, et cetera. But they are also very prone to any stimulus within the room, meaning, you know, a bell could go off or there could be a sound out in the hallway and they'll orient to that, and then they'll orient to the clinician, and then they'll orient to something in their pocket. So, they're- they're all over the place. You could think of this a little bit like ADHD or attention deficit disorder, but it's very extreme. So, highly distractible, highly impulsive. Impulsivity relates to actions. So, the person might be fidgeting with something and then they might try and leave the room or, 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 for instance, I happen to know someone whose, um, ex-spouse had bipolar disorder and their ex-spouse went out and bought 10 plus air fryers, right? I mean, I think unless you're a restaurant that's using a lot of air fryers, the idea that you would need more than one or two air fryers, um, might just seem a little bit out of the norm. And so that impulsivity can be at purchasing, it can be, um, other things as well. It could be booking, you know, 12 international trips in one afternoon or going and buying three cars, et cetera. So, impulsivity. The other is grandiosity. People who have manic bipolar disorder who are in a manic episode will often display words of or actions of grandiosity. And keep in mind, these are not lies in the sense that the person isn't lying in order to try and pull one over on anybody. These are actual beliefs that the person comes to have about their grandiose position in the world or grandiose opportunities or potential in the world. Typical forms of grandiosity in manic episodes would be that the person suddenly decides that they are going to win a Pulitzer Prize, they are the person selected to win a Pulitzer Prize, they're going to write a novel that afternoon, and they're going to win a Pulitzer Prize that year, which is more or less a delusion of grandeur, right? The idea that someone could do that in one afternoon, I suppose it is possible in the realm of all possibilities, but it's extremely unlikely. Other forms of grandiosity that often present themselves in people suffering from a manic episode will be that they're going to run for president or that they are the person that they believe is selected by the citizens of a given country or by the universe to be the president of that country or to be president of the universe, right? It sounds ridiculous, but those sorts of delusions of grandiosity are one condition that often presents itself or one set of symptoms that presents itself. Flight of ideas are also typical of manic episodes. So, this is a little bit like distractibility, but this would be people talking extensively about one thing and then switching and talking extensively about something else. It would be as if I was doing this podcast talking about manic bipolar disorder and then suddenly switching to OCD and then to deliberate cold exposure and then to, uh, the role of sugar and its impact on the brain, et cetera. So essentially, a random selection of the different topics that exist in science, all of which I happen to be very interested in and curious about. But just as we have episodes of the podcast that are about one or two topics and we focus on those in a fairly narrow trench of discussion, somebody who has a flight of ideas would be jumping between categories and topics, um, in a kind of pseudo-random way. So, they might take off down a path of one thing and then switch to another without any transition or with transitions that- that don't have any logical structure to them. The other aspect of manic bipolar disorder that often presents itself in the manic episodes are agitation, people feeling extremely physically agitated, so a lot of shaking and moving about. Um, this can venture into the realm of paranoia, but a lot of agitation, a difficulty sitting down and being still, a difficulty in just looking, feeling, and acting calm. And then another condition is no sleep. And when I say no sleep, I mean no sleep or very minimal sleep. As incredible as it sounds, people who are in a manic episode can often go seven days or more with zero sleep. And a key feature of this zero sleep is that they're not troubled by it. They're not thinking, "Oh, I'm suffering from insomnia and I really, really want to sleep." Sometimes that's the case, but more often than not, they are simply not sleeping. They're staying up 24 hours, then another 24 hours. It just continues for an entire week. Again, inconceivable to those of us that don't suffer from manic episodes. Can only imagine how pulled apart most of us would feel under those conditions, and yet they are just going and going and going with no sleep, up all hours, shopping, talking.... running, doing all sorts of different things in the categories of other symptoms that we talked about before, and it doesn't bother them that they're not sleeping. And then the last sort of category of symptoms that the psychiatrist is evaluating for and seeing if they present is rapid pressured speech. The rapid pressured speech is something that when you hear it, you recognize it. This is somebody that almost seems to be hitting you with speech like machine gun fire. It's coming at you, coming at you, coming at you, and there's really no room for conversation. They're not offering any opportunity for a back and forth. Or if there is a back and forth, they might ask you how you feel about something and then you start, "Well, I th-" And then they're coming and then- then they're going to hit you with another barrage or a paragraph of- of- of information or of- of just speech that's pseudo-random. So, we've got distractibility, impulsivity, grandiosity, flight of ideas, agitation, no sleep, and rapid pressured speech. For someone to be diagnosed as in a manic episode, they do not have to be engaging in or displaying all of those symptoms. They do, however, need to present at least three of those symptoms and then in order to meet the condition of bipolar I, they have to be presenting those three symptoms for at least seven days. It could be longer, but at least seven days. Now, this seems pretty straightforward, right? At one level, the way that I describe this and the way that it exists in the clinical literature, you could think, well, this should be pretty easy to diagnose. And yet there's a complication there, a challenge there, because the psychiatrist, again, has to determine that these manic episodes are not due to something other than bipolar disorder. For instance, again, it could be TBI, traumatic brain injury, it could be seizures or meds or other sorts of drugs. Corticosteroids, which are often prescribed for a number of immune conditions or for wound healing, can also cause manic episodes. So, they have to determine that everything that's happening meets the criteria I described before, three out of seven of these symptom categories for seven days or more, and that it can't be better explained by something else going on in that person's life or immediate medical history. That's very important. Now, the other challenge, and this is something that's going to come up again and again today, not just in the description of the biology of bipolar disorder, but also in the description of different treatments and treatment approaches, is that typically when somebody is sitting in front of a psychiatrist, in particular for the first time, those two people are interacting, the psychiatrist is just getting one snapshot of the person at that moment, right? So, the person could be on day one of a manic episode, the person might be on day six of a manic episode, the person could be transitioning out of a manic episode, or the person could be suffering from a combination of manic episode where because of the impulsivity of bipolar disorder, they went out and used illicit drugs, they also used cocaine. So, the psychiatrist has a serious challenge. The psychiatrist has to determine based