Andrew Huberman explains the biology, diagnosis, and treatment of Bipolar Disorder
A solo educational episode from the Huberman Lab Essentials series covering bipolar disorder's symptoms, neuroscience, and treatment landscape.
Summary
Andrew Huberman, neuroscientist and professor at Stanford School of Medicine, presents a comprehensive overview of bipolar disorder — its diagnostic criteria, neurological underpinnings, and treatment options. He distinguishes between Bipolar 1 and Bipolar 2, detailing the specific symptom clusters psychiatrists use to diagnose each. A central section traces the remarkable historical discovery of lithium as a treatment, crediting Australian psychiatrist John Cade, whose prisoner-of-war observations and subsequent guinea pig experiments led to a landmark 1949 paper. Huberman explains lithium's mechanisms — including neuroprotection and anti-inflammatory effects — and discusses why the progressive atrophy of interoceptive neural circuits may be a defining feature of the disorder over time. He also covers the evidence base for talk therapies, electroconvulsive therapy, and supplements such as omega-3 fatty acids and inositol, while firmly stating that drug treatment from a board-certified psychiatrist is essential and that lifestyle or supplement approaches alone are insufficient given the disorder's severity and the 20–30 times elevated suicide risk.
Key Takeaways
FULL TRANSCRIPT
Introduction to Bipolar Disorder
Andrew Huberman: Today we are going to be discussing bipolar disorder, often called bipolar depression. Bipolar depression is a condition in which people undergo massive shifts in their energy, their perception, and their mood. However, it is very important to note that these shifts in mood, energy, and perception are all maladaptive. They can often cause tremendous damage to the person suffering from bipolar disorder and tremendous damage to the people in their lives. In fact, people suffering from bipolar disorder are at 20 to 30 times greater risk of suicide. So today is a serious discussion, and it's certainly one in which people who are suffering from manic bipolar disorder, or who know people that are suffering from manic bipolar disorder, can benefit from.
Prevalence, Age of Onset, and Diagnostic Overview
Andrew Huberman: Bipolar disorder impacts about 1% of people. That might seem like a small percentage, but if you think about a room of 100 people, that means that at least one of them is very likely to have bipolar disorder. The typical age of onset is anywhere from 20 to 25 years old, although it can be much earlier.
There are basically two kinds of bipolar disorder, referred to as Bipolar 1 and Bipolar 2. Bipolar 1 is characterized by a fairly extended period of mania. What is mania? Mania is a period of very elevated mood, energy, distractibility, impulsivity, and some other symptomatology that we'll talk about going forward. This manic episode is extreme. One of the key clinical criteria — or diagnostic criteria — for Bipolar 1 is that a person suffer from or display these manic episodes for 7 days or more.
Typically, a person will be brought into a clinic, or a person would bring themselves to a clinic, or meet with a psychiatrist. 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 something they saw the other day, and then something they want to purchase, and then a place they're going to travel to. They are also very prone to any stimulus within the room — highly distractible, highly impulsive.
Impulsivity relates to actions. 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 and who are in a manic episode will often display words 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. 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 manic episodes is agitation — people feeling extremely physically agitated, a lot of shaking and moving about. This can venture into the realm of paranoia, but there is 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. When I say no sleep, I mean no sleep or very minimal sleep. As incredible as it sounds, people who are in a manic episode can often go 7 days or more with zero sleep. A key feature of this is that they're not troubled by it. You 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 — and it doesn't bother them that they're not sleeping.
And then the last category of symptoms that the psychiatrist is evaluating for 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 being in a manic episode, they do not have to be displaying all of those symptoms. They do, however, need to present at least three of them, and then, in order to meet the condition of Bipolar 1, they have to be presenting those three symptoms for at least 7 days. It could be longer, but at least 7 days.
