Understanding & Conquering Depression | Huberman Lab Essentials

00:00:00.000 | Welcome to Huberman Lab Essentials,

00:00:02.280 | where we revisit past episodes

00:00:04.060 | for the most potent and actionable science-based tools

00:00:07.260 | for mental health, physical health, and performance.

00:00:09.940 | I'm Andrew Huberman,

00:00:12.600 | and I'm a professor of neurobiology and ophthalmology

00:00:15.280 | at Stanford School of Medicine.

00:00:16.760 | Today, we're discussing depression.

00:00:18.860 | In particular, we're going to talk about major depression.

00:00:21.400 | The phrase major depression is used to distinguish

00:00:24.240 | one form of depression from the other,

00:00:26.420 | the other one being bipolar depression.

00:00:29.300 | Major depression impacts 5% of the population.

00:00:34.040 | That is an enormous number.

00:00:36.140 | That means if you're in a class of 100 people,

00:00:39.220 | five of them are dealing with major depression

00:00:41.220 | or have at some point.

00:00:42.800 | Look around you in any environment,

00:00:45.000 | and you can be sure that a good portion of the people

00:00:49.060 | that you're surrounded by is impacted by depression

00:00:52.320 | or will be at some point.

00:00:53.780 | So this is something we really have to take seriously

00:00:55.620 | and that we want to understand.

00:00:57.480 | It is the number four cause of disability.

00:01:00.380 | A lot of people miss work, miss school,

00:01:03.900 | and before then likely perform poorly in work or school

00:01:07.900 | due to major depression.

00:01:09.500 | So let's talk about the things that are present

00:01:12.400 | in somebody that has major depression.

00:01:15.100 | First of all, there tends to be a lot of grief.

00:01:19.220 | There tends to be a lot of sadness.

00:01:20.580 | That's no surprise.

00:01:22.060 | There's also this thing that we call anhedonia,

00:01:24.500 | a general lack of ability to enjoy things.

00:01:27.240 | For the time being, we want to frame up anhedonia,

00:01:30.260 | this lack of ability to achieve or experience pleasure,

00:01:33.520 | a kind of a flat affect as it's called.

00:01:35.700 | Sometimes even delusional thinking,

00:01:38.720 | negative delusional thinking,

00:01:40.740 | and in particular, anti-self confabulation.

00:01:44.800 | What is anti-self confabulation?

00:01:46.360 | Well, first of all, confabulation is an incredible aspect

00:01:49.700 | of our mind and our nervous system.

00:01:51.380 | You sometimes see other forms of confabulation

00:01:54.640 | in people who have memory deficits,

00:01:57.080 | either because they have brain damage

00:01:58.580 | or they have age-related dementia.

00:02:01.360 | A good example of this would be

00:02:03.300 | someone with age-related dementia

00:02:05.220 | sometimes will find themselves

00:02:07.060 | in a location in the house

00:02:09.000 | and not know how they got there.

00:02:11.180 | And if you ask them,

00:02:12.420 | oh, what are you doing here?

00:02:13.760 | They will create these elaborate stories.

00:02:15.980 | Oh, you know, I was thinking about

00:02:17.120 | going to the shopping today

00:02:18.560 | and I was, you know,

00:02:19.800 | and I was going to take the bus

00:02:20.800 | and then I was going to do,

00:02:21.400 | they create these elaborate stories.

00:02:23.120 | They confabulate.

00:02:24.000 | It's as if a brain circuit that writes stories

00:02:27.240 | just starts generating content.

00:02:29.400 | In major depression,

00:02:31.600 | there's often a state of delusional

00:02:33.780 | anti-self confabulation

00:02:35.460 | where the confabulations are not directly

00:02:38.760 | or completely linked to reality,

00:02:40.440 | but they are ones that make the self,

00:02:43.760 | the person describing them,

00:02:45.080 | seem sick or in some way not well.

00:02:49.520 | A good example would be somebody

00:02:50.980 | who experiences a physical injury, perhaps.

00:02:53.080 | Maybe they break their ankle,

00:02:54.640 | maybe it's an athlete,

00:02:55.540 | and they also happen to become depressed.

00:02:58.480 | And you'll talk to them,

00:02:59.900 | you say, how are things going?

00:03:00.860 | How's your rehab?

00:03:01.480 | And they're like, oh, it's okay.

00:03:02.500 | And I don't know,

00:03:03.540 | I'm just, I feel like I'm getting weaker

00:03:04.960 | and weaker by the day.

00:03:06.080 | I'm just not performing well.

00:03:07.600 | And then you'll talk to the person

00:03:08.520 | that they're working with,

00:03:09.780 | their kinesiologist or whoever

00:03:12.520 | the physical therapist is,

00:03:13.960 | and they'll say, no,

00:03:14.640 | they're actually really improving.

00:03:15.800 | And I tell them they're improving,

00:03:16.920 | but somehow they're not,

00:03:17.840 | they're not seeing that improvement.

00:03:19.580 | They're not registering that improvement.

00:03:21.140 | They are viewing themselves

00:03:23.760 | and they are confabulating

00:03:25.140 | according to a view

00:03:26.320 | that is very self-deprecating

00:03:29.000 | to the point where

00:03:30.080 | it doesn't match up with reality.

00:03:31.960 | The other common symptomology

00:03:34.720 | of major depression

00:03:35.520 | is what they call vegetative symptoms.

00:03:39.120 | Okay.

00:03:39.780 | So vegetative symptoms

00:03:41.380 | are symptoms that occur

00:03:43.100 | without any thinking,

00:03:44.540 | without any doing,

00:03:46.100 | or without any confabulation.

00:03:47.480 | These are things

00:03:48.080 | that are related

00:03:48.600 | to our core physiology,

00:03:50.120 | things like constantly being exhausted.

00:03:52.620 | The person just feels exhausted.

00:03:55.340 | They don't have the energy

00:03:56.860 | they once had.

00:03:57.760 | So it's not in their heads.

00:04:00.260 | Something is disrupted

00:04:01.320 | in the autonomic

00:04:02.340 | or so-called vegetative nervous system.

00:04:04.340 | And one of the most common symptoms

00:04:05.800 | of people with major depression,

00:04:07.900 | one of the signs of major depression

00:04:09.960 | is early waking

00:04:11.560 | and not being able

00:04:13.120 | to fall back asleep

00:04:14.120 | despite being exhausted.

00:04:15.900 | So waking up at 3 a.m.

00:04:18.260 | or 4 a.m.

00:04:19.120 | or 5 a.m.

00:04:19.880 | just spontaneously

00:04:20.840 | and not being able

00:04:21.700 | to go back to sleep.

00:04:22.520 | It's well known

00:04:24.600 | that the architecture of sleep

00:04:26.760 | is disrupted in depression.

00:04:28.740 | What's the architecture of sleep?

00:04:30.560 | Early in the night,

00:04:32.220 | you tend to have slow-wave sleep

00:04:34.140 | more than REM sleep

00:04:35.160 | or rapid eye movement sleep.

00:04:36.240 | As the night goes on,

00:04:37.360 | you tend to have more

00:04:38.000 | rapid eye movement sleep.

00:04:39.220 | That architecture

00:04:40.680 | of slow-wave sleep

00:04:42.220 | preceding rapid eye movement sleep

00:04:44.540 | is radically disrupted

00:04:46.260 | in major depression.

00:04:48.660 | In addition,

00:04:50.200 | the pattern of activity

00:04:51.340 | in the brain

00:04:51.940 | during particular phases of sleep

00:04:53.860 | is disrupted.

00:04:54.460 | And then there are some other things

00:04:56.220 | that relate

00:04:56.820 | to the autonomic nervous system,

00:04:58.280 | but that we normally think of

00:05:00.860 | as more voluntary in nature.

00:05:02.480 | And these are things

00:05:03.660 | like decreased appetite.

00:05:04.900 | So you could imagine

00:05:06.160 | that one could have decreased appetite

00:05:09.120 | because of the anhedonia,

00:05:10.620 | the lack of pleasure from food.

00:05:12.400 | So you can see

00:05:13.140 | that the symptomology

00:05:14.120 | of major depression

00:05:15.080 | impacts us at multiple levels.

00:05:17.380 | There's the conscious level

00:05:18.700 | of how excited we are generally.

00:05:21.200 | Well, that's reduced.

00:05:22.780 | There's grief,

00:05:23.840 | there's guilt,

00:05:24.560 | there's crying,

00:05:26.300 | but then there's also

00:05:27.080 | these vegetative things.

00:05:28.380 | There's disruptions in sleep,

00:05:29.640 | which of course make everything

00:05:30.780 | more challenging

00:05:31.580 | when we're awake.