on a conversation, right, this isn't a blood test, this isn't a measurement that you can take on a scale or with a biomarker, they have to use language, a conversation with somebody who, by all accounts, is pretty impaired at conversation to determine whether or not they're suffering from a manic episode that is the consequence of bipolar disorder. You can imagine this in the real world as somebody says, "Well, how long has it been since you slept?" And the person starts to answer, "Oh, well, the other day I went down to the- the basement, I was going to get something out of the- the refrigerator, I thought I might take a nap," and then all of a sudden they're talking about something completely different. So, they might not even have an answer. So, the psychiatrist has to be a really good detective, a benevolent detective, but a detective nonetheless in determining whether or not these symptoms have existed for seven days or more and whether or not they meet the at least three, could be more, but at least three of the criteria of symptom categories I talked about before. Now, assuming that they do, assuming that the patient meets those criteria, they are likely to be diagnosed with bipolar I. Now, bipolar I disorder means they're having these extended manic episodes, seven days or more, but it does not necessarily mean that they are dropping into a depressive episode as well. This is a common misconception about bipolar disorder because as it's often called, bipolar disorder is referred to as bipolar depression, and yet many people with bipolar disorder don't necessarily experience the deep depressive episodes. Many of them do, but many of them do not. So, somebody can truly be diagnosed accurately with bipolar I even though they're only experiencing manic episodes and then dropping down to baseline, manic episode, then dropping down to baseline. That's very important to understand. Now, the second

Andrew Huberman 28:58 category of bipolar disorder is bipolar II. So, BP-II or bipolar disorder two is somewhat different than bipolar disorder I. First of all, it's characterized most often by the presence of both manic episodes, mania, and depressive episodes or what's referred to as hypomania. Now, anytime in biology or in medicine you hear hypo, it's the opposite of hyper, okay? So, we've got normal, hyper, and hypo. Hypomania is a somewhat suppressed level of mania. So, this is not going to be as extreme as the mania that we typically think of. And yet the hypo can be due to the duration, not the intensity of mania. That's right, hypomania can mean a lessened intensity of mania, but it can also be used to refer to a shorter duration of mania. In fact, that's one of the key criteria for bipolar II. Bipolar II is often diagnosed on the basis of the presence of manic episodes that are lasting four days or even less. So, someone with BP-II might have four days of this increased energy, goal-directed activity, they're irritable, they're euphoric, they're not sleeping, et cetera, but it's only lasting for about four days. Or they could be having longer extended periods of mania, but they are hypomanic episodes. They're not quite as intense. So, the pressured speech isn't quite as pressured, the impulsivity isn't quite as severe, et cetera, et cetera. The other aspect of bipolar II is one that I 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 I can indeed go from manic episodes to severe, what we call major depression. So, they can oscillate like a sine wave, really high highs, really low lows. And very important to understand in terms of understanding both bipolar I and bipolar II is that it's not always a sine wave. This is really important and it's something that, uh, frankly, I did not know until I started researching this episode and talking to some psychiatrists. I should mention, I've talked to several board certified psychiatrists in preparation for this episode. I'll give some references to them, and in fact, some of them are going to be coming on the podcast as guests in the future for more in-depth discussion about bipolar and other, uh, psychiatric disorders. But all the psychiatrists I spoke to confirmed what the other was saying, which was that the way that bipolar disorder can present can vary tremendously between individuals. One person might go from very high highs that last seven days or more to very low lows, bouts of depression, major depression that could last 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 erase that picture in your mind that manic bipolar disorder is this sine wave, this cycling up and down between mania and depression. It can take a lot of different forms. And again, this is a serious challenge for the psychiatrist to diagnose people because of that fact that they're only getting a snapshot of the person unless they've known them for some time and are working with them for some time. But this is also especially important for those of you that either have bipolar depression or suspect that you might, or that know someone with bipolar depression or suspect somebody might have bipolar depression, AKA bipolar disorder. Because if you're noticing that somebody is very manic and then normal, well, that's a very different picture than somebody who's going from very manic to very deep bouts of depression. The very manic to deep bouts of depression is easier to recognize because of the extremes of those highs and lows. Now, this might seem somewhat obvious to all of you as I describe it, and yet it's very important as a, frankly, a citizen of the planet who knows other human beings to keep an eye out for these manic episodes. Because again, whether or not it's four days or less, or whether or not it's seven days or more, these manic episodes really are the d- the defining criteria of bipolar disorder, AKA bipolar

Andrew Huberman 33:07 depression. There are a couple other key features about bipolar I and bipolar II that can allow us to get better insight into whether or not somebody has bipolar I or bipolar II, and that's the percentage of time that people with bipolar I versus bipolar II spend in a manic state, a depressed state, or a symptom-free state. And this is also important to discuss because it turns out that people with genuine diagnosed bipolar I or bipolar II are often symptom-free, which again, can make it difficult for us as people that know them or for people that are treating people with bipolar disorder to identify whether or not somebody is in a manic episode or a depressive episode, or whether or not they are headed into a manic or depressive episode. So, the numbers on this have been studied. This is from a paper, actually two papers. Uh, first author, Judd, J-U-D-D et al., published, um, some years ago, 20 years ago, but the data hold up really nicely over time. These were both published in, um, Journal of American Medical Association Psychiatry, so JAMA Psychiatry, a superb journal. And basically, people w- who have bipolar I, on average, spend about 50%, it's actually 53% was the, was the number that was eventually converged upon, but about 50% of their time symptom-free. That's interesting, right? Somebody who has genuine bipolar I disorder can spend as much as half of their life symptom-free, sleeping normally, speaking normally, et cetera. About 32% of the time depressed, and when we say depressed, we mean major depression. So, severe challenges with waking up at 2:00 or 3:00 in the morning and having trouble falling back asleep, that's one of the defining characteristics of depression, or sleeping far too much, having a hard time getting out of bed in the morning, suppressed appetite, suppressed libido, suppressed motivation, all the general symptoms of major depression, which we'll talk about a little bit more later and in an upcoming episode about major depression in particular. And then about 15% of their time in this kind of manic state or mixed manic state where they, uh, are showing long, again, seven days or more, bouts