Bipolar 1 vs. Bipolar 2
Andrew Huberman: Now, Bipolar 1 disorder means the person is having these extended manic episodes — 7 days or more — but it does not necessarily mean that they are dropping into a depressive episode as well. This is a common misconception about bipolar disorder, because, as it's often called, bipolar disorder is referred to as bipolar depression, and yet many people with bipolar disorder don't necessarily experience the deep depressive episodes.
The second category of bipolar disorder is Bipolar 2. BP2 is somewhat different from Bipolar 1. First of all, it's characterized most often by the presence of both manic episodes and depressive episodes, or what's referred to as hypomania. Bipolar 2 is often diagnosed on the basis of manic episodes lasting 4 days or even less. Someone with BP2 might have 4 days of increased energy, goal-directed activity — they're irritable, they're euphoric, they're not sleeping — but it's only lasting for about 4 days. Or they could be having longer extended periods of mania, but they are hypomanic episodes — not quite as intense. The pressured speech isn't quite as pressured, the impulsivity isn't quite as severe, and so forth.
The other aspect of Bipolar 2 is that it's often associated with drops into depressive episodes. One person might go from very high highs that last 7 days or more to very low lows — bouts of major depression that can last 2 weeks or more. Other people are rapid cycling: 3 days manic, 3 days normal, 3 days manic, and then dropping into 3 days of depression.
So you want to erase that picture in your mind that manic bipolar disorder is a sine wave, a cycling up and down between mania and depression. It can take a lot of different forms. This is a serious challenge for the psychiatrist to diagnose, because they're only getting a snapshot of the person unless they've known them for some time. But this is also especially important for those of you who either have bipolar disorder or suspect that you might, or who know someone with bipolar disorder or suspect someone might have it. If you're noticing that somebody is very manic and then normal, that's a very different picture than somebody 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.
This might seem somewhat obvious as I describe it, and yet it's very important — frankly, as a citizen of the planet who knows other human beings — to keep an eye out for these manic episodes, because whether it's 4 days or less or 7 days or more, these manic episodes really are the defining criteria of bipolar disorder.
The Discovery of Lithium: John Cade's Story
Andrew Huberman: I'd like to talk about some of the treatments for bipolar disorder. In the discussion of those treatments, there's an absolutely incredible history of discovery of one particular treatment that still shows great success in many patients, although some people can't take it for reasons that we'll talk about.
The key player in this story is a physician by the last name of Cade. Cade was an Australian psychiatrist who also was a soldier. During World War II, after the fall of Singapore to Japan, he became a prisoner of war — from 1942 until 1945. So he had some time for observation. During his imprisonment, he observed some of his fellow inmates going through pretty wild vacillations in mood and energy, essentially going from manic episodes to depressed episodes, or from manic to normal episodes.
For one reason or another — and we don't know why, because I couldn't find any report as to why — he hypothesized that there was some build-up of some chemical in these people's brains that they would then 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 prison in 1945 and started doing experiments in addition to seeing patients in his clinic. What he did was take urine from people who exhibited mania and urine from people who were not manic, and inject it into guinea pigs as an experimental model. His general observation was that there was something in the urine that was indeed making the guinea pigs more manic when they were injected with urine from a manic patient. The exact measures he was taking in these guinea pigs weren't entirely clear — this was an era in science when you could report things a little 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. He also knew that there are two toxic substances in urine: urea and uric acid. He was able to separate the urea and uric acid from people with mania and from patients without mania, and he figured out that the urea was the same in both groups. 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 to dilute it. Certain things just don't go into solution easily — you put the powder in a vial, add some water or saline or another solution, mix it up, and the powder stays suspended. It just doesn't actually 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. Lithium worked. What he was doing, for those of you with a chemistry background, was taking uric acid, adding lithium, and making a solution of lithium urate.
This is a lot of details, but it's important, because what he eventually found was that when he diluted the uric acid with lithium and created lithium urate, lithium urate could actually calm down the guinea pigs that had been injected with the toxic urea. He also found that lithium urate had a generally calming effect on these guinea pigs.
