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Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science based tools for mental health, physical health and performance. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today we are going to be discussing bipolar disorder, often called bipolar depression. Bipolar depression is a condition in which people undergo massive shifts in their energy, their perception and their mood. However, it is very important to note that these shifts in mood, energy and perception are all maladaptive. They can often cause tremendous damage to the person suffering from bipolar disorder and tremendous damage to the people in their lives. In fact, people suffering from bipolar disorder are at 20 to 30 times greater risk of suicide. So today is a serious discussion, and it's certainly one in which people who are suffering from manic bipolar disorder or who know people that are suffering from manic bipolar disorder disorder can benefit from. So bipolar disorder impacts about 1% of people. That might seem like a small percentage, but if you think about a room of 100 people, that means that at least one of them is very likely to have bipolar disorder. The typical age of onset is anywhere from 20 to 25 years old, although it can be much earlier. There are basically two kinds of bipolar disorder, referred to as bipolar 1 and bipolar 2. Bipolar 1 is characterized by a fairly extended period of mania. What is mania? Mania is a period of very elevated mood, energy, distractibility, impulsivity, and some other symptomology that we'll talk about going forward. But this manic episode is extreme. One of the key clinical criteria or diagnostic Criteria for bipolar 1 is that a person suffer from these manic episodes or display these manic episodes for seven days or more. Typically, a person will be brought into a clinic, or a person would bring themselves to a clinic or meet with a psychiatrist. And the psychiatrist is going to start to evaluate for a couple of different things. But first of all, what they're going to try and figure out is whether or not the person has at least three of the following symptoms. The first symptom is distractibility. People who are in a manic episode will be talking about a pen, and then they'll be talking about, you know, something they saw the other day and then something they want to purchase, and then a place they're going to travel to, etc. They, but they are also very prone to any stimulus within the room. So highly distractible, highly impulsive impulsivity relates to actions. So the person might be fidgeting with something and Then they might try and leave the room. The other is grandiosity. People who have manic bipolar disorder who are in a manic episode will often display words of or actions of grandiosity. These are actual beliefs that the person comes to have about their grandiose position in the world or grandiose opportunities or potential in the world. Flight of ideas are also typical of manic episodes. So this is a little bit like distractibility, but this would be people talking extensively about one thing and then switching and talking extensively about something else. The other aspect of manic bipolar disorder that often presents itself in the manic episodes are agitation. People feeling extremely physically agitated. So a lot of shaking and moving about. This can venture into the realm of paranoia. But a lot of agitation, a 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 it. Can only imagine how pulled apart most of us would feel under those conditions. And yet they are just going and going and going with no sleep, up all hours, shopping, talking, running, doing all sorts of different things in the categories of other symptoms that we talked about before. And it doesn't bother them that they're not sleeping. And then the last sort of category of symptoms that the psychiatrist is evaluating for and seeing if they present is rapid pressured speech. It's coming at you, coming at you, coming at you. And there's really no room for conversation. So we've got distractibility, impulsivity, grandiosity, flight of ideas, agitation, no sleep, and rapid pressured speech. For someone to be diagnosed as in a manic episode, they do not have to be engaging in or displaying all of those symptoms. They do, however, need to present at least three of those symptoms. And then in order to meet the condition of bipolar I, they have to be presenting those three symptoms for at least seven days. It could be longer, but at least seven days. Now, bipolar 1 disorder means they're having these extended manic episodes seven days or more, but it does not necessarily mean that they are dropping into a depressive episode as well. This is a common misconception about bipolar disorder because as it's often called, bipolar disorder is referred to as bipolar depression. And yet many people with bipolar disorder don't necessarily experience the deep depressive episodes. The second category of Bipolar disorder is bipolar 2. So BP 2 or bipolar disorder 2 is somewhat different than bipolar disorder 1. First of all, it's characterized most often by the presence of both manic episodes, mania and depressive episodes, or what's referred to as hypomania. 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 BP2 might have four days of this increased energy goal directed activity. They're irritable, they're euphoric, they're not sleeping, et cetera, but it's only lasting for about four days. Or they could be having longer extended periods of mania, but they are hypomanic episodes. They're not quite as intense. So the pressured speech isn't quite as pressured, the impulsivity isn't quite as severe, et cetera, et cetera. The other aspect of bipolar 2 is one that I mentioned briefly a moment ago, which is that it's often associated with the drops into the depressive episodes. One person might go from very high highs that last 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 defining criteria of bipolar disorder, AKA bipolar depression.