of sleeplessness, irritability, pressured speech, grandiosity, et cetera. Contrast that with people who have bipolar II disorder who are spending about half of their time in a depressed state. So, that's interesting. People with bipolar II disorder, while not always displaying depressed states or oscillations between mania or hypomania and depressed states, they tend to be in the depressed state more often. And again, this is major depression. This isn't just a little bit of a low, this is a serious depression of their nervous system, their mood, and as we say, their affect, their outlook on life. And that's one of the key distinguishing features of major depression is that people's outlook on life becomes very diminished in the sense that they don't see a future. You ask them about, you know, how's work going, how are relationships, and it- it's not just that they feel that that's going poorly, they really feel as if there's no opportunity for those things to improve. Those people with bipolar II tend to be symptom-free about 45% of the time. Again, th- these are averages, so about 45% of the time. That's a considerable amount of the time. And they tend to be in these hypomanic states only about 4 or 5% of the time. Again, the criteria for BP II, bipolar II is these four days or less of mania or hypomania, but only 4% of the time or 5% of the time is a small enough sliver of the pie that is these people's existence that you can imagine why it would be easy for them or other people to overlook the fact that they have bipolar disorder and not major depression. Think about it, this is a person who, or I should say, a collection of people who are spending about half of their time depressed, close to half, 45%, u-...their time symptom-free, and then about 5% of their time in a hypomanic state, so either shortened bouts of high intensity mania or hypomania, that is, of reduced intensity. One of the reasons that I mention these percentages of time spent in a symptom-free depressed manic or hypomanic state is because one of my major goals for today's episode is that it will increase awareness of whether or not you or somebody you know, could be a coworker, could be a family member, et cetera, might be suffering from bipolar I or bipolar II. I think it's fair to say that if somebody is suffering from bipolar I, that is likely to be revealed or to reveal itself before too long because of the fact that people have these extended periods of mania, and mania is such an extreme state, not just for the person who's experiencing it, but the way that it presents is just so extreme and out of the ordinary. But bipolar II, you can imagine, could really duck under the radar of our awareness. And you could imagine that we might just think somebody is low or depressed, especially if that person tends to self-medicate with alcohol or other substances. We might think, "Oh, well they're drinking more than often- uh, more than usual," excuse me. Or, "They're spending more time alone and isolating." But then when they're in their hypomanic state, that might a- 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 kind of tune our antennae to the possibility that people out there who might appear depressed or that we haven't heard from in a while might actually be suffering from bipolar II disorder.

Andrew Huberman 38:20 Before we move into a in-depth discussion about the different kinds of treatments for bipolar disorder, I'd like to touch on just a few additional aspects of what bipolar disorder can do in terms of its negative consequences, and also talk about some of the inherited risk, that is, the genetic factors and the environmental factors that can contribute to bipolar disorder. In terms of the- the burden, the- the very real emotional, and occupational, and educational burden that can occur for somebody with bipolar disorder, th- that's actually been studied. There's a measure of this. It's called global burden, which is defined as the years lost in engaging in normal life due to some disability. So, that disability could be cancer. That disability in this case is bipolar disorder. And basically, the way this sort of study is done is that through questionnaires, I should say quite in-depth questionnaires, there's a probing for whether or not somebody has lost two consecutive weeks or more of interest in normal activities. Now, for people who have depression, that's a kind of straightforward thing to address, right? Um, you ask somebody, you know, "When was the last time you ate?" Or, "When was the last time that you went a few days without food or lost interest in- in relationships, or work, or sex," or things of that sort. And they 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 I and even bipolar II is massive. In fact, having bipolar disorder sits as one of the highest risk factors for being in the top 10 c- of all categories of disabilities leading to global burden. Put in plain English, what that means is having bipolar I or bipolar II disorder is extremely debilitating. It really slows down one's life trajectory unless it's treated properly. Now, the other aspect of bipolar disorder is its heritability. And this gets into a little bit of some tricky science related to inheritability versus the genetic contribution of a given disease. So, that might sound like the same thing. You think, "Okay, genes relate to heritability. Heritability relates to genes." But of course, everything about the way that our nervous system works and functions and expresses itself, healthy or otherwise, is an interaction between our genes and our environment. And so typically, the way these studies are done is you address what is the risk of somebody having a given condition in the general population? We talked about that before. Bipolar disorder is a- a 1% of the world's population. Compare that to people who have only major depression, so this would be repeated bouts of two weeks or more of serious depression, not just low mood or something due to a life loss, but major depression, which is 10 to 17% of people have major depression. Okay? They- they suffer from major depressive disorder, compared to bipolar disorder, which again is 1%. Now, you can address how much of the 1% of bipolar disorder that exists is due to genes versus environment in a somewhat exact way. This is never an exact science. And the way that this is typically done is to look at concordance, that is, the likelihood that two identical twins will both have a given condition as opposed to two fraternal twins, which have diff- more different genes than identical twins, of course, and then two siblings who have similar genes, of course, but less similar than identical or fraternal twins, and so on and so forth. So, what you basically do is you evaluate the probability that two people in the general population who are completely unrelated will have the same condition versus two people in the g- in the general population who are very related, identical twins. And what you find... Is that in identical twins, if one identical twin has true major depression or major depressive disorder, there's a 20 to 45% chance that their identical twin will also have major depressive disorder. Now, that tells you right there that it can't all be genes. That it's not a gene for major depression per se, or if it is a gene that- or a collection of genes, that those genes are also subject to environmental influences, either prenatal within the womb or after children are born. Now, the large range there of 20 to 45% could be due to any number of things. It could be experimental, meaning the techniques that were used in experiments. It could be due to, um, regional differences, right? Different- one part of the world versus another. There are a lot of different factors. Um, right now we-Probably shouldn't delve into all that. At some point, we'll probably do an episode all about the genetics of nervous system heritability and heritability of features in mental health, et