The Science & Treatment of Bipolar Disorder

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.260 | where we discuss science and science-based tools

00:00:04.900 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.220 | and I'm a professor of neurobiology and ophthalmology

00:00:13.060 | at Stanford School of Medicine.

00:00:14.980 | Today, we are going to be discussing bipolar disorder,

00:00:17.600 | often called bipolar depression.

00:00:20.140 | Bipolar depression is a condition

00:00:22.420 | in which people undergo massive shifts in their energy,

00:00:26.140 | their perception, and their mood.

00:00:28.340 | However, it is very important to note

00:00:29.920 | that the shifts in mood, energy, and perception

00:00:32.600 | are all maladaptive.

00:00:34.340 | They can often cause tremendous damage

00:00:36.200 | to the person suffering from bipolar disorder

00:00:39.020 | and tremendous damage to the people in their lives.

00:00:42.280 | Today, we're going to parse the biology

00:00:44.620 | that leads to the shifts in mood, energy, and perception,

00:00:48.180 | and we are going to talk about

00:00:49.740 | the various treatments that exist.

00:00:51.560 | Some of those treatments have been around

00:00:52.820 | for a very long time, and indeed, one of those treatments,

00:00:55.760 | lithium, has an incredible backstory about its discovery,

00:01:00.380 | and in understanding how lithium works

00:01:02.960 | and some of the ways in which it does not work well,

00:01:05.820 | it reveals a tremendous amount

00:01:07.300 | about how the brain works normally in all individuals.

00:01:10.500 | So that's a miraculous story

00:01:11.860 | that I look forward to sharing with you.

00:01:13.900 | As we go forward in this discussion about bipolar disorder,

00:01:16.980 | I want everyone to keep in mind

00:01:18.060 | that it is a very severe condition.

00:01:20.380 | In fact, people suffering from bipolar disorder

00:01:22.760 | are at 20 to 30 times greater risk of suicide.

00:01:26.680 | So today is a serious discussion,

00:01:28.860 | and it's certainly one in which people

00:01:30.720 | who are suffering from manic bipolar disorder

00:01:32.780 | or who know people that are suffering

00:01:34.180 | from manic bipolar disorder can benefit from.

00:01:37.180 | However, for those of you that might know people

00:01:39.580 | or who themselves suffer from major depression,

00:01:43.020 | we will also be talking about important treatment

00:01:45.020 | developments for major depression.

00:01:46.860 | Major depression is a very common thing for many people.

00:01:50.360 | In fact, most people will suffer from depression

00:01:53.180 | of some sort at some point in their life,

00:01:55.580 | although not necessarily a major depressive episode,

00:01:58.140 | and yet major depression is very common.

00:02:00.980 | So you'll soon learn up to 20% of people

00:02:02.860 | will suffer from major depression.

00:02:04.940 | So today's discussion will encompass all of that,

00:02:07.180 | and it will also encompass basic brain mechanisms

00:02:10.220 | of neuroplasticity, the brain's ability to change

00:02:12.740 | in response to experience both for good and for worse,

00:02:16.300 | and you'll learn a lot about the basic biology

00:02:19.500 | of how the brain regulates mood, energy, and perception.

00:02:23.280 | I'm pleased to announce that the Huberman Lab Podcast

00:02:25.140 | is now partnered with Momentous Supplements.

00:02:27.480 | We often talk about supplements on the Huberman Lab Podcast,

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00:02:34.300 | for things like enhancing the quality and speed

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00:02:41.660 | The reason we partnered with Momentous Supplements

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00:03:42.780 | Before we dive into the discussion

00:03:44.100 | about manic bipolar disorder,

00:03:45.260 | I want to highlight some recent findings

00:03:46.900 | in an area totally separate from mental health

00:03:49.780 | that I think are really important for everyone to know about.

00:03:52.180 | This is a paper published in the journal Cell,

00:03:54.180 | which is a Cell Press journal, an excellent journal.

00:03:56.260 | In fact, one of the three apex journals.

00:03:58.100 | So for those of you that are curious,

00:03:59.660 | papers published in the journal Nature, Science, and Cell

00:04:02.780 | are considered the sort of Super Bowl, Stanley Cup,

00:04:06.260 | and NBA championships of publishing.

00:04:08.400 | And this paper entitled

00:04:10.500 | An Interorgan Neural Circuit for Appetite Suppression

00:04:13.580 | illustrates a very important principle

00:04:15.360 | that I think everyone should know about.

00:04:16.940 | And that's the principle of so-called parallel pathways.

00:04:20.420 | Parallel pathways, as the name suggests, are pathways.

00:04:23.500 | They could be neural pathways or hormonal pathways

00:04:26.880 | or otherwise that operate independently of one another

00:04:30.400 | to accomplish a common goal.

00:04:33.000 | And what this paper really shows

00:04:34.740 | is that there's a set of peptides in the body.

00:04:38.620 | And the peptide that I'm referring to today

00:04:40.660 | is called GLP-1, glucagon-like peptide one,

00:04:44.380 | and some related peptides.

00:04:45.700 | I've talked about these on the podcast before

00:04:47.940 | for two reasons.

00:04:48.780 | First of all, I'm a big proponent and consumer of Yerba Mate.

00:04:53.780 | Yerba Mate is a tea that can promote the release

00:04:56.620 | of glucagon-like peptide one.

00:04:58.960 | And there are also new prescription drugs

00:05:01.620 | that are now hitting the market

00:05:02.940 | and for which there are really impressive clinical trials

00:05:05.040 | for diabetes and obesity

00:05:06.940 | that are essentially glucagon-like peptide one stimulator.

00:05:11.180 | So they stimulate the release of that,

00:05:12.440 | or they are in fact a synthetic version

00:05:15.260 | of glucagon-like peptide one.

00:05:16.900 | What is glucagon-like peptide one?

00:05:19.100 | It is a peptide, which is a small little protein

00:05:21.940 | that can dramatically suppress appetite.

00:05:25.120 | So that's why these drugs are being explored

00:05:27.460 | and are showing quite impressive results

00:05:30.300 | for things like treatment of type two diabetes

00:05:33.200 | and other forms of diabetes, as well as obesity.

00:05:36.480 | So they lead to weight loss.

00:05:38.020 | Now, in terms of the Yerba Mate stimulation

00:05:39.960 | of glucagon-like peptide one,

00:05:41.260 | that's going to be a much lower amount of glucagon-like

00:05:43.880 | peptide one that's released from drinking Yerba Mate

00:05:46.640 | as opposed to say, taking a drug that stimulates GLP-1

00:05:50.120 | or taking a drug that is GLP-1.

00:05:52.520 | Nonetheless, I should also point out

00:05:55.280 | that Yerba Mate comes in a bunch of different forms.

00:05:58.600 | There is some concern about certain smoky flavored forms

00:06:03.040 | of Yerba Mate being carcinogenic.

00:06:05.280 | So that's why I avoid those forms of Yerba Mate.

00:06:07.800 | But for me, Yerba Mate is one of the preferred sources

00:06:10.160 | of caffeine for me.

00:06:11.280 | I like the way it tastes.

00:06:12.480 | It does provide that sort of caffeine kick

00:06:14.420 | that I like to have early in the day

00:06:15.660 | for focus and for work and for exercise.

00:06:18.200 | And yet I actively avoid the smoked varieties

00:06:20.920 | of Yerba Mate because of the potential carcinogenic effects

00:06:24.040 | of the smoked varieties.

00:06:26.280 | Glucagon-like peptide one, as I mentioned earlier,

00:06:29.000 | can suppress appetite.

00:06:30.740 | But what this paper shows is it does that

00:06:33.920 | by at least two mechanisms through parallel pathways.

00:06:37.680 | What this paper shows is that glucagon-like peptide one

00:06:41.320 | acts on receptors in the body

00:06:43.160 | in a portion of the nervous system

00:06:44.600 | called the enteric nervous system, E-N-T-E-R-I-C,

00:06:48.200 | enteric nervous system.

00:06:49.960 | This is a component of your nervous system

00:06:51.240 | that you don't really have control over.

00:06:52.820 | It's autonomic or automatic.

00:06:55.220 | GLP-1 binds to what are called

00:06:57.240 | intestinal fugal enteric neurons.

00:06:59.820 | You don't need to know the name,

00:07:01.000 | but those neurons do two things.

00:07:02.700 | First of all, they cause some gut distension.

00:07:06.220 | So they actually make you feel full.

00:07:08.380 | This is incredible, right?

00:07:09.480 | A peptide, not actual physical food,

00:07:11.860 | but a peptide that stimulates neurons

00:07:15.240 | that cause changes in the so-called mechanoreceptors

00:07:18.380 | of the gut of the enteric nervous system

00:07:20.860 | and make people feel full.

00:07:22.580 | So it can lead to actually mild,

00:07:24.540 | or I suppose if levels of GLP-1 are very high,

00:07:27.100 | to major gut distension, okay?

00:07:29.380 | I think that the levels of GLP-1

00:07:30.980 | that would come from drinking Yerba Mate

00:07:32.420 | and hopefully from appropriate dosaging

00:07:34.460 | of the synthetic forms of GLP-1

00:07:37.580 | or drugs that stimulate GLP-1 would cause mild,

00:07:40.060 | not major gut distension

00:07:41.220 | 'cause major gut distension would be uncomfortable.

00:07:43.680 | So GLP-1 is acting at the level of gut

00:07:46.060 | to increase gut distension

00:07:48.380 | and by way of a pathway that goes from the gut

00:07:51.660 | up to the hypothalamus, this little cluster of neurons

00:07:54.180 | about the size of a marble

00:07:55.460 | that sits above the roof of your mouth

00:07:57.060 | is also suppressing appetite through brain mechanisms.

00:08:00.580 | So this is really beautiful, right?

00:08:01.980 | You have a peptide, a small little protein

00:08:04.140 | that's released in the gut

00:08:06.060 | and that release within the gut causes gut distension,

00:08:10.520 | which makes you feel full

00:08:11.700 | and by way of neural stimulation of the hypothalamus

00:08:14.780 | also activates neural pathways within the brain

00:08:17.320 | that trigger satiety, the feeling of having had enough food.

00:08:20.660 | So to me, GLP-1 is both impressive and important, why?

00:08:24.420 | Because this recent category of drugs

00:08:26.760 | that's now hitting the market seems to adjust obesity

00:08:30.680 | or can help people with weight loss

00:08:32.060 | in order to help their health

00:08:33.780 | and it's doing so by at least two mechanisms.

00:08:36.400 | One is within the brain

00:08:37.460 | and the other is within the gut

00:08:39.460 | and communication through the so-called gut brain access

00:08:42.620 | because again, these enteric neurons

00:08:44.400 | are communicating to the brain, the hypothalamus

00:08:47.380 | by way of this what's called

00:08:48.820 | the sympathogastrospinal reticular hypothalamic pathway.

00:08:52.580 | You absolutely do not need to know all of that.

00:08:54.700 | That's a mouthful.

00:08:55.520 | That's enough to make your mouth feel distended

00:08:57.500 | but at the same time, things like yerba mate

00:09:00.460 | and I'm sure there are other compounds out there as well

00:09:02.320 | but certainly yerba mate can stimulate the release of GLP-1.

00:09:05.380 | So for those of you that are looking

00:09:06.500 | for some mild appetite suppression

00:09:08.380 | and want to accomplish that while also ingesting caffeine,

00:09:11.420 | yerba mate might be a good option for that

00:09:13.380 | and just know that it's operating through two mechanisms

00:09:16.220 | on the body, through mild gut distension

00:09:18.040 | to make you feel full and on the brain

00:09:19.500 | to increase satiety or make you feel less hungry

00:09:22.260 | and then for everybody, not just those

00:09:24.380 | that are interested in appetite suppression,

00:09:26.420 | I think it's important to understand

00:09:28.440 | that these parallel pathways are fundamental

00:09:30.660 | to how we are organized.

00:09:32.140 | Another good example of this would be

00:09:33.500 | when we are excited by something, positive or negative,

00:09:36.000 | so it could be stressful or we're positively aroused,

00:09:38.520 | there is a parallel activation of epinephrine, adrenaline,

00:09:41.840 | both from your adrenals and from an area in the brain

00:09:44.040 | called the locus coeruleus.

00:09:45.480 | So again and again, we see this in biology

00:09:47.780 | and in neuroscience, that your brain and your body

00:09:50.340 | are acting in concert, they're acting together

00:09:53.240 | through mechanisms that either are independent,

00:09:55.860 | so separately in the brain and separately in the body

00:09:58.140 | but directed towards a common goal

00:10:00.640 | or through communication between brain and body

00:10:03.140 | and almost always that communication

00:10:05.300 | is going to be bi-directional, body to brain

00:10:07.420 | and brain to body.

00:10:08.580 | So I think these results are really interesting

00:10:10.420 | and really important for sake of weight loss,

00:10:12.420 | for sake of appetite suppression

00:10:14.340 | and just generally for the way that they illustrate

00:10:16.780 | this very important theme of the way

00:10:19.220 | that we are constructed at a biological level

00:10:21.260 | which is parallel pathways.

00:10:23.200 | Before we begin, I'd like to emphasize that this podcast

00:10:25.820 | is separate from my teaching and research roles at Stanford.

00:10:28.520 | It is however, part of my desire and effort

00:10:30.620 | to bring zero cost to consumer information about science

00:10:33.180 | and science related tools to the general public.

00:10:35.780 | In keeping with that theme,

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00:14:23.380 | Let's talk about bipolar disorder.

00:14:25.100 | And today I'm going to refer to bipolar disorder

00:14:27.180 | interchangeably with bipolar depression.

00:14:30.340 | Although, as you will soon learn,

00:14:32.340 | not everyone with bipolar disorder

00:14:34.340 | necessarily goes through highs and lows.

00:14:37.540 | There is a subset of people who suffer from bipolar disorder

00:14:40.900 | who experienced the manic phases,

00:14:42.820 | the highly elevated mood and energy,

00:14:45.940 | and then drop down to so-called baseline.

00:14:48.620 | So they don't necessarily go down into a depressive state.

00:14:51.760 | They often will return to a somewhat normal state.

00:14:54.420 | In fact, we will talk about the percentage of time

00:14:57.640 | that people with bipolar disorder

00:14:59.340 | tend to be symptom-free, manic, or depressed

00:15:02.820 | in the context of the different categories

00:15:04.440 | of bipolar disorder.

00:15:05.700 | But as we wade into this topic, that is bipolar disorder,

00:15:09.140 | I just want to give you a little bit

00:15:10.040 | of the background statistics

00:15:11.860 | to anchor us in just how serious

00:15:14.040 | and prevalent bipolar disorder is.

00:15:16.860 | So bipolar disorder impacts about 1% of people.

00:15:20.260 | That might seem like a small percentage.

00:15:22.580 | If you think about a room of a hundred people,

00:15:25.240 | that means that at least one of them

00:15:27.100 | is very likely to have bipolar disorder.

00:15:30.700 | And as I mentioned earlier in the introduction,

00:15:32.900 | bipolar disorder is very serious.

00:15:35.260 | It has a 20 to 30% greater incidence of suicide

00:15:39.720 | than the general population,

00:15:41.420 | which is, first of all, extremely tragic

00:15:43.740 | and extremely concerning.

00:15:45.540 | So anyone that thinks they might have bipolar disorder

00:15:48.540 | or who knows someone with bipolar disorder

00:15:50.260 | should be especially vigilant about this.

00:15:52.100 | And we'll talk about some of the signs and risk factors,

00:15:55.840 | age of onset, et cetera, as we move forward.

00:15:58.740 | So 1% of people have bipolar disorder.

00:16:01.100 | The typical age of onset is anywhere from 20 to 25 years old

00:16:05.180 | although it can be much earlier.

00:16:07.580 | And the earlier the onset of a bipolar episode,

00:16:11.420 | which we will define in a few minutes,

00:16:13.140 | the earlier the onset of that episode,

00:16:15.640 | the higher likelihood that the bipolar disorder

00:16:18.460 | is going to be a stable feature

00:16:20.260 | of that person's psychology going forward.

00:16:22.960 | And yet I also want to point out

00:16:24.740 | that there are some very good treatments

00:16:27.140 | for bipolar disorder

00:16:28.040 | that those people could still benefit from.

00:16:30.660 | There are basically two kinds of bipolar disorder

00:16:33.940 | referred to as bipolar one and bipolar two.

00:16:36.980 | So let's just talk about bipolar one first.

00:16:39.740 | Bipolar one is characterized

00:16:41.840 | by a fairly extended period of mania.

00:16:45.080 | What is mania?

00:16:46.220 | Mania is a period of very elevated mood, energy,

00:16:50.220 | distractibility, impulsivity, and some other symptomology

00:16:53.540 | that we'll talk about going forward.

00:16:55.600 | But this manic episode is extreme.

00:16:59.640 | This is a condition in which the energy lift, the mood lift,

00:17:04.820 | and the sort of impulsivity and actions and words

00:17:07.860 | of the person suffering from manic bipolar disorder

00:17:10.660 | are very noticeable and very extreme.

00:17:13.820 | Now, a key thing, however,

00:17:15.140 | is that it's not always noticeable

00:17:16.960 | to the person suffering from it that they are in this mode.

00:17:20.440 | Sometimes they recognize that, sometimes they don't,

00:17:22.740 | but it's always highly recognizable to other people

00:17:25.940 | that the person suffering from manic bipolar disorder

00:17:29.220 | is not like other people.

00:17:30.940 | So let's talk about bipolar one in a little bit more depth.

00:17:34.480 | One of the key clinical criteria

00:17:36.700 | or diagnostic criteria for bipolar one

00:17:39.100 | is that a person suffer from these manic episodes

00:17:42.640 | or display these manic episodes for seven days or more.

00:17:46.600 | That turns out to be very key.

00:17:47.700 | The stability of that manic episode for seven days or more

00:17:51.760 | turns out to be very important.

00:17:53.880 | And for those seven days,

00:17:55.880 | the person is in an elevated mood, expansive thought

00:17:59.260 | all day, every day for those seven days.

00:18:02.380 | Now, there are a lot of reasons

00:18:03.520 | why somebody could be in a manic mode.

00:18:06.220 | It doesn't necessarily mean

00:18:07.660 | that somebody has bipolar disorder.

00:18:09.700 | In fact, someone could be in a manic mode

00:18:11.820 | for seven days or more

00:18:13.620 | and still not be diagnosed with bipolar disorder.

00:18:15.860 | Why?

00:18:16.700 | Well, there are other things

00:18:18.700 | that can create manic episodes,

00:18:20.620 | things like traumatic brain injury, things like seizure,

00:18:23.820 | things like various prescription drugs or illicit drugs,

00:18:26.420 | things like amphetamine and cocaine.

00:18:28.580 | That is not the same as bipolar disorder,

00:18:30.800 | even though from a symptomology perspective,

00:18:34.060 | they might look even identical.

00:18:36.060 | So let's think about these symptoms

00:18:37.340 | and the diagnostic criteria that a psychiatrist would use

00:18:41.020 | in order to ask whether or not someone is manic

00:18:44.020 | because they have manic bipolar disorder

00:18:46.500 | or whether or not that person is manic for some other reason

00:18:50.040 | such as traumatic brain injury, illicit drugs, et cetera.

00:18:53.500 | So typically a person will be brought into a clinic

00:18:57.800 | or a person would bring themselves to a clinic

00:19:00.660 | or meet with a psychiatrist.

00:19:02.480 | It seems more likely

00:19:03.400 | that they would be directed toward a psychiatrist

00:19:05.520 | because oftentimes people who are in a manic episode

00:19:08.140 | just simply won't have the perspective

00:19:10.320 | or the foresight to bring themselves into the clinic.

00:19:13.480 | And the psychiatrist is going to start to evaluate

00:19:16.200 | for a couple of different things.

00:19:17.780 | But first of all, what they're going to try and figure out

00:19:20.240 | is whether or not the person has at least three

00:19:22.700 | of the following symptoms.

00:19:24.700 | The first symptom is distractibility.

00:19:28.300 | Is the person distractible?

00:19:29.420 | Are they going from one thing to the next?

00:19:30.940 | People who are in a manic episode

00:19:32.260 | will be talking about a pen

00:19:33.220 | and then they'll be talking about

00:19:34.580 | something they saw the other day

00:19:35.580 | and then something they want to purchase

00:19:36.700 | and then a place they're going to travel to, et cetera.

00:19:38.700 | But they are also very prone to any stimulus within the room

00:19:42.460 | meaning a bell could go off

00:19:44.300 | or there could be a sound out in the hallway

00:19:45.500 | and they'll orient to that.

00:19:46.460 | And then they'll orient to the clinician

00:19:47.780 | and then they'll orient to something in their pocket.

00:19:49.500 | So they're all over the place.

00:19:50.780 | You could think of this a little bit like ADHD

00:19:53.260 | or attention deficit disorder, but it's very extreme.

00:19:56.340 | So highly distractible, highly impulsive,

00:19:59.060 | impulsivity relates to actions.

00:20:01.660 | So the person might be fidgeting with something

00:20:03.620 | and then they might try and leave the room

00:20:05.220 | or the person might, if they were out in the real world,

00:20:09.300 | somebody might notice that the person is going

00:20:11.720 | and purchasing multiples of something

00:20:14.360 | that would be unusual for someone to purchase.

00:20:16.740 | So for instance, I happen to know someone

00:20:18.580 | whose ex-spouse had bipolar disorder

00:20:21.060 | and their ex-spouse went out

00:20:22.800 | and bought 10 plus air fryers, right?

00:20:25.980 | I mean, I think unless you're a restaurant

00:20:27.660 | that's using a lot of air fryers,

00:20:28.840 | the idea that you would need more than one or two air fryers

00:20:32.240 | might just seem a little bit out of the norm.

00:20:34.900 | And so that impulsivity can be purchasing,

00:20:37.980 | it can be other things as well.

00:20:39.940 | It could be booking 12 international trips in one afternoon

00:20:43.340 | or going and buying three cars, et cetera.

00:20:45.480 | So impulsivity.

00:20:46.640 | The other is grandiosity.

00:20:48.620 | People who have manic bipolar disorder

00:20:51.260 | who are in a manic episode will often display words of

00:20:55.440 | or actions of grandiosity.

00:20:57.140 | And keep in mind, these are not lies

00:20:59.700 | in the sense that the person isn't lying

00:21:01.540 | in order to try and pull one over on anybody.