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to talk about some of the treatments for bipolar disorder. And in the discussion of those treatments, there's an absolutely incredible history of the discovery of one particular treatment that still shows great success in many patients, although some people can't take it for reasons that we'll talk about. The key player in this story is a physician by the last name Cade. Cade was an Australian psychiatrist who also was a soldier. And during World War II, after the fall of Singapore to Japan, he became a prisoner of war. And he was a prisoner of War from 1942 until 1945. So he had some time for observation. And during his imprisonment, he observed some of his fellow inmates as going through pretty wild vacillations in mood and energy, essentially going from manic episodes to depressed episodes or from manic to normal episodes. And for one reason or another, we don't know why, because I couldn't find any report as to why he hypothesized this, but he hypothesized that There was some 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. Eventually, he got out of this prison, as we mentioned, in 1945, and he started doing experiments in addition to seeing patients in his clinic. And what he did is he started to take urine from people who exhibited mania and urine from people who were not manic. And he took that urine and he would inject it into guinea pigs as an experimental model. And his general observation was that there was something in the urine that was indeed making the guinea pigs more manic. If they were injected with urine from a manic patient, the exact measures that he was taking in these guinea pigs wasn't exactly clear. This is at a time or an era in science when you could just sort of report things a little bit more subjectively. Although there were still numbers and statistics, what Cade figured out was that the urine from manic patients seemed to be more toxic for these guinea pigs. And he also knew that there are two toxic substances in urine, urea and uric acid. So he was able to separate the urea and uric acid from people with mania and patients that did not have mania. And he figured out that the urea was the same in both these mentally ill manic patients and the non manic patients. So instead he focused on the uric acid. Now, in order to put the uric acid into solution so that he could inject it into these guinea pigs, he had to try a number of different compounds in order to dilute it. It just so happens that, and you chemists will be familiar with this, but there's certain things that just don't go into solution easily. You put the powder in a 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 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, right? We're talking about urine from patients that's separating out urea and uric acid. We're adding lithium to the uric acid. We're injecting this into guinea pigs. This is getting pretty wild and pretty weird, but this is medicine. And from time to time, this is medicine and science. Cade was a good scientist in addition to being a good physician. And by good scientists, I mean that he did control experiments.

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Here.

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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 the these guinea pigs. And indeed that was the case when he did the proper control experiment and injected only lithium solution into these guinea pigs. They calmed down from there. He, in sort of 1940s style medicine, this would not happen. Now, he very quickly moved from that animal model into human patients and started injecting human patients with lithium or providing lithium orally to those patients, and lo and behold, found an absolutely profound and positive effect of lithium in reducing symptoms of mania. And as all good physician scientists do, he wrote up his results, and he wrote it up in a paper entitled Lithium Salts and the Treatment of Psychotic Excitement. Okay, Back then, they didn't call it mania, they called it psychotic excitement. This is a paper that was published September 3, 1949 in the Medical Journal of Australia, a classic study in the field of psychiatry. Lithium, I should mention mention, has a number of important features, but also a number of important side effects that need to be considered. First of all, it does have a certain toxicity, and so levels of lithium in the blood need to be monitored extremely carefully. So it's not the sort of thing that people can just take at a given dose, and every patient responds the same. There's a lot of oversight and a lot of blood tests that have to be done, especially in the first three months of lithium treatment. Now, with that said, scientists and clinicians have been quite rigorous in trying to understand why and how lithium works in order to understand the why and how of bipolar disorder. Scientists and physicians understand that just because we have one treatment that works, if it has any side effects at all, there is the possibility for better treatments. And only by understanding how lithium works at the cellular level, at the neural circuit level, et cetera, do we really stand to find those New discoveries. Lithium seems to be able to suppress inflammation, and importantly, it can suppress inflammation in neural tissues and