00:05:32.320 | We know that.

00:05:33.040 | Sleep is so vital

00:05:33.880 | for resetting.

00:05:34.640 | You're waking up early,

00:05:35.780 | you can't get back to sleep.

00:05:36.700 | That's going to adjust

00:05:39.080 | your affect,

00:05:40.560 | your emotions

00:05:41.200 | in negative ways.

00:05:42.100 | We know this.

00:05:42.800 | And appetite is off.

00:05:44.660 | And there are hormones

00:05:46.360 | that get disrupted.

00:05:47.140 | So cortisol levels

00:05:48.800 | are increased.

00:05:49.400 | In particular,

00:05:49.920 | there's a signature pattern

00:05:51.300 | of depression

00:05:52.040 | whereby cortisol,

00:05:54.020 | this stress hormone

00:05:55.020 | that normally is released

00:05:56.420 | in a healthy way

00:05:57.400 | only in the early part

00:05:58.780 | of the day

00:05:59.380 | is shifted

00:06:00.380 | to late in the day.

00:06:02.120 | In fact,

00:06:02.880 | a 9 p.m. peak

00:06:04.320 | in cortisol

00:06:04.880 | is one of the

00:06:06.260 | physiological signatures

00:06:08.040 | of depressive-like states.

00:06:10.560 | It's not the only one,

00:06:11.580 | but it is an important one.

00:06:13.500 | So let's just take

00:06:14.600 | a few minutes

00:06:15.140 | and talk about

00:06:16.320 | some of the underlying biology

00:06:17.780 | that creates

00:06:19.400 | this cloud

00:06:20.920 | or this constellation

00:06:21.900 | of symptomology.

00:06:23.120 | One of the most important

00:06:24.400 | early findings

00:06:25.420 | in the search

00:06:26.980 | for a biological basis

00:06:28.720 | of depression

00:06:29.340 | was this finding

00:06:31.240 | that there are drugs

00:06:32.800 | that relieve

00:06:34.200 | some of the symptoms

00:06:35.020 | of depression.

00:06:35.640 | Those drugs

00:06:37.600 | generally fall

00:06:38.660 | into three major categories,

00:06:40.480 | but the first set

00:06:41.740 | of ones

00:06:42.120 | that were discovered

00:06:42.840 | were the so-called

00:06:44.060 | tricyclic antidepressants

00:06:46.020 | and the MAO inhibitors,

00:06:49.140 | the monoamine oxidase inhibitors.

00:06:51.300 | And these tricyclic antidepressants

00:06:54.000 | and the MAO inhibitors

00:06:55.880 | largely worked

00:06:58.120 | by increasing levels

00:06:59.940 | of norepinephrine

00:07:01.520 | in the brain

00:07:02.480 | as well as in the body

00:07:03.600 | in some cases.

00:07:04.380 | They were discovered

00:07:05.640 | because of the exploration

00:07:07.240 | for drugs

00:07:08.240 | that alter blood pressure.

00:07:09.920 | Norepinephrine impacts

00:07:12.120 | blood pressure

00:07:12.880 | and drugs

00:07:14.380 | that lower

00:07:15.120 | blood pressure,

00:07:16.120 | reduce levels

00:07:17.680 | of norepinephrine,

00:07:18.540 | and that

00:07:19.500 | in many cases

00:07:20.680 | was shown

00:07:21.080 | to lead to

00:07:21.980 | depression

00:07:22.700 | or depressive-like

00:07:23.780 | symptoms.

00:07:24.360 | These tricyclic drugs

00:07:26.100 | and the MAO inhibitors

00:07:27.440 | actually increase

00:07:29.080 | norepinephrine

00:07:29.800 | and frankly,

00:07:31.020 | they do

00:07:31.660 | quite a good job

00:07:32.720 | of relieving

00:07:33.560 | some,

00:07:34.260 | if not all,

00:07:34.940 | of the symptoms

00:07:35.620 | of major depression.

00:07:37.780 | However,

00:07:38.300 | they carry with them

00:07:39.200 | many side effects.

00:07:40.300 | Some of those side effects

00:07:41.680 | are side effects

00:07:43.020 | related to blood pressure

00:07:43.980 | itself.

00:07:44.380 | By increasing

00:07:45.060 | noradrenaline,

00:07:46.060 | norepinephrine

00:07:46.640 | as it's called,

00:07:47.220 | you raise blood pressure.

00:07:48.360 | That can be dangerous.

00:07:49.360 | But they also have

00:07:50.900 | a lot of other side effects.

00:07:52.580 | The reason they have

00:07:54.020 | other side effects

00:07:54.800 | is because they impact

00:07:56.040 | systems in the brain

00:07:57.120 | and in the body

00:07:58.100 | that impact things

00:07:59.300 | like libido,

00:08:00.280 | appetite,

00:08:01.540 | digestion,

00:08:02.680 | and others.

00:08:03.720 | They made some people

00:08:04.560 | so uncomfortable

00:08:05.200 | that they preferred

00:08:05.980 | not to take them

00:08:06.800 | even though

00:08:07.340 | when they didn't

00:08:08.360 | take them,

00:08:08.700 | they had a worsening

00:08:09.900 | or a maintenance

00:08:10.440 | of their depressive symptoms.

00:08:11.640 | A decade or so later,

00:08:13.200 | there was the discovery

00:08:14.540 | of the so-called

00:08:15.440 | pleasure pathways

00:08:16.320 | in the brain.

00:08:16.920 | This pleasure pathway

00:08:18.840 | as it's sometimes called

00:08:20.220 | involves areas

00:08:21.080 | like the nucleus accumbens

00:08:22.480 | and the ventral tegmental area.

00:08:24.060 | These are areas

00:08:25.180 | of the brain

00:08:25.720 | that are rich

00:08:26.380 | with neurons

00:08:27.000 | that make dopamine.

00:08:28.080 | And if you think

00:08:29.580 | to the symptoms

00:08:30.380 | of depression,

00:08:31.260 | of anhedonia,

00:08:32.300 | lack of pleasure,

00:08:33.160 | a lack of ability

00:08:34.140 | to experience pleasure,

00:08:35.300 | well,

00:08:36.520 | that was a smoking gun

00:08:37.820 | that there's something wrong

00:08:39.860 | with the dopamine pathway

00:08:40.940 | in depression.

00:08:42.440 | So it's not just norepinephrine,

00:08:44.000 | it's also the dopamine

00:08:45.320 | or pleasure pathway

00:08:46.340 | is somehow disrupted.

00:08:47.360 | And then in the 1980s,

00:08:49.220 | there was the discovery

00:08:50.060 | of the so-called SSRIs.

00:08:51.860 | Most people are now familiar

00:08:52.860 | with the SSRIs,

00:08:54.120 | the selective serotonin

00:08:55.420 | reuptake inhibitors.

00:08:56.780 | The SSRIs worked

00:08:58.940 | by distinct mechanisms

00:09:00.320 | from the tricyclic antidepressants

00:09:03.280 | and the MAO inhibitors.

00:09:04.440 | As their name suggests,

00:09:05.900 | SSRI,

00:09:06.900 | selective serotonin

00:09:08.100 | reuptake inhibitors,

00:09:09.020 | prevent serotonin

00:09:11.400 | from being wiped up

00:09:13.800 | from the synapse

00:09:15.040 | after two neurons

00:09:16.400 | talk to one another.

00:09:17.160 | What do I mean by that?

00:09:18.040 | Well,

00:09:18.280 | here's some very basic

00:09:19.740 | neurobiology 101.

00:09:20.620 | If you don't know

00:09:21.260 | any neurobiology,

00:09:22.100 | you're going to know

00:09:22.920 | some in about 15 seconds.

00:09:24.820 | Neurons communicate

00:09:26.180 | with one another

00:09:26.860 | by spitting out chemicals

00:09:29.280 | into the little gap

00:09:30.440 | between them.

00:09:31.180 | The little gap between them

00:09:32.340 | is called the synapse.

00:09:33.340 | Those chemicals

00:09:34.320 | bind to the neuron

00:09:35.880 | on the opposite side

00:09:36.940 | and cause changes

00:09:38.220 | in the electrical activity

00:09:39.380 | of that neuron

00:09:40.140 | on the other side

00:09:41.140 | of the synapse.

00:09:41.740 | Serotonin is one

00:09:43.920 | such neurotransmitter

00:09:45.320 | or more specifically,

00:09:46.340 | it's a neuromodulator.

00:09:47.960 | It can change the activity

00:09:49.060 | of large groups of neurons

00:09:50.520 | in very meaningful ways.