cetera. But we can compare major depression and the heritability or the genetic concordance between identical twins in major depression and bipolar disorder, and ask, if one twin of an identical twin pair has ma- bipolar depression, what is the likelihood that the other twin will have it? And it turns out that number is much higher, it's 40% to 70% likelihood or probability that if one twin has bipolar disorder, that their identical twin will also have bipolar disorder. So again, the total incidence of bipolar disorder in the general population is much lower than it is for major depression. It's 1% for bipolar versus 10% to 17% for major depression. But the genetic component is much higher, 40% to 70% for bipolar disorder versus 20% to 45% for major depression. I know I'm throwing a lot of numbers, um, out there. Um, but basically what this means is that researchers have been able to take those numbers and filter them through a number of different risk factors that are related to early development, ask questions like, if two twins were raised separately or together or in one part of the world versus another, or had a two-parent household versus one-parent household, you know, evaluate a lot of different variables. What they were able to discover, and this has been shown again and again, is that the genetic contribution to bipolar disorder is very, very high. That is, the heritability of bipolar disorder is 85%. Okay? So again, I want to be really clear what this means. The total occurrence in the general population, fairly low. Still serious, 1%, but fairly low compared to other things like major depression. However, if someone has bipolar disorder, it's very likely that they inherited some gene or sets of genes or, more accurately, a susceptibility within their genes to environmental influences that can trigger bipolar disorder. There are a lot of different ways to discuss and to conceptualize heritability. So, I want to be very careful with the way that I'm wording this. What this means is that people with bipolar disorder very likely have a gene, or more typically it's going to be a set of genes, that creates a susceptibility for bipolar disorder to present itself. Now, what environmental factors trigger or increase that susceptibility is not entirely clear. This always seems to center back onto the same sets of things like early life stress, trauma, et cetera. Certainly, those are going to exacerbate the likelihood that someone who has a genetic propensity for bipolar disorder will express that bipolar disorder in its full array of symptomatology. But 85%, while very, very high, is not 100%. Again, 85%, while a very high number for heritability, is not 100%. What that means is that there is no single gene or identified gene cluster for bipolar disorder. The reason I keep drilling into this over and over is that I think we can confidently say that if someone has bipolar disorder, that there was something in their genetic lineage that led to that, or that very likely led to that. And yet, it's not like eye color or some other physical feature which we can actually do the, the direct, so it's called Mendelian genetics, and figure out whether or not somebody directly inherited that gene from one parent or the other parent. So, the takeaway here is that if you have an i- certainly an identical twin or a fraternal twin or a sibling or a parent or even a cousin or an uncle that has bipolar disorder, and particularly Bipolar I, well then, you need to be on the lookout for bipolar disorder, perhaps in yourself and for the family members of

Andrew Huberman 46:53 that person. My goal within this episode up until now has been to provide a clear and detailed picture of bipolar disorder and its various forms. Before we start to talk about treatments for bipolar disorder and some of the neural circuit basis for bipolar disorder, I want to make sure that I distinguish bipolar disorder from borderline personality disorder. We will do an entire episode, or maybe even several episodes, about borderline personality disorder. Borderline personality disorder can indeed present itself in ways that resemble bipolar disorder, and vice versa, but there are some key distinctions that need to be made, because it turns out that bipolar disorder and borderline personality disorder are quite distinct in terms of their defining criteria. The key distinction between somebody with borderline personality disorder and bipolar disorder is that in borderline personality disorder, there can be episodes that can resemble mania or hypomania. So, periods of flights of ideas, or where people are spending money excessively or 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, "Let's, you know, enter a relationship together of one form or another." The person with bipolar disorder will have episodes of mania or episodes of major depression without any need for an external stimulus or environmental trigger. But the person with borderline personality disorder almost always, again, there's never an "always" in biology and psychiatry, but almost always is going to exhibit-... flights of mania or depressive episodes, or other types of mood shifts that are dramatic and maladaptive in response to things that are coming in through the external environment or relationships of some kind. In fact, one of the defining characteristics of borderline personality disorder is this thing that's referred to as splitting. A good example of splitting in a person with borderline personality disorder is that they will feel that they absolutely adore you and want to spend all their time with you and just think the world of you, you can do no wrong. And in fact, they genuinely can feel that way, and can genuinely think that way about you. And then, for whatever reason, it could be a perception of something that you did or something that you said, or suspicion that you're thinking something about them, they can suddenly shift or split their emotions in what's called move you from a good object, or a can-do-no-wrong object, to a bad object. They'll suddenly decide that you are cheating on them, or that you are being mean to them, or that you're insulting them, or that something that you're doing is in violation to their self-worth, their well-being, et cetera, and that can send them down a pathway of being very angry, very depressed, et cetera. As I describe the contour of a person with borderline personality disorder as somebody who splits very suddenly in response to some environmental trigger, real or perceived, there's the risk, of course, that it makes the person with borderline personality disorder sound like a bad person, 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 disorder, whether or not they're romantic relationships or familial or coworkers, et cetera, can be very challenged, can be very high friction because of the good object-bad object shifts, et cetera, it's bidirectional, meaning the person with borderline personality disorder, as you can imagine, is also going through a lot of suffering. At one moment, they feel as if someone is wonderful and can do no wrong to them and they want to be so strongly affiliated with them, and then in the next moment, they feel as if that person is attacking them through their actions or even through their non-actions. So again, we will return to borderline personality disorder in a separate episode. It's a serious disorder, both for the person that has it and for people around them. Fortunately, there are some emerging treatments that are showing promise, and, uh, it's a fairly common disorder. But it's important that we distinguish borderline personality disorder from bipolar disorder mostly on the basis of this need for a trigger. Again, in bipolar disorder, there is no need for a trigger to create a manic episode or a major depressive episode. They just happen, or they can just happen, whereas in borderline personality disorder, almost always there's an external trigger or a perception that something happened in the environment or that somebody is behaving a certain way that dramatically shifts the person with borderline personality disorder from one mode to the