within the brain in particular. The other thing about lithium is that lithium is neuroprotective. Neuroprotection is an ability for neurons to be better able to handle stress of different kinds, in particular, excitotoxicity. There's a phenomenon in bipolar disorder and a lot of other psychiatric conditions in which hyperactivity of certain brain areas and actually starts to kill off neurons. Hyperactivity doesn't always do this, but it turns out that if certain brain circuits are too active for too long, some of the chemicals associated with neuronal activity, things like calcium and neurotransmitters like glutamate, can actually kill the very neurons that are active. So it seems that lithium can prevent some of that neurotoxicity. I've talked about this a little bit on the Huberman Lab podcast before, but there are two modes of perception. Exteroception is literally an attention to things that are happening beyond the confines of our skin. Then there's interoception, which is perception of things that are happening internally. So we are always existing in a balance between exteroception and interoception. But as it turns out, people with bipolar disorder, over time, and especially into the second and third decade of having bipolar disorder, seem to have progressively diminished levels of interoception. And that very likely is important in their inability to register, for instance, that, wow, they are talking at an excessive rate, or they haven't slept in five days, or they haven't eaten in a long period of time. This atrophy of neural circuits for interoception is starting to emerge as one of the defining neural circuit characteristics, or underpinnings, of bipolar. Now, I bridge to this conversation about neural circuits from the statement that lithium can protect against some of the neurotoxic effects of neural circuits being very active. The reality is that people with bipolar depression very likely have a hyperactivity that is an increased level of activity in certain circuits within the brain early in the expression of their disease. And that typically, as I mentioned earlier, sets in around the early 20s, although sometimes that can be even earlier in the teens, and so forth. But that hyperactivity, we think, leads to a toxicity, an excitotoxicity of certain elements of the neural circuits that are responsible for interoception. And it appears that lithium very likely protects us against some of that atrophy of those circuits for interoception.

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Now I would like to also talk about some of the not so typical therapeutics for bipolar disorder and also point to the things that have been tried and failed for successful treatment of bipolar disorder. Because some of those things are often talked about and suggested, especially in online communities. And while it's not clear that any of them are particularly hazardous on their own, although some of them do carry some hazards, I do think it's important because of the critical time sensitive nature of bipolar disorder and the urgency of getting treatments early to try and prevent some of the longer lasting neural circuit changes that if people can avoid some of the less effective or demonstrated to be ineffective treatments, that they stand to combat bipolar disorder much more successfully. First of all, a key point about drug therapies versus non drug therapies or talk therapies. Without question, drug therapies are going to be most effective when done also with talk therapies. And we'll talk about which talk therapies have been demonstrated to be most effective. There is some argument about what I'm about to say next, but in general most psychiatrists will tell you, or certainly the ones I've spoken To have told me that talk therapy on its own is rarely if ever effective for bipolar depression and bipolar disorder, Whether or not it's BP1 or BP2. That's just the reality of it. They're both established and more novel forms of talk therapy being used again in concert with drug treatments for bipolar disorder. Cognitive behavioral therapy is the one that seems to be best, at least by way of the statistics and papers that exist. It's also the one that's been explored the most. So one of the reasons why it's often considered the most popular or effective is because it's also been around longer and it's been explored the most. Cognitive behavioral therapy in general is a progressive exposure of the patient in a very controlled way in a clinical setting to some of the triggers or the conditions that would exacerbate bipolar disorder. And then there's a category of therapy called interpersonal and social rhythm therapy. This is deserving of its own entire episode, really. Interpersonal and social rhythm therapy is sort of an expansion on family focused therapy, Although it's distinct in certain ways as well, and really focuses on how people are relating to others in their life and in the workplace and in the school environment, and also within the family, etc. And I should say that a overall theme that's emerging in psychiatry and psychology is to start wherever possible to incorporate more of the social aspects and the interpersonal aspects. In other words, not just talking to and examining a patient as one biological system, one nervous system, one set of chemicals and one life, but rather a set of