00:09:51.980 | Selective serotonin

00:09:53.620 | reuptake inhibitor

00:09:54.700 | means when a person

00:09:56.500 | takes this drug,

00:09:58.360 | some of those drugs

00:09:59.040 | include things like

00:09:59.700 | Prozac or Zoloft.

00:10:01.100 | The more typical names

00:10:02.320 | or more generic names

00:10:03.620 | are things like fluoxetine.

00:10:04.900 | When people take those,

00:10:06.740 | more serotonin

00:10:08.080 | hangs out in the synapse

00:10:09.760 | and is able to be taken up

00:10:11.380 | by the neuron

00:10:12.080 | on the opposite side

00:10:13.320 | because of this selective

00:10:15.840 | reuptake inhibition.

00:10:18.340 | It prevents the clearance

00:10:21.140 | of serotonin

00:10:22.040 | from the synapse

00:10:22.740 | and thereby more serotonin

00:10:24.740 | can have an effect.

00:10:25.600 | So SSRIs

00:10:26.920 | don't increase

00:10:27.920 | the total amount

00:10:28.880 | of serotonin

00:10:29.520 | in the brain.

00:10:30.040 | They change

00:10:31.300 | how effective

00:10:32.400 | the serotonin

00:10:33.600 | that's already

00:10:34.240 | in the brain

00:10:34.820 | is at changing

00:10:36.360 | the activity

00:10:37.060 | of neurons.

00:10:38.580 | About a third

00:10:39.960 | of people

00:10:40.420 | that take SSRIs

00:10:41.780 | don't derive

00:10:43.160 | any benefit.

00:10:43.840 | It doesn't relieve

00:10:44.900 | their symptoms

00:10:45.380 | of depression.

00:10:45.980 | However,

00:10:46.680 | for the other two-thirds,

00:10:47.820 | there's often a relief

00:10:49.220 | of some,

00:10:49.860 | if not all,

00:10:50.500 | of the symptoms

00:10:50.980 | of major depression.

00:10:52.340 | the problem

00:10:53.020 | is the side effects

00:10:54.060 | that accompany

00:10:54.940 | those SSRIs.

00:10:56.220 | And so these days,

00:10:57.740 | SSRIs are a complicated topic.

00:10:59.680 | It's sort of what I would call

00:11:00.620 | a barbed wire topic,

00:11:01.720 | but these drugs also

00:11:02.900 | have saved a lot of lives.

00:11:04.060 | They've also improved

00:11:05.400 | a lot of lives.

00:11:06.180 | The issue

00:11:08.300 | is that they tend

00:11:09.220 | to have varying effects

00:11:10.280 | on different individuals

00:11:11.400 | and sometimes varying effects

00:11:12.700 | over time.

00:11:13.480 | So they'll work for a while,

00:11:15.040 | then they won't work for a while.

00:11:16.140 | There are also a lot

00:11:16.760 | of mysteries

00:11:17.380 | about the SSRIs

00:11:18.960 | and those mysteries

00:11:19.960 | bother people.

00:11:20.880 | SSRIs increase

00:11:23.260 | the amount of serotonin

00:11:24.480 | or more specifically,

00:11:25.480 | they increase

00:11:26.560 | the efficacy

00:11:27.100 | of serotonin

00:11:27.940 | at the synapse.

00:11:28.680 | That happens immediately

00:11:30.780 | or very soon

00:11:32.080 | after people start

00:11:32.740 | taking SSRIs,

00:11:33.820 | but people generally

00:11:35.020 | don't start experiencing

00:11:36.120 | any relief

00:11:36.800 | from their symptoms

00:11:37.640 | of depression

00:11:38.260 | if they're going

00:11:39.100 | to experience them

00:11:40.660 | at all

00:11:41.060 | until about two weeks

00:11:42.260 | after they start

00:11:42.940 | taking these drugs.

00:11:43.820 | So it's very clear

00:11:45.700 | that there are

00:11:46.400 | at least three

00:11:47.560 | major chemical systems

00:11:48.780 | in the brain,

00:11:49.360 | norepinephrine,

00:11:50.200 | dopamine,

00:11:50.680 | and serotonin

00:11:51.800 | that relate to

00:11:53.600 | and can adjust

00:11:54.780 | the symptoms

00:11:55.460 | of depression.

00:11:56.320 | And those actually

00:11:57.440 | can be divided

00:11:58.280 | into separate categories.

00:11:59.880 | So for instance,

00:12:00.600 | epinephrine

00:12:01.400 | or norepinephrine

00:12:03.700 | is thought to relate

00:12:04.800 | to the so-called

00:12:05.520 | psychomotor defects.

00:12:07.060 | This is the lethargy.

00:12:08.140 | This is the exhaustion.

00:12:09.520 | This is the inability

00:12:10.600 | to get out of bed

00:12:11.360 | in the morning.

00:12:11.840 | Dopamine

00:12:13.140 | is thought to relate

00:12:14.200 | to the anhedonia

00:12:15.180 | or I should say

00:12:16.680 | lack of dopamine

00:12:17.680 | in depressive patients

00:12:19.480 | is thought to lead

00:12:20.220 | to the anhedonia,

00:12:21.680 | the lack of ability

00:12:22.780 | to experience pleasure.

00:12:24.140 | And serotonin

00:12:26.640 | is thought to relate

00:12:27.680 | to the grief,

00:12:28.920 | the guilt,

00:12:29.720 | some of the more cognitive

00:12:31.160 | or more emotional aspects

00:12:33.060 | of depression.

00:12:34.160 | So we've got

00:12:35.320 | the norepinephrine system

00:12:36.300 | related to activity

00:12:37.600 | and alertness,

00:12:38.260 | the dopamine system

00:12:39.400 | relating to motivation,

00:12:40.560 | pleasure,

00:12:41.560 | and the ability

00:12:42.160 | to seek

00:12:42.680 | and experience pleasure

00:12:43.820 | and then the serotonin system

00:12:45.700 | that's related to grief.

00:12:47.440 | And unfortunately,

00:12:48.800 | brains and organisms

00:12:50.280 | don't work

00:12:51.020 | in a simple mathematical way

00:12:53.380 | where you just say,

00:12:54.040 | oh, well,

00:12:54.420 | this person's experiencing

00:12:55.400 | a lot of grief,

00:12:56.080 | but they don't have

00:12:56.880 | any problems with,

00:12:57.900 | you know,

00:12:58.980 | lethargy.

00:12:59.740 | And so let's just boost

00:13:01.000 | up their serotonin.

00:13:01.840 | On paper,

00:13:02.420 | it works,

00:13:02.840 | but oftentimes

00:13:03.420 | it doesn't work clinically.

00:13:04.760 | A really good psychiatrist

00:13:05.920 | will work with someone

00:13:06.680 | to try and pull

00:13:07.880 | and push

00:13:08.280 | on these various systems

00:13:09.180 | to find the combination

00:13:10.140 | of drugs

00:13:11.320 | that may be

00:13:12.040 | or may not be

00:13:12.900 | correct for them.

00:13:13.760 | So next,

00:13:14.620 | I'd like to talk

00:13:15.160 | about hormones

00:13:15.800 | and how they relate

00:13:16.600 | to depression.

00:13:17.140 | And I'd also like

00:13:18.840 | to talk about stress

00:13:19.780 | and how it relates

00:13:20.600 | to depression,

00:13:21.140 | as well as talk

00:13:22.120 | about some of the genetics

00:13:23.260 | or the predispositions

00:13:24.700 | to depression.

00:13:26.120 | 20% of people

00:13:28.020 | that have major depression

00:13:29.140 | have low thyroid hormone.

00:13:31.020 | And that leads

00:13:32.400 | to low energy,

00:13:33.420 | low metabolism

00:13:34.700 | in the brain

00:13:35.540 | and body.

00:13:36.740 | Sometimes a psychiatrist

00:13:38.000 | will prescribe

00:13:39.060 | thyroid medication

00:13:40.200 | to increase thyroid output

00:13:41.840 | in people

00:13:42.320 | that are depressed

00:13:43.040 | and that will work

00:13:43.720 | to relieve the symptoms.

00:13:44.620 | So there are certain

00:13:45.780 | situations or conditions

00:13:47.100 | that can impact

00:13:48.360 | the thyroid hormone system

00:13:49.960 | and make people

00:13:51.300 | more susceptible

00:13:52.160 | to depression

00:13:52.960 | or make a pre-existing

00:13:54.080 | depression worse.

00:13:55.040 | And those are things

00:13:56.340 | like childbirth.

00:13:57.500 | So it's well known

00:13:58.580 | that women who give birth

00:13:59.600 | can often undergo

00:14:00.760 | what's called

00:14:01.180 | postpartum depression

00:14:02.320 | and that's thought

00:14:03.000 | to be hormonally related

00:14:04.280 | either directly

00:14:06.040 | to the thyroid system

00:14:07.240 | or perhaps

00:14:07.960 | to the cortisol system

00:14:09.020 | as well.