00:21:04.120 | These are actual beliefs that the person comes to have

00:21:06.980 | about their grandiose position in the world

00:21:09.820 | or grandiose opportunities or potential in the world.

00:21:13.200 | Typical forms of grandiosity in manic episodes

00:21:16.100 | would be that the person suddenly decides

00:21:18.100 | that they are going to win a Pulitzer Prize,

00:21:20.060 | they are the person selected to win a Pulitzer Prize,

00:21:22.180 | they're going to write a novel that afternoon

00:21:24.200 | and they're going to win a Pulitzer Prize that year,

00:21:26.320 | which is more or less a delusion of grandeur, right?

00:21:29.480 | The idea that someone could do that in one afternoon,

00:21:31.340 | I suppose it is possible in the realm of all possibilities,

00:21:35.220 | but it's extremely unlikely.

00:21:37.720 | Other forms of grandiosity that often present themselves

00:21:41.100 | in people suffering from a manic episode

00:21:43.460 | will be that they're going to run for president

00:21:45.420 | or that they are the person that they believe is selected

00:21:50.420 | by the citizens of a given country

00:21:53.480 | or by the universe to be the president of that country

00:21:56.980 | or to be president of the universe, right?

00:21:58.780 | It sounds ridiculous,

00:21:59.780 | but those sorts of delusions of grandiosity

00:22:02.340 | are one condition that often presents itself

00:22:04.720 | or one set of symptoms that presents itself.

00:22:07.740 | Flight of ideas are also typical of manic episodes.

00:22:11.140 | So this is a little bit like distractibility,

00:22:13.020 | but this would be people talking extensively about one thing

00:22:16.060 | and then switching and talking extensively

00:22:17.960 | about something else.

00:22:18.800 | It would be as if I was doing this podcast

00:22:20.460 | talking about manic bipolar disorder

00:22:21.780 | and then suddenly switching to OCD

00:22:23.600 | and then to deliberate cold exposure

00:22:25.200 | and then to the role of sugar

00:22:27.040 | and its impact on the brain, et cetera.

00:22:28.480 | So essentially a random selection

00:22:31.560 | of the different topics that exist in science,

00:22:34.800 | all of which I happen to be very interested in

00:22:36.520 | and curious about,

00:22:37.580 | but just as we have episodes of the podcast

00:22:40.920 | that are about one or two topics

00:22:42.560 | and we focus on those in a fairly narrow trench

00:22:45.120 | of discussion, somebody who has a flight of ideas

00:22:48.460 | would be jumping between categories and topics

00:22:51.960 | in a kind of pseudo random way.

00:22:53.580 | So they might take off down a path of one thing

00:22:55.700 | and then switch to another without any transition

00:22:58.340 | or with transitions that don't have

00:22:59.960 | any logical structure to them.

00:23:02.000 | The other aspect of manic bipolar disorder

00:23:05.060 | that often presents itself in the manic episodes

00:23:07.160 | are agitation, people feeling extremely physically agitated,

00:23:10.060 | so a lot of shaking and moving about.

00:23:12.240 | This can venture into the realm of paranoia,

00:23:14.560 | but a lot of agitation, a difficulty sitting down

00:23:17.880 | and being still, a difficulty

00:23:20.780 | and just looking, feeling and acting calm.

00:23:24.920 | And then another condition is no sleep.

00:23:28.000 | And when I say no sleep, I mean no sleep

00:23:30.820 | or very minimal sleep.

00:23:32.960 | As incredible as it sounds,

00:23:35.200 | people who are in a manic episode

00:23:36.920 | can often go seven days or more with zero sleep.

00:23:40.920 | And a key feature of this zero sleep

00:23:43.000 | is that they're not troubled by it.

00:23:44.240 | They're not thinking, oh, I'm suffering from insomnia

00:23:46.520 | and I really, really want to sleep.

00:23:47.720 | Sometimes that's the case, but more often than not,

00:23:50.320 | they are simply not sleeping.

00:23:51.940 | They're staying up 24 hours, then another 24 hours,

00:23:54.760 | it just continues for an entire week.

00:23:56.940 | Again, inconceivable to those of us

00:23:59.020 | that don't suffer from manic episodes.

00:24:01.520 | Can only imagine how pulled apart most of us would feel

00:24:04.960 | under those conditions and yet they are just going

00:24:07.680 | and going and going with no sleep up all hours,

00:24:11.480 | shopping, talking, running,

00:24:14.680 | doing all sorts of different things in the categories

00:24:16.960 | of other symptoms that we talked about before.

00:24:19.160 | And it doesn't bother them that they're not sleeping.

00:24:22.280 | And then the last sort of category of symptoms

00:24:25.620 | that the psychiatrist is evaluating for

00:24:27.780 | and seeing if they present is rapid pressured speech.

00:24:31.560 | The rapid pressured speech is something

00:24:33.440 | that when you hear it, you recognize it.

00:24:35.200 | This is somebody that almost seems to be hitting you

00:24:37.120 | a speech like machine gun fire.

00:24:39.640 | It's coming at you, coming at you, coming at you.

00:24:41.640 | And there's really no room for conversation.

00:24:43.840 | They're not offering any opportunity for a back and forth.

00:24:46.860 | Or if there is a back and forth,

00:24:47.840 | they might ask you how you feel about something

00:24:49.160 | and then you started, well, then they're going to hit you

00:24:51.520 | with another barrage or a paragraph of information

00:24:55.680 | or of just speech that's pseudo random.

00:24:58.080 | So we've got distractibility, impulsivity, grandiosity,

00:25:01.080 | flight of ideas, agitation, no sleep,

00:25:04.120 | and rapid pressured speech.

00:25:06.240 | For someone to be diagnosed as in a manic episode,

00:25:09.120 | they do not have to be engaging in

00:25:11.960 | or displaying all of those symptoms.

00:25:15.300 | They do, however, need to present

00:25:17.640 | at least three of those symptoms.

00:25:19.560 | And then in order to meet the condition of bipolar one,

00:25:23.060 | they have to be presenting those three symptoms

00:25:25.260 | for at least seven days.

00:25:27.800 | It could be longer, but at least seven days.

00:25:30.880 | Now, this seems pretty straightforward, right?

00:25:34.160 | At one level, the way that I described this

00:25:36.620 | and the way that it exists in the clinical literature,

00:25:38.440 | you could think, well, this should be pretty easy

00:25:40.380 | to diagnose and yet there's a complication there

00:25:43.080 | or a challenge there because the psychiatrist, again,

00:25:45.640 | has to determine that these manic episodes

00:25:48.220 | are not due to something other than bipolar disorder.

00:25:53.220 | For instance, again, it could be TBI, traumatic brain injury,

00:25:56.400 | it could be seizures or meds or other sorts of drugs,

00:25:58.920 | corticosteroids, which are often prescribed

00:26:00.880 | for a number of immune conditions or for wound healing

00:26:03.620 | can also cause manic episodes.

00:26:05.760 | So they have to determine that everything that's happening

00:26:09.320 | meets the criteria I described before,

00:26:10.960 | three out of seven of these symptom categories

00:26:13.020 | for seven days or more and that it can't be better explained

00:26:16.560 | by something else going on in that person's life

00:26:19.200 | or immediate medical history.

00:26:21.320 | That's very important.

00:26:22.520 | Now, the other challenge, and this is something

00:26:24.220 | that's going to come up again and again today,

00:26:26.200 | not just in the description of the biology

00:26:28.220 | of bipolar disorder, but also in the description

00:26:31.300 | of different treatments and treatment approaches,

00:26:33.580 | is that typically when somebody is sitting

00:26:36.980 | in front of a psychiatrist, in particular

00:26:39.760 | for the first time, those two people are interacting,

00:26:44.020 | the psychiatrist is just getting one snapshot

00:26:46.880 | of the person at that moment, right?

00:26:49.000 | So the person could be on day one of a manic episode,

00:26:52.160 | the person might be on day six of a manic episode,

00:26:54.680 | the person could be transitioning out of a manic episode,

00:26:57.680 | or the person could be suffering from a combination

00:27:00.560 | of manic episode where because of the impulsivity

00:27:03.780 | of bipolar disorder, they went out and used illicit drugs,

00:27:06.040 | they also used cocaine.

00:27:07.680 | So the psychiatrist has a serious challenge.

00:27:10.860 | The psychiatrist has to determine based on a conversation,

00:27:13.900 | right, this isn't a blood test, this isn't a measurement

00:27:17.120 | that you can take on a scale or with a biomarker,

00:27:19.480 | they have to use language, a conversation with somebody

00:27:22.860 | who by all accounts is pretty impaired at conversation

00:27:25.720 | to determine whether or not they're suffering

00:27:28.040 | from a manic episode that is the consequence

00:27:31.540 | of bipolar disorder.

00:27:33.360 | You can imagine this in the real world as somebody says,

00:27:35.480 | "Well, how long has it been since you slept?"

00:27:37.280 | And the person starts to answer,

00:27:39.260 | "Oh, well, the other day I went down to the basement,

00:27:41.840 | I was going to get something out of the refrigerator

00:27:44.040 | and I thought I might take a nap."

00:27:44.880 | And then all of a sudden they're talking

00:27:45.720 | about something completely different.

00:27:46.700 | So they might not even have an answer.

00:27:48.880 | So the psychiatrist has to be a really good detective,

00:27:53.000 | a benevolent detective, but a detective nonetheless

00:27:56.040 | in determining whether or not these symptoms have existed

00:27:58.120 | for seven days or more and whether or not they meet

00:28:00.400 | the at least three, it could be more,

00:28:02.040 | but at least three of the criteria of symptom categories

00:28:04.860 | that I talked about before.

00:28:06.300 | Now, assuming that they do,

00:28:08.240 | assuming that the patient meets those criteria,

00:28:10.760 | they are likely to be diagnosed with bipolar I.

00:28:14.100 | Now, bipolar I disorder means they're having

00:28:17.440 | these extended manic episodes, seven days or more,

00:28:19.840 | but it does not necessarily mean that they are dropping

00:28:23.080 | into a depressive episode as well.

00:28:25.800 | This is a common misconception about bipolar disorder

00:28:28.760 | because as it's often called,

00:28:30.720 | bipolar disorder is referred to as bipolar depression

00:28:34.240 | and yet many people with bipolar disorder

00:28:36.840 | don't necessarily experience the deep depressive episodes.

00:28:40.000 | Many of them do, but many of them do not.

00:28:42.460 | So somebody can truly be diagnosed accurately

00:28:46.240 | with bipolar I even though they're only experiencing

00:28:49.800 | manic episodes and then dropping down to baseline,

00:28:52.200 | manic episode, then dropping down to baseline.

00:28:54.320 | That's very important to understand.

00:28:56.860 | Now, the second category of bipolar disorder is bipolar II.

00:29:00.640 | So BP2 or bipolar disorder II is somewhat different

00:29:04.360 | than bipolar disorder I.

00:29:05.520 | First of all, it's characterized most often

00:29:08.560 | by the presence of both manic episodes,

00:29:10.980 | mania and depressive episodes,

00:29:13.280 | or what's referred to as hypomania.

00:29:15.840 | Now, anytime in biology or in medicine, you hear hypo,

00:29:19.920 | it's the opposite of hyper, okay?

00:29:22.000 | So we've got normal, hyper and hypo.

00:29:24.160 | Hypomania is a somewhat suppressed level of mania.

00:29:27.720 | So this is not going to be as extreme as the mania

00:29:30.580 | that we typically think of.

00:29:31.980 | And yet the hypo can be due to the duration,

00:29:36.100 | not the intensity of mania.

00:29:38.360 | That's right, hypomania can mean a lessened intensity

00:29:42.480 | of mania, but it can also be used to refer

00:29:45.140 | to a shorter duration of mania.

00:29:47.120 | In fact, that's one of the key criteria for bipolar II.

00:29:50.420 | Bipolar II is often diagnosed on the basis

00:29:52.840 | of the presence of manic episodes

00:29:54.880 | that are lasting four days or even less.

00:29:58.700 | So someone with BP2 might have four days

00:30:01.080 | of this increased energy, goal-directed activity,

00:30:03.600 | they're irritable, they're euphoric,

00:30:05.080 | they're not sleeping, et cetera,

00:30:06.600 | but it's only lasting for about four days.

00:30:09.100 | Or they could be having longer extended periods of mania,

00:30:12.520 | but they are hypomanic episodes.

00:30:15.240 | They're not quite as intense.

00:30:16.560 | So the pressured speech isn't quite as pressured.

00:30:19.480 | The impulsivity isn't quite as severe, et cetera, et cetera.

00:30:22.760 | The other aspect of bipolar II is one

00:30:24.320 | that I had mentioned briefly a moment ago,

00:30:26.480 | which is that it's often associated

00:30:28.980 | with the drops into the depressive episodes.

00:30:31.460 | So people are going from manic episodes

00:30:33.540 | for four days or less, then they're dropping

00:30:35.740 | into a depression, going back to normal, manic again.

00:30:39.640 | I do want to point out, however,

00:30:41.840 | that people who have bipolar I can indeed go

00:30:44.620 | from manic episodes to severe what we call major depression.

00:30:47.740 | So they can oscillate like a sine wave,

00:30:50.020 | really high highs, really low lows.

00:30:52.220 | And very important to understand in terms

00:30:56.320 | of understanding both bipolar I and bipolar II

00:30:59.680 | is that it's not always a sine wave.

00:31:01.720 | This is really important.

00:31:02.640 | And it's something that, frankly,

00:31:04.320 | I did not know until I started researching this episode

00:31:06.800 | and talking to some psychiatrists.

00:31:08.420 | I should mention I've talked

00:31:09.240 | to several board-certified psychiatrists

00:31:11.000 | in preparation for this episode.

00:31:12.800 | I'll give some references to them.

00:31:14.280 | And in fact, some of them are going to be coming

00:31:15.640 | on the podcast as guests in the future

00:31:17.520 | for a more in-depth discussion about bipolar

00:31:19.400 | and other psychiatric disorders.

00:31:21.640 | But all of the psychiatrists I spoke to

00:31:23.240 | confirmed what the other was saying,

00:31:25.680 | which was that the way that bipolar disorder can present

00:31:29.320 | can vary tremendously between individuals.

00:31:32.040 | One person might go from very high highs

00:31:34.120 | that last seven days or more to very low lows,

00:31:36.160 | bouts of depression, major depression

00:31:38.620 | that could last two weeks or more.

00:31:40.600 | Other people are rapid cycling by way of three days manic,

00:31:44.200 | three days normal, three days manic,

00:31:45.920 | and then dropping into three days depression.

00:31:48.020 | So you want to erase that picture in your mind

00:31:50.480 | that manic bipolar disorder is this sine wave,

00:31:53.480 | this cycling up and down between mania and depression.

00:31:56.480 | It can take a lot of different forms.

00:31:58.920 | And again, this is a serious challenge

00:32:02.160 | for the psychiatrist to diagnose people

00:32:04.400 | because of that fact

00:32:06.360 | that they're only getting a snapshot of the person

00:32:08.360 | unless they've known them for some time

00:32:09.840 | and are working with them for some time.

00:32:11.680 | But this is also especially important for those of you

00:32:14.560 | that either have bipolar depression

00:32:17.720 | or suspect that you might,

00:32:18.960 | or that know someone with bipolar depression

00:32:22.640 | or suspect somebody might have bipolar depression,

00:32:26.160 | AKA bipolar disorder.

00:32:27.880 | Because if you're noticing that somebody is very manic

00:32:31.160 | and then normal, well, that's a very different picture

00:32:34.240 | than somebody who's going from very manic

00:32:36.040 | to very deep bouts of depression.

00:32:38.560 | The very manic to deep bouts of depression

00:32:40.800 | is easier to recognize

00:32:42.480 | because of the extremes of those highs and lows.

00:32:44.760 | Now, this might seem somewhat obvious to all of you

00:32:46.940 | as I describe it.

00:32:47.840 | And yet it's very important as a,

00:32:50.720 | frankly, a citizen of the planet,

00:32:52.560 | who knows other human beings,

00:32:54.280 | to keep an eye out for these manic episodes.

00:32:56.360 | Because again, whether or not it's four days or less

00:32:59.000 | or whether or not it's seven days or more,

00:33:01.420 | these manic episodes really are the defining criteria

00:33:05.040 | of bipolar disorder, AKA bipolar depression.

00:33:08.000 | There are a couple other key features

00:33:10.600 | about bipolar one and bipolar two

00:33:12.760 | that can allow us to get better insight

00:33:14.560 | into whether or not somebody has bipolar one or bipolar two.

00:33:17.240 | And that's the percentage of time

00:33:19.440 | that people with bipolar one versus bipolar two

00:33:22.240 | spend in a manic state, a depressed state,

00:33:24.980 | or a symptom-free state.

00:33:26.660 | And this is also important to discuss

00:33:28.080 | because it turns out that people with genuine,

00:33:31.720 | diagnosed bipolar one or bipolar two

00:33:34.640 | are often symptom-free,

00:33:36.460 | which again can make it difficult

00:33:38.620 | for us as people that know them

00:33:40.780 | or for people that are treating people

00:33:43.420 | with bipolar disorder to identify

00:33:46.280 | whether or not somebody is in a manic episode

00:33:48.700 | or a depressive episode

00:33:49.680 | or whether or not they are headed

00:33:50.720 | into a manic or depressive episode.

00:33:52.960 | So the numbers on this have been studied.

00:33:55.680 | It's from a paper, actually two papers,

00:33:57.680 | first author Judd, J-U-D-D et al,

00:34:00.120 | published some years ago, 20 years ago,

00:34:02.120 | but the data hold up really nicely over time.

00:34:04.360 | These were both published

00:34:05.280 | in Journal of American Medical Association Psychiatry.

00:34:07.880 | So JAMA Psychiatry is a superb journal.

00:34:10.360 | And basically people who have bipolar one on average

00:34:13.920 | spend about 50%, it's actually 53%

00:34:17.040 | was the number that was eventually converged upon,

00:34:20.420 | but about 50% of their time symptom-free.

00:34:22.840 | That's interesting, right?

00:34:23.760 | Somebody who has genuine bipolar one disorder

00:34:27.160 | can spend as much as half of their life symptom-free,

00:34:29.920 | sleeping normally, speaking normally, et cetera,

00:34:32.420 | about 32% of the time depressed.

00:34:36.480 | And when we say depressed, we mean major depression.

00:34:38.520 | So severe challenges with waking up

00:34:41.440 | at two or three in the morning

00:34:43.020 | and having trouble falling back asleep,

00:34:44.520 | that's one of the defining characteristics of depression

00:34:46.520 | or sleeping far too much,

00:34:47.760 | having a hard time getting out of bed in the morning,

00:34:49.280 | suppressed appetite, suppressed libido, suppressed motivation,

00:34:52.640 | all the general symptoms of major depression,

00:34:54.440 | which we'll talk about a little bit more later

00:34:56.220 | and in an upcoming episode

00:34:57.800 | about major depression in particular.

00:34:59.660 | And then about 15% of their time

00:35:01.940 | in this kind of manic state or mixed manic state

00:35:04.840 | where they are showing long, again,

00:35:07.900 | seven days or more bouts of sleeplessness, irritability,

00:35:10.680 | pressured speech, grandiosity, et cetera.

00:35:12.820 | Contrast that with people who have bipolar two disorder

00:35:16.760 | who are spending about half of their time

00:35:20.000 | in a depressed state.

00:35:21.800 | So that's interesting.

00:35:22.860 | People with bipolar two disorder,

00:35:24.440 | while not always displaying depressed states

00:35:27.280 | or oscillations between mania or hypomania

00:35:29.960 | and depressed states,

00:35:31.140 | they tend to be in a depressed state more often.

00:35:33.640 | And again, this is major depression.

00:35:34.960 | This isn't just a little bit of a low.

00:35:36.460 | This is a serious depression of their nervous system,

00:35:39.300 | their mood, and as we say, their affect,

00:35:41.720 | their outlook on life.

00:35:42.840 | And that's one of the key distinguishing features

00:35:45.200 | of major depression

00:35:46.120 | is that people's outlook on life becomes very diminished

00:35:50.380 | in the sense that they don't see a future.

00:35:52.120 | You ask them about, you know, how's work going?

00:35:54.520 | How are relationships?

00:35:55.360 | And it's not just that they feel that that's going poorly.

00:35:58.280 | They really feel as if there's no opportunity

00:36:00.240 | for those things to improve.

00:36:01.700 | Those people with bipolar two tend to be symptom free

00:36:05.960 | about 45% of the time.

00:36:07.520 | Again, these are averages.

00:36:09.360 | So about 45% of the time,

00:36:11.360 | that's a considerable amount of the time.

00:36:13.340 | And they tend to be in these hypomanic states

00:36:15.820 | only about four or 5% of the time.

00:36:18.240 | Again, the criteria for BP2, bipolar two,

00:36:20.740 | is these four days or less of mania or hypomania,

00:36:24.340 | but only 4% of the time or 5% of the time

00:36:27.420 | is a small enough sliver of the pie

00:36:30.760 | that is these people's existence

00:36:32.800 | that you can imagine why it would be easy

00:36:36.200 | for them or other people to overlook the fact

00:36:38.820 | that they have bipolar disorder and not major depression.

00:36:41.620 | Think about it.

00:36:42.460 | This is a person who, or I should say,

00:36:44.640 | a collection of people who are spending

00:36:45.900 | about half of their time depressed,

00:36:48.240 | close to half, 45% of their time symptom-free,

00:36:52.480 | and then about 5% of their time in a hypomanic state.

00:36:56.100 | So either shortened bouts of high intensity mania

00:37:00.680 | or hypomania that is of reduced intensity.

00:37:04.480 | One of the reasons that I mentioned these percentages

00:37:07.020 | of time spent in a symptom-free depressed manic

00:37:09.280 | or hypomanic state is because one of my major goals

00:37:11.320 | for today's episode is that it will increase awareness

00:37:14.840 | of whether or not you or somebody you know,

00:37:17.820 | could be a coworker, could be a family member, et cetera,

00:37:19.960 | might be suffering from bipolar one or bipolar two.