chemicals, neural circuits, and a life that's embedded in the chemicals and neural circuits and lives of other people. One very exciting and emerging treatment that does show great promise and in some cases great outcomes for bipolar disorder is, believe it or not, electric shock therapy, generally used for treatment resistant depression. So these are people that have no positive response or ongoing positive response to drug therapies or other therapies. The problem with ECT is that it's really only useful for treatment resistant depression. It doesn't actually target the manic aspects of bipolar depression and bipolar disorder, but nonetheless is used when drug treatments don't work. Some of the negatives of electric shock therapy or electric convulsive therapy, ECT is that is the proper acronym and way it's described, is that it's quite invasive, right? This is something that you need to go to the hospital for, and oftentimes there's some inpatient care required after the electric convulsive therapy. It's a fairly high Cost, especially for those that don't have insurance. And of course it requires anesthesia. For most people, that's not going to be a problem. But for many people that could be a problem. And there's often some associated memory loss. And so the memory loss, the invasive nature of ECT and the cost oftentimes rule out ECT for most patients. And that's why it's sort of a late stage or kind of last resort type thing for treatment resistant depression. There are two naturopathic, or I should say nutrition supplement based approaches to bipolar disorder. They get talked about a lot and one of them shows some interesting promise or effectiveness even in a limited context. Before marching into this description of these two compounds, in fact, before even mentioning these two compounds, I do want to emphasize what's been said and written about over and over again and what was relayed to me from expert psychiatrists. It is not wise to rely purely on talk therapy or on natural approaches to the treatment of bipolar disorder, given the intensity of the disorder and the high propensity for suicide risk in people with bipolar disorder. It is a chemical and neural circuit disruption and it needs to be dealt with head on through the appropriate chemistry and prescription drug approaches. From a board certified psychiatrist. I don't say this to protect me. I say this truly to protect those who either suffer from or think they may suffer from bipolar disorder. If you know someone who you think might suffer from a bipolar disorder. Now all that is not to say that there aren't useful lifestyle interventions that can support people with bipolar disorder. So I just briefly want to mention those. And again, I'm lifting the statements I'm about to make from some excellent online lectures from psychiatrists at Stanford and elsewhere, which essentially say that of course, of course, of course, getting better sleep, getting adequate exercise, getting proper nutrition, having quality healthy social interactions, even getting regular sunlight in the day and avoiding bright light at night, all of those things are going to braid together to support the nervous system and the psyche of somebody with bipolar disorder. But they braid together to support the psyche and the neurochemistry and the neural circuits of anybody and everybody. With that said, there are two substances generally found as supplements, although there are other sources of them as well, including within nutritional sources that have been shown, at least in some studies, to be pretty effective in adjusting the symptoms of bipolar disorder. And those two things are inositol and omega 3 fatty acids. Now, inositol is a compound that is taken for a variety of reasons. It's something we've talked about on the podcast before I personally take Inositol not because I have bipolar disorder. In fact I am quite lucky that I don't have bipolar disorder, but I take inositol at 900 milligrams of myo inositol every third night or so in order to improve my sleep. It also seems to have a fairly potent anti anxiety effect during the day. So the ability for fish oil and in particular the omega 3 fatty acids which come in varieties like EPA and DHA have been explored at relatively high dosages for their ability to offset some of the effects of mania and to offset the effects of depressive episodes in bipolar disorder. There are several studies that have shown that supplementing with fish oil or omega 3 fatty acids at levels of, for instance 9.6 grams of fish oil per day for four months greatly reduced symptoms of bipolar depression compared to the control group which received olive oil. Olive oil is a different form of fat, monounsaturated fat, but doesn't contain as much of the omega 3 fatty acids and so forth. So 9.9.6 grams of fish oil per day over four months is a lot of fish oil to be ingesting on a given day. This was a double blind study. This was only carried out, I should mention, in 30 subjects, but it was males and females and the age range was pretty broad, anywhere from 18 all the way up to 64 years of age. Which is important given the sort of longitudinal or changes over time that one sees in bipolar disorder. Here's the major takeaway. Supplementing with high dose Omega 3s does seem to be beneficial for a good number of people with bipolar disorder.