00:14:09.300 | We'll talk about cortisol

00:14:10.100 | in a moment.

00:14:10.620 | As well,

00:14:11.480 | certain women

00:14:12.500 | during certain phases

00:14:13.460 | of their menstrual cycle

00:14:14.440 | experience symptoms

00:14:16.400 | that are very much

00:14:17.380 | like clinical depression

00:14:19.240 | and oftentimes

00:14:20.080 | are diagnosed

00:14:21.240 | with clinical depression

00:14:22.100 | appropriately.

00:14:22.640 | And of course,

00:14:24.080 | the menstrual cycle

00:14:24.700 | is associated

00:14:25.200 | with shifts

00:14:25.660 | in hormone levels.

00:14:26.460 | As well,

00:14:26.980 | menopause

00:14:27.500 | and postmenopausal

00:14:28.880 | women

00:14:29.740 | are more susceptible

00:14:31.020 | to major depression

00:14:32.840 | regardless of whether

00:14:33.760 | or not they've had

00:14:34.340 | that major depression

00:14:35.040 | earlier in their life.

00:14:35.940 | So these are things

00:14:36.540 | to be on the lookout for

00:14:37.600 | and to definitely

00:14:38.420 | talk to a doctor

00:14:39.280 | and get a blood panel

00:14:40.480 | that hopefully includes

00:14:41.660 | measures of thyroid hormone

00:14:43.000 | and cortisol hormone.

00:14:44.180 | Why cortisol hormone?

00:14:45.240 | Well,

00:14:45.740 | more stress

00:14:47.180 | is correlated

00:14:47.800 | with more bouts

00:14:48.660 | of major depression

00:14:49.580 | across the lifespan.

00:14:50.540 | How many bouts?

00:14:52.200 | Well,

00:14:52.540 | it turns out

00:14:53.900 | that as you go

00:14:55.020 | from having one

00:14:55.920 | to two

00:14:56.340 | to three,

00:14:56.820 | well,

00:14:57.160 | when you hit

00:14:57.840 | four to five bouts

00:14:59.020 | of really intense

00:15:00.260 | to stressful episodes

00:15:01.580 | in life,

00:15:02.120 | these tend to be

00:15:02.960 | long-term stressful episodes,

00:15:04.520 | your risk

00:15:05.340 | for major depression

00:15:06.380 | goes way up.

00:15:07.600 | And that's because

00:15:08.480 | the stress system

00:15:09.460 | is associated

00:15:09.980 | with the release

00:15:10.480 | of cortisol.

00:15:11.100 | The cortisol system

00:15:12.420 | can dramatically impact

00:15:13.960 | the way

00:15:14.240 | that these different

00:15:14.940 | neuromodulators,

00:15:16.040 | dopamine,

00:15:16.480 | norepinephrine,

00:15:17.100 | and serotonin function.

00:15:18.160 | One of the more

00:15:19.720 | important reasons

00:15:20.500 | for learning

00:15:21.160 | how to counter stress

00:15:22.180 | in order to offset

00:15:23.160 | depression

00:15:24.380 | is that there is

00:15:25.880 | a genetic predisposition

00:15:27.380 | that certain people

00:15:28.240 | carry to become depressed.

00:15:29.620 | How do we know?

00:15:30.600 | Well,

00:15:31.000 | in what are called

00:15:32.100 | concordant monozygotic twins.

00:15:34.860 | So these would be

00:15:35.720 | identical twins

00:15:36.720 | for which one

00:15:37.940 | of those twins

00:15:38.460 | goes on to have

00:15:39.160 | major depression.

00:15:39.820 | There's a 50% probability

00:15:41.280 | that the other one

00:15:42.200 | will have major depression.

00:15:43.380 | So it's not 100%.

00:15:44.540 | It's not 100% inherited.

00:15:46.440 | It's not 100% genetic,

00:15:48.340 | as you might say,

00:15:49.420 | but there's a much

00:15:50.620 | higher predisposition

00:15:51.800 | for depression.

00:15:53.940 | Whereas in fraternal twins

00:15:56.920 | that number drops

00:15:58.100 | and in siblings

00:15:59.200 | that number drops

00:15:59.920 | to about 25%

00:16:01.180 | and in half siblings

00:16:02.640 | it's about 10%.

00:16:04.120 | Basically,

00:16:04.680 | the more closely related

00:16:05.800 | you are to somebody

00:16:06.780 | who has major depression,

00:16:08.420 | the more likely it is

00:16:10.100 | that you will also

00:16:10.720 | get major depression.

00:16:11.500 | And therefore,

00:16:12.140 | if you haven't gotten

00:16:13.420 | major depression,

00:16:14.060 | the more likely it is

00:16:15.340 | that you should

00:16:15.980 | take steps

00:16:17.580 | to learn

00:16:18.660 | to mitigate stress

00:16:19.680 | because stress

00:16:20.300 | is the major factor

00:16:21.120 | that can trigger

00:16:21.780 | one of these

00:16:22.220 | depressive episodes.

00:16:23.180 | So next,

00:16:24.140 | I'd like to talk

00:16:24.740 | about some of the tools

00:16:25.720 | that people

00:16:26.240 | who both have depression

00:16:28.260 | or who are prone

00:16:29.620 | to depression

00:16:30.100 | as well as people

00:16:30.680 | who don't have depression

00:16:31.500 | and simply want

00:16:32.160 | to maintain a good mood,

00:16:34.060 | who want to maintain

00:16:34.840 | a positive affect

00:16:35.740 | and pursuit of things in life.

00:16:37.080 | What are the things

00:16:38.040 | that you can do?

00:16:38.600 | Any behavioral tool

00:16:39.900 | that adjusts the levels

00:16:41.420 | of a particular chemical

00:16:42.360 | ought to perhaps

00:16:43.980 | provide some relief

00:16:45.200 | for some of the symptoms

00:16:46.180 | of major depression.

00:16:46.960 | Let's take an example

00:16:48.280 | that I've talked about

00:16:50.000 | before on the podcast,

00:16:50.900 | which is if you get

00:16:51.820 | into a very cold shower,

00:16:52.880 | you take an ice bath,

00:16:53.940 | you will release

00:16:55.280 | norepinephrine

00:16:56.000 | and epinephrine

00:16:56.640 | in your brain and body.

00:16:57.680 | There's no question

00:16:58.380 | about that.

00:16:58.980 | If some aspects

00:17:01.000 | of depression

00:17:01.520 | are related to low levels

00:17:02.960 | of norepinephrine,

00:17:03.760 | will taking cold showers

00:17:05.320 | relieve your depression?

00:17:06.660 | Perhaps it might even

00:17:08.880 | relieve certain aspects

00:17:09.800 | of that depression.

00:17:10.540 | Will exercise help?

00:17:11.740 | Well, if you go out

00:17:12.520 | for a run,

00:17:13.160 | you're going to increase

00:17:14.560 | the amount of norepinephrine

00:17:15.600 | in your body.

00:17:16.200 | If you enjoy that run,

00:17:18.560 | it's likely that you'll

00:17:19.660 | increase the levels

00:17:20.540 | of dopamine

00:17:21.460 | and probably serotonin

00:17:22.660 | in your brain

00:17:23.380 | and body as well.

00:17:24.180 | Will that cure

00:17:25.220 | your depression?

00:17:25.680 | Well, there are a lot

00:17:26.600 | of studies exploring

00:17:27.600 | how exercise

00:17:28.620 | can impact depression

00:17:29.720 | and indeed,

00:17:30.220 | regular exercise

00:17:31.200 | is known to be

00:17:32.700 | a protective behavior

00:17:34.460 | against depression,

00:17:35.520 | but it also can help

00:17:37.980 | relieve some of the symptoms

00:17:38.840 | of depression.

00:17:39.440 | So you may ask yourself,

00:17:41.240 | why would you need drugs

00:17:42.260 | at all?

00:17:42.660 | Why would there be

00:17:44.020 | prescription drugs

00:17:44.940 | or the need

00:17:45.840 | for supplementation

00:17:46.740 | or other things

00:17:47.340 | to alleviate the symptoms

00:17:48.480 | of depression?

00:17:49.440 | Ah, well,

00:17:50.440 | that's the diabolical

00:17:51.480 | nature of depression,

00:17:52.360 | which is if people

00:17:54.400 | are far enough along

00:17:55.780 | in this thing,

00:17:57.540 | this sometimes called

00:17:58.800 | disease,

00:17:59.140 | sometimes called disorder,

00:18:00.160 | but major depression,

00:18:01.600 | oftentimes they can't

00:18:03.780 | get the energy

00:18:05.040 | to even get up

00:18:06.260 | and take a bath

00:18:07.360 | or a shower.