00:37:22.660 | I think it's fair to say that if somebody is suffering

00:37:24.560 | from bipolar one, that is likely to be revealed

00:37:29.160 | or to reveal itself before too long

00:37:32.340 | because of the fact that people have these extended periods

00:37:35.100 | of mania, and mania is such an extreme state,

00:37:37.360 | not just for the person who's experiencing it,

00:37:39.460 | but the way that it presents is just so extreme

00:37:41.680 | and out of the ordinary.

00:37:43.540 | But bipolar two, you can imagine could really duck

00:37:46.400 | under the radar of our awareness.

00:37:48.880 | And you could imagine that we might just think somebody

00:37:51.100 | is low or depressed, especially if that person

00:37:53.080 | tends to self-medicate with alcohol or other substances.

00:37:56.440 | We might think, oh, well, they're drinking more than often,

00:37:58.520 | more than usual, excuse me,

00:37:59.760 | or they're spending more time alone and isolating.

00:38:02.560 | But then when they're in their hypomanic state,

00:38:04.200 | that might actually present as normal to us

00:38:06.680 | because they were in such a depressed state before.

00:38:09.400 | So it's very important that we dial up our awareness,

00:38:11.960 | that we can tune our antennae to the possibility

00:38:14.260 | that people out there who might appear depressed

00:38:16.360 | or that we haven't heard from in a while

00:38:17.860 | might actually be suffering from bipolar two disorder.

00:38:20.600 | Before we move into a in-depth discussion

00:38:22.980 | about the different kinds of treatments

00:38:24.340 | for bipolar disorder, I'd like to touch on

00:38:26.580 | just a few additional aspects of what bipolar disorder

00:38:30.040 | can do in terms of its negative consequences,

00:38:32.720 | and also talk about some of the inherited risk,

00:38:35.320 | that is the genetic factors and the environmental factors

00:38:38.500 | that can contribute to bipolar disorder.

00:38:40.620 | In terms of the burden, the very real emotional

00:38:45.520 | and occupational and educational burden

00:38:47.880 | that can occur for somebody with bipolar disorder,

00:38:50.680 | that's actually been studied.

00:38:51.700 | There's a measure of this, it's called global burden,

00:38:53.960 | which is defined as the years lost

00:38:56.840 | in engaging in normal life due to some disability.

00:39:00.340 | So that disability could be cancer,

00:39:02.280 | that disability in this case is bipolar disorder.

00:39:05.080 | And basically the way this sort of study is done

00:39:07.900 | is that through questionnaires,

00:39:09.200 | I should say quite in-depth questionnaires,

00:39:11.600 | there's a probing for whether or not somebody has lost

00:39:15.380 | two consecutive weeks or more

00:39:17.600 | of interest in normal activities.

00:39:19.480 | Now, for people who have depression,

00:39:21.040 | that's a kind of straightforward thing to address, right?

00:39:23.560 | You ask somebody, when was the last time you ate?

00:39:25.900 | Or when was the last time that you went a few days

00:39:27.760 | without food or lost interest in relationships

00:39:31.200 | or work or sex or things of that sort?

00:39:32.880 | And they answer, and you can figure out the amount of time

00:39:35.960 | that you've essentially been withdrawn from normal levels

00:39:38.900 | of activity for them.

00:39:40.460 | With bipolar disorder, what it turns out

00:39:44.240 | is that the global burden of having bipolar I

00:39:47.760 | and even bipolar II is massive.

00:39:50.160 | In fact, having bipolar disorder sits

00:39:53.340 | as one of the highest risk factors

00:39:56.060 | for being in the top 10 of all categories of disabilities

00:40:00.920 | leading to global burden.

00:40:02.100 | Put in plain English, what that means is having bipolar I

00:40:05.360 | or bipolar II disorder is extremely debilitating.

00:40:08.520 | It really slows down one's life trajectory

00:40:12.220 | unless it's treated properly.

00:40:14.160 | Now, the other aspect of bipolar disorder

00:40:16.360 | is its heritability.

00:40:17.640 | And this gets into a little bit of some tricky science

00:40:20.720 | related to heritability versus the genetic contribution

00:40:25.720 | of a given disease.

00:40:28.040 | So that might sound like the same thing.

00:40:30.020 | You think, okay, genes relate to heritability.

00:40:32.320 | Heritability relates to genes.

00:40:33.720 | But of course, everything about the way

00:40:36.560 | that our nervous system works and functions

00:40:38.660 | and expresses itself, healthy or otherwise,

00:40:41.360 | is an interaction between our genes and our environment.

00:40:45.080 | And so typically the way these studies are done

00:40:47.080 | is you address what is the risk of somebody

00:40:50.460 | having a given condition in the general population?

00:40:52.740 | We talked about that before.

00:40:53.700 | Bipolar disorder is a 1% of the world's population.

00:40:57.160 | Compare that to people who have only major depression.

00:41:00.040 | So this would be repeated bouts of two weeks or more

00:41:03.520 | of serious depression, not just low mood

00:41:06.160 | or something due to a life loss, but major depression,

00:41:09.860 | which is 10 to 17% of people have major depression.

00:41:13.660 | Okay, they suffer from major depressive disorder

00:41:17.120 | compared to bipolar disorder, which again is 1%.

00:41:19.780 | Now, you can address how much of the 1% of bipolar disorder

00:41:24.780 | that exists is due to genes versus environment

00:41:28.460 | in a somewhat exact way.

00:41:30.220 | This is never an exact science.

00:41:31.760 | And the way that this is typically done

00:41:33.340 | is to look at concordance, that is the likelihood

00:41:37.760 | that two identical twins will both have a given condition

00:41:42.400 | as opposed to two fraternal twins,

00:41:44.200 | which have more different genes

00:41:46.880 | than identical twins, of course.

00:41:48.200 | And then two siblings who have similar genes, of course,

00:41:51.220 | but less similar than identical or fraternal twins

00:41:54.440 | and so on and so forth.

00:41:55.480 | So what you basically do is you evaluate the probability

00:41:57.900 | that two people in the general population

00:41:59.540 | who are completely unrelated will have the same condition

00:42:02.760 | versus two people in the general population

00:42:05.520 | who are very related identical twins.

00:42:07.320 | And what you find is that in identical twins,

00:42:10.900 | if one identical twin has true major depression

00:42:14.800 | or major depressive disorder,

00:42:16.640 | there's a 20 to 45% chance that their identical twin

00:42:21.280 | will also have major depressive disorder.

00:42:23.660 | Now, that tells you right there that it can't all be genes.

00:42:27.360 | That is not a gene for major depression per se,

00:42:29.660 | or if it is a gene or a collection of genes,

00:42:33.340 | that those genes are also subject to environmental influences

00:42:36.480 | either prenatal within the womb or after children are born.

00:42:40.140 | Now, the large range there of 20 to 45%

00:42:42.500 | could be due to any number of things.

00:42:44.420 | It could be experimental,

00:42:46.120 | meaning the techniques that were used in experiments.

00:42:48.020 | It could be due to regional differences, right?

00:42:51.540 | One part of the world versus another.

00:42:52.780 | There are a lot of different factors.

00:42:54.480 | Right now, we probably shouldn't delve into all that.

00:42:56.760 | At some point, we'll probably do an episode

00:42:58.180 | all about the genetics of nervous system heritability

00:43:01.740 | and heritability of features and mental health, et cetera.

00:43:04.580 | But we can compare major depression and the heritability

00:43:07.980 | or the genetic concordance between identical twins

00:43:10.780 | in major depression and bipolar disorder and ask,

00:43:13.120 | if one twin of an identical twin pair

00:43:16.860 | has bipolar depression,

00:43:18.820 | what is the likelihood that the other twin will have it?

00:43:22.300 | And it turns out that number is much higher.

00:43:25.700 | It's 40 to 70% likelihood or probability

00:43:29.000 | that if one twin has bipolar disorder,

00:43:32.800 | that their identical twin will also have bipolar disorder.

00:43:35.580 | So again, the total incidence of bipolar disorder

00:43:39.420 | in the general population is much lower

00:43:42.520 | than it is for major depression.

00:43:43.780 | It's 1% for bipolar versus 10 to 17% for major depression.

00:43:48.140 | But the genetic component is much higher,

00:43:51.260 | 40 to 70% for bipolar disorder versus 20 to 45%

00:43:55.860 | for major depression.

00:43:56.860 | I know I'm throwing a lot of numbers out there,

00:44:00.260 | but basically what this means is that

00:44:03.040 | researchers have been able to take those numbers

00:44:05.540 | and filter them through a number of different risk factors

00:44:08.820 | that are related to early development,

00:44:10.900 | ask questions like if two twins were raised separately

00:44:13.700 | or together in one part of the world versus another,

00:44:16.340 | or had a two-parent household versus one-parent household,

00:44:19.140 | evaluate a lot of different variables.

00:44:21.200 | What they were able to discover,

00:44:23.100 | and this has been shown again and again,

00:44:25.100 | is that the genetic contribution to bipolar disorder

00:44:30.100 | is very, very high.

00:44:32.020 | That is the heritability of bipolar disorder is 85%.

00:44:37.020 | Okay, so again, I want to be really clear what this means.

00:44:40.880 | The total occurrence in the general population, fairly low.

00:44:46.020 | Still serious, 1%, but fairly low

00:44:49.020 | compared to other things like major depression.

00:44:51.100 | However, if someone has bipolar disorder,

00:44:55.100 | it's very likely that they inherited some gene

00:44:58.500 | or sets of genes or more accurately a susceptibility

00:45:02.780 | within their genes to environmental influences

00:45:05.740 | that can trigger bipolar disorder.

00:45:08.240 | There are a lot of different ways to discuss

00:45:10.420 | and to conceptualize heritability.

00:45:12.320 | So I want to be very careful

00:45:13.460 | with the way that I'm wording this.

00:45:15.400 | What this means is that people with bipolar disorder

00:45:18.520 | very likely have a gene, or more typically,

00:45:21.520 | it's going to be a set of genes

00:45:23.080 | that creates a susceptibility for bipolar disorder

00:45:25.700 | to present itself.

00:45:27.520 | Now, what environmental factors trigger

00:45:30.380 | or increase that susceptibility is not entirely clear.

00:45:34.480 | This always seems to center back onto the same sets of things

00:45:37.220 | like early life stress, trauma, et cetera.

00:45:40.020 | Certainly those are going to exacerbate the likelihood

00:45:42.660 | that someone who has a genetic propensity

00:45:44.660 | for bipolar disorder will express that bipolar disorder

00:45:47.920 | in its full array of symptomology.

00:45:50.300 | But 85%, while very, very high is not 100%.

00:45:55.300 | Again, 85%, while a very high number for heritability

00:45:59.060 | is not 100%.

00:46:00.180 | What that means is that there is no single gene

00:46:03.580 | or identified gene cluster for bipolar disorder.

00:46:07.260 | The reason I keep drilling into this over and over

00:46:09.260 | is that I think we can confidently say

00:46:11.260 | that if someone has bipolar disorder,

00:46:12.800 | that there was something in their genetic lineage

00:46:15.160 | that led to that, or that very likely led to that,

00:46:18.220 | and yet it's not like eye color

00:46:22.380 | or some other physical feature

00:46:24.620 | which we can actually do the direct,

00:46:27.300 | so it's called Mendelian genetics,

00:46:28.700 | and figure out whether or not

00:46:31.000 | somebody directly inherited that gene

00:46:32.920 | from one parent or the other parent.

00:46:34.440 | So the takeaway here is that

00:46:36.980 | if you have certainly an identical twin

00:46:39.140 | or a fraternal twin or a sibling or a parent,

00:46:41.460 | or even a cousin or an uncle that has bipolar disorder,

00:46:44.660 | in particular, bipolar one,

00:46:46.900 | well, then you need to be on the lookout

00:46:49.360 | for bipolar disorder, perhaps in yourself

00:46:51.840 | and for the family members of that person.

00:46:53.840 | My goal within this episode up until now

00:46:56.360 | has been to provide a clear and detailed picture

00:46:59.700 | of bipolar disorder and its various forms.

00:47:03.040 | Before we start to talk about treatments

00:47:04.760 | for bipolar disorder

00:47:05.780 | and some of the neural circuit basis for bipolar disorder,

00:47:09.460 | I want to make sure that I distinguish bipolar disorder

00:47:12.180 | from borderline personality disorder.

00:47:15.260 | We will do an entire episode

00:47:16.740 | or maybe even several episodes

00:47:18.140 | about borderline personality disorder.

00:47:20.520 | Borderline personality disorder can indeed present itself

00:47:25.020 | in ways that resemble bipolar disorder and vice versa,

00:47:29.500 | but there are some key distinctions that need to be made

00:47:32.340 | because it turns out that bipolar disorder

00:47:34.460 | and borderline personality disorder are quite distinct

00:47:38.240 | in terms of their defining criteria.

00:47:40.980 | The key distinction between somebody

00:47:42.820 | with borderline personality disorder and bipolar disorder

00:47:47.220 | is that in borderline personality disorder,

00:47:50.340 | there can be episodes that can resemble mania or hypomania,

00:47:54.380 | so periods of flights of ideas

00:47:56.540 | or where people are spending money excessively

00:47:59.060 | or are sexually promiscuous in ways that seem manic

00:48:02.420 | or could even be a little bit manic or a lot manic,

00:48:05.980 | and yet more often than not,

00:48:08.300 | there is an environmental trigger for those manic episodes.

00:48:12.300 | That is distinctly different from bipolar disorder

00:48:15.980 | where the person will have manic episodes

00:48:18.340 | without any need for a trigger.

00:48:20.340 | There doesn't need to be a call from someone saying,

00:48:23.340 | hey, let's go on a vacation together,

00:48:25.300 | or there's something coming up this Friday

00:48:27.500 | that's really exciting,

00:48:28.780 | or let's enter a relationship together

00:48:31.160 | of one form or another.

00:48:32.400 | The person with bipolar disorder will have episodes of mania

00:48:35.460 | or episodes of major depression

00:48:37.620 | without any need for an external stimulus

00:48:40.500 | or environmental trigger,

00:48:42.180 | but the person with borderline personality disorder

00:48:44.980 | almost always, again,

00:48:46.260 | there's never an always in biology and psychiatry,

00:48:48.480 | but almost always is going to exhibit flights of mania

00:48:53.060 | or depressive episodes or other types of mood shifts

00:48:55.820 | that are dramatic and maladaptive in response to things

00:48:59.380 | that are coming in through the external environment

00:49:02.300 | or relationships of some kind.

00:49:03.860 | In fact, one of the defining characteristics

00:49:05.740 | of borderline personality disorder

00:49:07.860 | is this thing that's referred to as splitting.

00:49:10.080 | A good example of splitting

00:49:11.420 | in the person with borderline personality disorder

00:49:14.100 | is that they will feel that they absolutely adore you

00:49:17.820 | and want to spend all their time with you

00:49:19.660 | and just think the world of you.

00:49:21.060 | You can do no wrong.

00:49:22.220 | And in fact, they genuinely can feel that way

00:49:25.380 | and can genuinely think that way about you.

00:49:27.780 | And then for whatever reason,

00:49:30.020 | it could be a perception of something that you did

00:49:32.880 | or something that you said

00:49:34.260 | or suspicion that you're thinking something about them,

00:49:37.100 | they can suddenly shift or split their emotions

00:49:41.220 | and what's called move you from a good object

00:49:45.040 | or a can do no wrong object to a bad object.

00:49:48.220 | They'll suddenly decide that you are cheating on them

00:49:50.780 | or that you are being mean to them

00:49:53.220 | or that you're insulting them

00:49:54.540 | or that something that you're doing

00:49:56.740 | is in violation to their self-worth,

00:49:59.540 | their wellbeing, et cetera.

00:50:00.620 | And that can send them down a pathway

00:50:02.540 | of being very angry, very depressed, et cetera.

00:50:04.940 | As I described the contour of a person

00:50:06.800 | with borderline personality disorder

00:50:08.780 | as somebody who splits very suddenly

00:50:11.020 | in response to some environmental trigger,

00:50:12.680 | real or perceived, there's the risk, of course,

00:50:16.180 | that it makes the person

00:50:17.340 | with borderline personality disorder

00:50:18.860 | sound like a bad person, you know,

00:50:20.340 | that they're very volatile.

00:50:22.100 | And while they can be volatile,

00:50:23.780 | I want to be very careful to point out

00:50:25.400 | that the person with borderline personality disorder

00:50:27.640 | is also suffering in this context.

00:50:30.300 | So while those sorts of relationships

00:50:33.220 | with people with borderline personality disorder,

00:50:35.800 | whether or not they're romantic relationships

00:50:37.620 | or familial or coworkers, et cetera,

00:50:39.680 | can be very challenged, can be very high friction

00:50:42.020 | because of the good object, bad object shifts, et cetera,

00:50:46.460 | it's bi-directional, meaning the person

00:50:48.380 | with borderline personality disorder, as you can imagine,

00:50:50.720 | is also going through a lot of suffering.

00:50:52.300 | At one moment, they feel as if someone is wonderful

00:50:54.880 | and can do no wrong to them

00:50:55.920 | and they want to be so strongly affiliated with them.

00:50:57.980 | And then in the next moment,

00:50:59.260 | they feel as if that person is attacking them

00:51:01.420 | through their actions or even through their non-actions.

00:51:04.060 | So again, we will return to

00:51:06.100 | borderline personality disorder in a separate episode.

00:51:08.540 | It's a serious disorder, both for the person that has it

00:51:11.200 | and for people around them.

00:51:12.620 | Fortunately, there are some emerging treatments

00:51:14.460 | that are showing promise,

00:51:16.200 | and it's a fairly common disorder,

00:51:18.540 | but it's important that we distinguish

00:51:20.580 | borderline personality disorder from bipolar disorder,

00:51:23.840 | mostly on the basis of this need for a trigger.

00:51:25.980 | Again, in bipolar disorder,

00:51:28.200 | there is no need for a trigger to create a manic episode

00:51:31.140 | or a major depressive episode.

00:51:32.460 | They just happen or they can just happen.

00:51:35.680 | Whereas in borderline personality disorder,

00:51:38.340 | almost always there's an external trigger or a perception

00:51:41.500 | that something happened in the environment

00:51:43.720 | or that somebody is behaving a certain way

00:51:45.940 | that dramatically shifts the person

00:51:47.580 | with borderline personality disorder

00:51:49.600 | from one mode to the next.

00:51:51.500 | As we move into our discussion about the treatments for

00:51:53.820 | and neural circuits underlying bipolar disorder,

00:51:56.540 | I want to just nail down one more key point.

00:51:59.980 | This is a very brief point,

00:52:01.480 | but it's perhaps the most important point,

00:52:03.940 | which is the highs and lows,

00:52:07.140 | or we should say the highs,

00:52:09.160 | these manic episodes and sometimes lows,

00:52:11.500 | 'cause again, not everybody with bipolar disorder one or two

00:52:14.140 | suffers from depressive episodes.

00:52:15.900 | Sometimes yes, sometimes no.

00:52:17.600 | In particular in bipolar two, yes,

00:52:19.840 | but people with bipolar one can have extreme manic episodes

00:52:22.760 | and then just return to normal, as you recall.

00:52:25.040 | Well, those extreme lows and or extreme highs

00:52:28.460 | of people with bipolar disorder impact their lives

00:52:32.220 | in very negative ways.

00:52:34.000 | This is essential.

00:52:35.320 | And it's something that we're going to return to

00:52:37.020 | a little bit later when we talk about the relationship

00:52:39.020 | between bipolar disorder and creativity,

00:52:41.620 | because it turns out that there's

00:52:42.800 | a quite strong association there.

00:52:45.460 | One that would almost lead you to believe

00:52:47.200 | that being bipolar can be beneficial in certain contexts.

00:52:49.640 | And yet on whole, having bipolar disorder

00:52:54.220 | is extremely detrimental and challenging

00:52:56.880 | to the person suffering from it.

00:52:58.320 | And it's something that we want to keep in mind

00:52:59.960 | as we think about treatments and the underlying biology.

00:53:03.440 | Now I'd like to talk about some of the treatments

00:53:05.240 | for bipolar disorder.

00:53:06.920 | And in the discussion of those treatments,

00:53:08.880 | there's an absolutely incredible history

00:53:11.820 | of the discovery of one particular treatment

00:53:14.280 | that still shows great success in many patients,

00:53:18.120 | although some people can't take it

00:53:19.780 | for reasons that we'll talk about.

00:53:21.560 | And in the description of the discovery of this treatment

00:53:24.680 | for bipolar disorder, it also reveals to us

00:53:27.800 | that sometimes treatments come to the profession of medicine

00:53:32.800 | and through science in ways that precede the discovery

00:53:37.300 | of the underlying biology.

00:53:39.520 | That's right.

00:53:40.360 | Every once in a while, someone will discover a treatment

00:53:43.720 | for a disease without any understanding

00:53:46.300 | about the underlying biological basis of that disease.

00:53:49.940 | And in fact, that is the case for bipolar disorder.

00:53:52.800 | And the treatment that we are referring to is lithium.

00:53:56.600 | Lithium, as some of you know,

00:53:59.020 | is on the periodic table of elements.

00:54:01.480 | It is indeed a naturally occurring substance.

00:54:04.420 | It actually arrived on earth by way of stardust.

00:54:08.240 | Yes, we are talking about stardust on this podcast.

00:54:11.020 | But if you'd like to learn more about the origins of lithium

00:54:13.520 | and how lithium arrived here on earth for its discovery

00:54:17.080 | and applications in psychiatry,

00:54:18.960 | there's a beautiful talk that exists on YouTube.

00:54:21.640 | And we'll provide a link to this in the show note captions

00:54:24.720 | that describes the history of lithium

00:54:27.460 | in terms of its interplanetary travels and arrival on earth.

00:54:31.260 | This is a talk delivered by a physicist

00:54:34.120 | who's expert in quantum mechanics and is expert in lithium.

00:54:38.280 | And it's a just wonderful talk that I can refer you to.

00:54:40.720 | Less on the biology in that talk,

00:54:42.380 | but certainly a lot about lithium as an element.

00:54:44.380 | So for those of you nerds like me

00:54:46.840 | that love to know how things came to be here on the planet

00:54:50.820 | in one form or another,

00:54:52.360 | I'll encourage you to take a brief listen to that talk.

00:54:55.280 | We are going to discuss lithium

00:54:56.600 | in the context of its applications

00:54:58.620 | for treatment of bipolar disorder.