Andrew Huberman 51:51 next. As we move into our discussion about the treatments for and neural circuits underlying bipolar disorder, I want to just nail down one more key point. This is a very brief point, but it's perhaps the most important point, which is, the highs and lows, or we should say the highs, these manic episodes, and sometimes lows, 'cause again, not everybody with bipolar disorder I or II suffers from depressive episodes, sometimes yes, sometimes no. In particular, in bipolar II, yes, but people with bipolar I can have extreme manic episodes and then just return to normal, as you recall. Well, those extreme lows and/or extreme highs of people with bipolar disorder impact their lives in very negative ways. This is essential, and it's something that we're going to return to a little bit later when we talk about the relationship between bipolar disorder and creativity, because it turns out that there's a quite strong association there, one that would almost lead you to believe that being bipolar can be beneficial in certain contexts, and yet, on whole, having bipolar disorder is extremely detrimental and challenging to the person suffering from it. And it's something that we want to keep in mind as we think about treatments and the underlying biology. Now I'd like to talk about some of the treatments for bipolar disorder,

Andrew Huberman 53:07 and in the discussion of those treatments, there's an absolutely incredible history of the discovery of one particular treatment that still shows great success in many patients, although some people can't take it for reasons that we'll talk about. And in the description of the discovery of this treatment for bipolar disorder, it also reveals to us that sometimes treatments come to the profession of medicine and through science in ways that precede the discovery of the underlying biology. That's right. Every once in a while, someone will discover a treatment for a disease without any understanding about the underlying biological basis of that disease. And in fact, that is the case for bipolar disorder, and the treatment that we are referring to is lithium. Lithium, as some of you know, is on the periodic table of elements. It is indeed a naturally occurring substance. It actually arrived on earth by way of stardust. Yes, we are talking about stardust on this podcast. But if you'd like to learn more about the origins of lithium and how lithium arrived here on earth for its discovery and applications in psychiatry, there's a beautiful talk that exists on YouTube, and we'll provide a link to this in the show note captions, that describes the history of lithium in terms of its interplanetary travels and arrival on earth. This is a talk delivered by a physicist who's expert in quantum mechanics and is expert in lithium, and it's a just wonderful talk that I can refer you to. Less on the biology in that talk, but certainly a lot about lithium as an element, so for those of you nerds like me that love to know how things came to be here on the planet in one form or another, uh, I'll encourage you to take a brief listen to that talk. We are going to discuss lithium in the context of its applications for treatment of bipolar disorder, and the discovery of lithium as a treatment for bip- polar disorder... is truly a miraculous story that I think everyone should know. The key player in this story is a physician by the last name Cade. He was an Australian physician. And Cade has a very interesting story in his own right. Cade was an Australian psychiatrist, or Australian psychiatrist, who also was a soldier. And during World War II, after the fall of Singapore to Japan, he became a prisoner of war, and he was a prisoner of war from 1942 until 1945. So, he had some time for observation. And during his imprisonment, he observed some of his fellow inmates as going through pretty wild vacillations in mood and energy, essentially going from manic episodes to depressed episodes, or from manic to normal episodes. And for one reason or another, we don't know why, because I couldn't find any report as to why he hypothesized this, but he hypothesized that there was some buildup of some chemical in these people's brains that then they would urinate out, and that urinating out of whatever chemical was in there would allow them to be more relaxed and not manic. In other words, Cade hypothesized that there's a buildup of a chemical in certain people's brains that makes them manic, and they urinate that chemical out. So eventually, he got out of this prison, as we- as we mentioned, in 1945, and he started doing experiments in addition to seeing patients in his clinic. And what he did is he started to take urine from people who exhibited mania and urine from people who were not manic, and he took that urine and he would inject it into guinea pigs as an experimental model. And his general observation was that there was something in the urine that was indeed making the guinea pigs more manic if they were injected with urine from a manic patient. All right. The exact measures that he was taking in these guinea pigs wasn't exactly clear. This is, um, at a time or an era in science when you could, uh, just sort of report things a little bit more subjectively. Although there were still numbers and statistics, it was a little bit more of, like, uh, 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, uh, discoveries for psychiatric health. So, what he figured out was that the urine from manic patients seemed to be more toxic for these guinea pigs, and he also knew that there are two toxic substances in urine, urea and uric acid. So, he was able to separate the urea and uric acid from people with mania and patients that did not have mania, and he figured out that the urea was the same in both these mentally ill, manic patients and the non-manic patients. So, it did not seem that urea was the compound that was creating these manic episodes or related to manic episodes or held the toxicity. So instead, he focused on the uric acid. Now, in order to put the uric acid into solution so that he could inject it into these guinea pigs, he had to try a number of different compounds in order to dilute it. It just so happens that, and you chemists will be familiar with this, but there's certain things that just don't go into solution easily. You put the powder in a, a vial, you add some water or saline or another solution, you mix it up, and the powder stays suspended in there. It just doesn't, it doesn't actually, uh, ever become a clear liquid that you can inject. So, in order to try injecting different strengths of uric acid, he ended up using lithium to assist in the dilution, and lithium worked. So, what he basically was doing, again, for you chemists, is he was taking uric acid, he was adding lithium, and making a solution of lithium urate. Okay. This is a lot of details, but this is important because what he eventually found is that when he diluted the uric acid with lithium and created lithium urate, lithium urate could actually calm down these guinea pigs that were injected with the toxic urea. He also found that lithium urate had a generally calming effect on these guinea pigs. So, now we're really off in crazy territory, if you (laughs) ... Right? We're talking about urine from patients that's separating out urea and uric acid, we're adding lithium to the uric acid, we're injecting this into guinea pigs. This is getting pretty wild and pretty weird. But this is medicine, and from time to time, this is medicine and science. Cade was a good scientist in addition to being a good physician. And by good scientist, I mean that he did control experiments. Here he was injecting lithium urate into animals and seeing an effect, but he knew that that solution of lithium urate contained not just the uric