00:18:08.140 | They have no motivation

00:18:09.820 | to do it.

00:18:10.360 | They have no desire

00:18:12.060 | to go for a run,

00:18:12.920 | but it's very important

00:18:13.980 | to highlight the fact

00:18:14.780 | that these circuits

00:18:15.640 | that are accessible

00:18:17.120 | to some of us,

00:18:18.220 | the circuits for happiness,

00:18:19.520 | for pursuit of pleasure,

00:18:20.660 | for exercise,

00:18:22.360 | for getting in a cold shower,

00:18:25.680 | if that's your thing,

00:18:26.520 | that those circuits

00:18:28.320 | are present in all people,

00:18:29.860 | but for certain people

00:18:31.820 | that are experiencing

00:18:32.640 | major depression

00:18:33.420 | and are really

00:18:33.920 | in the depths

00:18:34.360 | of their depression,

00:18:35.660 | they can't really access

00:18:38.540 | those circuits

00:18:39.140 | in the same way

00:18:39.960 | that people

00:18:40.420 | who are not suffering

00:18:41.740 | from depression can.

00:18:43.040 | but let's look

00:18:43.880 | at depression

00:18:44.340 | from the standpoint

00:18:45.160 | of a deeper

00:18:46.300 | biological phenomenon,

00:18:47.380 | which is inflammation

00:18:48.980 | and the immune system.

00:18:50.180 | There's growing evidence now

00:18:52.160 | that many forms

00:18:53.420 | of major depression,

00:18:54.300 | if not all of them,

00:18:55.540 | relate to

00:18:57.020 | excessive inflammation.

00:18:59.060 | Now,

00:18:59.880 | inflammation plays

00:19:00.740 | an important role

00:19:01.440 | in wound healing

00:19:02.160 | is that it is

00:19:03.100 | a positive aspect

00:19:04.260 | of our immune system,

00:19:05.680 | our ability

00:19:06.180 | to combat

00:19:07.120 | wounds,

00:19:09.180 | combat illnesses,

00:19:10.240 | et cetera,

00:19:10.880 | but inflammation

00:19:12.340 | gone unchecked,

00:19:13.700 | inflammation

00:19:14.200 | that lasts too long

00:19:15.320 | or is of too high amplitude,

00:19:16.860 | meaning too many cytokines

00:19:19.060 | and things of that sort

00:19:19.800 | in the body

00:19:20.200 | is bad.

00:19:21.180 | And there's decent evidence

00:19:22.880 | now that inflammation

00:19:24.600 | can lead to

00:19:26.340 | or exacerbate depression

00:19:27.740 | and that if we want

00:19:28.820 | to control depression

00:19:29.960 | or limit

00:19:30.740 | or eliminate depression,

00:19:31.860 | that focusing

00:19:33.160 | on reducing inflammation

00:19:35.580 | and its associated pathways

00:19:37.060 | is a really good thing to do.

00:19:38.560 | And I think

00:19:39.120 | this is a really good thing

00:19:40.400 | for everybody to do

00:19:41.700 | regardless of whether or not

00:19:42.780 | you suffer from depression

00:19:44.000 | or not.

00:19:44.460 | Okay.

00:19:44.980 | So first of all,

00:19:46.300 | who are the major players

00:19:48.700 | in creating

00:19:49.540 | chronic inflammation

00:19:50.720 | in the brain and body?

00:19:51.600 | They are the inflammatory cytokines,

00:19:53.920 | things like IL-6,

00:19:56.000 | interleukin-6,

00:19:56.820 | things like tumor necrosis alpha,

00:19:59.240 | TNF alpha,

00:20:00.820 | things like C-reactive protein.

00:20:03.200 | All right.

00:20:04.100 | When we are stressed,

00:20:05.620 | chronically stressed,

00:20:06.660 | we get inflamed,

00:20:08.520 | our brain

00:20:09.200 | and various locations

00:20:10.240 | in the brain

00:20:10.680 | become inflamed

00:20:11.460 | because certain classes

00:20:12.360 | of cells,

00:20:12.780 | in particular,

00:20:13.240 | those glial cells,

00:20:14.420 | the cells that are

00:20:15.860 | typically thought

00:20:16.820 | to just be support cells,

00:20:17.920 | those cells

00:20:19.000 | and their biochemistry

00:20:20.060 | and their dialogue

00:20:20.860 | with the neurons

00:20:21.740 | of the brain and body

00:20:22.680 | starts to become disrupted.

00:20:24.020 | It turns out

00:20:25.500 | there is a set of actions

00:20:27.420 | that we can take

00:20:28.940 | in order to limit inflammation.

00:20:30.640 | One of those approaches

00:20:32.400 | is to increase

00:20:34.580 | our intake

00:20:35.220 | intake of so-called EPAs

00:20:36.540 | or essential fatty acids.

00:20:37.840 | Increasing our intake

00:20:39.480 | of these essential fatty acids,

00:20:41.000 | in particular,

00:20:41.700 | the EPA

00:20:42.480 | variety of omega-3s

00:20:45.060 | can lower

00:20:47.160 | the effective dose

00:20:48.520 | of things like SSRIs.

00:20:50.820 | The threshold level

00:20:52.020 | seems to be

00:20:53.060 | about one gram,

00:20:54.120 | a thousand milligrams

00:20:55.000 | of EPA.

00:20:56.280 | So you will sometimes

00:20:57.600 | see on a bottle

00:20:58.680 | of krill oil

00:20:59.460 | or fish oil

00:21:00.280 | or any other source,

00:21:01.340 | even, you know,

00:21:02.260 | plant source

00:21:03.140 | or other source

00:21:03.780 | of EPA

00:21:05.940 | that it's a thousand milligrams

00:21:07.900 | or 1,200 milligrams.

00:21:09.120 | But what's really important

00:21:10.480 | to look at

00:21:11.320 | is whether or not

00:21:12.380 | there's more

00:21:12.980 | than a thousand milligrams

00:21:14.440 | of EPA

00:21:15.340 | because the EPA

00:21:16.700 | in particular

00:21:17.240 | is what's important here.

00:21:18.280 | So how would this work?

00:21:19.700 | These inflammatory cytokines

00:21:21.400 | act in a variety

00:21:22.600 | of different ways,

00:21:23.700 | but they mainly act

00:21:24.820 | to inhibit the release

00:21:25.940 | of serotonin,

00:21:26.720 | norepinephrine,

00:21:27.340 | and dopamine

00:21:27.880 | or the synthesis

00:21:29.640 | of serotonin,

00:21:31.400 | norepinephrine,

00:21:32.000 | and dopamine.

00:21:32.560 | Dopamine,

00:21:33.560 | also called 5-HT,

00:21:35.040 | essentially derives

00:21:36.460 | from a precursor

00:21:37.740 | called tryptophan.

00:21:38.840 | Tryptophan arrives

00:21:40.660 | into our system

00:21:41.740 | through our diet,

00:21:42.760 | okay?

00:21:43.460 | Tryptophan is an amino acid.

00:21:44.920 | Tryptophan is eventually

00:21:46.720 | converted into serotonin.

00:21:48.200 | However,

00:21:49.020 | if there's excessive amounts

00:21:50.940 | of inflammation,

00:21:51.620 | these inflammatory cytokines

00:21:54.720 | cause tryptophan

00:21:56.460 | to be diverted

00:21:57.400 | down a different pathway.

00:21:58.620 | The pathway involves

00:22:01.160 | something called IDO,

00:22:02.220 | idolamine,

00:22:02.880 | which converts tryptophan

00:22:04.880 | into kynurine.

00:22:06.340 | Kynurine actually acts

00:22:08.380 | as a neurotoxin

00:22:09.440 | by way of converting

00:22:10.840 | into something called

00:22:11.800 | quinolinic acid,

00:22:13.320 | okay?

00:22:13.900 | And quinolinic acid

00:22:15.260 | is pro-depressive.

00:22:16.120 | So if that seems like

00:22:17.060 | a complicated

00:22:17.520 | biochemical pathway,

00:22:18.540 | what's basically happening here

00:22:19.980 | is that the tryptophan

00:22:21.040 | that normally

00:22:21.540 | would be made

00:22:22.320 | into serotonin

00:22:23.140 | under conditions

00:22:24.340 | of inflammation

00:22:24.940 | is being diverted

00:22:25.820 | into a neurotoxic pathway.