00:55:00.520 | And the discovery of lithium

00:55:01.820 | as a treatment for bipolar disorder

00:55:04.160 | is truly a miraculous story

00:55:05.940 | that I think everyone should know.

00:55:07.540 | The key player in this story is a physician

00:55:11.400 | by the last name Cade.

00:55:12.560 | He was an Australian physician.

00:55:14.880 | And Cade has a very interesting story in his own right.

00:55:18.200 | Cade was an Australian psychiatrist

00:55:20.080 | or Australian psychiatrist who also was a soldier.

00:55:24.800 | And during World War II,

00:55:27.280 | after the fall of Singapore to Japan,

00:55:29.120 | he became a prisoner of war

00:55:31.340 | and he was a prisoner of war from 1942 until 1945.

00:55:35.560 | So he had some time for observation.

00:55:37.800 | And during his imprisonment,

00:55:39.440 | he observed some of his fellow inmates

00:55:41.740 | as going through pretty wild vacillations

00:55:44.600 | in mood and energy,

00:55:46.240 | essentially going from manic episodes to depressed episodes

00:55:49.520 | or from manic to normal episodes.

00:55:51.820 | And for one reason or another,

00:55:54.880 | we don't know why because I couldn't find any report

00:55:57.080 | as to why he hypothesized this,

00:55:59.040 | but he hypothesized that there was some buildup

00:56:01.600 | of some chemical in these people's brains

00:56:05.400 | that then they would urinate out

00:56:08.000 | and that urinating out of whatever chemical was in there

00:56:12.520 | would allow them to be more relaxed and not manic.

00:56:15.600 | In other words,

00:56:16.820 | Cade hypothesized that there's a buildup of a chemical

00:56:19.240 | in certain people's brains that makes them manic

00:56:21.240 | and they urinate that chemical out.

00:56:23.620 | So eventually he got out of this prison,

00:56:27.120 | as we mentioned, in 1945,

00:56:29.040 | and he started doing experiments

00:56:30.960 | in addition to seeing patients in his clinic.

00:56:33.860 | And what he did is he started to take urine

00:56:36.060 | from people who exhibited mania

00:56:38.280 | and urine from people who were not manic.

00:56:41.000 | And he took that urine and he would inject it

00:56:43.480 | into guinea pigs as an experimental model.

00:56:46.440 | And his general observation

00:56:49.000 | was that there was something in the urine

00:56:51.480 | that was indeed making the guinea pigs more manic

00:56:55.160 | if they were injected with urine from a manic patient.

00:56:59.680 | The exact measures that he was taking in these guinea pigs

00:57:02.260 | wasn't exactly clear.

00:57:03.280 | This is at a time or an era in science

00:57:06.180 | when you could just sort of report things

00:57:08.260 | a little bit more subjectively,

00:57:09.720 | although there were still numbers and statistics,

00:57:12.240 | it was a little bit more of like case studies

00:57:14.560 | and descriptions,

00:57:15.600 | but it turns out that even though

00:57:16.960 | that all seems a little bit loose,

00:57:18.280 | it led to some incredible and still important discoveries

00:57:21.920 | for psychiatric health.

00:57:23.680 | So what he figured out was that the urine from manic patients

00:57:27.080 | seemed to be more toxic for these guinea pigs.

00:57:29.840 | And he also knew that there are two toxic substances

00:57:33.420 | in urine, urea and uric acid.

00:57:36.800 | So he was able to separate the urea and uric acid

00:57:40.160 | from people with mania and patients that did not have mania.

00:57:44.580 | And he figured out that the urea was the same

00:57:47.800 | in both these mentally ill manic patients

00:57:50.840 | and the non-manic patients.

00:57:52.640 | So it did not seem that urea was the compound

00:57:56.200 | that was creating these manic episodes

00:57:58.680 | or related to manic episodes or held the toxicity.

00:58:02.840 | So instead he focused on the uric acid.

00:58:05.800 | Now, in order to put the uric acid into solution

00:58:09.520 | so that he could inject it into these guinea pigs,

00:58:11.800 | he had to try a number of different compounds

00:58:13.920 | in order to dilute it.

00:58:14.820 | It just so happens that,

00:58:16.460 | and you chemists will be familiar with this,

00:58:18.200 | but there's certain things

00:58:19.540 | that just don't go into solution easily.

00:58:21.180 | You put the powder in a vial,

00:58:23.140 | you add some water or a saline or another solution,

00:58:25.440 | you mix it up and the powder stays suspended in there.

00:58:27.800 | It just doesn't actually ever become a clear liquid

00:58:32.600 | that you can inject.

00:58:33.940 | So in order to try injecting different strengths

00:58:36.920 | of uric acid, he ended up using lithium

00:58:40.540 | to assist in the dilution and lithium worked.

00:58:43.760 | So what he basically was doing, again for you chemists,

00:58:46.120 | is he was taking uric acid, he was adding lithium

00:58:49.440 | and making a solution of lithium urate, okay?

00:58:52.780 | This is a lot of details, but this is important

00:58:55.440 | because what he eventually found

00:58:57.520 | is that when he diluted the uric acid with lithium

00:59:01.520 | and created lithium urate, lithium urate

00:59:04.140 | could actually calm down these guinea pigs

00:59:07.140 | that were injected with the toxic urea.

00:59:10.280 | He also found that lithium urate

00:59:13.160 | had a generally calming effect on these guinea pigs.

00:59:16.860 | So now we're really off in crazy territory, right?

00:59:19.540 | We're talking about urine from patients

00:59:21.720 | that's separating out urea and uric acid.

00:59:24.900 | We're adding lithium to the uric acid.

00:59:27.020 | We're injecting this into guinea pigs.

00:59:28.620 | This is getting pretty wild and pretty weird,

00:59:30.740 | but this is medicine.

00:59:32.020 | And from time to time, this is medicine and science.

00:59:35.000 | Cade was a good scientist

00:59:37.880 | in addition to being a good physician.

00:59:39.900 | And by good scientists,

00:59:41.540 | I mean that he did control experiments.

00:59:43.420 | Here he was injecting lithium urate

00:59:47.440 | into animals and seeing an effect,

00:59:49.620 | but he knew that that solution of lithium urate

00:59:52.700 | contained not just the uric acid,

00:59:55.500 | but it also contained lithium.

00:59:57.060 | And so he quite appropriately asked,

01:00:00.020 | maybe the lithium alone

01:00:02.180 | is having this calming effect on these guinea pigs.

01:00:05.540 | And indeed that was the case.

01:00:07.260 | When he did the proper control experiment

01:00:09.220 | and injected only lithium solution into these guinea pigs,

01:00:14.220 | they calmed down.

01:00:15.500 | From there, he in sort of 1940s style medicine,

01:00:20.060 | this would not happen now,

01:00:21.780 | he very quickly moved from that animal model

01:00:24.020 | into human patients

01:00:25.580 | and started injecting human patients with lithium

01:00:28.620 | or providing lithium orally to those patients.

01:00:31.660 | And lo and behold,

01:00:33.300 | found an absolutely profound and positive effect of lithium

01:00:38.300 | in reducing symptoms of mania.

01:00:41.360 | And as all good physician scientists do,

01:00:44.020 | he wrote up his results.

01:00:45.700 | And he wrote it up in a paper entitled

01:00:48.900 | "Lithium Salts and the Treatment of Psychotic Excitement."

01:00:52.380 | Okay, back then they didn't call it mania,

01:00:53.620 | they called it psychotic excitement.

01:00:55.880 | This is a paper that was published September 3rd, 1949

01:00:58.720 | in the Medical Journal of Australia.

01:01:00.640 | We will provide a link to this study

01:01:02.180 | as now a classic study in the field of psychiatry.

01:01:05.520 | It's a really wonderful paper to read.

01:01:07.240 | And actually I encourage people,

01:01:09.240 | even if you're not a scientist or a clinician,

01:01:12.680 | to just take a quick look at the second page in this paper

01:01:15.640 | that we've made available to you,

01:01:17.800 | where he describes each of the various case studies

01:01:21.400 | or the individuals that he looked at.

01:01:23.840 | I'm not going to read these in detail now

01:01:25.160 | 'cause it would take a lot of unnecessary time.

01:01:27.120 | But things like case seven, MC, aged 40 years old,

01:01:31.660 | suffering from manic recurrent mania.

01:01:33.640 | In this episode, he'd been excited,

01:01:34.820 | restless and violent for over two months

01:01:36.920 | and was interfering so often

01:01:37.960 | that he had to be confined to a single room during the day.

01:01:40.520 | So this is very debilitating,

01:01:42.800 | what we now know to be bipolar depression.

01:01:44.960 | He commenced taking lithium citrate 20 grains,

01:01:48.320 | that's a measure of the amount of lithium,

01:01:50.360 | three times a day.

01:01:51.200 | In four days, he was distinctly quieter.

01:01:53.760 | And by February 13th, 1949, appeared practically normal.

01:01:58.440 | He continued well and on February 20th, 1949,

01:02:00.940 | the dose of citrate was reduced to 10 grains,

01:02:03.080 | et cetera, et cetera.

01:02:03.920 | He left the hospital.

01:02:05.360 | There are numerous descriptions of this sort

01:02:07.900 | within this paper, including some descriptions of patients

01:02:10.340 | that did not see such success

01:02:12.860 | and including some descriptions of patients

01:02:15.240 | that suffered from some negative side effects.

01:02:18.200 | So that's important to point out as well.

01:02:20.000 | But it's an absolutely wonderful paper

01:02:22.280 | and it's an absolutely wonderful voyage

01:02:24.720 | into the history of psychiatry,

01:02:26.300 | right down to the discussion

01:02:27.560 | where in just three short paragraphs,

01:02:30.320 | Cade really lays out the case

01:02:32.760 | for why lithium is such an important discovery

01:02:35.980 | in the treatment of what at that time

01:02:37.960 | they were calling psychotic excitement

01:02:39.480 | and what we now know to be manic bipolar depression.

01:02:43.300 | Lithium, I should mention,

01:02:44.800 | has a number of important features,

01:02:46.420 | but also a number of important side effects

01:02:48.680 | that need to be considered.

01:02:49.720 | First of all, it does have a certain toxicity

01:02:53.160 | and so levels of lithium in the blood

01:02:55.180 | need to be monitored extremely carefully.

01:02:57.700 | So it's not the sort of thing

01:02:58.680 | that people can just take at a given dose

01:03:00.820 | and every patient responds the same.

01:03:02.480 | There's a lot of oversight

01:03:03.760 | and a lot of blood tests that have to be done,

01:03:05.560 | especially in the first three months of lithium treatment.

01:03:08.840 | I should mention that lithium treatment is still used

01:03:11.600 | to some great degree of success in many,

01:03:14.160 | not all people suffering from bipolar depression

01:03:17.840 | or bipolar disorder rather,

01:03:20.360 | but there are a number of important things that happen

01:03:23.840 | between 1949 and present day that prevented lithium

01:03:28.240 | from reaching patients that really needed it.

01:03:31.460 | And that all can be summarized

01:03:33.140 | in two or three short sentences.

01:03:35.140 | Basically, by virtue of the fact

01:03:37.360 | that lithium is a naturally occurring element,

01:03:39.840 | it could not be patented.

01:03:41.320 | And as a consequence of that,

01:03:43.100 | there wasn't a lot of potential profit for drug companies

01:03:46.120 | to produce lithium, in fact, still to this day,

01:03:48.400 | it's very low cost.

01:03:50.680 | And still to this day, no one really owns the patent

01:03:54.080 | for lithium in its purest form.

01:03:56.280 | So that made it unattractive.

01:03:57.760 | It turns out that the FDA in the United States

01:04:00.080 | didn't allow lithium to be used as a treatment

01:04:02.560 | for manic bipolar disorder until 1970.

01:04:06.720 | So we're talking about a full 21 years

01:04:08.840 | from the publication of this paper

01:04:11.120 | by Cade in the Medical Journal of Australia

01:04:13.100 | showing quite beautifully the great potential

01:04:16.680 | and use of lithium for quelling the symptoms

01:04:19.740 | of bipolar disorder until the first patients

01:04:23.680 | in the United States were starting

01:04:24.840 | to access lithium regularly.

01:04:26.580 | And nowadays, of course, lithium is available,

01:04:28.280 | but still not able to be patented

01:04:30.480 | 'cause it's element number three on the periodic table.

01:04:32.800 | It's naturally occurring.

01:04:34.180 | It's not literally falling down from the stars

01:04:36.120 | as stardust and going into pill form,

01:04:37.740 | but rather it can be synthesized in laboratories,

01:04:41.940 | but it is available.

01:04:43.400 | It does show not only great potential in many patients,

01:04:47.040 | but great application in many patients

01:04:49.200 | despite its side effects.

01:04:51.120 | So lithium really stands as this kind of golden example

01:04:55.200 | of a treatment that works, at least in many individuals,

01:04:58.680 | prior to an understanding of the biological basis

01:05:01.960 | of the disease for which that treatment is needed.

01:05:04.920 | Now, with that said, scientists and clinicians

01:05:07.040 | have been quite rigorous in trying to understand

01:05:09.760 | why and how lithium works in order to understand

01:05:13.080 | the why and how of bipolar disorder.

01:05:15.260 | This is the way that proper medicine and science is done.

01:05:17.580 | Even if there's an excellent treatment for something,

01:05:20.120 | it's important to understand why that treatment works

01:05:22.980 | because first of all, not everyone responds

01:05:25.320 | to that treatment.

01:05:26.160 | Second of all, scientists and physicians understand

01:05:29.420 | that just because we have one treatment that works,

01:05:31.960 | if it has any side effects at all,

01:05:34.280 | there is the possibility for better treatments.

01:05:36.720 | So it's not just about trying to bypass a drug

01:05:39.840 | that doesn't make much money for drug companies.

01:05:41.700 | I know a lot of people think in those terms,

01:05:43.360 | they think, oh, well, there's this continued search

01:05:46.040 | for better treatments for bipolar disorder,

01:05:47.940 | even though lithium works

01:05:48.960 | because lithium doesn't allow drug companies

01:05:50.600 | to make much money.

01:05:51.640 | That's not really the case.

01:05:52.840 | The fact of the matter is, is that the toxicity,

01:05:55.240 | some of the other issues that are created with lithium,

01:05:58.600 | the fact that people need the ongoing blood testing,

01:06:01.560 | et cetera, really stimulates the need,

01:06:04.560 | really an urgent need for new and better treatments

01:06:07.240 | for bipolar disorder.

01:06:08.120 | And only by understanding how lithium works

01:06:10.320 | at the cellular level, at the neural circuit level, et cetera,

01:06:13.680 | do we really stand to find those new discoveries.

01:06:16.020 | If you were to do a literature search

01:06:18.280 | on the actions and mechanisms of lithium

01:06:21.960 | in terms of how it can calm people down

01:06:24.240 | and reduce their manic episodes,

01:06:26.280 | you would find an enormous array of papers,

01:06:29.000 | literally thousands of scientific studies

01:06:31.640 | in animals and in humans, which for instance,

01:06:35.020 | will tell you that lithium treatment

01:06:37.200 | will increase so-called BDNF,

01:06:39.680 | brain-derived neutrophic factor.

01:06:42.280 | BDNF is often talked about

01:06:43.960 | in the context of neuroplasticity,

01:06:45.700 | the brain and nervous system's ability to change

01:06:48.040 | in response to experience.

01:06:49.400 | And indeed, it does seem that ingesting lithium

01:06:53.340 | increases BDNF.

01:06:54.920 | BDNF is what we call permissive for neuroplasticity.

01:06:59.280 | It doesn't create specific changes in the brain,

01:07:02.080 | meaning it's not going to make your memory better

01:07:04.400 | or your coordination better

01:07:06.360 | or your emotional state better per se.

01:07:08.800 | What BDNF does is it permits the neurons, the nerve cells

01:07:13.560 | and their connections in the brain

01:07:15.040 | to be more likely to change

01:07:17.920 | if the proper environmental conditions are met.

01:07:21.600 | That is BDNF creates a kind of buoyancy to neuroplasticity.

01:07:26.560 | It opens the gates to neuroplasticity.

01:07:28.960 | So lithium does increase BDNF.

01:07:31.200 | We'll talk about why that's important

01:07:32.480 | in the context of the neural circuits involved

01:07:34.880 | with bipolar disorder in a few minutes.

01:07:37.400 | It also seems to be a potent anti-inflammatory.

01:07:41.240 | Now, inflammation is one of those words

01:07:42.880 | that's thrown around extensively nowadays,

01:07:45.200 | especially on social media

01:07:46.440 | and especially as it relates to any health condition.

01:07:48.760 | It's like inflammation, inflammation, inflammation

01:07:50.940 | always seems to be discussed

01:07:52.620 | in the context of inflammation being bad.

01:07:54.440 | But I do want to point out

01:07:56.080 | that inflammation is a natural adaptive response

01:07:59.160 | to physical injury to a cell or organ or tissue of any kind.

01:08:03.220 | Inflammation is the basis

01:08:05.040 | by which adaptations occur to exercise.

01:08:08.240 | So for instance, you were to weight train

01:08:10.760 | and use a heavier than normal weight

01:08:12.680 | and do a set to failure

01:08:14.040 | or create some little micro terrors in the muscle

01:08:16.240 | that are healthy in the sense

01:08:17.740 | that they would create adaptations

01:08:19.720 | and make that muscle stronger, maybe even grow that muscle.

01:08:22.400 | There's an inflammatory response associated with that

01:08:24.700 | that is critical to the positive adaptation.

01:08:27.400 | So inflammation isn't always bad,

01:08:29.480 | although excessive or as we say, runaway inflammation is bad.

01:08:33.920 | Lithium seems to be able to suppress inflammation

01:08:36.680 | and importantly, it can suppress inflammation

01:08:40.140 | in neural tissues and within the brain in particular.

01:08:43.160 | That is important and we will return to that

01:08:45.920 | and why it's important in a little bit.

01:08:48.340 | The other thing about lithium

01:08:49.860 | is that lithium is neuroprotective.

01:08:52.900 | That is, it can prevent neurons from dying

01:08:56.120 | under certain conditions.

01:08:57.280 | Why would neurons die?

01:08:58.400 | Well, there are a lot of reasons why neurons can die.

01:09:00.400 | There can be a physical insult to the neurons.

01:09:01.920 | You can get hit really hard in the head, a bullet,

01:09:05.160 | God forbid can enter the skull and kill neurons.

01:09:07.680 | There are a lot of reasons why neurons can die.

01:09:10.520 | Neuroprotection is a situation

01:09:13.920 | in which a neuron is given some sort of chemical

01:09:16.560 | or physical resiliency that allows it to suffer an insult

01:09:20.860 | and yet bounce back.

01:09:21.920 | So it's very similar to the way

01:09:23.200 | that we think about psychological resiliency.

01:09:25.000 | Neuroprotection is an ability for neurons

01:09:28.200 | to be better able to handle stress of different kinds.

01:09:31.700 | In particular, excitotoxicity.

01:09:34.240 | There's a phenomenon in bipolar disorder

01:09:36.600 | and a lot of other psychiatric conditions

01:09:38.660 | in which hyperactivity of certain brain areas

01:09:41.720 | actually starts to kill off neurons.

01:09:44.440 | Hyperactivity doesn't always do this,

01:09:46.280 | but it turns out that if certain brain circuits

01:09:48.140 | are too active for too long,

01:09:49.800 | some of the chemicals associated with neuronal activity,

01:09:52.560 | things like calcium and neurotransmitters like glutamate

01:09:55.360 | can actually kill the very neurons that are active.

01:09:57.840 | So it seems that lithium can prevent

01:09:59.600 | some of that neurotoxicity.

01:10:00.900 | Now, this turns out to be particularly important

01:10:03.800 | for this discussion about bipolar disorder

01:10:05.720 | and the neural circuit basis of bipolar disorder.

01:10:08.440 | Because if we are to just take a step back and ask,

01:10:10.600 | what's different in the brains

01:10:12.000 | of people with bipolar disorder?

01:10:14.040 | There are some very interesting answers that start to emerge.

01:10:16.900 | There are basically two main neural circuits

01:10:19.400 | that are present in normal individuals.

01:10:22.600 | I say normal, I say that respectfully

01:10:24.720 | to the people with bipolar disorder

01:10:26.000 | by referring to people who do not suffer

01:10:29.000 | from manic episodes or from manic depression.

01:10:32.480 | There are circuits that are present

01:10:33.780 | in people with bipolar disorder

01:10:35.280 | and in people that do not suffer from bipolar disorder.

01:10:40.520 | Both of those circuits do the same thing

01:10:43.560 | in both sets of individuals.

01:10:45.360 | And yet in people with bipolar disorder,

01:10:47.840 | there seems to be an atrophy

01:10:49.960 | or a removal of certain neural connections over time

01:10:53.240 | that leads to a situation

01:10:55.200 | in which people with bipolar disorder become very poor

01:10:59.600 | at registering their own internal state.

01:11:02.240 | In particular, their emotional states

01:11:04.140 | and their somatic states.

01:11:05.840 | What we're referring to here

01:11:06.780 | is something called interoception.

01:11:08.480 | I've talked about this a little bit

01:11:09.460 | on the Huberman Lab podcast before,

01:11:11.260 | but there are two modes of perception.

01:11:13.780 | Perception, of course, is a attention

01:11:16.680 | to something that's happening in our environment

01:11:18.800 | or to us on or within our body.

01:11:21.940 | Exteroception is literally an attention

01:11:25.100 | to things that are happening

01:11:26.040 | beyond the confines of our skin.

01:11:27.880 | So seeing that person's face over there

01:11:29.960 | or seeing that color of leaf over there

01:11:32.660 | or hearing a sound over to my left.

01:11:34.660 | That is exteroception,

01:11:36.400 | perception of things beyond the confines of one's skin.

01:11:39.640 | Then there's interoception,

01:11:41.400 | which is perception of things that are happening internally.

01:11:44.240 | Like how full does my gut feel?

01:11:46.160 | How fast is my heart beating?

01:11:48.540 | Some people can measure that quite accurately

01:11:50.500 | just by thinking about it.

01:11:51.520 | Other people can't.

01:11:53.300 | How happy am I?

01:11:54.480 | How sad am I?

01:11:55.680 | How energetic am I?

01:11:56.920 | How lethargic am I?