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However again I want to highlight however,

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it should not be viewed as the only treatment approach for bipolar disorder. But I don't think I can overemphasize enough that especially for bipolar disorder and the great risk of suicide and suffering and you know, inappropriate spending, or I should say maladaptive spending and impulsivity that's associated with bipolar disorder that it's hard to imagine a scenario in which just talk therapy and fish oil and lifestyle interventions are going to completely suppress or treat bipolar disorder. People with bipolar disorder really need to consider the full picture of treatments, the drug treatments, the talk therapy treatments and lifestyle treatments and nutraceutical or we can say supplement based treatments such as omega 3 supplementation as a full and necessary picture for dealing with their illness.

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Before we begin to conclude our discussion about bipolar disorder, I want to talk a little bit about this word disorder. And this is a theme that doesn't just relate to bipolar disorder, but. But other psychiatric disorders as well. And when we think of a disorder, we think of something that is really detrimental to us, something that really impairs our ability to function in work and school and relationships and really starts to pull down our health status in a variety of ways. And certainly bipolar disorder meets those criteria. However, there is this idea that things like bipolar disorder, even things like schizophrenia in some cases, are responsible for some of the creative aspects or the creative works that have been observed and carried out by human beings for many centuries. And believe it or not, there are good data to support the fact that certain aspects of mania are associated with creativity. It's been explored at a research level, really. There are data pointed to the fact that certain individuals of certain occupations tend to be more creative and that creativity is associated with. Again, associated. This isn't causal. It's associated or correlated with higher levels or incidence of bipolar depression and maybe even other forms of depression. So this is a study looking at Mood disorders in eminent individuals. So these are people that are not just good at what they do, but are exceptional at what they do. And explored the percentage of people in given professions with either depression or mania. And this was actually a data set gleaned from more than a thousand 20th century Westerners based on their biographies that were reviewed by other people. So it's a bit of an indirect measurement. This isn't, you know, psychiatrist data, this is data, or I should say these are data that were compiled from self reports or from reads of self reports. And they explored a number of different professions. So for instance, they looked at people in the military or people who were professional athletes or natural scientists or social scientists, people who occupied positions in public office or were musical performers, artists, nonfiction writers, poetry, etc. Turns out that if you were to look at the profession, those in the military and those who are professional athletes or had jobs in the social or natural sciences had the. Of those, there was a lower percentage of those that had depression or mania. In some cases, like those who are professional athletes, didn't seem to have. There was no incidence of mania, at least in this data set. Whereas at the opposite extreme of the graph, those that were poets, so these are eminent individuals, people that were exceptional poets, exceptional fiction writers, exceptional artists, or nonfiction writers. Well, there, especially for the poets, you find that as many as 90% of these very successful poets had either depression or mania. Again, associative correlative, no causal relationship here. But it is really striking to see how the creative occupations, poetry, fiction, art, nonfiction writing, even though nonfiction writing is about nonfiction, it's still creative. And music composition, theater, much higher incidence of things like mania. And in fact, for the people in theater, the actors, even though the overall occurrence of depression and mania is lower than that in poets, the fraction of those individuals that have mania is exceedingly high. It's about 30% of those that they looked at who are actors, have manic episodes or have full blown mania. So I'm referring to these data because first of all, I find them incredibly interesting. Right up until now, we've been talking about bipolar disorder and other mood disorders for their maladaptive effects. And again, they're extremely maladaptive, Much, much higher incidence of suicide, et cetera. But we'd be wrong to say that certain aspects of manic episodes don't lend themselves well to creativity or that certain aspects of major depression don't lend themselves well to, to creativity or to the performing arts or to poetry. So today we've really done a deep dive into bipolar disorder and to both the manic and the depressive components that are present or can be present in bipolar disorder and the different forms of bipolar disorder and some of the major treatments for bipolar disorder, in particular lithium and its underlying mechanisms. I do hope you found it beneficial, both for yourself and for others. I just want to remind people that bipolar disorder is an extremely serious condition. If you suspect that you have bipolar disorder or you know somebody who does, please make sure that you or they talk to a qualified health professional. So once again, thank you for joining me today for our discussion about the biology and treatment of bipolar disorder. And last, but certainly not least, thank you for your interest in science.