00:22:27.640 | And ingestion

00:22:28.780 | of EPAs,

00:22:29.740 | because it limits

00:22:31.020 | these inflammatory cytokines,

00:22:33.000 | things like IL-6,

00:22:33.980 | C-reactive protein,

00:22:34.960 | et cetera,

00:22:35.460 | can cause

00:22:38.060 | more of the tryptophan

00:22:40.020 | that one ingests

00:22:41.740 | or has in their body

00:22:42.740 | to be diverted

00:22:43.720 | towards the serotonergic pathway.

00:22:45.400 | Exercise,

00:22:46.380 | it turns out,

00:22:47.560 | also has a positive effect

00:22:49.720 | on the tryptophan

00:22:52.020 | to serotonin

00:22:53.000 | conversion pathway.

00:22:54.000 | The activation

00:22:54.860 | of the muscles

00:22:55.780 | through rhythmic

00:22:57.040 | repeated use,

00:22:57.680 | in particular,

00:22:58.080 | aerobic exercise,

00:22:58.900 | but also resistance

00:22:59.920 | training has been shown

00:23:01.380 | to do this

00:23:01.760 | to some extent,

00:23:02.420 | tends to sequester

00:23:04.420 | or shuttle

00:23:05.540 | the kynurine

00:23:06.880 | into the muscle

00:23:07.820 | so that it isn't

00:23:08.960 | converted

00:23:09.380 | into this neurotoxin

00:23:10.840 | that is

00:23:11.540 | pro-depression.

00:23:12.900 | From the data

00:23:14.080 | that are published

00:23:14.680 | in quality peer-reviewed journals,

00:23:16.100 | it really appears

00:23:16.720 | that this inflammation pathway

00:23:17.940 | does function

00:23:18.660 | to increase depression

00:23:19.920 | through these pathways.

00:23:21.340 | And so knowing

00:23:22.260 | that there are behavioral steps

00:23:23.580 | and supplementation-based steps,

00:23:25.220 | or if you prefer

00:23:26.140 | getting your EPAs

00:23:27.160 | from typical food,

00:23:28.480 | from nutritional approaches,

00:23:30.980 | I find that

00:23:32.360 | very reassuring

00:23:33.620 | that the mechanisms

00:23:34.700 | all converge

00:23:35.520 | on a common pathway,

00:23:36.500 | serotonin.

00:23:37.240 | There's a common

00:23:38.220 | biochemical pathway

00:23:39.300 | that can explain

00:23:40.080 | why these things

00:23:41.120 | not just work,

00:23:42.260 | but why they should work.

00:23:43.840 | They should work

00:23:44.820 | because they operate

00:23:45.680 | in the very same

00:23:46.460 | biochemical pathways

00:23:47.580 | that antidepressants

00:23:50.480 | that are prescribed

00:23:51.120 | to people do.

00:23:51.740 | Now I want to talk

00:23:53.220 | about something

00:23:54.320 | that at least for me

00:23:55.520 | was quite surprising

00:23:56.560 | when I first learned

00:23:57.380 | about it

00:23:57.900 | for sake of

00:23:59.320 | treatment of mood disorders,

00:24:01.180 | and that's creatine.

00:24:02.380 | Creatine has

00:24:03.960 | a number of very important

00:24:05.300 | functions throughout the body.

00:24:06.580 | For those of you

00:24:07.900 | that are into

00:24:08.700 | resistance training,

00:24:09.640 | and actually

00:24:11.060 | for those of you

00:24:11.620 | that are into

00:24:12.740 | endurance training as well,

00:24:13.700 | creatine has achieved

00:24:14.980 | a lot of popularity

00:24:15.940 | in recent years

00:24:17.880 | because supplementation

00:24:19.560 | with creatine

00:24:20.300 | can draw more water

00:24:21.800 | into muscles

00:24:22.500 | and can increase

00:24:23.260 | power output

00:24:24.040 | from muscles.

00:24:24.920 | However,

00:24:25.480 | there's also a

00:24:26.900 | so-called phosphocreatine

00:24:28.200 | system in the brain,

00:24:29.360 | and that phosphocreatine

00:24:30.840 | system has everything

00:24:32.420 | to do with the dialogue

00:24:33.360 | between neurons

00:24:34.260 | and these other cell types

00:24:35.700 | called glia,

00:24:36.460 | but the phosphocreatine

00:24:38.520 | system

00:24:39.020 | in the forebrain

00:24:40.860 | in particular,

00:24:41.480 | in the front of our brain,

00:24:42.360 | has been shown

00:24:43.040 | to be involved

00:24:44.260 | in regulation

00:24:45.920 | of mood

00:24:46.680 | and some of the

00:24:47.220 | reward pathways

00:24:48.020 | as well as in

00:24:49.860 | depression.

00:24:50.540 | The American Journal

00:24:51.960 | of Psychiatry

00:24:52.720 | in 2012

00:24:53.540 | published a study

00:24:55.600 | which was a randomized

00:24:57.020 | double-blind placebo-controlled

00:24:58.320 | trial of oral creatine

00:24:59.620 | monohydrate,

00:25:00.260 | and what it found

00:25:01.740 | is that it could

00:25:02.520 | augment or enhance

00:25:03.960 | the response

00:25:04.620 | to a selective

00:25:05.260 | serotonin reuptake

00:25:06.320 | inhibitor,

00:25:06.800 | in particular in women

00:25:07.940 | with major depressive

00:25:08.980 | disorder.

00:25:09.440 | So like EPA,

00:25:11.560 | creatine supplementation

00:25:13.420 | seems to either

00:25:14.600 | lower the required

00:25:15.660 | dose of SSRI

00:25:17.220 | that's required

00:25:17.840 | to treat depression

00:25:18.740 | or can improve

00:25:20.280 | the effectiveness

00:25:21.400 | of a given dose

00:25:22.520 | of SSRI.

00:25:24.520 | However,

00:25:25.760 | there are other studies

00:25:26.540 | that have looked

00:25:27.300 | directly at creatine

00:25:28.320 | supplementation

00:25:29.020 | in the absence

00:25:29.660 | of SSRIs,

00:25:30.560 | and those are

00:25:30.920 | interesting as well.

00:25:31.700 | So let's talk

00:25:32.660 | a little bit more

00:25:33.220 | about novel therapeutic

00:25:34.420 | compounds for the treatment

00:25:35.560 | of major depression.

00:25:36.640 | one is ketamine,

00:25:37.760 | which is getting

00:25:39.220 | increasing interest

00:25:40.240 | in psychiatric clinics

00:25:41.800 | in various experimental

00:25:43.260 | and clinical studies.

00:25:44.180 | They create

00:25:44.980 | dissociative

00:25:45.920 | anesthetic states,

00:25:47.500 | so dissociative states

00:25:48.620 | where people

00:25:49.060 | don't feel

00:25:50.000 | as closely meshed

00:25:52.340 | with their emotions

00:25:53.240 | and their perceptions.

00:25:54.640 | Clinically,

00:25:56.020 | what's described

00:25:56.940 | in the trials

00:25:58.320 | for ketamine

00:25:59.060 | and things like it

00:26:00.420 | are that people

00:26:01.300 | who are depressed

00:26:02.180 | will take ketamine,

00:26:03.420 | will experience

00:26:05.380 | a kind of separate

00:26:06.620 | shortness

00:26:07.020 | from their grief

00:26:08.200 | and from their emotions

00:26:09.260 | and that possibly

00:26:11.480 | there's plasticity.

00:26:12.900 | There actually shifts

00:26:13.740 | in the neural circuitry

00:26:14.860 | such that their emotions

00:26:16.220 | don't weigh

00:26:17.640 | on them so heavily.

00:26:18.800 | It's not always

00:26:19.840 | about just getting

00:26:20.660 | people peppy

00:26:21.380 | and excited

00:26:22.020 | and happy.

00:26:22.600 | There also seems

00:26:24.280 | to be a requirement

00:26:24.960 | for getting them

00:26:25.780 | distanced

00:26:26.920 | from their own grief.

00:26:28.280 | And this brings us

00:26:29.560 | back to something

00:26:30.160 | that we talked

00:26:30.640 | about way back

00:26:31.440 | at the beginning

00:26:31.860 | of this episode,

00:26:32.780 | which was

00:26:33.500 | this particular feature

00:26:35.680 | of the anti-self

00:26:37.360 | confabulation.

00:26:38.360 | That everything

00:26:39.400 | that happens

00:26:40.060 | is a reflection

00:26:40.920 | that I should say

00:26:42.000 | for the depressed person

00:26:43.040 | that everything

00:26:43.540 | that happens

00:26:44.120 | is a reflection

00:26:44.780 | of how life is bad

00:26:46.120 | and their experiences

00:26:46.940 | just point to the fact

00:26:49.040 | that nothing

00:26:49.440 | is going to get better.