01:11:58.040 | Et cetera, et cetera.

01:11:59.020 | So we are always existing in a balance

01:12:00.720 | between exteroception and interoception.

01:12:03.440 | But as it turns out,

01:12:04.840 | people with bipolar disorder over time

01:12:07.720 | and especially into the second and third decade

01:12:10.400 | of having bipolar disorder

01:12:11.960 | seem to have progressively diminished levels

01:12:15.240 | of interoception.

01:12:16.480 | And that very likely is important

01:12:18.280 | in their inability to register, for instance,

01:12:20.520 | that, wow, they are talking at an excessive rate

01:12:23.760 | or they haven't slept in five or even 10 days

01:12:27.280 | or they haven't eaten in a long period of time.

01:12:30.200 | This atrophy of neural circuits for interoception

01:12:35.200 | is starting to emerge

01:12:37.040 | as one of the defining neural circuit characteristics

01:12:40.020 | or underpinnings of bipolar.

01:12:42.120 | Now, I bridged to this conversation about neural circuits

01:12:44.880 | from the statement that lithium can protect

01:12:48.720 | against some of the neurotoxic effects

01:12:51.640 | of neural circuits being very active.

01:12:53.420 | Now, this can get a little bit complicated,

01:12:55.320 | but I promise I'm going to make it clear

01:12:57.060 | for any of you that are watching and/or listening.

01:12:59.800 | The reality is that people with bipolar depression

01:13:03.900 | very likely have a hyperactivity,

01:13:06.280 | that is an increased level of activity

01:13:08.000 | in certain circuits within the brain

01:13:09.560 | early in the expression of their disease.

01:13:12.080 | And that typically, as I mentioned earlier,

01:13:14.300 | sets in around the early 20s,

01:13:15.920 | although sometimes that can be even earlier

01:13:18.040 | in the teens and so forth.

01:13:19.820 | But that hyperactivity, we think, leads to a toxicity,

01:13:24.820 | an excitotoxicity of certain elements of the neural circuits

01:13:29.160 | that are responsible for interoception.

01:13:31.640 | In other words, the overuse of certain circuits

01:13:34.440 | can lead to a diminishing, an atrophy,

01:13:37.480 | or even a death of certain elements within those circuits.

01:13:40.000 | And it appears that lithium,

01:13:41.560 | through its anti-inflammatory and neuroprotective effects,

01:13:45.420 | and through its ability to increase BDNF,

01:13:49.160 | very likely protects us against some of that atrophy

01:13:52.140 | of those circuits for interoception.

01:13:54.260 | So this isn't a case in which, you know,

01:13:56.400 | people with bipolar have a neural circuit

01:13:59.020 | or lack a neural circuit,

01:14:00.060 | and people without bipolar are the opposite.

01:14:02.200 | This is a case in which

01:14:03.040 | everyone more or less starts out the same,

01:14:05.100 | but it seems that there's a hyperactivity

01:14:07.240 | of certain neural circuits in people with bipolar disorder

01:14:09.860 | that over time actually causes those circuits to diminish.

01:14:13.440 | Now, this is very important

01:14:14.560 | because some of the more recent longitudinal studies

01:14:17.320 | doing brain imaging on people with bipolar disorder

01:14:19.400 | and those without, and doing that over time

01:14:21.960 | in patients starting as early as their teens,

01:14:23.840 | but into their 20s and 30s,

01:14:25.800 | reveals just that,

01:14:27.620 | that there can be hyperactivity of circuits early on,

01:14:29.900 | but then hypo, reduced activity of those very same circuits

01:14:33.800 | at a time five or 10 years later.

01:14:36.360 | Again, this speaks to the complicated nature

01:14:38.240 | of bipolar disorder and the complicated nature of psychiatry

01:14:41.800 | and linking specific psychiatric disorders

01:14:44.960 | to neural circuits in general.

01:14:46.840 | Because if you have a situation in which,

01:14:49.500 | you know, in one disease,

01:14:50.600 | let's just hypothesize here for a second that,

01:14:53.840 | for instance, in certain forms of schizophrenia,

01:14:55.860 | there's elevated dopamine,

01:14:57.040 | and were we to just reduce the amount of dopamine

01:14:58.900 | that they would receive relief

01:15:00.100 | from those schizophrenic symptoms?

01:15:02.160 | Well, that's all pretty straightforward on the face of it.

01:15:04.400 | But in this situation with bipolar disorder,

01:15:06.400 | what we're talking about is hyperactivity, too much activity,

01:15:09.240 | leading to hypoactivity through death

01:15:12.000 | of those very circuits.

01:15:12.960 | And so now you can especially appreciate why

01:15:16.800 | when the patient shows up to the psychiatrist

01:15:19.080 | or when the psychiatrist shows up to the patient

01:15:20.800 | in the total course of their disease

01:15:23.200 | is going to be very important.

01:15:24.420 | And then layer on top of that the complexity of the fact

01:15:26.880 | that the very defining characteristic of bipolar disorder

01:15:30.160 | is that there are oscillations in mood.

01:15:31.860 | So now we need to think about treatments

01:15:33.760 | not just for the manic episodes,

01:15:35.600 | but also treatments for the depressive episodes.

01:15:38.060 | And that's, in fact, what psychiatrists do.

01:15:40.360 | Turns out that they apply different treatments

01:15:42.720 | or combinations of treatments

01:15:44.400 | for patients that are in manic episodes

01:15:46.540 | versus depressive episodes,

01:15:47.960 | and they have to infer all that from discussions.

01:15:51.460 | Again, just exchange of words,

01:15:53.140 | depending on when that person walked into their office,

01:15:56.740 | where they are in terms of manic episodes,

01:15:59.440 | no symptomology or depressive symptomology,

01:16:02.080 | and whether or not they've had that symptomology

01:16:04.500 | for an extended period of time.

01:16:06.000 | And then just to make the situation even more complicated,

01:16:08.640 | the very circuits that atrophy

01:16:10.300 | that start to wane and disappear

01:16:12.040 | in people with bipolar disorder

01:16:13.500 | are the circuits for interoception,

01:16:15.580 | for understanding of what's going on in one's own body.

01:16:17.800 | So you can imagine if you sit down and ask somebody,

01:16:20.280 | well, how long has it been since you slept?

01:16:23.400 | That person may genuinely not know.

01:16:26.120 | Or if you ask the very depressed person,

01:16:28.680 | how depressed are you?

01:16:29.720 | That person may not be able to articulate that.

01:16:32.560 | So fortunately, there are solutions to this.

01:16:34.900 | And the solution is that more often than not,

01:16:38.600 | the accurate understanding of whether or not

01:16:40.300 | someone has bipolar depression or not,

01:16:43.280 | and what stage of the illness they might be in or not,

01:16:47.200 | is going to depend on the reports of people around them

01:16:50.320 | and not the patient themselves.

01:16:52.260 | Hence, the importance of having a rather detailed

01:16:55.420 | and admittedly a rather intense discussion

01:16:57.560 | about the symptomology of bipolar disorder,

01:16:59.880 | so that you can have an understanding

01:17:03.440 | of the people around you and have an eye and an ear

01:17:06.160 | to whether or not those people

01:17:07.360 | might be suffering from bipolar,

01:17:08.720 | and if so, at what stage of the disease

01:17:10.680 | they might happen to be at.

01:17:11.960 | Now, I'd like to talk a little bit more

01:17:13.240 | about what is known about the neural circuits

01:17:15.280 | that lead to the manic states,

01:17:17.380 | as well as the depressive states,

01:17:18.640 | but mainly the manic states of bipolar disorder.

01:17:22.320 | We already discussed the fact that interoception,

01:17:25.320 | registering of one's own internal emotions

01:17:27.520 | and bodily states,

01:17:28.520 | is diminished in people with bipolar disorder.

01:17:31.160 | But we haven't really talked about the neural circuits

01:17:33.280 | that are responsible for that lack of recognition.

01:17:35.820 | For that reason, I'd like to point out a paper.

01:17:38.960 | This is a fairly recent paper, just came out this year,

01:17:41.720 | but it's an excellent one,

01:17:43.520 | looking at the changes over time in neural circuitry

01:17:46.360 | in people with high genetic risk for bipolar disorder,

01:17:50.380 | and in particular, in young people.

01:17:51.840 | And studies of this sort are rare,

01:17:54.320 | but are exceedingly important because of the fact

01:17:56.660 | that they track individuals over time.

01:17:58.680 | The title of this paper is "Longitudinal Changes

01:18:01.180 | in Structural Connectivity in Young People

01:18:03.460 | at High Genetic Risk for Bipolar Disorder."

01:18:05.880 | We will provide a link to this study

01:18:07.580 | in the show note captions.

01:18:09.200 | There are a lot of data in this paper,

01:18:12.080 | in particular, neuroimaging data,

01:18:14.840 | and it's quite extensive in terms of analyzing

01:18:17.520 | the so-called connectomics.

01:18:19.580 | You've probably heard of genomics,

01:18:21.080 | which is the analysis of genes and their display

01:18:24.000 | in different individuals or different animals, et cetera.

01:18:26.940 | You have proteomics, which is the display of,

01:18:29.680 | or the existence of different proteins.

01:18:31.180 | So omics is a big thing now in science.

01:18:33.260 | You kind of throw omics behind anything,

01:18:35.000 | and it becomes its own Wikipedia page,

01:18:37.340 | which means it becomes its own thing.

01:18:39.220 | So to speak, I say that only partially in jest.

01:18:42.400 | Nonetheless, connectomics is the analysis of connections

01:18:46.940 | between different neurons and neural circuit elements.

01:18:50.100 | And what this paper really showed

01:18:52.000 | by analyzing the connectomics of neural circuits

01:18:54.360 | in the brains of many different people

01:18:57.180 | with different categories of, and onset of,

01:19:01.840 | and severity of bipolar disorder,

01:19:05.420 | as well as controls in different age groups, et cetera,

01:19:10.180 | is that people who are a particularly high risk

01:19:14.940 | for having bipolar disorder

01:19:16.380 | or that have full-blown bipolar disorder

01:19:19.220 | have deficits and actually reductions

01:19:22.280 | in the amount of connectivity

01:19:23.720 | between what are called the parietal brain regions

01:19:25.920 | and the limbic system.

01:19:27.240 | Now, the limbic system I've talked about before

01:19:28.800 | in this podcast, if you're not familiar with it,

01:19:30.620 | I'll explain what it is in a moment.

01:19:32.900 | It's simply a collection of brain structures,

01:19:34.780 | not one brain structure,

01:19:35.800 | but a collection of brain structures

01:19:37.760 | that generally are responsible

01:19:39.600 | for shifting the overall state that we're in

01:19:43.220 | from states of more relaxed and calm

01:19:46.360 | to states of more alert and focused.

01:19:48.820 | The limbic system is intimately related

01:19:51.980 | to the so-called autonomic nervous system,

01:19:53.940 | which regulates our sleep-wake cycles

01:19:56.080 | and a number of other things like our digestion, et cetera,

01:19:59.000 | our level of hunger and on and on.

01:20:01.000 | So the limbic system is really kind of like a volume control

01:20:05.060 | or as nerd scientists like to say,

01:20:07.500 | a kind of game control on the overall level

01:20:11.140 | or amplitude of alertness or calmness.

01:20:13.980 | In fact, if we're very, very calm,

01:20:15.600 | we are asleep or even more calm, we can be in a coma.

01:20:18.620 | If we are very alert, we can be wide awake

01:20:20.960 | and ready to work and run, et cetera.

01:20:22.760 | Or if we are very, very, very alert

01:20:25.020 | by way of limbic autonomic interactions,

01:20:27.540 | well, then we can be in anxiety,

01:20:29.340 | we can be in full-blown panic attack,

01:20:31.100 | or we can be in mania.

01:20:33.380 | We can have so much energy

01:20:35.020 | that we feel like we don't need to sleep.

01:20:36.440 | And in fact, disruptions in the circuitry

01:20:38.780 | really seems to be what's going on

01:20:41.100 | in people who have bipolar disorder.

01:20:43.820 | Now, if disruptions in the circuitry

01:20:46.960 | are present in the limbic system,

01:20:48.300 | that doesn't necessarily mean

01:20:49.460 | that the limbic system is at fault,

01:20:51.720 | because the way that neural circuits work

01:20:53.140 | is that different brain areas are talking to one another

01:20:55.500 | through electrical chemical signaling,

01:20:57.060 | and they are regulating one another.

01:20:58.540 | And what this paper really tells us

01:21:01.060 | is that there are elements within the parietal lobe,

01:21:03.300 | which is a kind of a section of the brain

01:21:04.900 | that sits off to the side, it's not really off to the side,

01:21:07.380 | but in neuroanatomical nomenclature,

01:21:10.740 | the parietal lobe is connected in two ways,

01:21:15.160 | bidirectionally, so parietal lobe

01:21:17.060 | is connecting to limbic system

01:21:18.180 | and limbic system is connecting to parietal lobe.

01:21:20.380 | And in people with bipolar disorder,

01:21:21.980 | it seems that the parietal lobe

01:21:23.380 | is able to exert less top-down control,

01:21:26.580 | that is, less suppression

01:21:28.540 | of certain elements of the limbic system,

01:21:30.740 | which, at least right now,

01:21:33.300 | is leading researchers to hypothesize

01:21:35.420 | that the limbic system is sort of revving at higher levels,

01:21:39.580 | it's kind of like RPM in your car,

01:21:41.160 | it's kind of redlining,

01:21:43.140 | at times and for durations that are inappropriate

01:21:45.820 | or at least abnormal.

01:21:47.220 | So we have two major sets of neural circuit deficits

01:21:51.700 | or changes in people with bipolar.

01:21:53.620 | Their lack of internal awareness is reduced,

01:21:55.700 | and that turns out to be by way of neural structures

01:21:58.300 | like the insula, which is a brain region

01:22:00.940 | that is connected in a very direct way

01:22:03.580 | to our somatosensory cortex,

01:22:05.700 | so the part of our cortex that registers how we feel,

01:22:09.820 | literally, sense of touch and internal state.

01:22:13.100 | So those circuits, excuse me,

01:22:15.380 | for those of you listening, I just bumped the microphone,

01:22:17.740 | excuse me, those circuits are disrupted

01:22:20.780 | in people with bipolar,

01:22:22.060 | and the top-down control,

01:22:24.260 | the kind of accelerator and brake

01:22:26.060 | on our overall levels of energy are also disrupted.

01:22:30.040 | Now, that's all fine and good because, well, it's true,

01:22:34.100 | at least according to what the data

01:22:35.740 | at this point in time tell us,

01:22:37.340 | there may be new discoveries to come,

01:22:38.760 | but that all seems to be the case,

01:22:40.620 | but it doesn't tell us how to modulate

01:22:42.340 | or change that circuitry.

01:22:43.980 | It also doesn't tell us how something like lithium

01:22:47.260 | can actually benefit a large number of patients

01:22:50.180 | or how a good number of the other treatments

01:22:53.060 | for bipolar disorder, which we'll talk about going forward,

01:22:56.000 | can benefit patients with bipolar.

01:22:58.060 | So it appears that lithium is exerting its positive effects

01:23:00.460 | on bipolar depression treatment, at least in part,

01:23:04.100 | by preventing the loss of certain neural circuits,

01:23:06.300 | namely the neural circuits for interoception

01:23:08.140 | and the top-down control over the limbic system.

01:23:10.900 | Now, it turns out that by examining lithium's effects

01:23:14.160 | at an even more reductionist level,

01:23:16.400 | we can gain really important insight

01:23:18.420 | into what's going on in bipolar depression

01:23:20.540 | and some of the other treatments for bipolar depression,

01:23:23.380 | including behavioral treatments,

01:23:25.380 | things like transcranial magnetic stimulation,

01:23:27.420 | and even some of the more natural

01:23:29.580 | or so-called nutraceutical treatments,

01:23:31.780 | including things like high-dose omega-3 supplementation,

01:23:35.360 | which we're going to talk about extensively.

01:23:37.440 | Now, in order to understand

01:23:38.700 | what we're going to talk about next,

01:23:40.060 | it's important that everybody understand

01:23:42.040 | a key concept of neuroplasticity.

01:23:44.020 | And this is a key concept,

01:23:45.540 | regardless of whether or not

01:23:46.460 | one is talking about bipolar depression.

01:23:48.440 | In fact, it's something I think everybody,

01:23:50.060 | every citizen of Earth should know about,

01:23:52.540 | and that's called homeostatic plasticity.

01:23:55.060 | Homeostatic plasticity is a particular form

01:23:57.740 | of neuroplasticity in which if a neural circuit

01:24:01.140 | is overactive for a period of time,

01:24:04.500 | there are changes that occur at the cellular level

01:24:07.500 | that lead to a balance or a homeostatic regulation

01:24:12.040 | of that circuit so that it's no longer overactive.

01:24:15.140 | Conversely, if a neural circuit is underactive

01:24:18.060 | for a period of time,

01:24:19.240 | certain changes happen within the cells of that circuit

01:24:22.160 | to ramp up their activity

01:24:23.620 | or make them more likely to be active.

01:24:26.140 | And whether or not a neural circuit

01:24:27.880 | and the neurons within it become more active

01:24:30.940 | or less active in the context of homeostatic plasticity

01:24:34.120 | largely depends on one mechanism,

01:24:36.200 | and it's a beautiful mechanism

01:24:37.580 | that I'll make very clear to you right now,

01:24:38.980 | even if you don't have a background in biology.

01:24:41.300 | Neurons communicate with one another

01:24:43.000 | by releasing so-called neurotransmitters,

01:24:44.760 | which are just chemicals.

01:24:45.760 | Those neurotransmitters are vomited out.

01:24:48.280 | They're not actually vomited,

01:24:49.120 | but they're spit out into the so-called synaptic cleft,

01:24:51.480 | often called the synapse.

01:24:52.500 | The synapse is just a little gap between neurons.

01:24:54.960 | And when they are released into the synapse,

01:24:58.360 | they don't just stay there.

01:24:59.280 | They actually park or bind to receptors

01:25:01.840 | on what's called the postsynaptic neuron.

01:25:03.840 | And depending on how many receptors they bind to

01:25:07.120 | and how many receptors are available, et cetera,

01:25:09.200 | they can have a greater or lesser effect

01:25:10.820 | on the postsynaptic neuron.

01:25:12.320 | This scenario of neurotransmitters

01:25:14.240 | being released into synapses,

01:25:16.040 | then binding to receptors on postsynaptic neurons

01:25:18.720 | and influencing the electrical excitability

01:25:21.100 | of those postsynaptic neurons,

01:25:22.540 | sits central to not just the treatment of bipolar disorder,

01:25:25.680 | but to all treatments of all psychiatric conditions,

01:25:28.760 | and indeed to things like neuropathic pain as well.

01:25:31.520 | For example, the so-called SSRIs,

01:25:35.000 | Prozac, Zoloft, and others, et cetera,

01:25:37.920 | stands for selective serotonin reuptake inhibitor.

01:25:41.280 | What does that mean?

01:25:42.120 | Well, serotonin is a neurotransmitter.

01:25:44.000 | It's actually a neuromodulator

01:25:45.040 | that's released into the synapse.

01:25:46.560 | And then the SSRI,

01:25:48.720 | the selective serotonin reuptake inhibitor,

01:25:51.380 | allows more of that serotonin

01:25:53.640 | to sit within the synapse for longer, right?

01:25:55.780 | It's a reuptake inhibitor.

01:25:57.360 | It prevents reuptake by the presynaptic neuron.

01:26:00.040 | And that serotonin therefore can park in

01:26:02.780 | or dock in the receptors, as it's called,

01:26:05.480 | of the postsynaptic neuron in greater numbers

01:26:08.080 | and have a greater impact on that postsynaptic neuron.

01:26:11.960 | So the drugs that are used to treat depression

01:26:14.360 | or other things of that sort, things like SSRIs,

01:26:18.000 | work by changing the availability

01:26:20.400 | of neurotransmitter in the synapse.

01:26:22.120 | Other things like MAO inhibitors,

01:26:24.360 | monoamine oxase inhibitors, work a different way.

01:26:27.480 | They inhibit the enzyme.

01:26:28.660 | Anytime you hear ASE in biology,

01:26:30.480 | it's very likely an enzyme which breaks things down.

01:26:33.880 | So MAO inhibitors prevent the breakdown,

01:26:38.000 | not the reuptake, but the breakdown of neurotransmitter,

01:26:40.900 | and therefore allow more neurotransmitter to be available

01:26:44.320 | in the synapse and influence the postsynaptic cell.

01:26:47.500 | Homeostatic plasticity is a form of neuroplasticity

01:26:52.280 | in which overall circuits can become much more excitable

01:26:55.760 | or much less excitable by the addition of more receptors

01:27:00.020 | in the postsynaptic neuron,

01:27:01.500 | or by the removal of more receptors

01:27:03.500 | from the postsynaptic neuron.

01:27:04.680 | And the way this happens is just beautiful.

01:27:06.660 | It was first discovered in the visual system,

01:27:09.260 | and the person primarily responsible

01:27:11.420 | for the discovery of homeostatic plasticity,

01:27:13.300 | although there are several,

01:27:14.460 | is a woman by the name of Gina Turgiano.

01:27:16.200 | She's a professor at Brandeis University.

01:27:18.700 | And what the Turgiano laboratory showed was that,

01:27:21.980 | for instance, if we are in the dark for a long period

01:27:25.980 | of time, literally, and we're not seeing much

01:27:27.720 | for a long period of time,

01:27:28.840 | there's an increase in the number of receptors

01:27:31.020 | in the postsynaptic neurons,

01:27:32.400 | so that a smaller amount of light and excitability

01:27:35.520 | within the visual system can lead to greater amounts

01:27:38.780 | of activity in the visual system.

01:27:40.480 | Conversely, if there's an overactivity

01:27:42.840 | or an increase in activity in the visual system

01:27:45.000 | for some period of time,

01:27:46.640 | then a number of receptors in the postsynaptic neuron

01:27:49.900 | are removed from that postsynaptic neuron surface,

01:27:52.940 | making any neurotransmitter that's available

01:27:55.760 | only able to bind the receptors that are left

01:27:58.120 | and have less of an influence on those cells.

01:28:00.540 | In other words, keeping a circuit

01:28:02.360 | in so-called homeostatic balance

01:28:04.720 | in a particular range of excitability.