Now we're really off in unusual territory — we're talking about urine from patients, separating out urea and uric acid, adding lithium to the uric acid, and injecting this into guinea pigs. This is getting pretty wild and pretty weird. But from time to time, this is medicine and science.
Cade was a good scientist in addition to being a good physician. 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 the solution of lithium urate contained not just the uric acid but also 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, in sort of 1940s-style medicine — and this would not happen now — he very quickly moved from that animal model into human patients and started providing lithium orally to those patients. And lo and behold, he found an absolutely profound and positive effect of lithium in reducing symptoms of mania.
As all good physician-scientists do, he wrote up his results in a paper entitled "Lithium Salts in the Treatment of Psychotic Excitement." Back then they didn't call it mania; they called it psychotic excitement. This paper was published September 3rd, 1949, in the Medical Journal of Australia — a classic study in the field of psychiatry.
How Lithium Works: Mechanisms and Side Effects
Andrew Huberman: Lithium 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. It's not the sort of thing where people can just take a given dose and every patient responds the same. There's a lot of oversight and a lot of blood tests that have to be done, especially in the first 3 months of lithium treatment.
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. They 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, 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 it is neuroprotective. Neuroprotection is the ability for neurons to better 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. Lithium can prevent some of that neurotoxicity.
Interoception and the Neural Circuits of Bipolar Disorder
Andrew Huberman: 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. We are always existing in a balance between exteroception and interoception.
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. That very likely is important in their inability to register, for instance, that they are talking at an excessive rate, or that they haven't slept in 5 days, or that 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 disorder.
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. People with bipolar depression very likely have a hyperactivity — an increased level of activity in certain circuits within the brain — early in the expression of their disease. That typically sets in around the early 20s, although sometimes it can be even earlier, in the teens. 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 against some of that atrophy of those circuits for interoception.
Talk Therapies: What Works and What Doesn't
Andrew Huberman: I would like to talk about some of the not-so-typical therapeutics for bipolar disorder, and also point to the things that have been tried and failed, because some of those things are often talked about and suggested — especially in online communities. While it's not clear that any of them are particularly hazardous on their own, although some 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, they stand to combat bipolar disorder much more successfully.
First, 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 — and 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 it's BP1 or BP2. That's just the reality of it.
There are both established and more novel forms of talk therapy being used 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 it's often considered the most popular or effective is because it's also been around longer.
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 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 — in the workplace, in the school environment, and within the family. An overall theme that's emerging in psychiatry and psychology is to start, wherever possible, to incorporate more of the social and interpersonal aspects — in other words, not just examining a patient as one biological system, one nervous system, one set of chemicals, and one life, but rather as a set of chemicals, neural circuits, and a life that's embedded in the chemicals and neural circuits and lives of other people.
Electroconvulsive Therapy
Andrew Huberman: 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, this applies to people who have no positive response or ongoing positive response to drug therapies or other therapies.
The problem with ECT — electroconvulsive therapy — is that it's really only useful for treatment-resistant depression. It doesn't actually target the manic aspects of bipolar disorder, but nonetheless is used when drug treatments don't work.
Some of the negatives of electroconvulsive therapy are that it's quite invasive. This is something that you need to go to the hospital for, and often there's some inpatient care required afterward. It's a fairly high cost, especially for those who don't have insurance. It requires anesthesia, which for most people won't be a problem, but for many people it could be. And there's often some associated memory loss. The memory loss, the invasive nature of ECT, and the cost often rule it out for most patients, which is why it's a late-stage or last-resort type of option for treatment-resistant depression.
Supplements: Omega-3 Fatty Acids and Inositol
Andrew Huberman: There are two naturopathic — or I should say, nutrition supplement-based — approaches to bipolar disorder that get talked about a lot, and one of them shows some interesting promise or effectiveness even in a limited context.
Before 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.
Now, all of that is not to say that there aren't useful lifestyle interventions that can support people with bipolar disorder. Getting better sleep, getting adequate exercise, getting proper nutrition, having quality healthy social interactions, 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, including nutritional sources — that have been shown, at least in some studies, to be pretty effective in adjusting the symptoms of bipolar disorder. Those two things are inositol and omega-3 fatty acids.