00:26:50.220 | This is the common

00:26:50.920 | language of depression.

00:26:52.140 | If this is very depressing

00:26:53.120 | to hear me talk about,

00:26:54.800 | it is heavy.

00:26:55.940 | And that's what it's like

00:26:57.120 | to hear these things.

00:26:58.460 | It's even heavier,

00:26:59.160 | of course,

00:26:59.500 | for somebody

00:27:00.020 | to experience them.

00:27:00.920 | And those beliefs,

00:27:03.940 | those patterns of guilt

00:27:06.120 | and grief

00:27:06.900 | and anhedonia

00:27:07.800 | and delusional

00:27:08.740 | anti-self confabulations,

00:27:10.320 | those are the things

00:27:11.680 | that eventually,

00:27:12.320 | if they get severe enough,

00:27:13.800 | start to convert

00:27:16.220 | into things

00:27:16.740 | like self-harm,

00:27:17.480 | mutilation,

00:27:18.020 | and in the most tragic

00:27:19.540 | of cases,

00:27:20.040 | of course,

00:27:20.580 | suicide.

00:27:21.280 | And so I think

00:27:23.700 | we can look

00:27:24.160 | to these treatments

00:27:25.000 | such as ketamine

00:27:26.340 | and its use

00:27:26.960 | in the clinic

00:27:27.580 | as ways for people

00:27:29.220 | to get distanced

00:27:30.540 | from the negative affect

00:27:31.980 | that they feel

00:27:32.860 | isn't just inside them

00:27:35.020 | or overwhelms them,

00:27:36.100 | but that for the very

00:27:37.500 | severely depressed person,

00:27:38.760 | they feel is them.

00:27:40.320 | Another category

00:27:41.500 | of treatments

00:27:42.240 | that's being actively

00:27:43.740 | explored now

00:27:44.500 | in laboratories

00:27:45.280 | and in the psychiatry realm

00:27:47.540 | are the psychedelics.

00:27:49.140 | And that's a huge

00:27:50.220 | category of compounds.

00:27:52.100 | However,

00:27:53.140 | one in particular,

00:27:54.320 | psilocybin is one

00:27:55.780 | that's being

00:27:56.360 | most intensely

00:27:57.600 | and actively pursued

00:27:58.980 | for its capacity

00:27:59.900 | to treat major

00:28:00.840 | depressive disorder.

00:28:01.700 | But let's focus

00:28:02.940 | on psilocybin

00:28:03.800 | for its capacity

00:28:05.200 | to rewire neural circuits

00:28:06.680 | and alleviate depression.

00:28:08.640 | There have been

00:28:10.720 | anecdotal data

00:28:12.600 | or evidence

00:28:13.540 | over the years

00:28:14.100 | that psilocybin

00:28:15.320 | has this capacity.

00:28:16.200 | How does psilocybin work?

00:28:17.300 | Well, psilocybin engages

00:28:20.880 | or increases

00:28:21.860 | serotonin transmission,

00:28:23.320 | meaning it increases

00:28:24.780 | the amount of serotonin

00:28:25.880 | mainly by acting

00:28:27.340 | at these 5H2A receptors.

00:28:29.220 | But where in the brain

00:28:31.160 | does it happen

00:28:32.280 | and what are the major effects?

00:28:33.520 | First, let's talk

00:28:34.100 | about the major effects

00:28:34.960 | because I think

00:28:35.360 | that's what people

00:28:35.880 | are interested in.

00:28:36.620 | The study that I'd like

00:28:38.000 | to highlight

00:28:38.540 | is a fairly recent one.

00:28:40.760 | It was published

00:28:41.680 | in May of 2021

00:28:43.480 | in journal,

00:28:44.720 | journal, excuse me,

00:28:45.940 | of the American

00:28:46.600 | Medical Association

00:28:47.620 | Psychiatry,

00:28:48.400 | so JAMA Psychiatry,

00:28:50.040 | and it's entitled

00:28:50.780 | Effects of Psilocybin

00:28:52.080 | Assisted Therapy

00:28:52.980 | on Major Depressive Disorder,

00:28:54.340 | a Randomized Clinical Trial.

00:28:55.880 | Basically, what they did

00:28:57.500 | was they screened

00:28:59.480 | for patients

00:28:59.980 | to come into the clinic.

00:29:00.900 | These were people

00:29:01.380 | that suffered

00:29:01.940 | from major depressive disorder

00:29:03.400 | and administered

00:29:06.200 | either one

00:29:07.320 | or two rounds

00:29:08.580 | of psilocybin.

00:29:09.600 | Typically,

00:29:10.300 | it was 20 milligrams

00:29:12.060 | per kilogram of body weight,

00:29:13.360 | so it depends on body weight.

00:29:14.500 | What's really striking

00:29:15.820 | about this study

00:29:16.680 | is that there was

00:29:18.320 | a very significant

00:29:19.840 | improvement

00:29:21.060 | in mood and affect

00:29:22.680 | and relief

00:29:23.360 | from depressive symptoms

00:29:24.580 | in anywhere

00:29:26.640 | from 50 to 70%

00:29:28.580 | of the people

00:29:29.500 | that were subjects

00:29:31.240 | in the study

00:29:31.840 | who received

00:29:33.080 | the psilocybin treatment.

00:29:36.440 | These are really enormous

00:29:38.180 | and significant effects.

00:29:39.720 | what's really interesting

00:29:40.460 | is there are some

00:29:42.580 | common themes

00:29:43.600 | to psilocybin administration

00:29:45.800 | and experience

00:29:47.440 | that lead to relief

00:29:48.560 | from depressive symptoms,

00:29:49.720 | but they are subjectively,

00:29:52.400 | excuse me,

00:29:53.140 | subjectively very varied,

00:29:55.520 | meaning that whether

00:29:57.800 | or not people feel

00:29:58.880 | they had a good experience

00:29:59.880 | or a bad experience,

00:30:00.880 | whether or not people

00:30:01.660 | thought about their parents

00:30:02.980 | or thought about

00:30:03.740 | the color of the ceiling

00:30:05.500 | doesn't seem to have

00:30:07.000 | too much of an impact

00:30:08.500 | on whether or not

00:30:09.140 | they receive relief

00:30:10.860 | during these studies,

00:30:13.080 | in these clinical studies.

00:30:14.480 | It seems like

00:30:16.100 | different people

00:30:16.960 | can have lots

00:30:17.520 | of different experiences

00:30:18.400 | and still receive benefit.

00:30:20.840 | it's somehow rewiring

00:30:22.900 | associations between events,

00:30:24.660 | emotional events,

00:30:25.500 | past events,

00:30:26.300 | current events,

00:30:27.200 | and future events

00:30:28.140 | in ways that allow people

00:30:30.080 | to get some sort of relief

00:30:31.820 | or distance

00:30:32.480 | from these narratives,

00:30:34.080 | these depressive stories

00:30:36.060 | about their past

00:30:37.100 | and present

00:30:37.640 | and allow them

00:30:38.480 | to see new opportunity

00:30:39.780 | and optimism

00:30:40.420 | in the future.

00:30:41.380 | One of the most common

00:30:42.220 | questions I get

00:30:43.060 | for this podcast

00:30:43.800 | is about different diets,

00:30:46.460 | different regimes,

00:30:47.420 | different nutritional plans,

00:30:48.720 | things like keto,

00:30:50.080 | ketogenic diet,

00:30:51.120 | or vegan diets,

00:30:52.660 | or intermittent fasting,

00:30:54.500 | or the all-meat diet,

00:30:55.920 | the so-called lion diet,

00:30:56.920 | et cetera.

00:30:57.700 | There are actually

00:30:59.580 | really interesting data

00:31:00.880 | relating nutrition and diet

00:31:03.060 | to major depressive disorder.

00:31:04.860 | There have been

00:31:06.460 | some explorations

00:31:08.100 | of whether or not

00:31:08.660 | a vegan diet

00:31:09.520 | can improve symptoms

00:31:11.300 | of depression.

00:31:11.880 | Not a lot of data,

00:31:13.140 | not impressive data.

00:31:14.300 | There have been

00:31:15.120 | very few controlled studies

00:31:16.600 | looking at the carnivore

00:31:18.860 | all-meat diet.

00:31:19.700 | However,

00:31:20.300 | the ketogenic diet

00:31:22.040 | has been explored

00:31:23.000 | for its ability

00:31:25.240 | to relieve

00:31:26.140 | certain symptoms

00:31:26.960 | of depression,

00:31:28.500 | in particular

00:31:30.120 | to what's called

00:31:31.860 | maintain euthymia.