01:28:07.780 | Now, while that's a mouthful and an earful

01:28:10.160 | and a conceptful, I don't know if a conceptful is a word,

01:28:13.040 | but in any case, that's a lot to think about,

01:28:15.160 | but all you need to know is that if a neural circuit

01:28:17.360 | is very active for a period of time,

01:28:19.040 | in normal individuals, there will be a reduction

01:28:22.240 | in the amount of activity by way of removing receptors

01:28:25.520 | that bind neurotransmitter,

01:28:26.540 | whereas if a neural circuit is very quiet,

01:28:29.280 | it's not activated for a period of time,

01:28:30.800 | maybe your leg is in a cast, for instance,

01:28:33.040 | and you're not activating your quadricep and calves

01:28:35.900 | very much, well, when that cast comes off,

01:28:38.540 | sure, the muscle might be atrophied,

01:28:40.120 | but the nerves that connect to that muscle

01:28:41.980 | are actually in a position to influence that muscle

01:28:44.480 | even more once you start using that muscle or those muscles,

01:28:48.800 | because whatever neurotransmitter is released

01:28:51.220 | now has the opportunity to bind to more receptors,

01:28:54.800 | in that case, in muscle or in the case of brain circuits

01:28:57.920 | in postsynaptic neurons.

01:28:59.240 | So homeostatic plasticity is this beautiful

01:29:01.960 | balancing mechanism that makes sure that neural circuits

01:29:04.380 | are never too active nor too quiet for too long.

01:29:08.240 | And in a beautiful display of how treatments

01:29:13.240 | can lead to a better understanding of biology,

01:29:15.860 | which can lead to the discovery of even better treatments,

01:29:19.240 | lithium and another compound,

01:29:22.400 | which we'll talk about ketamine,

01:29:24.680 | seem to exert their actions largely through effects

01:29:28.820 | on homeostatic neuroplasticity.

01:29:31.440 | There's a wonderful paper that describes

01:29:33.180 | all the nitty gritty of this.

01:29:34.840 | Certainly most people listening, I'm guessing,

01:29:37.200 | are not going to be interested in all this detail,

01:29:40.540 | but for those of you that you are

01:29:41.720 | and you want to delve deep into this,

01:29:43.600 | this paper was published in Neuron Cell Press Journal,

01:29:46.080 | excellent journal.

01:29:47.680 | It's titled Targeting Homeostatic Plasticity

01:29:50.040 | for the Treatment of Mood Disorders.

01:29:51.700 | And there's one particular figure in this paper

01:29:53.460 | that I'll just describe to you

01:29:54.900 | in which measurements were made from neurons

01:29:58.500 | and the number of receptors in those neurons.

01:30:00.540 | It's done somewhat indirectly through a method

01:30:02.340 | that's detailed and neuroscientists are familiar with.

01:30:05.020 | Basically what it measures is how excited a given neuron is,

01:30:08.720 | electrically excited a given neuron is

01:30:10.580 | to a given amount of neurotransmitter, okay?

01:30:13.400 | So that the amount of neurotransmitter

01:30:15.420 | that's vomited onto a neuron is essentially kept constant.

01:30:18.600 | And then the response of the postsynaptic neuron

01:30:21.000 | is measured.

01:30:21.840 | So it can be of one level or higher or lower

01:30:24.400 | depending on homeostatic plasticity.

01:30:27.380 | And what this paper shows

01:30:30.120 | and what's been shown over and over again

01:30:31.960 | is that when neurons are exposed to lithium

01:30:36.660 | for a period of time,

01:30:37.700 | there is a reduction in the excitability

01:30:41.680 | of the postsynaptic neuron.

01:30:42.820 | That is, neurons within the brain become less excitable

01:30:46.900 | over time if lithium is present,

01:30:50.060 | whereas ketamine, which is now a common FDA approved,

01:30:53.840 | at least in the US,

01:30:54.680 | it's approved for the treatment of major depression,

01:30:57.480 | ketamine does the opposite.

01:30:59.240 | Ketamine seems to increase the number of receptors

01:31:01.680 | in the postsynaptic neuron

01:31:02.820 | and lead to greater levels of excitability

01:31:06.120 | and electrical activity within neural circuits

01:31:08.360 | to a given fixed amount of neurotransmitter.

01:31:11.360 | So this is super interesting

01:31:12.640 | 'cause what it means is that lithium

01:31:14.140 | is causing circuits to be less active.

01:31:16.560 | Ketamine is causing circuits to be more active.

01:31:19.140 | And we know from excellent clinical data now

01:31:22.160 | that ketamine seems to be a very effective treatment

01:31:25.400 | for major depression

01:31:27.280 | and for the major depressive episodes

01:31:30.300 | of people that suffer from bipolar depression

01:31:33.100 | that includes these major depressive episodes

01:31:35.040 | of two weeks or longer of suppressed mood,

01:31:37.500 | appetite, sleep issues, et cetera.

01:31:39.860 | Now, the key thing about ketamine

01:31:42.080 | that's often not discussed

01:31:44.000 | is that while its effects are very potent,

01:31:47.440 | they are transient.

01:31:48.840 | So one major drawback to ketamine therapy for depression

01:31:52.820 | is that it has to be done repeatedly.

01:31:54.560 | And how repeatedly or how often rather

01:31:57.440 | depends of course on a discussion

01:31:59.200 | between the psychiatrist and the patient.

01:32:00.920 | This is not something to cowboy on your own.

01:32:04.520 | I know that, and many of you are probably familiar

01:32:07.040 | with the fact that ketamine also is abused recreationally.

01:32:11.200 | It is a so-called NMDA,

01:32:13.000 | N-methyl-D-aspartate receptor antagonist.

01:32:16.040 | So it blocks the very receptor

01:32:17.620 | that's responsible for neuroplasticity

01:32:19.680 | for changes in neural circuits.

01:32:21.680 | It also changes excitability in neurons as I just described.

01:32:24.160 | So ketamine is a very potent chemical

01:32:26.300 | that has been shown over and over again

01:32:28.800 | and is now FDA approved for the treatment

01:32:30.560 | of major depression,

01:32:31.400 | but its effects seem to be transient.

01:32:33.640 | Lithium, as I described earlier,

01:32:35.560 | seems to reduce the manic episodes

01:32:39.560 | or the intensity of manic episodes and symptomology

01:32:41.760 | in people with bipolar disorder.

01:32:43.280 | It's doing that through neural protection.

01:32:45.160 | So protecting neural circuits from dying away

01:32:47.340 | that initially are overactive

01:32:48.980 | and that overactivity causing excitotoxicity.

01:32:50.920 | It blocks that excitotoxicity, we believe.

01:32:54.460 | And it seems to do that in part

01:32:58.200 | by diminishing the amount of activity in those circuits.

01:33:01.460 | So this is a beautiful mechanistic story.

01:33:04.040 | And it's the sort of story that you'd love to have

01:33:06.360 | for a great number of psychiatric illnesses.

01:33:08.840 | And fortunately, we have for bipolar disorder.

01:33:10.960 | Overactivity of a given circuit

01:33:12.400 | eventually leads to neurotoxicity, excuse me.

01:33:16.440 | Lithium is preventing that neurotoxicity

01:33:18.280 | by reducing the number of receptors

01:33:20.280 | in certain elements within those circuits,

01:33:22.360 | so-called homeostatic scaling.

01:33:24.360 | It's down-regulating the number of receptors,

01:33:26.840 | leading to less excitability

01:33:28.240 | and preventing, we think, excitotoxicity.

01:33:31.000 | And in that sense,

01:33:33.200 | you can see exactly why it's important

01:33:35.520 | to get lithium treatment in there early

01:33:37.280 | for people with bipolar disorder.

01:33:38.960 | Ketamine as a treatment for major depression

01:33:41.580 | seems to be effective, but transient.

01:33:43.640 | And you can also see why it would be important

01:33:45.740 | not just to reduce the manic episodes

01:33:48.580 | for people with bipolar disorder,

01:33:49.820 | but to also treat the depressive episodes.

01:33:52.180 | So this is a key feature of the treatment

01:33:53.840 | for bipolar depression and for bipolar disorder.

01:33:56.880 | There needs to be treatment both of the mania

01:33:59.080 | and of the depressive episodes if they're present.

01:34:01.680 | And fortunately, there are excellent drugs to do that.

01:34:04.540 | And I should mention that ketamine and lithium

01:34:07.420 | are just two of the drugs within the kit

01:34:10.380 | that psychiatrists have access to.

01:34:12.400 | There are many things, olanzapine

01:34:14.820 | and a number of different things, including clozapine.

01:34:18.260 | Clozapine is an antipsychotic,

01:34:20.300 | which is commonly prescribed as a sedative in some cases

01:34:24.700 | that allows people in manic episodes to sleep.

01:34:26.820 | It's classically described

01:34:28.420 | as so-called dopamine receptor four antagonist,

01:34:31.220 | although it does other things as well.

01:34:32.900 | Clozapine has a number of side effect features

01:34:35.780 | related to white blood cell and things of that sort

01:34:39.020 | that require careful monitoring.

01:34:40.620 | So there are an enormous number now,

01:34:44.180 | literally dozens and dozens of different drugs,

01:34:46.700 | each designed to target either the manic phase,

01:34:49.860 | the depressive phase, or some, what we call acute,

01:34:53.700 | sort of early phases versus ongoing treatments.

01:34:56.260 | This is a vast galaxy of drug treatments

01:34:59.420 | that really should be navigated, I should say,

01:35:02.020 | absolutely should be navigated

01:35:03.780 | by a board certified psychiatrist.

01:35:06.300 | And of course, in close discussion

01:35:08.700 | with both the person suffering from bipolar disorder,

01:35:11.800 | but also ideally the family members

01:35:14.340 | of the person suffering from bipolar disorder.

01:35:16.800 | But I think at least up until now,

01:35:19.940 | we've focused on the two major pathways for treatment,

01:35:23.940 | lithium and ketamine.

01:35:25.740 | And we talked about why lithium and ketamine work,

01:35:28.380 | that they're working on opposite ends

01:35:29.700 | of this homeostatic scaling.

01:35:30.900 | We talked a bit about the circuits that are involved

01:35:33.540 | in generating what we think are the manic symptomology

01:35:37.080 | and the lack of interoception,

01:35:38.340 | why people can just persist in staying awake,

01:35:40.440 | awake, awake, not eating, et cetera.

01:35:43.040 | Now you have in mind how all that is put together.

01:35:45.940 | And I think you have in mind

01:35:47.420 | some of the well-demonstrated treatments

01:35:49.920 | for the different component parts of bipolar disorder,

01:35:52.620 | which now I'm hoping you're also well-versed in

01:35:54.700 | based on our early, early discussion

01:35:57.140 | of what constitutes bipolar I and bipolar II.

01:36:00.020 | Now I would like to also talk about

01:36:02.220 | some of the not so typical therapeutics

01:36:04.900 | for bipolar disorder,

01:36:06.460 | and also point to the things that have been tried and failed

01:36:10.260 | for successful treatment of bipolar disorder,

01:36:12.760 | because some of those things are often talked about

01:36:16.620 | and suggested, especially in online communities.

01:36:19.220 | And while it's not clear that any of them

01:36:21.220 | are particularly hazardous on their own,

01:36:24.300 | although some of them do carry some hazards,

01:36:26.960 | I do think it's important

01:36:28.140 | because of the critical time-sensitive nature

01:36:30.900 | of bipolar disorder and the urgency

01:36:32.940 | of getting treatments early

01:36:34.780 | to try and prevent some of the longer lasting

01:36:36.940 | neural circuit changes,

01:36:38.200 | that if people can avoid some of the less effective

01:36:40.660 | or demonstrated to be ineffective treatments,

01:36:43.860 | that they stand to combat bipolar disorder

01:36:46.420 | much more successfully.

01:36:47.580 | First of all, a key point about drug therapies

01:36:50.040 | versus non-drug therapies or talk therapies.

01:36:53.240 | Without question,

01:36:56.380 | drug therapies are going to be most effective

01:36:59.160 | when done also with talk therapies.

01:37:02.020 | And we'll talk about which talk therapies

01:37:03.380 | have been demonstrated to be most effective.

01:37:06.180 | There is some argument about what I'm about to say next,

01:37:08.540 | but in general, most psychiatrists will tell you,

01:37:11.980 | or certainly the ones I've spoken to have told me,

01:37:14.900 | that talk therapy on its own

01:37:17.460 | is rarely, if ever, effective for bipolar depression

01:37:22.380 | and bipolar disorder, whether or not it's BP-1 or BP-2.

01:37:25.660 | That's just the reality of it.

01:37:27.340 | Contrast that with our discussion

01:37:29.080 | about obsessive compulsive disorder,

01:37:30.780 | which we talked about a few episodes ago.

01:37:32.700 | If you haven't seen that episode,

01:37:33.940 | we have an in-depth episode all about OCD

01:37:36.600 | and obsessive compulsive personality disorder.

01:37:39.460 | There, it seems that drug therapies and talk therapies

01:37:42.620 | can be done independently or in combination.

01:37:45.700 | As expected, combined drug and talk therapies

01:37:49.140 | are more effective there than either one alone,

01:37:51.300 | but there are pretty impressive effects of talk therapy alone

01:37:54.480 | provided that they are initiated at the right time

01:37:56.320 | and it's the right form of talk therapy.

01:37:58.540 | That's OCD, but in terms of bipolar disorder,

01:38:01.340 | it really seems that the drug therapies are necessary,

01:38:04.860 | at least in most all cases.

01:38:07.920 | That said, talk therapies are terrific augment or support

01:38:12.580 | for those drug therapies and sometimes can allow people

01:38:14.740 | to take lower doses of those drug therapies,

01:38:16.680 | which turns out to be important

01:38:17.860 | because of the side effect profiles

01:38:19.260 | of a lot of drug therapies and sometimes the cost as well.

01:38:22.040 | I guess we can think of cost

01:38:22.980 | just as another side effect, really.

01:38:24.780 | There are both established and more novel forms

01:38:28.780 | of talk therapy being used, again,

01:38:31.520 | in concert with drug treatments for bipolar disorder.

01:38:34.220 | Cognitive behavioral therapy is the one that seems to be best

01:38:38.740 | at least by way of the statistics and papers that exist.

01:38:41.660 | It's also the one that's been explored the most.

01:38:43.340 | So one of the reasons why it's often considered

01:38:45.460 | the most popular or effective

01:38:46.680 | is 'cause it's also been around longer

01:38:48.120 | and it's been explored the most.

01:38:49.100 | Cognitive behavioral therapy in general is a progressive

01:38:53.460 | exposure of the patient in a very controlled way

01:38:56.400 | in a clinical setting to some of the triggers

01:38:59.140 | or the conditions that would exacerbate bipolar disorder.

01:39:02.780 | Now, earlier I said borderline personality disorder

01:39:05.420 | has all these triggers and triggered elements

01:39:07.900 | from the external environment,

01:39:08.940 | whereas bipolar disorder does not.

01:39:10.900 | And that's still true, but it is the case

01:39:15.140 | that somebody with bipolar can have worse symptoms

01:39:18.680 | if life conditions get worse or more stressful.

01:39:20.520 | So cognitive behavioral therapy in the discussion about,

01:39:24.100 | and sometimes the direct exposure

01:39:25.820 | to anxiety-provoking elements of life

01:39:29.360 | can be very helpful for adjusting the responses

01:39:33.700 | to those otherwise triggering events

01:39:35.400 | and sometimes making the drug treatments more effective

01:39:37.460 | even at lower doses.

01:39:38.600 | There are also forms of therapy

01:39:40.480 | including family-focused therapy,

01:39:42.800 | which is especially important in terms of bipolar disorder

01:39:46.520 | because family members,

01:39:49.740 | provided that they are not themselves in a manic episode

01:39:52.280 | due to the close heritability of bipolar disorder,

01:39:55.820 | but family members can often be excellent windows

01:39:59.640 | into whether or not somebody is doing well or poorly

01:40:02.760 | or is veering toward or is emerging

01:40:04.860 | from a manic or depressive episode

01:40:06.940 | because they understand that person.

01:40:08.180 | They have a lot of data.

01:40:09.740 | It could be purely subjective data,

01:40:11.180 | but they have a lot of exposure to how long or well

01:40:13.240 | somebody has been sleeping or eating, et cetera.

01:40:15.380 | So family-focused therapy involves other members

01:40:17.380 | of the person suffering from bipolar disorders,

01:40:19.340 | family, as well as conversations about family members

01:40:24.080 | in a way that helps patients with bipolar disorder

01:40:26.980 | navigate not just through manic episodes

01:40:28.860 | and depressive episodes,

01:40:29.800 | but start to learn to predict what are the conditions,

01:40:32.900 | psychological, physical, and otherwise,

01:40:35.060 | that can trigger bipolar episodes.

01:40:38.100 | And then there's a category of therapy

01:40:41.040 | called interpersonal and social rhythm therapy.

01:40:44.080 | This is deserving of its own entire episode, really.

01:40:48.120 | Interpersonal and social rhythm therapy

01:40:49.980 | is sort of an expansion on family-focused therapy,

01:40:53.020 | although it's distinct in certain ways as well,

01:40:55.340 | and really focuses on how people are relating to others

01:40:59.220 | in their life and in the workplace

01:41:01.420 | and in the school environment

01:41:03.000 | and also within the family, et cetera.

01:41:04.980 | And I should say that a overall theme that's emerging

01:41:08.740 | in psychiatry and psychology is to start wherever possible

01:41:12.260 | to incorporate more of the social aspects

01:41:15.500 | and the interpersonal aspects.

01:41:17.060 | In other words, not just talking to and examining a patient

01:41:19.900 | as one biological system, one nervous system,

01:41:22.560 | one set of chemicals, and one life,

01:41:24.560 | but rather a set of chemicals, neural circuits,

01:41:27.040 | and a life that's embedded in the chemicals

01:41:28.940 | and neural circuits and lives of other people.

01:41:31.740 | Just by way of example, you can imagine that

01:41:33.580 | if somebody is in a very healthy relationship

01:41:35.940 | or a very abusive relationship,

01:41:37.820 | that that's going to strongly impact

01:41:39.900 | the outcomes of manic episodes.

01:41:41.720 | You can imagine that if the financial situation

01:41:44.380 | is one in which people can recover from manic episodes,

01:41:47.580 | I did mention this earlier, but I should have, forgive me,

01:41:50.360 | that oftentimes people who are in a manic episode

01:41:52.460 | will go out and spend immense amounts of money

01:41:54.780 | that they simply cannot afford to lose.

01:41:56.900 | And then the depressive episodes that in many cases follow

01:42:00.860 | are made far worse by the financial anxiety

01:42:05.100 | and the financial stress that results

01:42:07.260 | from those manic episodes of spending, et cetera.

01:42:09.500 | And then of course, this carries over to sexual promiscuity

01:42:13.280 | where people might be dealing with unwanted pregnancy

01:42:15.840 | or STIs or very fractured interpersonal dynamics

01:42:20.760 | with existing or new relationships.

01:42:22.360 | I mean, you can imagine how these manic episodes

01:42:25.960 | as well as the depressive episodes can really wick out

01:42:28.600 | into an enormous amount of destruction,

01:42:31.100 | which brings us back to the initial criteria of BP1 and BP2

01:42:35.360 | is that these manic episodes are not a good thing.

01:42:39.160 | These depressive episodes are not a good thing.

01:42:41.520 | They create this sense of euphoria

01:42:44.640 | in the person experiencing mania,

01:42:46.380 | or they create the sense that anything is possible,

01:42:48.860 | but at the end of the day, and actually every day,

01:42:52.400 | these episodes are quite maladaptive.

01:42:54.720 | They really destroy people's lives,

01:42:56.440 | and it's not just the life of the person

01:42:58.020 | that's suffering from bipolar disorder.

01:42:59.460 | And so hence, cognitive behavioral therapy,

01:43:01.720 | family-focused therapy,

01:43:02.940 | and interpersonal and social rhythm therapies

01:43:04.840 | are the primary three talk therapies

01:43:07.000 | that are most often combined with drug therapies

01:43:09.520 | in order to try and really reduce the harm.

01:43:12.860 | It's really all about harm reduction

01:43:15.780 | from manic episodes and depressive episodes.

01:43:18.280 | One very exciting and emerging treatment

01:43:20.220 | that does show great promise,

01:43:22.440 | and in some cases, great outcomes for bipolar disorder

01:43:26.220 | is, believe it or not, electric shock therapy.

01:43:29.180 | Electric shock therapy may sound barbaric,

01:43:31.280 | and in fact, it tends to look barbaric,

01:43:33.280 | although this is done in the controlled setting

01:43:34.900 | of a hospital.

01:43:35.760 | If any of you have seen "One Flew Over the Cuckoo's Nest,"

01:43:38.680 | the final scene or near final scene in that movie

01:43:41.640 | was Jack Nicholson with the sort of bite protector

01:43:45.360 | in his mouth and getting electric shock therapy,

01:43:47.560 | and it's, as the name suggests,

01:43:50.620 | it's kind of inducing a global seizure,

01:43:53.280 | either low-level or grand mal-type seizure

01:43:57.080 | in the patient's brain and nervous system.

01:43:59.760 | You might ask, well, why would one want to do that?

01:44:02.600 | Well, it turns out that this is a well-established

01:44:06.040 | and in many cases, very effective treatment

01:44:08.400 | for major depression.

01:44:09.640 | Electric shock therapy is generally used

01:44:12.440 | for treatment-resistant depression,

01:44:14.320 | so these are people that have no positive response

01:44:17.640 | or ongoing positive response to drug therapies

01:44:19.820 | or other therapies.

01:44:20.860 | Electric shock therapy is thought to work primarily

01:44:23.920 | by stimulating the massive kind of indiscriminate release

01:44:27.720 | of things like serotonin, dopamine, acetylcholine,

01:44:31.280 | a huge variety of neuromodulators,

01:44:33.840 | as well as things like BDNF,

01:44:35.560 | brain-derived neurotrophic factor,

01:44:36.800 | which then allows neuroplasticity to take place.

01:44:39.280 | Again, BDNF being permissive for neuroplasticity.

01:44:42.320 | The problem with ECT is that it's really only useful

01:44:45.160 | for treatment-resistant depression.