acid, but it also contained lithium. And so, he quite appropriately asked, "Maybe the lithium alone is having this calming effect on these guinea pigs." And indeed, that was the case. When he did the proper control experiment and injected only lithium solution into these guinea pigs, they calmed down. From there, he, in sort of 1940s-style (laughs) medicine, now this even would not happen now, he very quickly moved from that animal model into human patients and started injecting human patients with lithium or providing lithium orally to those patients. And lo and behold, found an absolutely profound and positive effect of lithium in reducing symptoms of mania. And as all good physician scientists do, he wrote up his results, and he wrote it up in a paper entitled Lithium Salts and the Treatment of Psychotic Excitement. Okay. Back then, they didn't call it mania, they called it psychotic excitement. This is a paper that was published September 3rd, 1949 in The Medical Journal of Australia. We will provide a link to this study. It is now a classic study in the field of psychiatry. It's a really wonderful paper to read, and actually, I encourage people, even if you're not a scientist or a clinician, to just take a quick look at the second page in this paper that we've made available to you....where he describes each of the various case studies or the individuals that he looked at. Um, I'm not going to read these in detail now 'cause it would take a lot of unnecessary time. But things like, um, "Case VII, MC, aged 40 years old, re- suffering from manic recurrent mania. In this episode, he'd been excited, restless, and violent for over two months and was interfering so often that had to be confined to a single room during the day." Right? So this is very debilitating, what we now know to be bipolar depression. Um, "He commenced taking lithium citrate, 20 grains," that's a, a measure of, of the amount of lithium, "three times a day. In four days, he was distinctly quieter and by February 13th, 1949 appeared practically normal. He continued well and on February 20th, 1949, the dose of citrate was reduced to 10 grains..." et cetera, et cetera. "He left the hospital." There are numerous descriptions of this sort within this paper, including some descriptions of patients that did not see such success and including some descriptions of patients that suffered from some negative side effects. So, that's important to point out as well. But it's an absolutely wonderful paper and it's an absolutely wonderful voyage into the history of psychiatry, right down to the discussion where, in just three short paragraphs, Cade really lays out the case for why lithium is such a important discovery in the treatment of what, at that time, they were calling psychotic excitement and what we now know to be manic bipolar depression. Lithium, I should

Andrew Huberman 1:02:44 mention, has a number of important features, but it- also a number of important side effects that need to be considered. First of all, it does have a certain toxicity, and so levels of lithium in the blood need to be monitored extremely carefully. So it's not the sort of thing that people can just take at a given dose and every patient responds the same. There's a lot of oversight and a lot of blood tests that have to be done, especially in the first three months of lithium treatment. I should mention that lithium treatment is still used to some great degree of success in many, not all people suffering b- from bipolar depression or bipolar disorder, rather. But there are a number of important things that happened between 1949 and present day that prevented lithium from reaching patients that really needed it. And that all can be summarized in two or three short sentences. Basically, by virtue of the fact that lithium is a naturally occurring element, it could not be patented. And as a consequence of that, there wasn't a lot of potential profit for drug companies to produce lithium. In fact, still to this day, it's very low-cost and still to this day, no one really owns the patent for lithium in its purest form. So that made it unattractive. It turns out that the FDA in the United States didn't allow lithium to be used as a treatment for manic bipolar disorder until 1970. So we're talking about a full 21 years from the publication of this paper by Cade in The Medical Journal of Australia showing, quite beautifully, the great potential and use of lithium for quelling the symptoms of bipolar disorder until the first patients in the United States were starting to access lithium regularly. And nowadays, of course, lithium is available, but still not able to be patented 'cause it's element number three on the periodic table. It's naturally occurring. It's not literally falling down from the stars as stardust and going into pill form, but rather it can be synthesized, (smacks lips) uh, in laboratories. Uh, but it is available. It does show not only great potential in many patients, but great application in many patients despite its side effects. So lithium really stands as this kind of golden example of a treatment that works, at least in many individuals, prior to an understanding of the biological basis of the disease for which that treatment is needed.

Andrew Huberman 1:05:05 Now with that said, scientists and clinicians have been quite rigorous in trying to understand why and how lithium works in order to understand the why and how of bipolar disorder. This is the way that proper medicine and science is done. Even if there's an excellent treatment for something, it's important to understand why that treatment works because first of all, not everyone responds to that treatment. Second of all, scientists and physicians understand that just because we have one treatment that works, if it has any side effects at all, there is the possibility for better treatments. So it's not just about trying to bypass a drug that doesn't make much money for drug companies. I know a lot of people think in those terms. They think, "Oh, well, you know, there's this continued search for better treatments for bipolar disorder even though lithium works because lithium doesn't allow drug companies to make much money." That's not really the case. The fact of the matter is, is that the toxicity, some of the other issues that are created with lithium, (smacks lips) the fact that people need the ongoing blood testing, et cetera, really stimulates the need, really an urgent need for new and better treatments for bipolar disorder. And only by understanding how lithium works at the cellular level, at the neural circuit level, et cetera, do we really stand to find those new discoveries. If you were to do a literature search on the actions and mechanisms of lithium in terms of how it can calm people down and reduce their manic episodes, you would find an enormous array of papers, literally thousands of scientific studies in animals and in humans, which, for instance, will tell you that lithium treatment will increase so-called BDNF, brain-derived neurotrophic factor. BDNF is often talked about in the context of neuroplasticity, the brain and nervous system's ability to change in response to experience. And indeed, it does seem that ingesting lithium increases BDNF. BDNF is what we call permissive for neuroplasticity. It doesn't create specific changes in the brain, meaning it's not going to make your memory better or your coordination better or your emotional state better per se. What BDNF does is it permits the neurons, the nerve cells and their connections in the brain, to be more likely to change if the proper environmental conditions are met. That is, BDNF creates a kind of buoyancy....to neuroplasticity. It opens the gates to neuroplasticity. So, lithium does increase BDNF. We talk about why that's important in the context of the neural circuits involved with bipolar disorder in a few minutes. It also seems to be a potent anti-inflammatory. Now, inflammation is one of those words that's