Inositol is a compound taken for a variety of reasons. I personally take inositol — not because I have bipolar disorder, but at 900 mg of myo-inositol every third night or so in order to improve my sleep. It also seems to have a fairly potent anti-anxiety effect during the day.
The ability of fish oil, and in particular the omega-3 fatty acids — which come in varieties like EPA and DHA — to offset some of the effects of mania and depressive episodes in bipolar disorder has been explored at relatively high dosages. There are several studies that have shown that supplementing with fish oil or omega-3 fatty acids at levels of, for instance, 9.6 g of fish oil per day for 4 months greatly reduced symptoms of bipolar depression compared to the control group, which received olive oil. Olive oil is a different form of fat — monounsaturated fat — and doesn't contain as much of the omega-3 fatty acids. So 9.6 g of fish oil per day over 4 months is a lot of fish oil to be ingesting on a given day.
This was a double-blind study. It was only carried out in 30 subjects, I should mention, but it included 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 longitudinal changes one sees in bipolar disorder over time.
Here's the major takeaway: supplementing with high-dose omega-3s does seem to be beneficial for a good number of people with bipolar disorder. However, it should not be viewed as the only treatment approach. I don't think I can overemphasize enough that, especially given the great risk of suicide and suffering and maladaptive spending and impulsivity associated with bipolar disorder, 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 and supplement-based treatments such as omega-3 supplementation — as a full and necessary picture for dealing with their illness.
Bipolar Disorder and Creativity
Andrew Huberman: Before we conclude our discussion about bipolar disorder, I want to talk a little bit about this word "disorder." This is a theme that doesn't just relate to bipolar disorder, but to other psychiatric disorders as well. When we think of a disorder, we think of something that is really detrimental to us, something that really impairs our ability to function in work, in school, in relationships, and really starts to pull down our health status in a variety of ways. 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.
There are data pointing to the fact that certain individuals in certain occupations tend to be more creative, and that creativity is associated — again, associated, not causal — with higher levels or incidence of bipolar depression and maybe even other forms of depression.
There is a study looking at mood disorders in eminent individuals — people who are not just good at what they do, but exceptional at what they do — exploring the percentage of people in given professions with either depression or mania. This was a dataset gleaned from more than a thousand 20th-century Westerners, based on their biographies reviewed by other people. So it's a bit of an indirect measurement — not psychiatrist data, but data compiled from self-reports or reads of self-reports.
They explored a number of different professions: people in the military, professional athletes, natural scientists, social scientists, people who occupied positions in public office, musical performers, artists, non-fiction writers, poets, and so on.
It turns out that those in the military and those who were professional athletes, or who had jobs in the social or natural sciences, had a lower percentage of individuals with depression or mania. In some cases, like professional athletes, there was no incidence of mania at all, at least in this dataset.
Whereas at the opposite extreme of the graph, those who were poets — exceptional, eminent poets — exceptional fiction writers, exceptional artists, or non-fiction writers showed that as many as 90% of these very successful poets had either depression or mania. Again, this is associative and correlative — no causal relationship. But it is really striking to see how the creative occupations — poetry, fiction, art, non-fiction writing, music composition, theater — show a much higher incidence of things like mania.
In fact, for 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 who have mania is exceedingly high. About 30% of the actors they looked at have manic episodes or full-blown mania.
I'm referring to these data because I find them incredibly interesting. Up until now, we've been talking about bipolar disorder and other mood disorders for their maladaptive effects — and again, they are extremely maladaptive, with a 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 creativity, or to the performing arts, or to poetry.
Conclusion
Andrew Huberman: Today we've really done a deep dive into bipolar disorder — into both the manic and the depressive components that are present or can be present in bipolar disorder, the different forms of bipolar disorder, and some of the major treatments, 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. Thank you for your interest in science.