01:44:47.160 | It doesn't actually target the manic aspects

01:44:49.460 | of bipolar depression and bipolar disorder,

01:44:52.360 | but nonetheless is used when drug treatments don't work.

01:44:56.000 | Some of the negatives of electric shock therapy

01:44:59.740 | or electroconvulsive therapy, ECT is the proper acronym

01:45:03.680 | and way it's described, is that it's quite invasive, right?

01:45:06.680 | This is something that you need to go to the hospital for

01:45:09.120 | and oftentimes there's some inpatient care required

01:45:11.560 | after the electric shock convulsive therapy.

01:45:14.100 | It's a fairly high cost,

01:45:15.420 | especially for those that don't have insurance.

01:45:17.820 | And of course it requires anesthesia.

01:45:20.160 | For most people, that's not going to be a problem,

01:45:21.640 | but for many people that could be a problem.

01:45:24.720 | And there's often some associated memory loss.

01:45:28.380 | And so the memory loss, the invasive nature of ECT

01:45:33.360 | and the cost oftentimes rule out ECT for most patients.

01:45:37.640 | And that's why it's sort of a late stage

01:45:39.200 | or kind of last resort type thing

01:45:41.080 | for treatment-resistant depression.

01:45:42.740 | Nowadays, ketamine type therapy is done repeatedly

01:45:45.600 | or other treatments, for instance,

01:45:47.560 | transcranial magnetic stimulation,

01:45:50.120 | which is basically noninvasive.

01:45:52.120 | It's a coil that's placed on the outside of the skull,

01:45:55.160 | excuse me, and we can more accurately refer to it

01:45:59.760 | as repetitive or RTMS,

01:46:02.300 | repetitive transcranial magnetic stimulation.

01:46:04.900 | Transcranial magnetic stimulation is a tool

01:46:07.660 | that allows researchers and clinicians

01:46:09.700 | to reduce the amount of activity in specific neural circuits

01:46:12.500 | so they can actually target the magnetic field

01:46:15.140 | to particular neural circuits

01:46:16.180 | to reduce activity in those neural circuits.

01:46:18.340 | Again, it's minimally invasive.

01:46:20.020 | It has been shown to be effective

01:46:21.680 | in both increasing neuroplasticity in positive ways,

01:46:25.480 | as well as reducing depressive episodes,

01:46:27.560 | and in a few instances in reducing the amplitude

01:46:31.960 | or the intensity of manic episodes

01:46:33.620 | in people with bipolar disorder.

01:46:35.760 | The problem is it's still a very early technique.

01:46:39.060 | There aren't a lot of clinics and labs doing it.

01:46:41.080 | I'm starting to see more advertisements,

01:46:42.920 | literally commercial clinics

01:46:45.200 | that are advertising RTMS or TMS.

01:46:48.120 | I encourage you to approach those clinics with caution.

01:46:50.600 | I'm of the mind that if those clinics

01:46:53.380 | are not either closely or maybe even distantly associated

01:46:57.000 | with a research institution

01:46:58.200 | that's really up on the latest of RTMS,

01:47:00.580 | you'd be wise to at least do your research, right,

01:47:03.400 | and explore, talk to other patients

01:47:05.900 | who've done these treatments.

01:47:07.360 | But certainly in university hospitals

01:47:09.520 | and in clinical settings and research settings,

01:47:11.640 | RTMS is being used as a way to, for instance,

01:47:15.180 | reduce the activity of certain limbic circuitries

01:47:17.760 | so that people are just overall less excitable and manic,

01:47:20.460 | or to activate,

01:47:22.460 | because it can also be used for activation now,

01:47:24.280 | certain neural circuits,

01:47:25.120 | activate, for instance, the parietal inputs,

01:47:27.180 | the top-down control over the limbic system.

01:47:29.180 | This is all happening right now.

01:47:30.960 | So we have ECT, repetitive TMS, or RTMS,

01:47:34.940 | and then as I mentioned earlier, ketamine therapies,

01:47:36.980 | most of those are targeted

01:47:38.260 | toward the depressive aspects of manic depression.

01:47:41.400 | So for people with bipolar disorder

01:47:42.920 | that doesn't include depression,

01:47:44.300 | those are going to be less effective.

01:47:45.940 | But overall, it's going to be the talk therapies

01:47:48.500 | of the sort that we discussed earlier or a moment ago,

01:47:51.900 | plus drug treatments,

01:47:54.560 | almost always lithium will be explored,

01:47:56.280 | plus some treatments for the depressive episodes,

01:47:58.940 | in particular, if those depressive episodes are present.

01:48:01.900 | Nowadays, there's a lot of excitement about psilocybin,

01:48:04.940 | which is a psychedelic.

01:48:06.380 | In the US, psilocybin is still illegal.

01:48:09.160 | It is not legal,

01:48:10.740 | meaning you can get in a lot of trouble for possessing it,

01:48:14.120 | certainly for selling it, et cetera.

01:48:15.860 | But psilocybin is being explored as a clinical therapy

01:48:18.560 | in certain laboratory settings,

01:48:20.020 | in particular, at Johns Hopkins School of Medicine.

01:48:22.660 | It's being explored in human patients

01:48:24.220 | for the treatment of major depression,

01:48:25.740 | for OCD, I believe, as well,

01:48:28.460 | but certainly for major depression and for eating disorders.

01:48:31.200 | And it seems from the initial wave of publications

01:48:34.300 | from that work done by the incredible Matthew Johnson

01:48:37.860 | or Dr. Matthew Johnson,

01:48:38.980 | who was a guest on this podcast before.

01:48:40.620 | He's also been on the Tim Ferriss podcast.

01:48:43.340 | He's been on the Lex Friedman podcast.

01:48:45.540 | Dr. Matthew Johnson came on this podcast,

01:48:48.060 | has talked about some of the work with psilocybin

01:48:49.720 | for the treatment of depression.

01:48:51.620 | Very impressive results there.

01:48:54.100 | And as you can imagine,

01:48:55.300 | very impressive results for the major depressive episodes

01:48:57.660 | for bipolar.

01:48:58.500 | However, at least to my knowledge, again, to my knowledge,

01:49:02.580 | there have not been any controlled clinical trials

01:49:04.940 | exploring psilocybin for the mania

01:49:07.300 | associated with bipolar disorder.

01:49:08.980 | If someone out there is aware of those clinical trials,

01:49:11.320 | please let me know.

01:49:12.160 | I'll do an update in a future podcast.

01:49:13.940 | But right now, no knowledge from me

01:49:16.900 | about psilocybin clinical trials

01:49:18.620 | for the manic component of bipolar disorder.

01:49:22.340 | A number of people are probably also going to wonder about

01:49:24.780 | whether or not cannabis or medical marijuana

01:49:28.360 | is useful for bipolar disorder.

01:49:31.020 | To address this, I looked to some previous lectures

01:49:34.220 | and some clinicians at Stanford Psychiatry.

01:49:37.620 | This question was asked of them.

01:49:38.980 | And as it turns out,

01:49:40.960 | cannabis does not seem to be effective

01:49:43.400 | for the treatment of the manic phases of bipolar disorder

01:49:46.980 | or for the treatment of the major depressive component.

01:49:50.340 | The only treatment perhaps,

01:49:52.740 | or I should say the only situation perhaps

01:49:55.160 | in which it might be useful,

01:49:56.100 | and this is what was relayed to me,

01:49:57.720 | is that it may help with sleep in certain people

01:50:00.600 | that are having trouble with insomnia.

01:50:03.460 | Though nowadays it's far more common

01:50:05.500 | for people in manic episodes to be prescribed things

01:50:08.000 | like trazodone or other benzos, benzo diazepines,

01:50:11.760 | in order to try and get sleep within the manic episodes.

01:50:14.300 | And benzo diazepines and trazodone, et cetera,

01:50:16.980 | work largely through the so-called GABA system.

01:50:19.240 | This is a neurotransmitter

01:50:21.240 | that causes reductions in excitability of neurons,

01:50:25.140 | hence why it's being used to try and calm people down

01:50:27.780 | and allow them to sleep during their manic episodes.

01:50:29.880 | So not a lot, or essentially no data,

01:50:32.020 | supporting the use of cannabis

01:50:33.280 | for the treatment of bipolar disorder per se,

01:50:35.780 | nor data supporting the use of psilocybin

01:50:38.480 | for the treatment of bipolar disorder per se.

01:50:40.460 | But I realized as I say that,

01:50:43.040 | that there are going to be a number of people

01:50:44.420 | that may have had positive or negative experiences

01:50:48.360 | with cannabis or psilocybin

01:50:49.560 | as they relate to bipolar disorder.

01:50:51.000 | So please, if you're willing or comfortable,

01:50:53.840 | put that if you're comfortable

01:50:54.960 | into the comment section on YouTube.

01:50:57.520 | And of course, if you are aware of any studies

01:50:59.640 | on cannabis or psilocybin showing positive outcomes

01:51:03.060 | for the treatment of bipolar disorder,

01:51:04.920 | please provide links or PubMed ideas to those.

01:51:07.420 | I'd love to peruse those studies.

01:51:10.200 | There are two naturopathic,

01:51:12.300 | or I should say nutrition supplement-based approaches

01:51:15.720 | to bipolar disorder they get talked about a lot.

01:51:18.740 | And one of them shows some interesting promise

01:51:22.000 | or effectiveness even in a limited context.

01:51:26.180 | Before marching into this description

01:51:28.280 | of these two compounds,

01:51:29.860 | in fact, before even mentioning these two compounds,

01:51:32.200 | I do want to emphasize what's been said

01:51:35.460 | and written about over and over again,

01:51:37.480 | and what was relayed to me from expert psychiatrists.

01:51:41.120 | It is not wise to rely purely on talk therapy

01:51:45.720 | or on natural approaches

01:51:48.360 | to the treatment of bipolar disorder,

01:51:49.700 | given the intensity of the disorder

01:51:52.680 | and the high propensity for suicide risk

01:51:56.260 | in people with bipolar disorder.

01:51:57.820 | It is a chemical and neural circuit disruption,

01:52:00.600 | and it needs to be dealt with head on

01:52:02.240 | through the appropriate chemistry

01:52:05.000 | and prescription drug approaches from a board-certified

01:52:07.960 | psychiatrist.

01:52:09.080 | I don't say this to protect me.

01:52:11.320 | I say this truly to protect those who either suffer from

01:52:14.760 | or think they may suffer from bipolar disorder.

01:52:16.800 | If you know someone who you think might suffer

01:52:18.720 | from bipolar disorder.

01:52:19.980 | Now, all that is not to say

01:52:22.600 | that there aren't useful lifestyle interventions

01:52:24.960 | that can support people with bipolar disorder.

01:52:26.840 | So I just briefly want to mention those.

01:52:28.460 | And again, I'm lifting the statements I'm about to make

01:52:30.960 | from some excellent online lectures

01:52:33.760 | from psychiatrists at Stanford and elsewhere,

01:52:36.480 | which essentially say that of course, of course, of course,

01:52:41.480 | getting better sleep, getting adequate exercise,

01:52:45.120 | getting proper nutrition,

01:52:46.640 | having quality, healthy social interactions,

01:52:50.600 | even getting regular sunlight in the day

01:52:52.400 | and avoiding bright light at night.

01:52:53.700 | All of those things are going to braid together

01:52:57.000 | to support the nervous system and the psyche of somebody

01:53:00.640 | with bipolar disorder,

01:53:02.360 | but they braid together to support the psyche

01:53:04.880 | and the neurochemistry and the neural circuits

01:53:06.480 | of anybody and everybody.

01:53:08.380 | So they have generally a modulatory effect.

01:53:11.240 | That is they're indirectly shifting the likelihood

01:53:15.040 | that somebody might have an episode

01:53:17.200 | or the intensity of an episode,

01:53:19.240 | in particular, the depressive episodes, right?

01:53:21.160 | You can imagine how someone who's heading

01:53:22.380 | into a depressive episode,

01:53:23.800 | maybe they're on a lower amount of medication

01:53:25.560 | or they haven't yet medicated

01:53:27.160 | for the depressive episode of bipolar.

01:53:29.200 | And now they're making sure,

01:53:31.400 | or their family is making sure

01:53:32.500 | that they're getting exercise, sunshine, eating correctly,

01:53:35.080 | social engagement, et cetera.

01:53:36.780 | Of course, it makes perfect sense

01:53:38.080 | why they would have perhaps a shallower drop into depression

01:53:41.380 | or maybe even offset a depressive episode.

01:53:43.920 | That said, most all, if not all people with bipolar disorder

01:53:48.740 | are likely to need some sort of drug therapy intervention

01:53:52.620 | in order to help them.

01:53:53.880 | So lifestyle factors are always important

01:53:56.800 | in all individuals,

01:53:58.280 | those suffering from psychiatric conditions or not.

01:54:01.400 | But in some conditions of the mind and body,

01:54:05.460 | those lifestyle interventions can have a greater effect

01:54:08.140 | in offsetting symptoms.

01:54:09.560 | Whereas in bipolar disorder, I think it's naive

01:54:12.480 | and in fact wrong to say that lifestyle interventions alone

01:54:16.320 | are going to prevent especially the extreme forms

01:54:18.800 | of mania and depression.

01:54:20.600 | Again, bipolar disorder being so serious

01:54:23.120 | and carrying such high suicide risk,

01:54:25.420 | we just have to point this out again and again.

01:54:27.500 | Now, with that said, there are two substances

01:54:29.760 | generally found as supplements,

01:54:31.840 | although there are other sources of them as well,

01:54:33.780 | including within nutritional sources that have been shown,

01:54:37.400 | at least in some studies, to be pretty effective

01:54:39.760 | in adjusting the symptoms of bipolar disorder.

01:54:43.340 | And those two things are inositol and omega-3 fatty acids.

01:54:48.340 | Now, inositol is a compound

01:54:51.680 | that is taken for a variety of reasons.

01:54:53.380 | It's something we've talked about on the podcast before.

01:54:55.440 | I personally take inositol

01:54:56.740 | not because I have bipolar disorder.

01:54:58.140 | In fact, I am quite lucky that I don't have bipolar disorder,

01:55:02.120 | but I take inositol at 900 milligrams of myo-inositol

01:55:05.240 | every third night or so in order to improve my sleep.

01:55:07.780 | It's something that I've added to my sleep stack.

01:55:09.640 | It's something that I found greatly enhances the depth

01:55:12.840 | and quality of my sleep.

01:55:14.480 | And if I wake up in the middle of the night

01:55:16.100 | to use the bathroom, et cetera,

01:55:17.360 | it's greatly enhanced my ability to fall back asleep

01:55:20.620 | when I want to go back to sleep.

01:55:22.000 | It also seems to have a fairly potent anti-anxiety effect

01:55:25.880 | during the day.

01:55:26.800 | And as I discussed in our episode

01:55:29.180 | about obsessive compulsive disorder,

01:55:30.800 | inositol has been used at high dosages.

01:55:34.040 | Again, I should say myo-inositol has been used

01:55:35.860 | at high dosages, levels of even 10, 18 grams.

01:55:40.320 | Those are massive dosages, by the way,

01:55:42.440 | to deal with certain symptoms of OCD to limited success.

01:55:46.680 | And I should mention that high dosages

01:55:48.360 | of 10 or 18 grams of inositol

01:55:51.680 | can cause a lot of gastric discomfort, et cetera.

01:55:54.480 | If you want to learn more about inositol

01:55:57.240 | and its various uses,

01:55:58.280 | I encourage you to go to examine.com

01:56:00.920 | where there's the so-called human effect matrix

01:56:03.520 | and that human effects matrix will describe the many places

01:56:07.120 | in which myo-inositol and other forms of inositol

01:56:10.000 | have been shown to be effective in, for instance,

01:56:12.400 | reducing anxiety, enhancing sleep, and on and on.

01:56:15.780 | Myo-inositol is important because myo-inositol,

01:56:19.340 | and we can just say inositol,

01:56:21.440 | is related to so-called second messenger pathways.

01:56:24.160 | I don't want to get too deep

01:56:25.000 | into a second messenger pathways,

01:56:26.240 | but when certain substances bind like neurotransmitters

01:56:29.680 | to a receptor on a cell surface,

01:56:31.640 | oftentimes those receptors themselves will open

01:56:34.180 | and allow the passage of ions and other things into a cell.

01:56:37.280 | Oftentimes they will engage

01:56:39.200 | what are called second messenger systems.

01:56:41.000 | That is, they will trigger mechanisms within the cell

01:56:43.880 | to then go do other things.

01:56:45.480 | This is probably something we should get into

01:56:47.040 | in real detail in a future episode

01:56:48.720 | for those of you that really want to nerd out

01:56:50.380 | on cell-cell signaling, which is a favorite topic of mine.

01:56:53.440 | In any case, inositol is related

01:56:56.040 | to a number of so-called second messenger systems,

01:56:58.380 | this handoff or this kind of stimulating

01:57:01.400 | of changes within a cell that can inspire changes

01:57:05.500 | in what's called a membrane fluidity,

01:57:07.600 | can actually make the membranes of cells,

01:57:10.360 | the outside fence around a cell,

01:57:12.840 | which is made up of fatty stuff,

01:57:14.600 | it can change the fluidity,

01:57:17.520 | meaning how readily things can float around in the membrane.

01:57:21.680 | We think of cells as very rigid,

01:57:23.160 | like there's a cell, there's a neuron,

01:57:24.760 | or there's a immune cell,

01:57:25.980 | but actually those cells have a fatty outside,

01:57:29.840 | in particular neurons have a fatty outside,

01:57:31.960 | it's a thin fatty outside and it's called the cell membrane.

01:57:35.380 | And things are floating around in that cell membrane,

01:57:37.820 | but it's kind of like jello that hasn't quite fixed.

01:57:40.240 | And so things like receptors moving into the synapse

01:57:43.360 | or moving out of the synapse for homeostatic plasticity,

01:57:46.360 | things like the ability for certain genes

01:57:50.720 | to be turned on in a cell or not turned on

01:57:52.560 | can depend a lot on things that are happening

01:57:54.960 | in that cell membrane and how readily things move around

01:57:57.460 | in the cell membrane.

01:57:58.340 | One way to think about this whole picture

01:57:59.920 | of membrane fluidity is that just imagine

01:58:02.720 | that every one of your cells has this layer,

01:58:05.040 | it's kind of a gelatinous-like layer,

01:58:07.400 | and there are lots of little rafts floating around in there,

01:58:10.640 | but those rafts are able to move more quickly

01:58:15.280 | from one place to another,

01:58:16.280 | or get more stuck in one place or another,

01:58:18.520 | depending on how set that jello is.

01:58:21.040 | Inositol and lithium, and as we'll talk about next,

01:58:26.040 | omega-3 fatty acids seem to change

01:58:29.960 | the fluidity of those membranes.

01:58:32.080 | In other words, they allow things to move

01:58:33.960 | in and out of those membranes more readily or not.

01:58:37.320 | And this is no surprise given that those membranes

01:58:42.320 | are made out of fatty stuff.

01:58:44.800 | In particular, the membranes of neurons

01:58:47.160 | are called a lipid bilayer.

01:58:49.200 | It's two layers of fat, okay, bi means two, lipid fat,

01:58:54.200 | and omega-3 fatty acids of the sort

01:58:57.000 | that are found in certain fish,

01:58:59.240 | and that fatty fish in particular,

01:59:01.500 | and that are found in fish oil and cod liver oil, et cetera.

01:59:05.200 | Omega-3 fatty acids, when we ingest them,

01:59:09.080 | are used for a lot of different things,

01:59:11.200 | but they can be readily incorporated into pathways

01:59:14.580 | or directly incorporated into cell membranes,

01:59:17.600 | changing the way those cell membranes work,

01:59:19.680 | and if those cell membranes are the cell membranes

01:59:21.880 | of neurons, changing the way that neurons work.

01:59:24.360 | So the ability for fish oil, and in particular,

01:59:28.520 | the omega-3 fatty acids, which come in varieties

01:59:31.200 | like EPA and DHA, we'll talk about that in a moment,

01:59:34.120 | have been explored at relatively high dosages

01:59:36.800 | for their ability to offset some of the effects of mania

01:59:41.520 | and to offset the effects of depressive episodes

01:59:44.860 | in bipolar disorder.

01:59:46.080 | And actually, the data there are pretty impressive,

01:59:48.560 | although they are varied,

01:59:52.780 | meaning you will find several studies,

01:59:55.320 | and I'll mention a few, that found no effect

01:59:57.800 | of omega-3 supplementation through fish oil.

02:00:00.080 | Usually it's capsuled fish oil,

02:00:01.540 | although fish oil can also be taken in liquid form.

02:00:04.760 | Oftentimes, taking in liquid form

02:00:06.080 | is the more cost-efficient way to do it.

02:00:07.800 | Taking in capsule form is the more palatable way to do it,

02:00:10.920 | because fish oil, for a lot of people, doesn't taste good.

02:00:13.600 | But nonetheless, there are several studies that have shown

02:00:17.540 | that supplementing with fish oil or omega-3 fatty acids

02:00:21.560 | at levels of, for instance, four grams per day

02:00:25.040 | for a period of time.

02:00:25.920 | This is a study that we will link in the show notes.

02:00:27.660 | This is Murphy et al. 2012.

02:00:29.920 | This is a fatty acid supplementation of 70% EPA to DHA,

02:00:34.920 | actually worsened symptoms of mania

02:00:37.560 | over a period of about 16 weeks,

02:00:39.920 | which on the face of it makes it seem like, okay,

02:00:42.040 | omega-3 fatty acid supplementation,

02:00:43.800 | very likely to not be good for bipolar disorder.

02:00:47.120 | And yet, that was the manic phase.

02:00:50.440 | When one looks at some of the other studies

02:00:52.120 | of omega-3 fatty acid supplementation,

02:00:54.700 | there is, for instance, a study published in 1999.

02:00:58.080 | This is a much higher dosage supplementation

02:01:01.200 | with omega-3 fatty acid.

02:01:02.320 | This is a 9.6 grams of fish oil per day for four months.

02:01:06.800 | And that actually greatly reduced symptoms

02:01:10.320 | of bipolar depression compared to the control group,

02:01:14.800 | which received olive oil.

02:01:16.280 | Olive oil is a different form of fat,

02:01:18.080 | monounsaturated fat, but doesn't contain

02:01:20.540 | as much of the omega-3 fatty acids and so forth.