thrown around extensively nowadays, especially on social media, and especially as it relates to any health condition. It's like inflammation, inflammation, inflammation always seems to be discussed in the context of inflammation being bad. But I do want to point out that inflammation is a natural adaptive response to physical injury to a cell or organ or tissue of any kind. Inflammation is the basis by which adaptations occur to exercise. So if, for instance, you were to weight train and use a heavier than normal weight and you do a set to failure, or create some little micro-tears in the muscle that are healthy in the sense that they would create adaptations and make that muscle stronger, maybe even grow that muscle. There's an inflammatory response associated with that that is critical to the positive adaptation. So, inflammation isn't always bad, although excessive, or as we say, runaway inflammation is bad. Lithium seems to be able to suppress inflammation and, importantly, it can suppress inflammation in neural tissues and within the brain in particular. That is important, and we will return to that and why it's important in a little bit. The other thing about lithium is that lithium is neuroprotective. That is, it can prevent neurons from dying under certain conditions. Why would neurons die? Well, there are a lot of reasons why neurons can die. There can be a physical insult to the neurons. You can get hit really hard in the head, a bullet, you know, g- god forbid, can enter the skull and kill neurons. There are a lot of reasons why neurons can die. Neuroprotection is a situation in which a neuron is given some sort of chemical or physical resiliency that allows it to suffer an insult and yet bounce back. So, it's very similar to the way that we think about psychological resiliency. Neuroprotection is an ability for neurons to be better able to handle stress of different kinds, in particular excitotoxicity. There's a phenomenon in bipolar disorder and a lot of other psychiatric conditions in which hyperactivity of certain brain areas actually starts to kill off neurons. Hyperactivity doesn't always do this, but it turns out that if certain brain circuits are too active for too long, some of the chemicals associated with neuronal activity, things like calcium and neurotransmitters like glutamate, can actually kill the very neurons that are active. So, it seems that lithium can prevent some of that neurotoxicity. Now, this i- turns out to be particularly important for this discussion about bipolar disorder and the neural circuit basis of bipolar disorder, because if we are to just take a step back

Andrew Huberman 1:10:10 and ask, "What's different in the brains of people with bipolar disorder?" There are some very interesting answers that start to emerge. There are basically two main neural circuits that are present in normal individuals, and when I say normal, I say that respectfully to the people with bipolar disorder by referring to people who do not suffer from manic episodes or from manic depression. There are circuits that are present in people with bipolar disorder and in people that d- do not suffer from bipolar disorder. Both of those circuits do the same thing in both sets of individuals, and yet, in people with bipolar disorder, there seems to be an atrophy or a removal of certain neural connections over time that leads to a situation in which people with bipolar disorder become very poor at registering their own internal state, in particular, their emotional states and their somatic states. What we're referring to here is something called interoception. I've talked about this a little bit on the Huberman Lab podcast before, but there are two modes of perception. Perception, of course, is a attention to something that's happening in our environment or to us, on or within our body. Exteroception is literally an attention to things that are happening beyond the confines of our skin, so seeing that person's face over there, or seeing that color of leaf over there, or hearing a sound over to my left. That is exteroception, perception of things beyond the confines of one's skin. Then there's interoception, which is perception of things that are happening internally, like how full does my gut feel, how, um, how fast is my heart beating? Some people can measure that quite accurately just by thinking about it. Other people can't. How happy am I? How sad am I? How energetic am I? How lethargic am I? Et cetera, et cetera. So, we are always existing in a balance between exteroception and interoception, but as it turns out, people with bipolar disorder, over time, and especially into the second and third decade of having bipolar disorder, seem to have progressively diminished levels of interoception. And that very likely is important in their inability to register, for instance, that, wow, they are talking at an excessive rate, or they haven't slept in 5 or even 10 days, or they haven't eaten in a long period of time. This atrophy of neural circuits for interoception is starting to emerge as one of the defining neural circuit characteristics or underpinnings of bipolar. Now, I bridge to this conversation about neural circuits from the statement that lithium can protect against some of the neurotoxic effects of neural circuits being very active. Now, this can get a little bit complicated, but I promise I'm going to make it clear for any of you that are watching and/or listening. The reality is that people with bipolar depression very likely have a hyperactivity that is an increased level of activity in certain circuits within the brain early in the expression of their disease, and that typically, as I mentioned earlier, sets in around the early 20s, although sometimes it- that can be even earlier, in the teens and so forth. But that hyperactivity, we think, leads to a toxicity......an excitotoxicity of certain elements of the neural circuits that are responsible for interoception. In other words, the overuse of certain circuits can lead to a diminishing, an atrophy, or even a death of certain elements within those circuits. And it appears that lithium, through its anti-inflammatory and neuroprotective effects, and through its ability to increase BDNF, very likely protects us against some of that atrophy of those circuits for interoception. So, this isn't a case in which, you know, people with bipolar have a neural circuit or lack of a neural circuit and people without bipolar are the opposite. This is a case in which everyone more or less starts out the same, but it seems that there's a hyperactivity of certain neural circuits in people with bipolar disorder that, over time, actually causes those circuits to diminish. Now, this is very important because some of the more recent longitudinal studies doing brain imaging on people with bipolar disorder and those without, and doing that over time in patients starting as early as their teens but into their 20s and 30s, reveals just that, that there can be hyperactivity of circuits early on, but then hypo, reduced activity of those very same circuits at a time 5 or 10 years later. Again, this speaks to the complicated nature of bipolar disorder and the complicated nature of psychiatry and linking specific psychiatric disorders to neural circuits in general. Because if you have a situation in which, you know, in one disease, let's just, uh, let's just, uh, hypothesize here for a second that, for instance, in certain forms of schizophrenia, there's elevated dopamine, and were we to just reduce the amount of dopamine, that they would receive relief from those schizophrenic symptoms, well, that's all pretty straightforward on the face of it. But in this situation with bipolar disorder, what we're talking about is hyperactivity, too much activity, leading to hypoactivity through death of those very circuits. And so now you can especially appreciate why when the patient shows up to the psychiatrist or when the psychiatrist shows up to the patient