00:31:33.460 | Euthymia is the kind

00:31:34.980 | of state of equilibrium

00:31:35.900 | between a manic episode

00:31:37.720 | and a depressive episode

00:31:39.300 | in a manic bipolar person.

00:31:40.760 | euthymia is that kind

00:31:41.900 | of place in the middle

00:31:43.700 | where people feel

00:31:44.960 | neither too high

00:31:45.800 | nor too low.

00:31:46.520 | And there are

00:31:48.620 | some interesting studies

00:31:49.740 | looking at the ketogenic diet

00:31:51.400 | for maintaining euthymia

00:31:52.960 | in manic depressives,

00:31:54.000 | but also in people

00:31:55.400 | with major depressive disorder.

00:31:56.700 | The ketogenic diet,

00:31:58.200 | by way of increasing

00:31:59.420 | ketone metabolism

00:32:00.420 | or shifting brain's metabolism

00:32:02.440 | over to ketones,

00:32:03.660 | tends to modulate GABA

00:32:06.860 | such that GABA

00:32:08.220 | is more active

00:32:09.680 | and adjusts

00:32:11.560 | the so-called

00:32:12.060 | GABA glutamate balance.

00:32:13.580 | This is getting technical,

00:32:14.580 | but glutamate

00:32:15.300 | is an excitatory

00:32:16.200 | neurotransmitter.

00:32:17.320 | GABA is inhibitory

00:32:18.780 | neurotransmitter

00:32:19.380 | and their balance

00:32:20.160 | is vital

00:32:20.680 | for neuroplasticity,

00:32:21.780 | for maintaining

00:32:22.960 | healthy levels

00:32:23.660 | of activity

00:32:24.220 | in the brain,

00:32:24.880 | et cetera.

00:32:25.920 | And so there is

00:32:27.860 | decent evidence

00:32:29.360 | that people

00:32:31.240 | with major depressive disorders,

00:32:32.720 | in particular,

00:32:33.940 | the people

00:32:34.920 | with major depressive disorders

00:32:36.580 | that are refractory,

00:32:38.140 | meaning they don't respond

00:32:39.860 | to classical antidepressants,

00:32:42.540 | can benefit,

00:32:44.440 | it seems,

00:32:45.160 | from the ketogenic diet.

00:32:47.720 | It's really interesting

00:32:49.360 | that eating

00:32:50.240 | in a particular way,

00:32:51.080 | lowering carbohydrates

00:32:52.480 | to the point

00:32:53.280 | where you rely

00:32:53.960 | on ketogenic metabolism

00:32:55.920 | in the brain

00:32:56.820 | increases GABA

00:32:58.120 | and can provide

00:32:59.540 | some relief

00:33:00.040 | for depressive symptoms

00:33:01.640 | and that in particular

00:33:03.100 | that seems to have

00:33:04.060 | positive effects

00:33:04.920 | in people that are refractory

00:33:06.220 | or don't respond

00:33:06.980 | to classic antidepressants.

00:33:09.060 | So today we've covered

00:33:10.300 | what at least feels to me

00:33:11.880 | like a tremendous amount

00:33:13.040 | of material.

00:33:13.640 | This topic of depression

00:33:15.040 | is indeed an enormous topic

00:33:16.700 | to try and get our arms around.

00:33:18.000 | We talked about

00:33:18.900 | the symptomology,

00:33:19.620 | we talked about

00:33:20.260 | some of the underlying

00:33:20.960 | neurochemistry and biology,

00:33:22.260 | and then we talked

00:33:23.640 | about approaches

00:33:24.260 | to deal with it

00:33:24.960 | that are really grounded

00:33:25.940 | in the neurochemistry

00:33:27.260 | and biology.

00:33:27.920 | I just want to recap

00:33:29.260 | a few of those tools

00:33:31.200 | and what those things are.

00:33:32.260 | So number one,

00:33:33.780 | don't overwhelm

00:33:35.420 | your pleasure centers

00:33:36.340 | either through activities

00:33:37.720 | or compounds.

00:33:38.500 | It might seem counterintuitive,

00:33:40.020 | but you're setting yourself up

00:33:41.240 | for anhedonia

00:33:41.960 | and depression

00:33:42.580 | if you do that.

00:33:43.960 | Second of all,

00:33:45.120 | talked about

00:33:46.500 | the norepinephrine system

00:33:47.600 | and how the norepinephrine system

00:33:48.960 | is really deficient

00:33:50.220 | in many forms

00:33:52.760 | of major depression

00:33:53.900 | and in depression.

00:33:54.640 | There is now

00:33:55.840 | more deliberate pursuit

00:33:57.480 | of norepinephrine

00:33:58.880 | inducing activities

00:33:59.760 | that are healthy,

00:34:00.420 | that aren't

00:34:01.280 | adrenaline seeking

00:34:02.800 | per se.

00:34:03.360 | Things like exercise

00:34:05.140 | that will increase

00:34:05.940 | our levels

00:34:06.380 | of noradrenaline.

00:34:07.180 | I'd be remiss

00:34:08.140 | if I said

00:34:09.160 | that these activities

00:34:10.160 | could completely

00:34:11.660 | eliminate

00:34:12.680 | depressive symptoms

00:34:13.540 | in people

00:34:13.920 | with major depressive disorder.

00:34:15.100 | I don't think

00:34:15.540 | that's the case.

00:34:16.120 | And again,

00:34:16.440 | I want to acknowledge

00:34:17.100 | that people

00:34:17.480 | with major

00:34:18.300 | depressive symptoms

00:34:19.120 | often don't have

00:34:20.480 | the energy,

00:34:21.120 | the willingness

00:34:22.000 | or the capacity

00:34:23.780 | to engage

00:34:24.440 | in some of these activities,

00:34:25.340 | but things

00:34:25.960 | like cold showers,

00:34:27.180 | deliberate cold showers,

00:34:28.220 | things like

00:34:29.160 | regular exercise,

00:34:30.440 | they aren't

00:34:31.100 | just feel-good activities.

00:34:32.720 | They actually engage

00:34:34.620 | the norepinephrine system

00:34:35.680 | and keep that system

00:34:36.880 | tuned up

00:34:37.420 | and allow us

00:34:37.960 | to increase

00:34:38.360 | our norepinephrine levels

00:34:39.440 | at will

00:34:40.000 | on a regular basis

00:34:40.860 | and their mood-enhancing effects

00:34:42.860 | are real effects

00:34:43.660 | at the level

00:34:44.360 | of neurochemistry.

00:34:45.220 | Then we talked

00:34:46.600 | about EPAs,

00:34:47.280 | these essential fatty acids,

00:34:48.420 | and it's clear

00:34:48.960 | that for most people

00:34:50.480 | getting above

00:34:52.020 | 1,000 milligrams

00:34:52.940 | and probably even closer

00:34:53.920 | to 2,000 milligrams

00:34:55.120 | per day of EPAs

00:34:56.560 | can be beneficial

00:34:57.240 | for mood,

00:34:57.760 | especially in attempts

00:34:59.440 | to treat

00:34:59.940 | or offset

00:35:00.640 | major depressive disorder.

00:35:01.980 | We also talked

00:35:03.040 | about exercise

00:35:03.700 | and how EPA

00:35:04.600 | and exercise

00:35:05.200 | on a regular basis

00:35:06.280 | can offset

00:35:07.080 | these inflammatory pathways.

00:35:08.320 | And then we talked

00:35:09.320 | about the prescription

00:35:10.620 | compounds

00:35:11.160 | and the compounds

00:35:11.820 | that are being used

00:35:12.680 | mainly in the course

00:35:13.620 | of studies

00:35:14.100 | and of psychiatry

00:35:15.280 | and depression,

00:35:16.160 | things like ketamine,

00:35:16.840 | psilocybin,

00:35:17.520 | and related compounds.

00:35:18.580 | And then lastly,

00:35:19.400 | we talked about ketosis,

00:35:20.460 | which may not be right

00:35:21.480 | for everybody,

00:35:21.940 | but might be right

00:35:22.720 | for certain individuals

00:35:24.380 | out there

00:35:24.940 | who are grappling

00:35:25.680 | with this.

00:35:26.180 | I want to thank you

00:35:27.400 | for embarking

00:35:27.980 | on this journey

00:35:28.660 | of trying to understand

00:35:30.200 | what is depression,

00:35:31.100 | how does it work,

00:35:31.980 | and how to treat it.

00:35:33.000 | And thank you

00:35:34.040 | for your interest

00:35:34.640 | in science.

00:35:35.200 | you

00:35:37.260 | you

00:35:37.760 | you

Understanding & Conquering Depression | Huberman Lab Essentials

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