02:01:22.880 | So 9.6 grams of fish oil per day over four months

02:01:27.440 | is a lot of fish oil to be ingesting on a given day.

02:01:31.580 | This was a double-blind study.

02:01:33.920 | This was only carried out, I should mention, in 30 subjects,

02:01:36.760 | but it was males and females.

02:01:38.400 | And the age range was pretty broad,

02:01:39.880 | anywhere from 18 all the way up to 64 years of age,

02:01:42.520 | which is important given the sort of longitudinal

02:01:45.460 | or changes over time that one sees in bipolar disorder.

02:01:49.040 | Here's the major takeaway.

02:01:50.840 | Supplementing with high-dose omega-3s

02:01:52.840 | does seem to be beneficial for a good number of people

02:01:56.040 | with bipolar disorder.

02:01:57.600 | However, again, I want to highlight,

02:01:59.260 | however, it should not be viewed

02:02:01.560 | as the only treatment approach for bipolar disorder.

02:02:04.560 | This goes back to what I was saying before

02:02:06.360 | about the essential need, in most every case,

02:02:09.080 | for high potency prescription drug treatments

02:02:12.360 | prescribed by a board-certified psychiatrist

02:02:14.120 | for bipolar disorder.

02:02:15.000 | However, omega-3 supplementation does seem to improve

02:02:19.840 | or reduce the depressive symptoms

02:02:22.480 | in the major depressive episodes of bipolar.

02:02:24.400 | And there are a couple of studies,

02:02:25.880 | and we'll link to these in the show notes as well,

02:02:27.880 | that show that it may even improve

02:02:29.640 | some of the manic episodes as well,

02:02:31.980 | meaning it reduces some of the manic symptoms.

02:02:34.880 | Now, I say all this from a place of great caution

02:02:38.080 | because I know, especially for listeners of this podcast,

02:02:41.160 | there's a lot of interest in the behavioral tools,

02:02:42.920 | the supplement-based tools, the nutrition tools

02:02:44.560 | that can support bipolar disorder.

02:02:46.280 | But I don't think I can overemphasize enough

02:02:48.600 | that especially for bipolar disorder

02:02:50.560 | and the great risk of suicide and suffering

02:02:53.080 | and inappropriate spending,

02:02:55.120 | or I should say maladaptive spending and impulsivity

02:02:57.480 | that's associated with bipolar disorder,

02:02:59.300 | that it's hard to imagine a scenario

02:03:01.360 | in which just talk therapy and fish oil

02:03:03.440 | and lifestyle interventions are going to completely suppress

02:03:06.840 | or treat bipolar disorder.

02:03:08.280 | People with bipolar disorder really need to consider

02:03:10.840 | the full picture of treatments, the drug treatments,

02:03:13.840 | the talk therapy treatments and lifestyle treatments

02:03:18.160 | and nutraceutical, or we can say supplement-based treatments

02:03:22.800 | such as omega-3 supplementation,

02:03:24.800 | as a full and necessary picture

02:03:28.040 | for dealing with their illness.

02:03:29.880 | I'd be remiss, however, if I didn't emphasize

02:03:32.400 | that the omega-3 fatty acid supplementation

02:03:35.600 | is very interesting,

02:03:36.880 | not just in terms of the subjective effects,

02:03:40.240 | people saying they feel less depressed

02:03:41.760 | or able to sleep better,

02:03:42.760 | or maybe even some reduction in manic symptoms.

02:03:45.160 | There's actually been some really good brain imaging

02:03:47.080 | to try and understand how omega-3 fatty acid treatments

02:03:50.600 | are actually changing the brains and neural circuits

02:03:53.100 | of people with bipolar.

02:03:54.040 | And I will put a reference to this.

02:03:55.320 | This is a paper that was published

02:03:56.840 | in the American Journal of Psychiatry.

02:03:58.760 | It's entitled "Omega-3 Fatty Acid Treatment

02:04:00.940 | and T2 Whole Brain Relaxation Times in Bipolar Disorder."

02:04:05.500 | I don't have the opportunity

02:04:06.980 | to go into a lot of detail right now

02:04:08.700 | about what T2 whole brain relaxation times are,

02:04:11.140 | but basically when people go into a MRI

02:04:13.860 | or F, functional MRI scanner,

02:04:16.340 | magnetic resonance imaging scanner,

02:04:21.340 | what they're getting essentially

02:04:23.380 | is pulses of magnetic fields.

02:04:25.800 | And the way that brain structures

02:04:27.880 | and neural activity can be evaluated

02:04:29.380 | has a lot to do with the sort of spinning,

02:04:32.420 | or not sort of, it has to do with the spinning

02:04:34.520 | and the relaxation times of different elements,

02:04:38.340 | literally the protons and electrons within the neuron.

02:04:41.740 | So it gets really detailed there.

02:04:43.740 | And the relaxation time is essentially looking

02:04:46.180 | at how quickly some of that spinning returns to rest.

02:04:49.940 | And in particular, the fact that the relaxation times

02:04:54.940 | are different for aqueous, that is liquid,

02:04:58.420 | versus lipid, fatty, versus other components of brain tissue.

02:05:03.060 | And basically what this study shows

02:05:05.120 | is that the membranes of neurons within the brains

02:05:08.780 | of these people with bipolar disorder showed more fluidity,

02:05:11.720 | more ability of things to move in and around the membranes,

02:05:14.940 | which we know is an important component of neuroplasticity,

02:05:17.900 | in bipolar subjects that were treated

02:05:20.960 | with omega-3 fatty acids as compared to bipolar subjects

02:05:24.380 | that did not receive omega-3 fatty acids.

02:05:27.320 | And fortunately, this study also included

02:05:29.480 | a healthy comparison group

02:05:31.220 | where they could essentially find that people

02:05:33.900 | with bipolar disorder who supplemented with omega-3s

02:05:36.140 | had changes at the cellular level

02:05:38.560 | and the neural circuit level that brought their brains

02:05:42.460 | and neural circuits closer to that

02:05:44.300 | of the healthy comparison subjects.

02:05:46.300 | So while I don't want to point

02:05:48.660 | to omega-3 fatty acid supplementation

02:05:50.660 | as the be all end all of treatment for bipolar disorder,

02:05:53.060 | certainly it is not,

02:05:54.260 | it does have a strong mechanistic basis

02:05:57.660 | for its possible support of neural circuitry,

02:06:02.660 | of neuroplasticity,

02:06:04.420 | and in particular the ability to make changes

02:06:06.540 | in cell membranes that are very reminiscent

02:06:09.680 | of some of the neural circuit changes

02:06:11.300 | and changes in membrane fluidity

02:06:12.920 | that are seen with lithium treatment

02:06:14.700 | and other known prescription drug treatments

02:06:17.300 | that have been established now for decades

02:06:20.220 | to be very effective for bipolar disorder.

02:06:22.940 | So what that says is that omega-3 supplementation,

02:06:26.420 | while not the only intervention that one should consider,

02:06:30.000 | is something to consider and talk about with your doctor,

02:06:33.100 | and it's operating in powerful ways.

02:06:35.660 | It's not just that it's changing, for instance,

02:06:38.220 | your gut microbiome, which is powerful,

02:06:40.340 | but is indirect to the brain.

02:06:41.500 | It does seem to be having direct effects

02:06:43.180 | on neurons and neural circuits.

02:06:44.900 | Before we begin to conclude our discussion

02:06:46.520 | about bipolar disorder,

02:06:48.180 | I want to talk a little bit about this word disorder.

02:06:50.980 | And this is a theme that doesn't just relate

02:06:52.900 | to bipolar disorder,

02:06:54.260 | but other psychiatric disorders as well.

02:06:56.980 | And when we think of a disorder,

02:06:58.700 | we think of something that is really detrimental to us,

02:07:02.100 | something that really impairs our ability to function

02:07:05.060 | in work and school and relationships,

02:07:06.760 | and really starts to pull down our health status

02:07:10.060 | in a variety of ways.

02:07:11.220 | And certainly bipolar disorder meets those criteria.

02:07:14.940 | However, there is this idea

02:07:17.780 | that things like bipolar disorder,

02:07:19.740 | even things like schizophrenia in some cases,

02:07:22.620 | are responsible for some of the creative aspects

02:07:25.540 | or the creative works that have been observed

02:07:27.840 | and carried out by human beings for many centuries.

02:07:31.100 | And believe it or not,

02:07:32.180 | there are good data to support the fact

02:07:34.140 | that certain aspects of mania

02:07:36.380 | are associated with creativity.

02:07:38.860 | Now, we are long overdue for an episode about creativity.

02:07:42.220 | It's neural circuit basis,

02:07:43.380 | it's chemical basis here on the Huberman Lab podcast.

02:07:45.780 | And certainly we will have that conversation.

02:07:48.260 | But in the meantime,

02:07:49.440 | I'd like to just briefly touch upon this idea

02:07:52.100 | that certain occupations are associated

02:07:54.900 | with a higher incidence of bipolar depression.

02:07:57.840 | And in fact, it's been explored at a research level.

02:08:02.180 | Really, there are data pointing to the fact

02:08:04.580 | that certain individuals of certain occupations

02:08:07.780 | tend to be more creative,

02:08:09.540 | and that creativity is associated with,

02:08:11.660 | again, associate, this isn't causal,

02:08:13.740 | it's associate or correlated with higher levels

02:08:16.900 | or incidents of bipolar depression

02:08:19.060 | and maybe even other forms of depression.

02:08:21.100 | So this is a study looking at mood disorders

02:08:24.220 | in eminent individuals.

02:08:25.820 | So these are people that are not just good at what they do,

02:08:28.940 | but are exceptional at what they do

02:08:30.940 | and explored the percentage of people in given professions

02:08:35.640 | with either depression or mania.

02:08:39.000 | And this was actually a data set gleaned

02:08:41.420 | from more than 1,000 20th century Westerners

02:08:45.100 | based on their biographies

02:08:46.620 | that were reviewed by other people.

02:08:49.020 | So it's a bit of an indirect measurement.

02:08:50.580 | This isn't psychiatrist data.

02:08:52.580 | This is data, or I should say these are data,

02:08:55.740 | that were compiled from self-reports

02:08:59.340 | or from reads of self-reports.

02:09:02.140 | And they explored a number of different professions.

02:09:03.860 | So for instance, they looked at people in the military

02:09:06.500 | or people who were professional athletes

02:09:08.440 | or natural scientists or social scientists,

02:09:11.060 | people who occupied positions in public office

02:09:13.380 | or were musical performers, artists, nonfiction writers,

02:09:17.220 | poetry, et cetera.

02:09:18.580 | There are a lot of professions here.

02:09:20.260 | I will post this, or I'll post a link to it

02:09:22.700 | in the show note captions for you to peruse,

02:09:25.000 | but I'll just give you a sense of the extremes on this graph

02:09:27.820 | because they're very interesting.

02:09:29.420 | It turns out that if you were to look at the profession,

02:09:32.520 | or I should say among the professions

02:09:34.140 | they looked at in this study,

02:09:35.540 | 'cause they didn't look at all professions,

02:09:38.220 | those in the military

02:09:39.940 | and those who are professional athletes

02:09:42.020 | or had jobs in the social or natural sciences had the,

02:09:46.660 | of those, there was a lower percentage of those

02:09:49.680 | that had depression or mania.

02:09:51.960 | In some cases, like those who were professional athletes

02:09:53.900 | didn't seem to have, there was no incidents of mania,

02:09:56.400 | at least in this data set.

02:09:58.160 | Whereas at the opposite extreme of the graph,

02:10:00.580 | those that were poets, so these are eminent individuals,

02:10:04.200 | people that were exceptional poets,

02:10:06.060 | exceptional fiction writers, exceptional artists

02:10:09.360 | or nonfiction writers.

02:10:11.320 | Well, they are especially for the poets.

02:10:14.100 | You find that as many as 90%

02:10:17.940 | of these very successful poets

02:10:20.480 | had either depression or mania.

02:10:23.680 | As high as 90%.

02:10:26.260 | That's incredible.

02:10:27.220 | Contrast that with military,

02:10:28.580 | where it's as few as 10% or professional athletes,

02:10:31.240 | where it's as few as 20%.

02:10:32.460 | And for the professional athletes, as I mentioned before,

02:10:34.580 | none of them had mania.

02:10:36.220 | So does this mean that being a poet

02:10:39.060 | will make you manic or depressed?

02:10:40.600 | Well, first of all, let's look at the poetry category.

02:10:43.320 | It turns out that 75% of these eminent poets,

02:10:47.920 | these highly accomplished poets had major depression.

02:10:51.780 | Whereas only about 20% of those poets had manic episodes.

02:10:57.640 | So again, it's not that being a poet

02:11:02.680 | is going to give you mania.

02:11:03.600 | Certainly we're not saying that.

02:11:04.600 | It's not that being a poet is going to give you depression,

02:11:06.440 | but it turns out that people with depression

02:11:09.620 | and people with depression and mania

02:11:12.220 | seem to gravitate towards poetry,

02:11:14.160 | or at least are very successful at poetry.

02:11:16.440 | Again, associative, correlative,

02:11:19.980 | no causal relationship here.

02:11:22.480 | But it is really striking to see

02:11:24.340 | how the creative occupations, poetry, fiction,

02:11:28.500 | art, nonfiction writing,

02:11:30.340 | even though nonfiction writing is about nonfiction,

02:11:32.140 | it's still creative, music, composition, theater,

02:11:34.940 | much higher incidents of things like mania.

02:11:37.620 | And in fact, for the people in theater, the actors,

02:11:41.020 | even though the overall occurrence of depression and mania

02:11:44.880 | is lower than that in poets,

02:11:47.240 | the fraction of those individuals that have mania

02:11:51.000 | is exceedingly high.

02:11:52.560 | It's about 30% of those that they looked at

02:11:55.320 | who are actors, have manic episodes,

02:12:00.840 | or have full-blown mania.

02:12:02.280 | So I'm referring to these data because,

02:12:04.580 | first of all, I find them incredibly interesting, right?

02:12:06.760 | Up until now, we've been talking about bipolar disorder

02:12:08.700 | and other mood disorders for their maladaptive effects.

02:12:11.700 | And again, they're extremely maladaptive,

02:12:13.360 | much, much higher incidents of suicide, et cetera.

02:12:16.460 | But we'd be wrong to say that certain aspects

02:12:19.020 | of manic episodes don't lend themselves well to creativity,

02:12:22.020 | or that certain aspects of major depression

02:12:23.900 | don't lend themselves well to creativity

02:12:26.980 | or to the performing arts or to poetry.

02:12:29.320 | That said, in no way, shape, or form

02:12:32.920 | do I believe that being depressed is a good thing

02:12:36.280 | or that being manic is a good thing.

02:12:37.880 | Again, we return to the basic foundational criteria

02:12:40.940 | for bipolar disorder and major depression,

02:12:42.500 | which is that the pressured speech, the not sleeping,

02:12:46.960 | the incredible increases in energy and the flights of ideas

02:12:51.760 | are generally not going to lead,

02:12:54.200 | or I think it's fair to say

02:12:56.060 | are not going to lead to good places.

02:12:58.140 | In fact, often lead to bad places.

02:13:00.840 | But we would also be wrong if we didn't consider the fact

02:13:04.140 | that there's a somewhat inextricable relationship

02:13:07.720 | between mania and creativity.

02:13:10.100 | And it could be that hypomania or brief periods of mania,

02:13:15.100 | maybe even an hour a day or 30 minutes a day

02:13:17.480 | of composing or writing poetry,

02:13:19.520 | maybe even some of the lows that we feel, right?

02:13:21.960 | Some of the sadness, some of the grief,

02:13:23.520 | some of the nostalgia that we feel,

02:13:25.200 | provided that it's not pathologic,

02:13:27.280 | that it's not persistent for the four or seven days

02:13:30.240 | that are diagnostic of bipolar II

02:13:32.380 | and bipolar I disorder respectively.

02:13:34.480 | Well, then we can start to view emotional states

02:13:38.080 | as something that can actually lend themselves

02:13:40.360 | to positive outcomes and maybe even to creativity

02:13:43.480 | and to improved occupations.

02:13:45.220 | So it's important that we have a nuanced view

02:13:47.520 | of what sadness versus depression

02:13:50.580 | versus major depression are.

02:13:52.360 | It's important that we distinguish between being erratic,

02:13:57.000 | being very energized and full-blown bipolar disorder.

02:14:00.760 | And I raise this for another reason as well.

02:14:02.760 | Nowadays, it's very common to hear people saying,

02:14:05.600 | "Oh, you know, that person is OCD."

02:14:07.600 | Well, on the episode about OCD that I did a few weeks back,

02:14:11.940 | that you can find if you like at hubermanlab.com,

02:14:15.120 | in that episode, I pointed out that OCD,

02:14:18.700 | obsessive compulsive disorder, is very maladaptive, right?

02:14:21.780 | I think it's number seven, as I recall,

02:14:23.880 | on the list of debilitating diseases,

02:14:26.100 | all diseases in terms of lost time at work,

02:14:29.160 | suffering relationships, et cetera.

02:14:30.840 | So it's a really serious condition.

02:14:32.600 | And yet we often hear, "Oh, that person is obsessive."

02:14:35.040 | And as I pointed out,

02:14:36.360 | there is obsessive compulsive personality disorder.

02:14:38.780 | And then there is obsessive compulsive tendencies

02:14:41.520 | which actually benefit people.

02:14:43.280 | But that is distinct from obsessive compulsive disorder

02:14:46.720 | as a clinically diagnosed thing.

02:14:49.440 | Similarly, we hear that, "Oh, somebody's being bipolar,"

02:14:53.000 | or, "They're all over the place, they're bipolar."

02:14:55.120 | Well, that's a very subjective and label

02:14:58.920 | that people give one another in passing.

02:15:01.840 | More and more often I'm hearing this.

02:15:03.240 | And yet bipolar disorder, whether or not it's BP1 or BP2,

02:15:08.020 | are extremely maladaptive and extremely associated

02:15:12.440 | with high suicide risk.

02:15:14.380 | So while I'm not here to police people,

02:15:17.480 | I'm not certainly not the word police

02:15:18.720 | or the nomenclature police,

02:15:20.280 | I do think that whether or not you refer to people as OCD

02:15:23.160 | or as bipolar, et cetera, that's up to you, all right?

02:15:25.240 | It's not my place to say.

02:15:26.480 | But I do think it's important that all of us understand

02:15:29.040 | that these psychiatric conditions carry with them

02:15:31.600 | tremendous maladaptive weight.

02:15:33.840 | So today we've really done a deep dive

02:15:35.960 | into bipolar disorder and to both the manic

02:15:39.400 | and the depressive components that are present

02:15:42.700 | or can be present in bipolar disorder

02:15:44.960 | and the different forms of bipolar disorder

02:15:46.960 | and some of the major treatments for bipolar disorder,

02:15:49.800 | in particular lithium and its underlying mechanisms

02:15:52.200 | and some of the neural circuit and chemical basis

02:15:54.520 | and neuroplasticity basis of the treatments

02:15:57.600 | for bipolar disorder, in particular homeostatic scaling

02:16:01.640 | or homeostatic plasticity.

02:16:03.800 | All of that, of course, is relevant to bipolar disorder

02:16:06.560 | and I hope will be useful in your understanding

02:16:08.720 | and maybe even in your pursuit of treatments

02:16:10.360 | for bipolar depression, bipolar disorder

02:16:12.680 | for you or other people.

02:16:14.240 | I also hope that it will be useful in your understanding

02:16:16.980 | of how brain circuits work in normal conditions

02:16:19.880 | or in conditions where there is no disease state

02:16:22.240 | or maladaptive conditions.

02:16:23.840 | Homeostatic plasticity is present in all of us.

02:16:27.460 | Membrane fluidity due to how easily things move around

02:16:31.140 | in the surface, the fatty layers on the outside of neurons

02:16:33.920 | and the movement of receptors in and out of neurons,

02:16:35.900 | that is present in all of us.

02:16:37.560 | The influence of omega-3 fatty acids

02:16:39.680 | is central to that discussion,

02:16:41.960 | as is the discussion about various drug treatments

02:16:44.600 | because even if you're not somebody

02:16:45.660 | who's taking a drug treatment

02:16:47.340 | or who is pursuing a drug treatment for bipolar disorder

02:16:49.840 | or another psychiatric condition,

02:16:51.720 | your serotonin levels, your dopamine levels,

02:16:53.720 | your acetylcholine levels,

02:16:54.680 | all of these play into what we call

02:16:56.080 | your mental and physical health.

02:16:57.800 | In fact, if any of you are interested

02:16:59.200 | in the various categories of neuromodulators

02:17:01.560 | and tools to adjust those neuromodulators

02:17:04.020 | under more standard non-disease conditions,

02:17:06.860 | we did an episode on neurochemicals and how to control them.

02:17:10.900 | You can find that at hubermanlab.com

02:17:12.820 | along with all other episodes of the Huberman Lab podcast.

02:17:15.660 | She mentioned everything is timestamped

02:17:17.320 | so you can navigate to the specific topics

02:17:18.920 | and tools of interest to you.

02:17:20.720 | And meanwhile, I just want to thank all of you

02:17:23.400 | for joining me on this voyage through the biology

02:17:27.140 | and the treatments for bipolar disorder.

02:17:29.180 | I do hope you found it beneficial

02:17:31.440 | both for yourself and for others.

02:17:33.320 | I just want to remind people that bipolar disorder

02:17:35.400 | is an extremely serious condition.

02:17:37.520 | If you suspect that you have bipolar disorder

02:17:39.660 | or you know somebody who does,

02:17:41.840 | please make sure that you or they

02:17:43.560 | talk to a qualified health professional.

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02:19:04.460 | It's called the Neural Network Newsletter.

02:19:06.560 | It's completely zero cost,

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02:19:12.240 | You can sign up for it by going to HubermanLab.com,

02:19:14.520 | go to the menu, and click on Neural Network Newsletter.

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02:19:27.320 | So once again, thank you for joining me today

02:19:28.980 | for our discussion about the biology

02:19:30.680 | and treatment of bipolar disorder.

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02:19:34.520 | thank you for your interest in science.

02:19:36.320 | [upbeat music]

02:19:38.900 | (upbeat music)

The Science & Treatment of Bipolar Disorder | Huberman Lab Podcast #82

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