in the total course of their disease is going to be very important. And then layer on top of that the complexity of the fact that the very defining characteristic of bipolar disorder is that there are oscillations in mood. So, now we need to think about treatments not just for the manic episodes, but also treatments for the depressive episodes. And that's, in fact, what psychiatrists do. Turns out that they apply different treatments or combinations of treatments for patients that are in manic episodes versus depressive episodes, and they have to infer all that from discussions, again, just exchange of words, depending on when that person walked into their office, where they are in terms of manic episodes, no symptomatology or depressive symptomatology, and whether or not they've had that symptomatology for an extended period of time. And then just to make the situation even more (laughs) complicated, the very circuits that atrophy, that start to wane and disappear in people with bipolar disorder are the circuits for interoception, for understanding of what's going on in one's own body. So, you can imagine where if you sit down and ask somebody, "Well, you know, how long have i- has it been since you've 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 or not someone has bipolar depression or not and what stage of the illness they might be in or not is going to depend on the reports of people around them and not the patient themselves. Hence, the importance of having a rather detailed and admittedly a rather intense discussion about the symptomatology of bipolar disorder so that you can have an understanding of the people around you and have an eye and an ear to whether or not those people might be suffering from bipolar, and if so, at what stage of the disease they might

Andrew Huberman 1:17:11 happen to be at. Now I'd like to talk a little bit more about what is known about the neural circuits that lead to the manic states, as well as the depressive states, but mainly the manic states of bipolar disorder. We already discussed the fact that interoception, registering of one's own internal emotions and bodily states, is diminished in people with bipolar disorder. But we haven't really talked about the neural circuits that are responsible for that lack of recognition. For that reason, I'd like to point out a paper. This is a fairly recent paper, just came out this year, but it's an excellent one looking at the changes over time in neural circuitry in people with high genetic risk for bipolar disorder, and in particular, in young people. And studies of this sort are rare, but are exceedingly important because of the fact that they track individuals over time. The title of this paper is Longitudinal Changes in Structural Connectivity in Young People at High Genetic Risk for Bipolar Disorder. We will provide a link to this study in the show note captions. There are a lot of data in this paper, um, in particular, neuroimaging data, and it's quite extensive in terms of analyzing the so-called connectomics. You've probably heard of genomics, which is the analysis of genes and their, um, display in different individuals or different animals, et cetera. You have proteomics, which is the display of or the existence of different proteins. So, omics is a big thing now in science. You kind of throw omics behind anything and it kind of becomes its own Wikipedia page, which means it becomes its own thing, so to speak. I say that only partially in jest. Nonetheless, connectomics is the analysis of connections between different neurons and neural circuit elements. And what this paper really showed by analyzing the connectomics of neural circuits in the brains of many different people with different categories of and onset of and severity of bipolar disorder, as well as controls in different age groups, et cetera, is that people who are of particularly high risk for having bipolar disorder or that have full-blown bipolar disorder have deficits and actually reductions in the amount of connectivity between what are called the parietal brain regions and the limbic system. Now, the limbic system I've talked about before on this podcast. If you're not familiar with it, I'll explain what it is in a moment.It's simply a collection of brain structures, not one brain structure, but a collection of brain structures that generally are responsible for shifting the overall state that we're in from states of more relaxed and calm to states of more alert and focused. The limbic system is intimately related to the so-called autonomic nervous system, which regulates our sleep-wake cycles and a number of other things like our digestion, et cetera, our level of hunger, and on and on. So the limbic system is really kind of like a volume control, or as nerd scientists like to say, a kind of gain control on the overall level or amplitude of alertness or calmness. In fact, if we're very, very calm, we are asleep, or in even more calm, we can be in a coma. If we are very alert, we can be wide awake, and ready to work and run, et cetera. Or if we are very, very, very alert by way of limbic-autonomic interactions, well, then we can be in anxiety, we can be in full-blown panic attack, or we can be in mania. We can have so much energy that we feel like we don't need to sleep. And in fact, disruptions in this circuitry really seems to be what's going on in people who have bipolar disorder. Now, if disruptions in this circuitry are present in the limbic system, that doesn't necessarily mean that the limbic system is at fault because the way that neural circuits work is that different brain areas are talking to one another through electrical chemical signaling, and they are regulating one another. And what this paper really tells us is that there are elements within the parietal lobe, which is a kind of a section of the brain that sits off to the side. It's not really off to the side, but in neuroanatomical, uh, nomenclature, the parietal lobe is connected in two ways, bidirectionally. So parietal lobe is connecting to limbic system, and limbic system is connecting to parietal lobe. And in people with bipolar disorder, it seems that the parietal lobe is able to exert less top-down control, that is less suppression of certain elements of the limbic system, which, at least right now, is leading researchers to hypothesize that the limbic system is sort of revving at higher levels, it's kind of like RPM in your car, so they're kind of redlining at times and for durations that are inappropriate or at least abnormal. So we have two major sets of neural circuit deficits or changes in people with bipolar. Their lack of internal awareness is reduced, and that turns out to be by way of neural structures like the insula, which is a brain region that is connected in a very direct way to our somatosensory cortex, so the part of our cortex that, uh, registers how we feel, literally, sense of touch and internal state. So those circuits, excuse me, those cir- for those of you listening, I just bumped the microphone. Excuse me. Those circuits are disrupted in people with bipolar and the top-down control, the kind of accelerator and brake on our overall levels of energy are also disrupted. Now, that's all fine and good because, well, it's true, at least according to what the data at this point in time tell us, there may be new discoveries to come, but that all seems to be the case. But it doesn't tell us how to modulate or change that circuitry. It also doesn't tell us how something like lithium can actually benefit a large number of patients or how a good number of the other treatments for bipolar disorder, which we'll talk about going forward, can benefit patients with bipolar.

Andrew Huberman 1:22:58 So it appears that lithium is exerting its positive effects on bipolar depression treatment, at least in part by preventing the loss of certain neural circuits, namely the neural circuits for interoception and the top-down control over the limbic